MXPA97006986A - Method for the treatment of amiloid - Google Patents
Method for the treatment of amiloidInfo
- Publication number
- MXPA97006986A MXPA97006986A MXPA/A/1997/006986A MX9706986A MXPA97006986A MX PA97006986 A MXPA97006986 A MX PA97006986A MX 9706986 A MX9706986 A MX 9706986A MX PA97006986 A MXPA97006986 A MX PA97006986A
- Authority
- MX
- Mexico
- Prior art keywords
- acid
- group
- therapeutic compound
- pharmaceutically acceptable
- amyloid
- Prior art date
Links
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Abstract
The present invention relates to: Therapeutic compounds and methods for inhibiting the deposition of amyloid in a patient, whatever their clinical condition, are described. The amyloid deposit is inhibited by administering to a patient an effective amount of a therapeutic compound comprising an anionic group and a carrier molecule, or a pharmaceutically acceptable salt thereof, such that an interaction between a protein is inhibited. amyloidogenic and a constituent of base membrane. The preferred anionic groups are sulfonates and sulfates. Preferred carrier molecules include carbohydrates, polymers, peptides, peptide derivatives, aliphatic groups, alicyclic groups, heterocyclic groups, aromatic groups and combinations thereof.
Description
METHOD FOR TREATMENT DF l AMILOIDOSIS BACKGROUND OF THE INVENTION The ami loi dosi _ • > I pff read a pathological condition characterized by the presence of amyloid. The term amyloid is a generic term that refers to a group of diverse but specific protein and tracer deposits that are observed in several different diseases. Although they present diversity in their occurrence, all amyloid deposits have common morphological properties, stain with specific dyes (eg red Congo), and have a red bi-reflective appearance in polarized light after staining. . They also share common ultrastructural features and common radar diffraction patterns. to i nfrarojos. Ailaidosis can be classified clinically as primary, secondary, family and isolated. Primary amyloidosis aperec de novo without any preceding disorder. Secondary ami loi dosi is the form that appears as a complication of a previously existing disorder. Familial amyloidosis is a genetically inherited form found in particular geographic populations. The isolated forms of a iloidosis are forms that tend to involve a single organ system. They also characterize different amyloids by means of the type of protein present in the deposit. For example, neurodegenerative diseases with, for example, bovine-form spongiform encephalitis, Creutzfelit-Jafcob disease and the like are characterized by the appearance and accumulation of a protease-resistant form of a prion protein (known as ASCR or PrP ~ - 27) in the central nervous system. In the same way, Alzheimer's disease, another neurodegenerative disorder, is characterized by congenital angiopathy, neurological plaques, and neurofibrils, all of which have the characteristics of amyloid. In this case, the amyloid plaques and blood vessels are formed by the beta protein. Other systemic diseases, such as adult-onset diabetes, long-term complications, long-term sequelae of inflammation, or plasma cell dyscrasias are characterized by the accumulation of iodine if it is astatic. In each of these cases, a different amidogenic protein is involved in the deposition of a loid. Once these amyloids are formed, there is no known therapy or treatment to significantly dissolve the deposits that can be used to great lengths. COMPENDIUM OF THE INVENTION This invention offers methods and compositions that are useful in the treatment of amyloidosis. The methods of the invention involve administering to a subject a therapeutic compound that inhibits the deposition of amyloids. Accordingly, the compositions and methods of the invention are useful for inhibiting the alysides in disorders in which amyloid deposition occurs. the methods of the invention can be used therapeutically to treat iloidosis or can they be used prophylactically in a patient susceptible to aml? } dose. The methods of the present invention are based, at least in part, on 1? inhibition of the interaction between a prateína to laidogénica and a constituent of a. base membrane to inhibit the deposit of iloid. The constituent of the base membrane is a glycoprotein or proteoglycan, preferably sulphate of hepar.no prateogl ican. A therapeutic compound employed in the method of the invention may interfere with the binding of a base membrane constituent on a white binding site to an amino acid protein, thereby inhibiting the deposition of a iloid. In one embodiment, the method of the present invention involves administering to a patient a therapeutic compound having at least one ammonium group covalently attached to a carrier molecule that can inhibit an interaction between a protein ai loidogéruca and a constituent of gl icapratelna or proteoglycan a base membrane to inhibit the deposition of iloid. In one embodiment, the ammonium group covalently attached to the carrier molecule is a sulphonate group. Accordingly, the therapeutic compound can have the formula: Q-Y-S03-X +) n where Q is a carrier molecule? X + is a cationic group; and n is an integer. In another embodiment, the ammonium group is a sulfate group. Accordingly, the therapeutic compound may have the formulas wherein Q is a carrier molecule; X + is a cationic group; and n is an integer. Carrier molecules which may be employed include carbohydrates, polymers, peptides, peptide derivatives, aliphatic groups, alicyclic groups, heterocyclic groups, aromatic groups and combinations thereof. Preferred therapeutic compounds for use in the invention include pol ivi or Isul fó co acid, ethansulonic acid, sucrose octasulfate, 1,2-ethanedic acid, sulfuric acid, 1,2-ethansulfonic acid, acid 1, 3 -propand fluoric acid, l-3-propanedisulfonic acid, 1,4-butandiol-sulphuric acid, 1,2,4-butanedi sulphonic acid, t-5-pentan isulphonic acid, taurine, A id 3 - (N-morpholine) propansulphate, Tetrahydric acid, ofen-1, 1-d? -i, do-3, 4-sulphonic, 4-hydrai *? Butan-1 -sul Phonic, or else pharmaceutically acceptable salts thereof Other preferred therapeutic compounds for use in the present invention include 1-butansulonic acid, t-decansulonic acid, 2-propansulonic acid, 3-pentansulphomic acid, acid 4-heptansul fom, and pharmaceutically accretable salts thereof In other preferred embodiments, the therapeutic compound is 1, 7-d? H? Dro? ~ 4-hep-sulphonic, or bi in a pharmaceutically acceptable salt thereof. In other preferred embodiments, the therapeutic compound is selected from the group consisting of 2-hydroxymethoxy-1, 3-prc.pand i oíd isulfuric acid, acid 2-li idroylme 11-2- met 11-1, 3-propand? old isul f, rich 1, 3-c? clohe: < and "old" sulfur as well as pharmaceutically acceptable salts thereof. In other preferred embodiments, the therapeutic compound is 2,3, 4,3 ', 4'-sucrose pentasul fuuric acid, or a pharmaceutically acceptable salt thereof. In other preferred embodiments, the therapeutic compound is selected from the group consisting of sulfuric acid of 2-hydroxy and sulphonic acid, sulfuric acid of 3-hydroxy acid. ipropí lsul f mico, and salts fa ma euti amente acceptbl s of them. In other preferred embodiments, the therapeutic compound is selected from the group consisting of 1,3,5,7-heptantetrasulfuric acid and 1, 3,5,7,9-nonanpentasulfuric acid, and pharmaceutically acceptable salts thereof. In another embodiment, the anionic group is a tetrazole group. Accordingly, in one embodiment, the invention features a method for inhibiting the deposition of amyloid in a patient, said method comprising administering to the patient an effective amount of a therapeutic chromatid, the therapeutic chromate comprising al. less a tetrazole group cov lently fixed on a carrier molecule, or a pharmaceutically acceptable salt thereof. In certain preferred embodiments, the therapeutic compound is selected from within. A group consisting of 3- (1H-tetrazol-5-y1> -9H-1-xanth-9-one 1, 10-d, <5> 5-dithiabisd-phenol tetrazol), IH- tetrazole, 5-phenyl-1H-tetrazole, and 5- (2-aminoethanoic acid) -lH-tetrazole, and pharmaceutically acceptable salts thereof. The therapeutic compounds of the present invention are administered to a patient by an effective route to inhibit the deposition of amyloid. Suitable administration routes include subcutaneous, intravenous and intraperitoneal injection. The therapeutic compounds of the present invention are effective when administered orally. Accordingly, a preferred route of administration is oral administration. The therapeutic compounds can be administered with a pharmaceutically acceptable carrier. The invention further provides pharmaceutical compositions for the treatment of amyloidosis. The pharmaceutical compositions include a therapeutic compound of the present invention in an amount effective to inhibit the deposition of amyloid and a pharmaceutically acceptable carrier. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a bar graph illustrating the effect of a sodium salt of sodium fluoride administered intratrapipe alone in a deposit of AA iloid AA live in mouse spleen. Figure 2 is a graph illustrating the effect of a salt of pol i <; I saw no sodium fonate) on prateoglical heparan sulfate bound to beta-APP in a tris-regulated saline solution (TBS). Figure 3 is a graph illustrating the effect of a sodium salt of sodium sulfate on proteolytic heparan sulfate bound to beta-APP in phosphate buffered saline < PBS). Figure 4 is a bar graph illustrating the effect of a salt of sodium fluoride administered orally in an AA amyloid deposit alive in a spleen. Figure 5 is a graph illustrating the blood level of the α-iloid precursor, SAA, over time for animals receiving an ammonium poly (ammonium sulfate) salt (empty circles) and control animals ( tri boxes). Figure 6 is a graph illustrating the effect of orally administering a salt of iviaulphone or sodium pal on the deposition course of amyloid AA in mouse spleen when deposited} Amyloid coughs were already present before the treatment of the animals. The triangles represent the control animals and the empty circles represent the treated animals. Figure 7 is a graph illustrating the effect of oral administration of a sodium salt of sodium fonate on the amyloid deposit of the passage when the inflammatory stimulus is maintained during the course of the experiment. The triangles represent the control animals and the empty circles represent the treated animals. Figure 8 is a graph illustrating the effect of a sodium salt of orally administered ethano monosulfate (EMS) on an a-sided deposit of spleen AA in vivo. The triangles represent the control animals, the open circles represent the animals that have 2.5 mg / ml of EMS in their water, and the empty squares represent the animals that receive or mg / ml of EMS in their water. Figures 9-17 represent the chemical structures of compounds described in the specification or contemplated for use in the invention.
DETAILED DESCRIPTION OF THE INVENTION This invention relates to methods and compositions useful for the treatment of amyloidosis. The methods of > The invention includes the administration to a patient of a therapeutic compound that inhibits the deposition of amyloid. The expression "inhibition of iloid deposition" encompasses the prevention of iloid formation, the inhibition of an additional deposition of iloid in a patient with ongoing iloidosis and the reduction of amylocyte deposits in a patron. with amyloidosis in progress. The inhibition of the amyloid deposit is determined in relation to an untreated patient or in relation to the patient treated before treatment. The amyloid deposit is inhibited by the inhibition of the interaction between an amino protein} dogémca and? n consti uyente of the base membrane. The term "base membrane" refers to an extracellular matrix comprising glycoproteins and roteogens, including the mimetic, collagen type IV, fibrillar 1 as well as heptaransolitrate proteoglycan (HSPG). In one embodiment, the deposition of iloid is inhibited by interfering with an interaction between an amylocygeogenic pyrethrum and a sulfated glycosylated glycosylate with, for example, HSP 8. Sulphated glycosaminogens are known to be found in all types of amylsides (see Bnow, AD et al. (1987) Lab. Invest. 56,120-123) and the deposition of amyloid and HSP8 deposit occur incidentally in animal models of amyloidosis (see Snow, AD et al. (1987) Lab. Invest. 56665-675.) In the methods of the present invention, molecules having a structure similar to a sulphonated non-glycolic glycosamine are employed to inhibit an interaction between an amyloidogenic protein and a base membrane constituent. In particular, the therapeutic eomps of the present invention comprise at least one sulphate group or a functional equivalent thereof, for example, a sulfonic acid group or another ammonium equivalent functional group bonded to a carrier molecule. In addition to functioning as a vehicle for ammonia functionality, the punching molecule can allow the substrate to pass through the biological membranes and can biodisturize without excessive or premature metabolism. Also, when encue > In the presence of numerous ammonic functionalities in a carrier molecule, the carrier molecule serves to space the ammonium groups in a correct geometrical septaration. In one embodiment, the method of the present invention includes administering to a patient an effective amount of a therapeutic ingredient that has at least one ammonium group covalently bound to a carrier molecule. The therapeutic compound can inhibit an interaction between a amyloidogenic protein and a glycoprotein or proteoglycan constituent of a base membrane to thereby inhibit amyloid deposition. The therapeutic compound can have the formulas Q - (- Y "X +) n where Y- is an anionic group at a physiological pH, G) is a carrier molecule, X - + - is a cationic group, and n is a whole number The number of ammonium groups ("n") is selected in such a way that the biodistribution of the compound for a predicted target site is not impeded while the activity of the compound is maintained, eg, the number of anionic groups is not it is so large as to inhibit the ability to traverse an anatomical barrier, chromium for example a cell membrane, or to penetrate through a physiological barrier, such as the blood-brain barrier, in situations in which such properties are desired. In one embodiment, n is an integer comprised between 1 and 10. In another embodiment, n is an enter number, comprised between 3 and 8. An anionic group of the therapeutic compound of the present invention is a negately charged moiety which, when fixed on a carrier molecule, it can inhibit an interaction between the amyloidogenic protein and a constituent of l. icoprot ína or proteogl. ican of a base membrane to inhibit the amyloid deposit in this way. For the purposes of e = - >According to the invention, the ammonium group is negatively charged at a phiological pH. or. Preferably, the ammonium therapeutic compound is the structure of a sulfated proteoglycan, that is, it is a sulphonated compound or a functional equivalent thereof. The expression "functional equivalents" of sulfates includes compounds such as e pyl sulfame to so or bioisosteres. The term bioisosteros encompasses both bio-sustaining equivalents. plastic as non-classical bioisostéric equivalents. Classical and non-classical bioisosteres of sulfate groups are known in the art (see, for example, Sulverman, RB The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc.: San Diego, CA, 1992, pp. 19- 2. 3). Accordingly, a therapeutic compound of the present invention may comprise at least one ammonium group including sulfonates, sulfates, sulphamates, phosphonates, phosphates, carboxylates, and heterocyclic groups of the following formulas
Depending on the carrier molecule, more than one ammonium group can be fixed on it. When more than one ammonium group is fixed on a carrier molecule, the multiple anionic groups can be the same structural group (for example all sultanates), or alternatively, a combination of different anionic groups can be used (for example, sultanates). and sulfate, etc.). The ability of a therapeutic chromophore of the present invention to inhibit an interaction between amyloidogenic pratean and a glycoprotein or proteoglycan derivative of a base membrane can be assessed by an in vitro binding assay, as for example according to the invention. described in the examples section to well in U.S. Patent No. 5,164,295 to Kisilevsky et al. In summary, a solid support such as a polystyrene microtiter plate is coated with amyloidogenic protein (for example, serum amyloid protein A or beta-amyloid precursor protein (beta-APP). )) and the residual hydrophobic surfaces are blocked. The coated solid support is incubated with various concentrations of a base membrane constituent, preferably HSPG, either in the presence or absence of a test compound. The solid support is extensively washed to remove unbound material. The binding of the base membrane constituent (e.g., HSP8) to the α-loidogenic protein (e.g. beta-APP) is measured using an antibody directed against it. constituent of base membrane conjugated with a detectable substance (eg, an enzyme, such as for example alkaline phosphatase) by detecting the detectable substance. A compound that inhibits an interaction between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a base membrane would reduce the amount of substance detected (for example, it will inhibit the amount of enzymatic activity detected). Preferably, a therapeutic compound of the present invention interacts with a binding site for an I. protein or base membrane protein in an amyloidogenic protein and thus inhibits the binding of the amyloidogenic protein with the. constituent of the base membrane. 61 base membrane icoproteins and proteoglycans include laminipa, type IV collagen, fibronectin as well as proteoglycan hepransulfate (HSPG). In a preferred embodiment, the therapeutic compound inhibits an interaction between an amyloidogenic protein and HSPG. Reasons for consensus binding site for HSPG in amyloidogenic proteins have been described (see, eg, Cardin and Weintraub (1989) Arteriesclerosis 921-32). For example, a HSPG consensus binding motif can be of the general formula X1-X2-X3-Y-X3, where XI, X2 and X3 are basic amino acids (eg, lysine or arginine) and Y is any amino acid. The modeling of the geometry of this site led to the determination of the following spacing between basic amino acid residues (carboxylate to carboxylate, in Angstroms): XI-XI 5.3 ± 1.5 Angstroms X1-X3 7.1 ± 1.5 Angstroms X2-X3 7.6 ± 1.5 Angstroms These values were determined using a combination of semi-empirical quantum mechanical calculations and molecular mechanics. Molecular mechanical calculations were performed using the force field equation MM2. The semi-empirical molecular orbit calculations were carried out using the equation ha iltonia a AM1. The conformational space of the site was sampled using a combination of molecular dynamics (both at high temperature and at low temperature) and Monte Cario simulations. Accordingly, in the therapeutic compounds of the present invention, when multiple anionic groups are linked to a carrier molecule, the relative spacing of the anionic groups can be selected in such a way that the anionic groups (e.g., sul. phonates) interact optimally with the basic residues within the HSPG binding site (thus inhibiting the interaction of HSPG with the site). For example, anionic groups may be spaced approximately 5.3 ± 1.5 Angstrams, 7.1 ± 1.5 Angstroms and / or 7.6 ± 1.5 Angstroms, or appropriate multiples thereof, so that the relative lapsing of the ammonium groups allows the optimal interaction with a binding site for a base membrane receptor (eg, HSPG) in a protein ai 3 oidogérn ca. A therapeutic compound of the present invention typically further comprises a countercation (ie, X + in the general formula: Q - (- Y ~ X +) n). Cationic groups include atoms and positively charged moieties. If the cationi group is hydrogen, H +, then the compound is considered acid, for example, acid etonic acid. If the hydrogen is replaced by a metal or its equivalent, the compound is a ^? of the acid. Pharmaceutically acceptable salts of the therapeutic compound are within the scope of the present invention. For example, X + may be an alkali metal, an alkaline earth, a higher valence cation (eg, aluminum salt), a polycationic cationic chloride or pharmaceutically acceptable ammonium. A preferred pharmaceutically acceptable salt is a sodium salt but other salts are also contemplated within its pharmaceutically acceptable range. Within the therapeutic compound, the group (s) <; s > Amon? or (s) is bonded (n), cov ently on a molecule piortadora. Suitable carrier molecules include carbohydrates, polymers, peptides, peptide derivatives, aliphatic groups, ß-groups, clusters, heterocyclic groups, aromatic groups or combinations thereof A carrier molecule can be substituted, for example, by one or There are several groups of atoms, nitro, halogen, iol or hydroxy, and the term "carbohydrates" is intended to include monosaccharides, oligosaccharides and substituted and unsubstituted polysaccharides. Only simple formulas of the formula C6H120A that can be combined to form oligosaccharides or to remove them, the monosaccharides include enantiomers and both stereoisomers D and L and onosaccharides. they can have numerous ammonium groups fixed on a large portion of monsacchards, for example, in actasulfal or sucrose, four sulphate groups are linked to each of 1 s. As used herein, the term "polymer" has the purpose of including molecules formed by the chemical union of two or more combinatorial subunits called monomers. The monomers are molecules or compounds that usually contain carbon and usually have a relatively low molecular weight and a simple structure. A monomer can be converted into a polymer by combining with it or other similar molecules or compounds. L > A polymer can consist of a single identical repetitive subunit or of many different repetitive subunits (copal e e). The polymers inside > j_- > The scope of this invention includes polymers of vinyl, acyl, styrene and substituted and unsubstituted carbonate derivatives as well as t. opol íme os and salts of the same. In one embodiment, the polymer has a molecular weight of approximately 800-1000 daltons. Examples of suitable covalently bonded anionic polymers (for example, sulphonates or sulfates) include poly (2-acryl-lame-methyl-11-1-p? Ropansul) acid, poly (2-acrylated acid) the? do-2-met 11-p-pnsnsul phonic-co-acri Ioni tp lo), pol i (acid 2-acp l mido-2- e 11-1-propansul fóniero-co-e i rein); acid pol ív my phonic lul; 4-isonic acid polysodic acid; as well as sulfates and sulphonates derived from: poly (acrylic acid); poli (metí lacri lato); poly (meti lmetacri lato); and alcohol pol linal 1 ico; thus with pharmaceutically acceptable salts thereof. Examples of carbohydrate-derived polymers with suitable covalently bonded anionic groups include those of the formula
where R is S03- or 0S034-; and pharmaceutically acceptable salts thereof.
Peptides and peptide derivatives can also act as carrier molecules. The term "peptide" includes two or more amino acids covalently linked through an ac & of peptide. Amino acids that can be used in peptide carrier molecules include the naturally occurring amino acids found in proteins such as glycine, alanine, vanadium, cysteine, leucma, isoleucm, be ina, treomna, methynom, glutamic acid, aspar acid. Tonic, glutamine, asparagine, lysine, arginine, praline, histidine, la la na, tyrosine, and tpptofan. The term "amino acid" also includes analogs, derivatives and congeners d > naturally occurring amino acids, one or more of those which can be embedded piresently in a peptide derivative. For example, analogs of the nobodies can have long or shortened side chains or alternatively side chains with appropriate functional groups. Also included are the D and L isomers of an amino acid when the structure of the amino acid admits the stereisomeric forms. The term "peptide derivative" further includes compounds that contain molecules that mimic a peptide structure but are not amino acids (what is known as pepit idomi ethicos), blunt for example benzod lacepin molecules (see for example James, GL et al. (1993) Science 260: 1937-1942). The ammonium groups can be fixed on a peptide or peptide derivative through a? 0
functional group in the side chain of certain amino acids or another suitable functional group. For example, a sulfonate or sulfonate group can be linked through the hydroxy side chain of a residue to be * ina. A peptide can be designed to interact with a binding site for a base membrane constituent (eg, HSPG) in an immunoglobulin protein (as described above). Therefore, in one embodiment, the peptide comprises 4 amino acid * 'and ammonium groups (eg sulfonates) are linked to the first amino acid, second amino acid and fourth amino acid. For example, the peptide can be Ser-Ser-Y-Ser-, where an ammonium group is fixed on the side chain of each seppa residue and Y is any amino acid. In addition to the peptides and peptide derivatives, chrome-bearing single ami oacids can be used in the therapeutic compounds of the invention. For example, it may be used to go cysteic, derivative sultanate of ri tei a. The term "amino group" is intended to include organic compounds characterized by straight or branched chains, typically having between 1 and 22 carbon atoms. "Istatic groups" include alkyl groups, alkenyl groups, and l groups; what? In structures »ramplejas, the chains can be branched or reticulated. Alkyl groups include saturated hydrocarbons having one or more carbon atoms, including straight chain alkyl groups: and branched chain alkyl groups. Such hydrocarbon portions may be substituted on one or more pure carbon atoms, for example, a halogen, hydroyl, thiol, amine, lco, Ico-Ibo, alkyl, or nitro group. Unless it is »_ > < Otherwise, the number of carbon atoms, the tmine, "lower aliphatic" as used herein, refers to an aliphatic group, of the above described nature (eg, lower alkyl, lower alkemyl, lower alipyl), but having 1 to 6 carbon atoms. Representatives of such lower aliphatic groups, for example lower alkyl groups, are methyl, ethyl, n-propoxy, isoprene, 2-chloroprapyl, n-butyl, se-b? ila, 2-a mobutyl, isobutyl, tert-butyl, 3-t? open i lo, and the like. As used herein, the term "amine" refers to -NH2; the term "nor ro" indicates -N02; the term "halogen" refers to -F, -Cl, -Br or -I; the term "iol" indicates SH; and »= > The term "hydroxyl" refers to -OH. Accordingly, the term "alkylamino" as used herein refers to an alkyl group, in accordance with the above defined, having an animus group bonded therein. The term "alkylthia" refers to an alkyl group, in accordance with the above defined, which has a sulphidyl group bonded therein. The end? "to which lcarbom 1" as used herein refers to an alkyl group, in accordance with > With the above defined, which has a carbonyl group, link it there! The term "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen atom linked to it. there. Representative alkoxy groups including ethoxy, ethoxy, propoxy, tert-butoxy and the like. The terms "alchem" and "alky" refer to aliphatic unsaturated groups analogous to alkyls, but containing at least one double or triple bond, respectively. The term "aliryl ether group" includes closed ring structures of 7, or more, carbon atoms. Grouts to the icicles include fine proteins or naphthenes that have saturated cyclic hydrocarbons, unsaturated hydrocarbons, and two or more double bonds, which have a triple bond. They do not include aromatic groups. Examples of cycloparaffins include iclopropane, cyclohexane, and cyclinose. Examples of the fine include clopentaclin and c icococ ate raeno. Alicyclic groups also include fused ring structures as well as substituted alicyclic groups such as for example al? Cy groups. alkyl-substituted rials. In the case of aliens, such substituents can break a dormant link at > _? U? Le > lower, lower alkoxy, lower alkoxy, lower alkylthio, lower alkylamino, lower alkoxy, lower, hydroxy, -CF3, -CN, or the like. The term "heterocyclic group" is intended to include closed, closed structures in which one or more of the ring atoms is an element, other than carbon, for example carbon or oxygen. I cts heterocyclic groups may be saturated > : .s or tu in unsaturated and hetericclic chromium groups for example pyrrole and furan may have an aromatic ratio. Dr * fused ring structures are included such as' quino! ina and isoquinnal ina. Other examples of heterocyclic groups include pipdin and turma. Suitable heterocyclic groups may also be substituted on one or several constituent atoms, for example, by a halogen, lower alkyl, lower alchemyl, lower alkoxy, lower alkylthio, lower alkylamine, lower alkyl carbonate, or ro, Hydroxy, -CF2, -CN, or else illars. The term "aromatic group" includes unscreened and cyclic hydrocarbons containing one or more rings. Aromatic groups include 5 and 6 membered single ring groups which can include 0 to 4 heteroatoms, for example benzene, pyrro! , furan, thiophene, imidazole, oxazole, tlazole, tpazol, pyrazole, p indina, pi acma, pipdacin and pipmidine and the like. The aromatic artillery may be substituted in one or several positions > ring, for example a halogen, or lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkylthio, a lower alkylamino, a lower alkyl, a nitro, a hydroxyl, -CF3 , -CN, or similar. The therapeutic compound of the present invention can be administered in a pharmaceutically acceptable vehicle. As used herein, the "pharmaceutically acceptable carrier" pressure refers to any solvent, dispersion medium, coating, aitt-ibactepane and anti-fungal agent, isotonic retardation and absorption agents, and the like compatible with the activity of the agent. compound and fi lologically acceptable to the patient. Ur »example of a pharmaceutically acceptable vehicle is a regulated normal saline solution (0.15 molar NaCl). The use of such media and carriers for pharmaceutically active substances is well known in the art. Except insofar as a medium or agent is enclosed, 1 is ncomp tibl with the therapeutic chromatin, its use is contemplated in the appropriate compositions for pharmaceutical administration. Additional active compounds can also be incorporated into the compositions. In a preferred embodiment of the method of the invention, the therapeutic compound administered to the subject is formed of at least one cavalente sulfctonate group linked to a carrier molecule, or a pharmaceutically acceptable salt thereof. Accordingly, the therapeutic compound may have the formula Q- (~ S03 ~ X +) n where Q is a carrier molecule; X + is a cationic group, and n is an integer. Carrier molecules and suitable cationic groups are those described above. The number of sulfonate groups ("n") is selected in such a way that the biodi str ibuer ion of the compound for a predicted target site is not impeded while maintaining the activity of the compound as set forth above. In one embodiment, n is an integer between l and 10. In another odaldiad, n is an integer between 3 and 8. As described above, therapeutic compounds with multiple sulfonata groups may have the sulfonate groups spaced such that the interaertue compound Optimally with an HSPG binding site within a protein ami loi dogénicra. In preferred embodiments, the carrier molecule for one or vanes sulfanata () is a lower aliphatic group (eg, lower alkyl, lower alkenyl or lower alkyl), a heterocyclic group, a disacchap, a polymer to a peptide or peptide derivative. In addition, the vehicle can be substituted, for example, by one or several methyl, nitro, halogen, thiol or hydroxy groups. In some embodiments, the ptortadora molecule for one or several, sulfate (s) is an aromatice group} .
Examples of suitable polymethoxysulfonated therapeutics include poly (2-ac p-lameth-2-met-11-3-propansulfur »? Co); pol i (arid 2-ac p lam-do-2-me i 1-1-propansulfonic-co-acp lom tp lo); poly (Acid 2-acrylamido-2-met j 1-t-p »ropansul fóm co-co-est ireno); pol i (vim 1 or phonic acid); poly (sodium acid-4-isosulphulic acid); a sulfonic acid derivative of poly (acrylic acid); ? n derivative of sulphonic acid of pol i facp lato of trilo); a derivative of sulphonic acid of pe.3 i ítatacp lat > r. of methyl); and a polyalkyl derivative (to the vinyl cohctl); and pharmaceutically accretable salts thereof. A preferred sulphonated polymer is poly (isonic acid) (PVS) or a pharmaceutically acceptable salt thereof, preferably the sodium salt thereof. In one embodiment, PVS having a molecular weight of about 8O0-1000 Daltons is used. In another embodiment, PVS is employed which has a molecular weight of approximately 2000 (for example XC, where n is, on average, approximately 15). You can use PVS chrome a mixture of e < shallow atereoi or as a unique active isomer. A preferred sulfonated disaccharide is either total or substantially sulphonated sucrose, or a pharmaceutically acceptable s 3, such as, for example, sucrose sucrose. Other sulphonated sacchads include 5-ethe acid. ~ ~ -1, 2-0-? sopropí 1 iden-al f -D-xi 1 ofuranosa-5-sulphonic (XXI 11, shown as sodium exits). Preferred lower aliphatic sulfonated compounds for their. Use in the present invention include ethansulonic acid; 2-aminoethanesulfonic acid (taurine); cysteic acid (3-sol foalaniña or either alpha-a and non-beta-sulfoprsp ionic acid); 1-propanesulfonic acid; 1,2-etand isul acid. phonic; 1,3-propand isul acid. phonic; 1,4-butanedisulfonic acid; 1, 5-pentand isulfonic acid; and 4-hydro? ibutan-1-sulphonic acid (VIII, shown as sodium sil); and pharmaceutically acceptable salts thereof. Other aliphatic sulfonated compounds contemplated for use in the present invention include 1-butanesulfonice acid. (XLVII, chromium sodium salt shown), 2-prop nsul fóniera acid (XLIX, chromium sodium salt shown), 3-pentanesulfonic acid (L, chrome sample, sodium salt), 4-heptanesulfonic acid (LII) , shown as the sodium salt), 1-decansulonic acid (XLVIII, shown as the sodium salt); and pharmaceutically acceptable salts thereof. Substituted aliphatic compounds sul. Faunates contemplated for use in the present invention include 3-amino-1-propansulonic acid (XXII, shown as the sodium salt), 3-hydroxyphosphonic acid sulfate (XXXV, shown as the disodium salt), 1, 7 ~ d ih idroxy-4-heptansulonic acid (Lili, chromium shown the sodium salt); and pharmaceutically acceptable salts thereof. Other sulfonated compounds? 8
contemplated for use in the present invention include 2- ((4-p? pd i m 1) amido) ethansonic acid (LIV, represented as the sodium salt), and pharmaceutically acceptable salts thereof. Preferred heterocyclic sulphonated compounds which contribute 3- (N-mctr fol? No) propansulonic acid; and tetrahydric acid ofen-1, 1-di or x? dc? -3,4-d? sulfero; as well as pharmaceutically acceptable salts thereof. Steroid-synthesized su1 compounds include 1,3-benzene sulfonic acid (XXXVI, shown as the disodium salt), 2,5-dethoic acid, 4-benzodium ion (represented as the disodium salt XXXVII, or well the dipotassium salt, XXXIX), acid or 4-am? no-3-h? drox? -l ~ naf talensul fóm ro (XI III), acid t. 't_ & 4 - d? Amms-l- naftálense »! phonic (XLIV); and pharmaceutically acceptable salts thereof. In another embodiment of the method of the invention, the therapeutic compound admixed to the ingredient is formed of at least one sulfate group covalently linked to a carrier molecule, or a pharmaceutically acceptable salt thereof. For this reason, the therapeutic com- pound may have the formula; Q-i-0S03 ~ X +) n where Q is a carrier molecule; X + is a cationic group, and n is an integer. Moly carriers and suitable cationic groups are those described above. The number of sulfate groups ("n") is selected such that the bi odi tion of the compound for a predicted target site is not impeded while maintaining the activity of the blunt compound raised above. In one embodiment, n is ur »integer inte 1 and 10. In another embodiment, n is an integer between 1 and 8. As described above, therapeutic compounds with multiple sulfate groups may have the sulfate groups spaced such that the compound mterartue optimally with a site gives ertla.e of HSPG within a protein am ido ido iera. In preferred embodiments, the carrier molecule for one sulfatates (s) is a lower aliphatic group (eg, lower alkyl, lower alkenyl or lower alkyl), an aromatic group, an isaccharide, a polymer or a peptide or peptide derivative. In addition, the carrier molecule can be substituted, for example, one or several ammo, nitro, halogen, uncle! or else hi dr? x i. Examples of suitable sulphonated polymepho-therapeutic compounds include poly (2-ar.r-lam-do-2-met?! -1-rop and isulfuric acid); 2-acp 2-acp 1 ami dct-2- et 11 - 1-prop i lsi.il fup co-o-acr i luní tp lo); pol i (acid or 2-ac.p lido-2- i 1-1-prop? I ul fúrico- o- s i reno); pol i (ác ido vi ni 1 sul fú i o); ptol i (4-est i rensul fa to sodium); ur »derived from poly (acrylic acid) sulfate; urt derived from polyl sulfate (methyl acrylate); a sulfate derivative of pol i (methyl ethacrylate); and a de? n vade. poly (vinyl alcohol) sulfate; and highly acceptable salts thereof. The preferred sulfated polymer is poly (vi or sulfuric acid) to a pharmaceutically acceptable salt of the same. A preferred sulfonated disaccharide is octasulfato ci sucrosa or a pharmaceutically acceptable salt thereof. Other sulfated saccharides contemplated for use in the present invention include the ida form of 2,3-cyanosulfonate ethyl-alpha-D-glucopy (XVI), 2,3-d? ul f to ethyl 4,5-0-benc 11 den-al-fa-D-gl uropyranose do (XVII), pentasulfa to 2,3,4,3 ', 4' -surrose (XXXIII), 2 , 5-d? Its! Fate of 1, 3: 4,6-di-0-benz 11 -idene-D-mam toi (XLT), 2,5-d-sulfate of D-am toi (XI. II), tetrasulfate of 2,5- d? -0-benc 11-D-mam to3 (XLV); and pharmaceutically acceptable salts thereof. Preferred lower aliphatic sulfated compounds for use in the present invention include ethylic acid; 2-aminoethane-1-sulfuric acid; 1-propanol ulic acid 1, 2-ethane ioíd i ul fúrico; gone 1,3-propandioldisul fluoride; acid 1, 4-butand l ldisul f n c.o; 1, 5-p ntaneiol ol sulphuric acid; and 1,4-butand-olmctnosul-furic acid; and pharmaceutically acceptable salts thereof. Other sullied aliphatic compounds contemplated for use in the present invention include the disulfate acid profile of 1, -c? Clohexand ictl (XL), 1, 3,5-heptanti'ic? Tpsulfate. (XIX), trisulfatci of tpdroKime111-2-1, 3-p opand io1 (XX), hydroxy ethyl t-sulfate "? -met? 1 -1, 3-propand? A! (XXT), tetrasulfate of 1, 3, 5,6-heptantetraol (XLVT) 1,3,5,7,9-nonane pentasulfate (LLI), and pharmaceutically acceptable salts thereof Other sulfated compounds prepared for use in the present invention include the acid form of tpsul fata from »2-am? no-2-hydroxymet-11-t, 3-propanediol (XXIV), 2-benzyl loxi-1, 3-ptropandyl (XXIX) disulfate, acid sulfate 3-h? Drax? Prctp? Farnic isul (XXX), disulphate of 2,2'-aminoethanol (XXXI), disulfate of N-acid, N-b is (hydroxiet 11) sulfamide (XXXII), as well as salts Their pharmaceutically acceptable compounds include tetrahydrofuran compounds, and include 3- (N-morpholino) prupansul úr? »ro, and tetrahydric acid ofen-1, 1-d? ox? do ~ 3,4-d? sulphonic; as well as pharmaceutically acceptable salts thereof. An additional aspect of the present invention includes coffipti.ic ions to treat the ami lonriosi s. The pharmaceutical compounds in the methods of the present invention, as described above, can be incorporated in a pharmaceutical composition read in an effective manner to inhibit amyloidosis in a pharmaceutically acceptable vehicle. In one embodiment, the pharmaceutical compositions of the present invention include a therapeutic compound having at least one sulfonate group covalently linked to a carrier molecule, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit the deposition of to iloid, and a pharmaceutically acceptable vehicle. The therapeutic composition can have the formula Q - (- S03"X +) n where Q is a carrier molecule, X + is a cationic group, and n is a whole number selected in such a way that your odistpbucíón of the compound for ur» The intended target site is not impeded while the activity of the compound is retained: In another embodiment, the pharmaceutical compositions of the present invention include a therapeutic compound having at least one sulfate group covalently linked to a carrier molecule, or a pharmaceutically salt acceptable thereof, in an amount sufficient to inhibit the deposition of aruloid, and a pharmaceutically acceptable carrier The therapeutic compound can have the following formula: O- (-0S03 ~ X +) n where Q is a carrier molecule; group catiómcct, and n is an integer selected in such a way that the biodi stnbuc ion of the compound ptara a predicted target site is not impeded while keeping the act Composition of other exemplary compounds contemplated for use in the present invention include in situ octasulfate, such as the octasodium salt, the sucrose actasulfate, the octasodium salt, the fa-D-glucopyranosidium methyl, the tetrasodium salt, and the heptasulfate. »3 methyl beta-D-3acts? Do, heptasodic salt; and c-omitted LXXVII-CVIII (figures 14-17) including, inter alia, ethanesulfone or sodium (CVII), 1-propansul sodium fortifier (CVI), and 1-pentanesulonic acid, sodium s (CVIII). The invention also contemplates the use of depressant drugs that are converted live in the therapeutic compounds of the invention (see, for example, RB Silverm, 1992, "The Orgartic Chemistry of Drug Design and Drug Action" (Organic Chemistry of Drug Design and Drug Action), Academic Press, chapter 8). Such prodrugs can be used to alter the biodistribution (for example, to allow compounds that would not typically cross the blood-brain barrier through the blood-brain barrier), or the pharmacotherapeutic properties of the therapeutic compound. For example, an ammonium group, for example a sulfate or sulfonate, can be activated, for example, with a methyl group either with a fatty group or to provide a sulfate ester or sultanate. When the sulfate or sulfonate ester is administered to a patient, the ester is dissociated, either enzymatically or not imatically, reductively or hydrolytically, to reveal the ammonium group. Such an ester may be cyclic, for example, a cyclic sulfate or sulfate, where two or more ammonium portions may be blocked through a linking group. Exemplary cyclic compounds include, for example, 2-sulfobenzene acid (LV), propartsul tone (LVI), butansultone (LVII), cyclic 1,3-butapcyol sulfite (LVIII), acid sultone - rhloro-a1 -hydroxy -o-toluensul phonic (I IX), and 2,2-d-o-6-m tronaft - < t, 8-cd) -l, 2-oxat ictl (LX). In a preferred embodiment, the prodrug is crical sulfate or sultone. An ammonium group can be esteri fi ed with portions (eg, iso esters of acyloxyethanol) dissociated to reveal an intermediate compound that subsequently decomposes to provide the active compound. In another modality, the prodrug is a reduced form of a sulfate or sulfonate, for example, thiol, oxidized in vitro in the therapeutic compound. In addition, an ammonia portion can be contained on a rump actively transported in vivo, or biotically absorbed by white organs. The ester can be selected to allow the specific designation of targets of the therapeutic portions on particular organs, as described below for the carrier portions. Carrier moieties useful in the therapeutic compounds include carrier molecules previously described, for example, carbohydrates, polymers, peptides, peptide derivatives, aliphatic groups, alicyclic groups, heterocyclic groups, aromatic groups or combinations of the same. Suitable polymers include polymers derived from substituted, unsubstituted vinyl, acryl, styrene and rhohydrate as well as copolymers and salts thereof. Carrier-containing molecules include a lower alkyl group, a heterocyclic group, a disacdo, a polymer or a peptide or derived peptide. Carrier molecules useful in the present invention may also include portions that allow the therapeutic compound to be selectively delivered to one or several target organs. For example, if it is desired to deliver a therapeutic agent to the brain, the carrier molecule may include a portion capable of directing therapeutic compound to the brain, either by active transport.; passive (a "directional portion"). Thus, the carrier molecule can include a reduction-oxidation moiety, in accordance with what is described, for example, in US Pat. Nos.
4,540,564 and 5,389,623, both from Bodor. These patents contain drugs linked to portions of dihydrospirma that can penetrate into the brain, where they are oxidized on a charged species trapped in the brain. Therefore, the drug accumulates in the brain. Exemplary pi r id ma / di propyl compounds of the present invention include 3 - (3-sul foprapi 1) - 1, 4-d? H? Drct | ii sodium pdina (LXI), 2- (nicotim licked) sodium acetate sulfonate (LXII), and betaine of 1- (3-sulfopropti 1) -pipdiruo (LXIII). Other carrier moieties include compounds, such as amino acids, for example, which may be passively or actively activated in vivo. An illustrative compound is feni lalanmtaupna (LXTX), wherein a molecule of taurine is conjugated with a fepilalamine (a large neutral amino acid). The carrier can be removed metallically, or it can remain int as a part of an active compound. Mimic estrue ura les of amino acids (and other actively transptartations) are also useful in the invention (for example, 1- (a11 inomet 11) ~ 3 - (sulfomet i3) -ciclcthe no (LXX)). Other exemplary amino acid mimetics include p- (sul fomet i 1) phenylalamine (LXXII), p (1,3-d? Sul foprop ~ 2 ~? L) frtillan (LXXIII), and 0-d, 3- di ul fctprop-2-? 1) 1 rosi rta (LXXIV). Mimetic specimens of ti rom na include compounds LXXV, I XVI, and LXXVII. Many management portions are known, and include, for example, asialoy licoproteitas (see, for example, Wu, U.S. Patent No. 5,166,320) and other ligands transported in cells through endocytosis mediated by receptors (see below for older adults). examples of directing portions which can be covalently or non-crosslinked with a carrier molecule). In addition, the therapeutic compounds of the present invention can be bound to ami le protein. idogénicas in the circulation and therefore be 1 levador to the site of action. The direction and prodrug strategies described above can be combined to produce a compound that can be transported as a prodrug to a desired air site, and then untapped to reveal an active compound. For example, Bodor's d ih idrsp ipd a strategy (see .rritaa) can be combined with a cyclical prodrug, such as in compound 2- (1-met 11 -1, 4-? Hi donicut i 1) < _? dom t 11 -propansul tona (LXXI). In one embodiment, the therapeutic compound in the pharmaceutical compositions is a sulfeated polymer, for example poly (2-atrip lamídct-2-met-11 -3-sulphonic acid); polish (acid? ~ 3c? lam i do-2 -met i 1-l-propansul fomco-co-31- n loni t i lo); pol i (áe i do 2-ac p 1 am? do-2-met i 1-3-propartsu1 fómero-c o-es- »t i reno); poli ci or vi ni 1 sulfóm co);
poly (sodium 4-styrene sulfonic acid); a sulfonate derivative. of poly (acrylic acid); a sulfonate derivative of pctl i (methyl arnide); urt deri ado sultanato de-1 pol i (methyl methacrylate); and a sulfonate derivative of pctl i (to the vinyl ohalte); and pharmaceutically acceptable salts of 1 os m i s ct. In one embodiment, the therapeutic compound or pharmacological compositions is a polymer, for example ptctli (2-acp-lamido-2-methyl-1-propionic acid) and phenyl (acid). 2 ~ ar 11 ai eio-2-met i 1 -1-propansul f úr i eo-co-aerri 1 ein itp lo); po 11 (ac i do 2-ac r 11 r i a 2 -me 113 - 3 -propansul a co-cct-e t i reno); paL i (acidic vinyl sulfuric acid); pol i (4-est? rensul fattt sodium); a derivative of poly (acrylic acid) sulfate; a derivative of pol i sulfate (methyl acrylate); a derivative of poli sulfate (methyl methacrylate); and a poly (vinyl alcohol) sulfate derivative; and pharmaceutically acceptable salts of the smcts). Preferred therapeutic compounds for their inclusion in a pharmaceutical composition for the treatment of a iloidosis of the present invention include poly (vi n sulfuric acid); poly (arid v m Isonic phonic); ocatasu) f ato de suerosa, a partially or fully sulphonated sucrose; acid and sulfuric lsul; to. gone etansul phonic; 2-antirtotetansulonic acid (taurine); arid 2- (ami noest 11) sul f ír i ro;
arid cysténcct (3-sulphalanine or alpha-amino-beta-sulfopropyram acid); 1-propansul phonyl acid; propyl sulfuric acid; acid 3, 2 ~ etand? phonic ulic acid, 3,2-etartdioldisul f? nco acid; 1, 3-propand acid? sulphonic 1,3-p rop ndiol di ulf unco acid; gone 1, 4-butand? phonic, acid
1, 4-butand? Ald? Sulfuric; 3, 5-pentand sulphonic acid; acid 3, 5-ptentc.nd? hear isu! fury 4-hydroxy-ttutan-1-sulphonic acid; ác i o tetrah i d rotriof en- 1, 1-? óx? do-3,4-d? ul f óni co; ác i o 3- (N-morfol i no) pt rop nsul tornero; and pharmaceutically acceptable salts thereof. In the methods of the invention, the amyloid depletion of a patient is inhibited by administering a pharmaceutical composition of the invention to the patient. The term patient erlye living organisms where it may occur »1 la a i 1 ptdosi s. Examples of the patient include humans, monkeys, goats, sheep, goats, dogs, cats, mice, rats as well as transgenic speci? Es thereof. It is administered by the compositions of the present invention. The ion to a patient to be treated can be carried out using known methods, in cycloses, and for periods of time effective to inhibit amyloid deposition in the relative. An affective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the amount of a iloid already deposited at the clinical site in the patient, the age, brain, as well as the patient's weight, and the capacity of the patient. therapeutic compound to inhibit the deposit of ai loide in the patient. Dcti fi ic ion regimens can be adjusted to provide the optimal therapeutic response. For example, vain »divided doses can be administered daily or the dose can be reduced piroprcional in accordance with what is indicated by the demands of the therapeutic situation. A non-limiting example of an effective dose range of a teraptide compound of the present invention (for example poly (sodium salt of vi ni lsul fonate)) is between 5 and 500 mg / kg of p * - »so corporal / by eia. Fn u a aqueous composition. Preferred concentrations of the active compound (ie, the therapeutic compound that can inhibit the deposition of the nucleotides) are between 5 and 5O0 mM, more preferably between 10 and 30 < ") M, and still more preferably between 20 and 50 M. In the case of taurine, the preferred aqueous concentrations of the species are between 10 and 20 M. As shown for example, the therapeutic compounds of the present invention are effective * when administered orally P r r i r i i n i, a route of administration is preferably oral administration, the active compound can be administered by other suitable routes, for example, p admin 43
subcutaneous, intravenous, intraperitoneal, etc. (for example by injection). According to the ad-insertion pathway, the active compound can be coated with a material to protect and compound against the action of aggregates and other natural concii nons that can risk the compound.
The compounds of the invention can be formulated to ensure adequate distribution. For example, the toelea (BBB) barrier excludes many highly hydrophobic compounds. To ensure that the therapeutic compounds of the invention cross the BBB, they can be formulated, for example, in liposomes. For methods of manufacturing liposomes, see, for example, US Pat. Nos. 4,522,813; 5,374,548; and 5,399,331. the liposctmas can rompreneier a ct several by ions that are transported selectively in cells or specific organs
("portions of direction towards white") thus providing a supply. directed drug (see, for example,
V.V.Ranade (1989) J. Clin. Pharmacol. 29: 685). Exemplary address portions include folate or biotin (see, for example, US Patent No. 5,436,016 to Low et al.); mannosides (Umezaina et al., (1988) Biarhe, Biophys.
Res. Com un. 153.3038); antibodies (P.G. Blcteman et al.
(3995) FEBS lett. 357: 140; M. Owais et al. (nineteen ninety five)
Anti icrob. Agents Chemother 39: 180); surfactant pratein A receptors (Bríscete et al. (1995) Am. T. Physiol.
1233: 134); gp320 (S hreier et al. (1994) J. Biol. Chem. 169: 9090); see also X. P í narían; M.L. Laul-Ianen (1994) FEBS lett. 346: 323; J.J. i 11 ion; ITEM. Fidler (3994) Immunomethods 4: 273. In a preferred embodiment, the teratoptive compounds of the present invention are formulated in I; in a more preferred embodiment, the liposomes include a targeting portion. The supply and in vivo distribution can also be affected by the alteration of an ammonium group of compounds of the invention. For example, ammonium groups such as crabethoxyl or tetrazole can be stacked in place of sulfate or sulfonate portions or in addition to said portions to provide compounds with favorable properties, bodily properties and other desirable properties. . Exemplary tetrazol-substituted compounds include 3, 1- i? i of 3 ~ (1H-t r zo! -5-? 1) ~ 9H ~ t i oxanten-9-one (L IV), 5,5 ~ d? 1 obi s (3-phenyl Itetrazetl) dXV), lH-tetrazal (LXVI), 5-phenyl-lH-tetrazrtl (IXVTI), and 5- (α-α2-aminoethane? Co) -lH-tetrazole (LXVIII), and the like »; and their pharmaceutically acceptable salts. Compounds substituted by exemplary carboxylates include dietary acids such as, for example, adipic acid, alkaline acid, 3, 3-d im 3 glutaric acid, sub-acid, succinic acid, and the like, and their pharmaceutically acceptable salts. camertte acceptable.
In order to administer the therapeutic compound by admission route other than the parenteral route of administration, it may be necessary to coat the compound or else to use the material in order to prevent its deactivation. For example, the therapeutic compound can be administered to a patient in an appropriate vehicle, for example, c-liposomes. a diluent. Pharmaceutically acceptable diluents contain saline solutions and aqueous solutions regulator. Lipctsomes include water-in-water-in-water-CGF emulsions as well as conventional liposomes (Strejan et al., (1984) J, Neur &imt; 3: 7: 27). The teraptéuti ce compound. It can also be administered parenterally, ie mt raper taneal, mtraesp or poorly prepared. 3. Dispersions can be prepared in glycerol, liquid polyols and blends, and mixtures thereof and in oils. In ordinary conditions, the preparation and use, these preparations may contain a preservative to prevent the growth of microorganisms. able pharmaceutical compounds for injection include sterile aqueous solutions (when soluble in water) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In cases of cases, the composition must be sterile and must flow in such a way that it can be easily relieved with a syringe. It must have stability under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms, such as bacteria and fungi. The vehicle can be a solvent or a dispersion medium containing, for example, water, ethanol, po3? O3 (for example glycerol, propylene glycol, propylene glycol, and the like), able mixtures thereof. , as well as vegetable oils, Adequate fluidity can be maintained, for example, by the use of a revetment, for example, leci ma, by maintaining the required particle size in case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be achieved by means of antibacterial and anti-bacterial openings such as ptaradencts, r 1ore-butane! , phenol, ascorbic acid, thimerosal, and the like, in many cases, it is preferable to include isotonic agents, for example sugars, sodium chloride, or polyalcohol, such as, for example, mannitol and sorbito, in the composition. A prolonged absorption of 3 injectable compositions can be carried out by the inclusion in the composition of an agent that retards absorption, for example aluminum monostearea or gel. Sterile injectable solutions can be prepared by incorporating the therapeutic compound in the required amount in a suitable solvent with an ingredient or a combination of ingredients listed above, as required, followed by filtered sterilization. Generally, dispersions are prepared by inoculation of the therapeutic compound in a sterile vehicle containing a basic dispersion medium and the other ingredients, required from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of. The preparations are dried by 1 and 13% by weight which provide a powder of the active ingredient (ie, the therapeutic compound) plus any additional desired ingredients from a previously sterile filtered solution therefrom. The therapeutic compound can be administered orally, for example, with an inert diluent or an available assimilable vehicle. The therapeutic compound and other ingredients may also be included in a soft gelatin hard gelatine capsule, it may also be compressed into tablets or incorporated directly into the patient's diet. In the case of oral therapeutic administration, the therapeutic breakthrough p & amp; amp; amp; amp;It is necessary to incorporate excipients and to be used in the form of tablets, gerbils, oral tablets, pills, capsules, alder resins, suspensions, jarates, wafers, and the like. The percentage of the therapeutic compound in the compositions and preparations of ions can obviously be varied. The amount of the therapeutic compound in such therapeutically useful compositions is such that an adequate dosage is obtained. It is particularly advantageous to formulate parenteral compositions in unit dosage forms for ease of administration and uniformity of dosage. The unit dosage form as used herein refers to physically discrete units suitable for unit dosages for the patients to be treated; each unit has a predetermined amount of therapeutic compound calculated to produce the therapeutic effect in association with the required pharmaceutical vehicle. The specifications for the unitary form of the invention of the present invention are dictated and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent therein. the technique of composition of such therapeutic compound for the treatment of amyloid deposits in patients. The active compounds are administered in a therapeutically effective dosage sufficient to inhibit the deposition of iloid in a patient. A "therapeutically effective dosage" preferably inhibits the deposition of amyloid ert at least approximately 20 * 4, more preferably at least approximately 4%, preferably at a higher degree of preference by at least about 60%? and with an even greater degree of ptreferenrr by at least approximately 80! in relation to untreated patients. The (rapacity of a compound to inhibit the deficiency of ami leude can be evacuated in an animal model system that can be predictive of efficacy to inhibit iloid deposition in human diseases, such as for example the subject of the model. Alternatively, the ability of a compound to inhibit the deposition of amyloid can be activated by examining the ability of the compound to inhibit an interaction between an amyloidogenic and urinary constituent base membrane, for example, by using a binding assay, for example, the one described above, the method of the present invention is useful for the tragic environment of the oidosis associated with any eclat ertc tion of amyloid deposition. Amyloidosis can be primary, secondary, familial, or isolated, and the ilaids have been treated according to the type of allergen protein contained within the amylctide. s non-limiting amyloid qu * »can be inhibited, setjún what identified by ßu my protein idogénic, are the following (with the? 18
associated disease in parentheses after "the ami loi dogénic protein"): beta-ami leude (Alzheimer's disease, Dowrt's syndrome, a thousand hereditary hereditary brain dose (Dutch)); ami luide A (ami loidasis reactivate (secondary)), median fever, family ailment, nephropathy, familial laceration, and deafness (Mu l 1 e-Wel Is syndrome); amyloid cié chain I-appare L or amyloid of eradena lambda L (idiopa ica (primary), associated with me the ornament or maeroejl obul i nemia); Abeta2M íhemodiál i si s chronicle); ATTR (pol eurctp ia family amylocle (Portuguese, Japanese, Swedish), familial cardiomyopathy (Dane), isolated amyloid cardiolus, amyloidosis seni s »? Stém? Ca); AIAPP or amylin (adult diabetes, i nsu 11 nom); atrial naturético factor (to isolated atrial loide); proc to le- 1 tonina (medullary carcinoma of the thyroid); gelsolina
(ami laidosi faittiliar (finl nd s.) cpstatin C (hereditary cerebral haemorrhage with a iloidosis (Irish)); AApoA-I (pertl meuropathy ami 3 oidot i_a familial (lowa)); AApoA-II (accelerated senescence in mice); ami loide associated with fibropogen; ani loide associated with lisori a; and AScr or
PrP - 27 (Creutzfeldt's disease - Jacob's syndrome)
S st nn-Straussl er-Sch i nk r, ertcef al i t is esptortgi forme boví n). The sulphated and sulphonated compounds used in the methods described herein are available as available (for example Sigma Chemical Co., St. Louis, MO, or Aldnrh Chemical Co. M? L? Aul-ee, Wl) and / or can be synthesized by standard techniques known in the art (see, eg, Stone, GCH (1936) J, Am. Chem. Soc., 58l4B8). In general terms, the sulphated compounds were synthesized from the corresponding alcohols. Alcohols corresponding to XIX and XX were obtained through the reduction of 1,3-ac etctiene carboxylic acid and tetrahydrocarboxylic acid, which are available commercially. Representative syntheses of active compounds empíted here will be described in greater detail on the pt 1 axis. In certain embodiments of the invention, Congo red was excluded from the sulphonated compounds employed in the method of the invention. In certain embodiments of the invention, the following sulfatade compounds are excluded from their use in the method of the invention, dextratase sulfate 500, ote-car raejeenart, lambda-e-arrageenart, eiextran sulfate 8, l-apparatin. carrageenan, pal isul, pentosan fato, and / or heparan. In some embodiments of the invention, the compositions and methods of the present invention are employed to inhibit the deficiency of a lodi ert amylaidosis where the a loidogenic protein is not the protease resistant form of a protein.
tport protein, ASer (also known as co or PrP-27). The invention is illustrated along the lines of the following Examples which should not be considered limiting of the present invention. The contents of all references, patents granted as well as or published patent applications mentioned in this application are incorporated by > . Next by reference. A demonstration of the efficacy of the therapeutic compounds of the present invention in the mouse model described in the examples predicts the effectiveness of human beings EXAMPLES In the following examples, a well-characterized mouse model of ami loi dosi was employed. In this in vivo system, animals received an inflammatory stimulus and urt amyloid increase factor. In the case of ami loi acute dose (ie, deposit of short-term a loide), the inflammatory stimulus is AgN03. In the case of chronic amyloid sis (continuous deposition of amyloid), the inflammatory stimulus is 1 ipopol i sac ndo (LPS). The deposition of a lodiide to iloid AA) in the spleens of mice was measured with and without therapeutic treatment. EXAMPLE t The following methods were used; ANIMALS All mice were from the CD cepta (Charles Rivers, Morttreal, Quebec) and had a chest of 25 to 30 g. TREATMENT OF THE ANIMALS All the animals received AgN03 (0.5 ml, 2 * 4 solution) subcutaneously in the sptalda, and 100 μg of the amyloid increase factor (AEF) intra-thickly. The penetration of the a iloid increase factor has been previously described in Axelr.d, M.A. et al. ("Further Characteri at ion of Am 1 oíd Enhancing Factor" (Additional Character of the Ami Loide Increment Factor), Lab, Invest. 47: 139-146 (3982)). The animals were divided into several groups, one of which was an untreated control group that was sacrificed 6 months later. The remaining artios were divided into those that were poly (salt of vi rtilsul sodium fctnate) (PVS) 50 mg, 40 g,? m, or 10 mg by intrapteri taneal injection every 32 hours ct either an ammonium salt of sucrose actasulfata (S0A), 73 mg or 36.5 g every B hours by IP injection. The PVS employed in this example and in all subsequent examples was a mixture of stereoisomers. Lcvs surviving animals were sacrificed on the 5th day of treatment. In all cases it. dissolved PVS ob ten S0A er »a water vehicle and 1. PREPARATION OF TISSUES At the end of the experiment and merit, the animals were sacrificed by cervical dislocation and the spleens, livers and kidneys were fixed in 96 * /. of ethanol, I V. of glacial acetic acid and 3 * 4 of water in accordance with that described in Lyon, A.W. et al. ("Ca-deposition of Basement Membrane Components During the Induction of Murine Splemc AA Airtyloid" (Ca-deposite of Membrane Components of B.se during the Induction of Ami leude AA of Ba or Muprta) Lab. Irtvest, 64, 785-790 (1991)). After fi ltration, the tissues were placed in paraffm, which cut sections of 8 to 10 microns, and said mane were stained with Ro or Congo without con tation in accordance with that described by Purtler, H. et al. al ("Appli ation of Thiazole Dyes to Amy lo id Unde Cond 111ons of Di rect Cot ton Dyei ng s CorrelatIon of Hi storhe iral to nd Chemical Data" (Application of Tlazol Dyes to Amiloicles under Direct Cotton Stain Cond icts: Correlation of Histochemical Intimate and Chemical Data), Hi stochemí try 77: 431-445 (1983)). The histological sections seen-. under polarized light were evaluated by image analysis to determine the percentage of spleen occupied by ami l ude. In the case of the experiments with sucrose octasulfate, the tissues were immunoblotted with an antibody to the SAA protein (described in Lyon AW et al., Lab Invest., 64; 785-790 (1991)) and the mmunoteam sections were evaluated by means of image analysis to determine the percentage of tissue section occupied by amylaid. FEASIBILITY OF ANIMALS All control animals survived the experiment without incident. In the case of the animals subjected to therapy, all animals, which received sucrose acetate in a dosage of 73 mg / injection, succumbed before the end of the experiment, the animals that received 36.5 mg of sucrose octasulfate / injection. They all survived. Among the animals that received PVS (molecular weight 900-1000) in each dosing group, about one-half to one-third of the animals succumbed before the end of the experiment. In all cases of death of the animals before the end of the experiments, the cause of death was non-controlled, intrauterine hemorrhage. EFFECTS OF AGENTS ON THE DEPOSIT OF AMIL 01DE The effect of octasulfate of suc rose at 36.5 mg / injection is presented below in Table 1. The mean area of the spleen occupied by the loi in control animals was 7.8 +/- 1.5 * 4 REM Ert animals that received the therapeutic agent, the average area was 3.2 * 4 +/- 0.5 * 4 S.E.M, The difference is significant with pfeifer or equal to o.02. TABLE 3 EFFECT OF AMMONIUM SALT OF SUCROSA OCTASULFATE ON DEPOSIT FROM AMI LOIDE TO IN VIVO IN BAZO DE PATÓN * 4 ciel Area or covered by Ami loide Not treated 7, 8 + • 3.5 n - 5 Oc taS04 of Sucrose 3.2 + 0.5 rt - 5 p greater than or equal to .2 n - 5 In the case of PVS, the data appear in Figure 3. A profound inhibition of the deposit was observed. amyloid at all doses with the suggestion of a dose-dependent effect. An effective dose range is between 5 and 50 mg / kg body weight / per day. The preliminary evaluation * of the plasma level of the ailaidosis precursors associated with inflammation, SAA, has shown that there is no difference between the animals »treated with PVS and those not treated. It is found that the method of adimination of the agents of the present invention has had an effect on the mortality rate of the animals. The nyecc i? R? Mtraper i toneal was selected because it provides a large membrane surface for easy access to the circulatory system. However, like the heparan, the compounds of the present invention exhibit anticoagulant properties. Repeated injections through the pentorteal wall induced severe hemorrhage and finally resulted in the filling of the peponeal cavity, with loss of blood causing death. While subcutaneous injection would result in a slower absorption of the active compound, this route is less likely to cause hemorrhages of such magnitude as to cause death. Oral administration of the compounds was carried out in subsequent experiments (see below). EXAMPLE 2 Swiss white mice with a weight of 25 to 30 g received a facto of increase of iloicie (AEF) and AgNQ3 in accordance with the previously described <; K? i levsfcy, R. and Boudreau, L. (1983) "The l-irteti es of amyloid deposition: I. The effect of amyloid ephartcirtg fac or and splertee to y" (The Kinetics of the Iloid Deposit I. E3 effect of the increase factor ei ami loide and espl rtec ct) Lab Invest. 48, 53-59), to induce ami loidos is. Twenty-four (24) hours later they were divided into 3 groups. The group served as a control group and was maintained in a standard lab laboratory for mice and received tap water ad lib. Urt second group received the standard dosage but their water contained 20 mg / ml of poly (salt vini lsul fonato de sodio) (PVS). The third group recieved 50 mg / ml of PVS from their water. The fluid intake in both groups was the same. All the animals were sacrificed on day sex (day 6) of experiment, their spleens were collected, pireparadas para sectr íona iento, spleen cuts were taken with Congo red (Puchtler, H., et al. (3983) "Application of Thiazole Dyes to A yloiei under Copditions of Direct Cottort Dyeing: Corollary of Histochemical anci Chemical Data" (Application of Tlazol Dyes to A iloid ba or Codes and Direct Dyeing of Cotton: Histochemical Data Correlation and Chemists), H? s »te» chem? stry, 77, 431-445), and the pctreetual area occupied by a survey was evaluated by means of an apparatus and image analysis software (MCID M2, Imagirtg Research Inc. , Broocl-Univ.r.ity, St. Cather inris, Ontario, Canada). As shown in FIG. 4, the adiminstration of PVS interferes with the deposit of ami loide in a way that is dependent on the dose. EXAMPLE 3 Since it was possible that PVS inhibited the hepatic synthesis of the ami loid precursor, and therefore that the absence of deposition of ai loide was due to the absence of a set of precursors, the effect of the PVS on the blood level was determined. from! amyloid precursor (SAA) during the course of the experiment, the animals received AEF + - AgN03 in accordance with what was described above and were divided into two groups. Group 1 did not receive any additional treatment. 24 hours later, group 2 received 50 mg of PVS by injection i rtt rapen toneal every 12 hours for a period of 5 days. To plot the level of SAA during this process, each animal (control animals and * experiment) were bled from the tail (approximately 25 μl) every day. The SAAs in these samples were determined by means of a solid-phase ELISA procedure (described in Bpssette, L., et al (1989) J. Biol. Chem., 264, 19327-19332). The results are shown in Figure 5. Empty lenses represent the data from the mice treated with PVS, while the triangles show the data coming from the animals or treated. The SAA levels were equivalent to treated and untreated animals, which shows that PVS does not mediate its effect by avoiding the synthesis of SAA. EXAMPLE 4 In the experiments described above, PVS therapy began 24 hours in the amyloid induction protocol. This does not mimic a clinical situation where the patient has a well-established amylside. In order to approach a more realistic clinical situation, several septated sessions were carried out where the treatment with PVS was initiated after the initiation. of the deposit of a ilo de. Animals received AEF + AgN03, in accordance with the let described above, and they remained with a feed of tap water for 7 days, after which they were separated into two groups. Group 1 remained with standard feed and tap water. Group 2 remained standard feeding but received 50 mg / ml of PVS through its water. To evaluate the effect of PVS on the course of the deposition of the cystosis locus of the amyloid presenepa, 5 animals of each group were sacrificed on days 7, 10, 14, and 17. The spleens were processed and evaluated for cropping with the arpLta. described. The data appear in figure 6. The control animals (triangle) followed with the amyloid deposit for 14 days after which the amount of amylaide began to decrease. This decrease is probably due to the fact that only one injection of AgN03, the inflammatory stimulus was administered and, after 34 days, qi and- * SAA levels are known to decrease Oii if 1 eky, P., Boudreau, L. and Foster, D. (1983) "inet íes de am the id of deptosi 11 or. "II The effects of the ethy Isul fox i of artel col chic irte therapy" (Kinetics of the deposit of amyloids is the effects of the therapy cor de dimet i Isul fox i do and col ch ic ina) Lab.? rt est., 48, 60-67). Frt the absence of precursor, not s *. puetie deposits »- to additional iloid and existing deposits are uncivilized Oí i si 1 evsl y, R. and Boueáreau, | . (1983) "L'irteties de amyloid deposition I. The effert of a yloid enhanc g factor * adsl rtectomy" (Kinetics of the deposition of ail udes II The effect of the amyloid increase factor and is lertec to í) Lab Invest., 48, 53-59). In contrast, the animals of the treated group (empty circles) suspended the deposit of iloid within 1 or 3 days of receiving PVS. This demonstrates that PVS is effective in inhibiting the current amyloid deposition. EXAMPLE 5 In order to maintain * the inflammation and 1 e_s blood levels of SAA, and to allow the loide to be deposited continuously during the course of a longer term experiment, the nature of the inflammatory stimulus was changed. To maintain the inflammation, the animals received 1 i ptopol i sae arid (IPS, 20 g) + AEF on day 0 and LPS was administered by intratrapep injection 1 every 3rd day. On seven (7), the animals were separated into two groups in accordance with what was described in example 4. The evaluation of? Iloid during the course of the prototyping experiment in accordance with what is described in Example 4. The figures appear in Figure 3. The control group (triangle) continued with the deposition of ilaide for the entire period of 37 days. Those who received PVS apparently suspended the myloid deposit by day 14 (empty circles and dashed lines). The.-Jatos on day 17 represent 4 animals per group since one animal was omitted from this period of time, the amount of amyloid in this particular animal was so far from the other data points (treated untreated, was of 21 * 4) that is ct * & that this was proc ess this valid i nity. If this animal is included, the curve is represented by the 3rd dotted line and the remaining empty circle. It should be noted that animals receiving PVS began to develop a specific strand as the experiment proceeded. EXAMPLE 6 In this experiment, another sulfonated compound, ethanolamic acid, was used to inhibit amyloidosis. The < gone phytonic tantalum, sodium salt, (EMS) is the structure of the manic unit of PVS. The animals received LPS + • AEF as in experiment 5, but on day 7 EMS was used in the water to blunt the agent t snuffed. On the 7th, the animáis were divided into three gurpas. Group 1 was the untreated group. Group 2 received 2.5 mg / ml of EMS from their drinking water *. Group 3 received 6 mg / ml of water for drinking, animals were sacrificed on days 7, 10, 34 and 17. These animals did not develop gastrointestinal problems, these are shown in figure d. 6 mg / ml of EMS in its water ptara tteber (squares va ues) stopped depositing loi after day 14. The animals »that received 2.5 mg / ml of FMS (broccoli) showed a therapeutic effect abortive, with a slight decrease in the speed of deposit of ami loide on day 14 that was not maintained for day 17. EXAMPLE? 63
THE INFLUENCE OF PVS ON THE LINK OF HSPG WITH THE PRECURSOR PROTEIN OF AM1L IDE OF AL 7HEIMER (BETA APP) The binding of proteagl icari d '_ sulfate of heparan on beta APP was evaluated by the use of an immuno assay technique - Absorbent linked with enzymes according to that described in Nan ndrasorasap, S. et al. ("High Affimty Interactions Between the Alzheimer's Beta-Amyloid Precursor Proteins and the Basement Membrane From Heiaran Sulfate Protc.ctgl ycan" (Interactions of high affinity between the precursor proteins of tteta-a i loitie of Ai rheimer and the fo-ma base membrane of ptroteogl lean of heparan sulfate), J. B? o 3. Chem. 266.12878-12883 (3993)). The plaques of myrrotection and pigmentation (Linbrct, Flow the horters *) were coated with a solution of 100 μl, 3 μl / ml of beta-APP, and 2 mM of NaHCO3 regulator. , p 9.6. After the overnight incubation at a temperature of 4 ° C, the rows were rinsed with 0.15 M NaCl, 20 mM Tns-Cl, pH 7.5 (TBS). The plates were then incubated with 150 μl of bovine ceric albumin to t * 4 (BSA) in TBS at a temperature of 37 ° C to block the residual hydrophobic surface on the wells. After rinsing with TBS containing 0. 5 * 4 (weight / vol) of Tween 2o (TBS-Tween), 300 μl was added to several sections of the HSPG in TBS-Tweert alone ct or 500 μg / ml of PVS, either ert a regulated saline cn Tris 6.
(TBS) or in a phosphate buffered saline solution (PBS), was included in the binding assay to evaluate the effect of PVS on the HSPG binding on beta-APP. Plates were left overnight at 4 ° C to release the maximum binding of HSP8 to beta-APP. The plates were then extensively washed and incubated 2 hours at a temperature of 37 ° C. on 3 OO μl of tti-HSPG diluted er »TBS-Tween containing BS? at 0.1 * 4. The plates were washed again and incubated for an additional 2 hours with 100 μl and goat anti-kinase IgG conjugated with alkaline phosphatase (dilution 1.2 00) in PVS-Tween containing E ^ S chromium above. Finally, after an additional wash, the antibodies bound. were detected by the addition of an alkaline phosphatase substrate solution (300 μl) containing 2 mg / ml of p- or trofeni 3 or, .3 M of 7nC32, 1 mM of MgC12, and 3 0 mM phosphate. glycine, pH 10. The plates were aeia at room temperature for 15-320 minutes. Enzyme rearrangement was suspended by the addition of 50 μl 2 M NaOH. Absorbance of p-pprofenol released was measured at 405 p.m. with a Ti tertet MuI t iscan / MCC 340 device (Flow Lab.). The amounts of bound HSPG were determined by the average of A405 net after subtracting the A from the white pozoa ert where the incubation step of the HSPG, the effect of PVS on HSPG, was omitted. the beta-APP link is illustrated in the 6_ »
figure 2 (in TBS) and figure 3 (in PBS). With this compound a binding inhibition of approximately 30-50 * 4 was demonstrated. EXAMPLE 8 An acute dose amylai was induced in mice with AgN03 and ami loid increase factor according to that described in Examples 1 and 2. 24 hours later the animals; They were divided into a control group and six test groups. The control group was maintained with a standard mouse laboratory and received tap water ad lib. The test groups received standard treatment, their water contained 50 mM of one of the following 6 compounds; et artsul fctrt sodium tct, 2-ami oetansu! fon = t to * j sodium (taurine), 1 -propansul fonate of sodium, 3, 2-etand? Sodium fonate, 1,3-ptrop- tand sulphonate of sodium, or 1, -butand? Sodium fonate The water intake was approximately equivalent for all groups. After 6 days the animals were sacrificed and their spleens were processed according to what is described in example 2. For preliminary analysisThe spleen sections were examined visually by a microscope to determine the differences in ami loide deposition in treated animals versus control animals. The results indicated that 1Q, animals treated with 1-prcpansi.il fortified sodium, 1, -etand sulfate sodium, or 3, 3-propand? ul phona or sodium had a lower amyloid deposit than the control animals. Under the conditions used in this experiment, the treated animals, sodium ethane sulfonate, sodium taurine salt, or sodium 3,4-butartd sulfate did not present a lower amyloid deposition than the control animals. However, these compounds may have effectiveness under other conditions, for example, it has been observed that sodium etaitsul fanate inhibits the chronic deposition of a iloid (see example 6) and taurine inhibits the acute deposition of amyloid in other concentrations (see example 9). This experiment suggests that the oral administration of free-radical internal ingredients, for example, 1-propansnl-fonate, sodium, 3, 2-sodium acetate and 3-pyrrotend. Sodium fonate can inhibit the deposition of amyloid in an acute myelogenous system. EXAMPLE 9 In view of the results of the procedures described in Example 8, further experiments were carried out to determine the supply of a panel of sulfated or sulphonated compounds on the acute amyloid deposit. Acute loidosis was induced in rones in accordance with that described in examples 3 and 2. 24 hours later, the animals were divided into a group of control and test groups. The control group was maintained with a.
Standard treatment for laboratory mice and received tap water ad lib. The test gruptcts received standard feed but their water contained 2.50 mM of one of the compounds 1 listed in Table 2, below (the chemical structures of the WAS compounds listed in Table 2 are presented in FIGS. 10. Composite Urt, taurine, was tested at concentrations of 5 mM, 30 M, 20 mM, and 50 mM All compounds are dissolved in water containing 3.0 * 4 sucrose, water intake was approximately equivalent After all 6 groups, after 6 days the animals were sacrificed and their conframed spleens were processed as described in Item 1c 2. The results are summarized in Table 2, below TABLE 2 Effect of Sulphated Compounds and Sulfonated on the deposit of Am lleude- »AA Tn vive, er» mouse spleen Compound Concentration Deposition - ** Error <mM) e standard r ami 1 oí of disulfonate of 1,5-pentane * 50 76 11 2o 60 20 1,6-hexane disulfonate * 50 137 17 2? 98 26 d i sul fa to 1, 2- tartd? to # 50 8 2 20 36 3 i ul sulphate 1, 3 ~ nd -prap ol * 50 11 4 20 32 13 disulfate 3, 4-butan lol * 50 54 22 20 44 33
Taurine (XXXIV) 50 68 15 45 23 3 34 36 5 95 33 di sulfate of »1, -pterttand? ol, 50 79 22 s l sodium (I) 20 80 23 5-deoxyric acid - 2, ~ 0 ~? sopro- 5 < "> 14 pi 11 hundred-beta-Dr iLtof ur nct- i ci- 5» - your 1 phoneme, 3 sódi C? (II) 20 114 3-c 1 clohexi 1 am? no- 1-50 55 propan-sul f omero (III 20 74 a c 1 do 4 - (2-h 1 d ro ¡1 e 11) - 1 - 50 81 pi pera 1 phonic neon (IV) 20 63 acid 4- (2 - hydroxy and 11) ~ 1- 50 135 27 pi p ae methanesulphonic, sodium salt (V) 20 83 28 acid 4- orfol i n-propansul • 0 56 33 phonic (I) 20 102 acid i do 4-mo rfo 1 i rt-p clothes nsu 1 50 48 phonic, sodium salt (VII) 20 98 30 a i do 4-h? dro? butansul f ó- 5 60 21 ruco, sal e eir (VIII) 20 54 31 disodium salt of ether of 50 110 35 Bi (4-sulfobutyl) 1 50 1, 3-di or + tectio n 5 63 33 te rah? Ro-3, 4- ti offense sul-f omero, sl di sodium (X) 2 < "'33' 28 acid 2,5-d? h? drox? -1, 4- 0 19 37 be nr e nd iu 1 phonic, dipotásiea salt (XI) 139 39 acid 4,5-d? H? Dro il, 3 5 158 19 bertc ndosul fóni o, salt 20 130 28 acid (+/-) - 10-camforsul fó- 50 83 19 meo, sl sodium (XIII) 2 155 28 aggregate 2-sul fomet i lbuta? t-1, 50 66 12
4-d? his! sonic co, salt tnsodiea (T V) 20 94 13 glycero tnsulfate !, 50 103 19 sodium tp salt (XV) 20 130 35
«And gone 5-deso? -al-fa-D- 50 100 18 arabic nofurans i do-5 - ulic of methyl, sodium (XVIII) 20 86 30 tp sul fato cié 1,3,5-penta - 50 56 rtnol, iodic salt (XIX) 20 53 hydrogen sulphate 2-5? 53 ammoethyl (XXV) 20 59 indigo carmine (XXVI) 50 51 2-hydroxy sulfate? -50 71 et i sulphonic acid, disodium sulfate (XXVTI) 3-ammonium sulfate? no-3-ptrop? 50,300 sodium salt (XXVIII) 20 107'1 di su1 f to 2-benc 11 oi-50 81 1, 3-propandol, disodium salt (XXIX) • * as sodium salt ** The deposit of ami Loide is provided as a percentage of control without treatment. All measurements are pramed i or anim 05.03 1 The results indicate that o-propandio 1.3! Animals treated with 1,2-disulfate etand ol sodium disulfate well Sodium showed at least a decrease of approximately 65 * 4 in terms of the deposition of a lodiide at 20 mM and at least a decrease of approximately 90 * 4 in regard to the deposition of amyloid at 5? mM. animals, treated with 1, 4-butand sodium lol disulfate (50 mM), sodium 1,5-pentane sulphonate (5 mM), taurine (sodium 2-ammonium ethane sulfonate) (10- 20 mM), sulfonate of 3- (cyclahexy lame) -l-prap na (III) (50 M), 4- (2-hi drox let 13) -lp? Pterac m-etansu) fonate (IV) ( 20 M), ac i do 3- (N-morpholone) propansulphonium (M0PS) (VI) or its sodium salt (VTI) (50 M), tetrahydrate tphydrate i ofen-1, 1-di Oxide-3, 4-the? Sodium Fate (X), 4-h? drox i butan-3 -sul cake ??
of sodium (VIII) (50 M), Tnsulfate of 1, 3,5-pentant ri o! Sodium (XIX) (20 and 50 M), sulfate of 2-aminole and lyrite (XXV) (20 and 50 mM), or bie indigo crimson (XXVI) (50 mM) had at least one decrease in »^ About 40 * 4 in terms of the iloid deposit compared to untreated control animals. Taurine was effective in concentrations of 30 to 20 M, as noted in this example, but less effective at concentrations of 5 M or 50 mM (see also Example 8). Some sulfated or sulphonated compounds were not effective in reducing the amount of amyloid deposition or concii tions used, but may be effective in other ways. Previously, ostrarott in vitro investigations that the melt sulfate and the 6-sulfata control tub do not interfere with the binding of beta amioid precursor protein on HSPG. (+/-) - 10-camforsul cake to sodium (XIII), acid 4, 5-d? h? drox i -1, 3-b nrend i su1 phonic, sal di indica (XTI) and acid 2.5 -d? hydraxi -1, 4-beneertd? sulphite co, diptotassium salt (XI) were tested in the mouse model described above and, as shown in Table 2, it was found that they did not cause any reduction in amyloid deposition. EXAMPLE 10 In these examples, representative syntheses of the compounds employed in the methods of the present invention are described. SODIUM ETAN-1,2-DISULF0NA70 A mixture of 3, 2-d was heated at reflux temperature for 20 h. bramoethane (37.6 g, 0.20 mol) and sodium sulfite (63.0 g, 0.5 mol) in water (225 mt). After cooling the mixture in the reflerator, the crystals were collected. The crude product was re-circulated repeatedly from water-ethanol. The smaller amount of sa 3 is inorganic was removed by treating the aqueous solution with kma small amount of silver oxide.(I) and barium hydroxide. The basic solution was neutralized with an ion exchange resin
Amberlite and treated three times with A berl i te ~ 120 (sodium form), ion exchange resin. After removal of water, the product was recited from water-ethanol to provide the compound from! title (30.5 g). 1,3-SODIUM PROPANDISULPHONATE This compound was prepared by a method of the method described in Storte, G.C.H. (1936) J. Am. Chem. Soc., 58s488. 3, 3-d ibromopropane (40.4 g, 0.2 O mol) was treated with sodium sulfite (60.3 g, 0.5 mol) in water at reflux temperature for 48 hours. The inorganic salts (sodium bromide and sodium sulfite tt) were removed by successive treatment of the mixture of. the resulting reaction -? "?
hydrated rort of bapo and silver oxide (I). The solution was then neutralized with A berl i te-320 (form A ida) and distilled with Norit-A. Barium ions were removed by treating the aqueous solution with Amberlite 120 5 (sodium form), ion exchange resin. The solvent was removed on a rotary evaporator, and the crude product was recrystallized from water-ethanol several times to reduce the title compound (42.4 g). The small < trapped ethanol was removed by 3a
The crystals dissolve in a minimum amount of water and then by concentrating the solution to dryness. The pure product was dried separately at high vacuum at 56 ° C for 24 hours! melting point above 300ßC; 3H NMR (D20) delta: 3.06-3.33 (, 4H, H-1 and H-3),
2.13-20.29 (,? H, H-?; 13C NMP (D20) delta 52.3 (Cl and 0-3), 23.8 (C-2) EQUIVALENTS The experts in the field will recognize, or can determine by the only use of experiment cié routine,
2 numerous equivalents to the specific procedures described here. The equivalents are considered to be within the scope of this invention and are covered by the following lenses.
¿. »
Claims (9)
1. - A method for inhibiting the deposition of amyloid in a patient, comprising administering to the patient an effective amount of a therapeutic compound, the therapeutic compound comprising at least one anionic group covalently linked to a carrier molecule, or a pharmaceutically acceptable salt thereof.
2. The method according to claim 1, wherein the therapeutic compound has the formula: wherein Y "is an anionic group at physiological pH, Q is a carrier molecule, X + is a cationic group, and n is a whole number selected such that the biodistribution of the therapeutic compound for a predicted target site is not impeded while maintains the activity of the therapeutic compound
3. The method according to claim 2, wherein the anionic group is a sulfonate group
4. The method according to claim 3, wherein the therapeutic compound is selected from the group consisting of ethanesulfonic acid, 1,2-ethanedisulfonic acid, 1-propanesulfonic acid, 1,3-propanedisulfonic acid, 1,4-butanedisulfonic acid, 1,5-pentadisulfonic acid, 2-aminoethanesulfonic acid, 4-hydroxybutan-1 -sulfonic, and salts Amended pharmaceutically acceptable sheet thereof.
5. The method according to claim 3, wherein the therapeutic compound is selected from the group consisting of 1-butanesulfonic acid, 1-decansulfonic acid, 2-propanesulfonic acid, 3-pentanesulfonic acid, 4-heptanesulfonic acid, and pharmaceutically acceptable salts thereof.
6. The method according to claim 3, wherein the therapeutic compound is 1,7-dihydroxy-4-heptanesulfonic acid, or a pharmaceutically acceptable salt thereof. 1 . - The method according to claim 2, wherein the anionic group is a sulfate group. 8. The method according to claim 7, wherein the therapeutic compound is selected from the group consisting of 2-hydroxymethyl-1,3-propandiol disulfuric acid, 2-hydroxymethyl-2-methyl-1,3-propandiol disulfuric acid, 1,3-cyclohexanedioldisulfuric acid, and pharmaceutically acceptable salts thereof. 9. The method according to claim 7, wherein the therapeutic compound is 2, 3, 4,3 ',' -sucrose pentasulfuric acid, or a pharmaceutically acceptable salt thereof. 10. The method according to claim 7, wherein the therapeutic compound is selected from the group Amended sheet consisting of sulfuric acid of 2-hydroxyethylsulfamic acid, sulfuric acid of 3-hydroxypropyl sulfamic acid, and pharmaceutically acceptable salts thereof. 11. The method according to the claim 7, wherein the therapeutic compound is selected from the group consisting of 1, 3, 5-pentantrisulfuric acid, 1,3,5,7-heptanesulfuric acid and 1,3,5,7,9-nonanpenta-sulfuric acid, and pharmaceutically acceptable salts thereof. 12. The method according to claim 2, wherein the anionic group is a tetrazole group. 13. The method according to claim 12, wherein the therapeutic compound is selected from the group consisting of 10, 10-dioxide of 3- (lH-tetrazol-5-yl) -9H-thioxanthen-9-one; 5, 5-dithiobis (1-phenyltetrazole); lH-tetrazole, 5-phenyl-lH-tetrazole, and 5- (2-aminoethanoic acid) -lH-tetrazole, and pharmaceutically acceptable salts thereof. 14. The method according to any of the preceding claims, wherein the carrier molecule comprises a targeting portion. 15. The method according to any of claims 1 to 13, wherein the therapeutic compound is administered orally. 16.- The method of compliance with any of the Amended Sheet claims 1 to 13, wherein the carrier molecule is selected from the group consisting of a carbohydrate, a polymer, a peptide, a peptide derivative, an aliphatic group, an alicyclic group, a heterocyclic group, an aromatic group and combinations thereof. 1
7. The method according to claim 16, wherein the carrier molecule is an aliphatic group. 1
8. A composition comprising 1,3,5-pentantrisulfuric acid, or a salt thereof, in a pharmaceutically acceptable carrier. 1
9. A composition comprising a compound selected from the group consisting of 10, 10-dioxide of 3- (lH-tetrazol-5-yl) -9H-thioxanthen-9-one; 5, 5-dithiobis (1-phenyl-tetrazole); lH-tetrazole; 5-phenyl-lH-tetrazole, and 5- (2-aminoethanoic acid) -lH-tetrazole; or a salt thereof, in a pharmaceutically acceptable carrier. 20. A composition for use to inhibit the deposition of emiloid in a patient, comprising a therapeutic compound, including at least one anionic group covalently linked to a carrier molecule, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier , the therapeutic compound having the formula: QtYX *] -, where Y "is an anionic group at physiological pH; Q is an Amended sheet carrier molecule; X + is a cationic group; and n is a whole number selected such that the biodistribution of the therapeutic compound for a predicted target site is not impeded while maintaining the activity of the therapeutic compound. 21. The composition according to claim 20, wherein the therapeutic compound is 1,7-dihydroxy-4-heptanesulfonic acid, or a pharmaceutically acceptable salt thereof. 22. The composition according to claim 20, wherein the therapeutic compound is selected from the group consisting of 2-hydroxymethyl-1,3-propandiol disulfuric acid, 2-hydroxymethyl-2-methyl-1,3-propandiol disulfuric acid, 1,3-cyclohexanedioldisulfuric acid, and pharmaceutically acceptable salts thereof. 23. The composition according to claim 20, wherein the therapeutic compound is selected from the group consisting of 2-hydroxyethylsulfamic acid sulfuric acid, 3-hydroxypropyl sulfamic acid sulfuric acid, and pharmaceutically acceptable salts thereof. 24. The composition according to claim 20, wherein the therapeutic compound is selected from the group consisting of 1,3,5,7-heptanesulfuric acid and 1,3,5,7,9-nonanpentanesulfuric acid, and Amended sheet pharmaceutically acceptable salts thereof. 25. The use of a therapeutic compound that includes at least one anionic group covalently linked to a carrier molecule, for the preparation of a medicament for inhibiting the deposition of amyloid in a patient. 26. The use according to claim 25, wherein the therapeutic compound has the formula: wherein Y "is an anionic group at physiological pH, Q is a carrier molecule, X + is a cationic group, and n is a whole number selected in such a way that the biodistribution of the therapeutic compound for a predicted target site is not impeded while maintaining the activity of the therapeutic compound 27. The use according to claim 25, wherein the anionic group is one of a sulfonate group , a sulfate group and a tetrazole group 28.- The method according to the claim 3, wherein the therapeutic compound is 3-amino-1-propanesulfonic acid, or a pharmaceutically acceptable salt thereof. 29.- The method of compliance with the claim 28, wherein the therapeutic compound is administered orally. 30.- A pharmaceutical composition comprising acid Amended 3-amino-1-propanesulfonic sheet, or a salt thereof, in a pharmaceutically acceptable carrier, to inhibit the deposition of amyloid in a patient. 31.- The use of the therapeutic compound 3-amino-1-propanesulfonic acid covalently linked to a carrier molecule, for the preparation of a medicament for inhibiting the deposition of amyloid in a patient. 32. A method for inhibiting the deposition of amyloid in a patient, comprising administering to the patient an effective amount of the pharmaceutical composition of claim 30. Amended sheet
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/403,230 US5643562A (en) | 1993-03-29 | 1995-03-15 | Method for treating amyloidosis |
US08403230 | 1995-03-15 | ||
US08463548 | 1995-06-05 | ||
US08/463,548 US5972328A (en) | 1993-03-29 | 1995-06-05 | Method for treating amyloidosis |
US08/542,997 US5840294A (en) | 1993-03-29 | 1995-10-13 | Method for treating amyloidosis |
US08542997 | 1995-10-13 |
Publications (2)
Publication Number | Publication Date |
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MX9706986A MX9706986A (en) | 1998-06-30 |
MXPA97006986A true MXPA97006986A (en) | 1998-10-30 |
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