MXPA00007217A - &agr;-KETOAMIDE INHIBITORS OF 20S PROTEASOME - Google Patents
&agr;-KETOAMIDE INHIBITORS OF 20S PROTEASOMEInfo
- Publication number
- MXPA00007217A MXPA00007217A MXPA/A/2000/007217A MXPA00007217A MXPA00007217A MX PA00007217 A MXPA00007217 A MX PA00007217A MX PA00007217 A MXPA00007217 A MX PA00007217A MX PA00007217 A MXPA00007217 A MX PA00007217A
- Authority
- MX
- Mexico
- Prior art keywords
- composition according
- substituted
- carbon atoms
- branched
- indole
- Prior art date
Links
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Abstract
a-ketoamide compounds useful for treating disorders mediated by 20S proteasome in mammals having structure (I).
Description
Α-Ketoamide inhibitors of the 20S Proteasome
Background of the Invention The multicatalytic proteinase or the proteasome is a highly conserved cell structure that is responsible for the ATP-dependent proteolysis of most cellular proteins (Coux, O., Tanaka, K. and Goldberg, A. 1996 Ann. Rev. Biochem. 65, 801-847). The 20S proteasome contains the catalytic core of the complex and has been crystallized from the archaeobacterium Thermoplasma acidophilum (Lowe, J., Stock, D., Jap, B., Zwicki, P., Bauminster, W. and Huber, R. 1995 Science 268, 553-539) and from the yeast Saccharomyces cerevisiae (Groll, M., Ditzel, L, Lowe, J., Stock, D., Bochtler, M., Bartunik, HD and Huber, R. 1997 Nature 386, 463-471). In contrast to the arcaebacterial proteasome, which basically inhibits chymotrypsin, as well as proteolytic activity (Dahlmann, B., COP, F., L, Niedel, B., Pfeifer, G. 1989 FEBSLett, 251, 125-131; Seemuller, E., Lupas, A., Zuw, F., Zwickl, P and Baumeister, W. FEBS Lett 359, 173, (1995) The eukaryotic proteasome contains at least five identifiable proteolytic activities, three of which are similar in specificity to chymotrypsin, trypsin and peptidylglutamyl peptidase The other two activities described exhibit a preference for the penetration of the peptide bonds on the carboxyl side of the branched chain of amino acids (BrAAP) and towards the peptide bonds between the neutral short chain of amino acids (SnAAP) (Orlowski, M. 1990 Biochemistry 29, 10289-10297).
Although the 20S proteasome contains the proteolytic core, it can not degrade proteins in vivo unless it forms a complex with a 19S layer, at either end of its structure, which itself contains multiple ATPase activities. This larger structure is known as the 26S proteasome and will rapidly degrade proteins that have been targeted for degradation by the addition of multiple 8.5-kDa polypeptide molecules, ubiquitin (reviewed in Coux, O., Tanaka, K. and Goldberg, A. 1996 Ann. Rev. Biochem. 65, 801-847). A considerable number of functionalities derived from the substrate have been used as potential inhibitors of serine and thiol protease. Several of these subjects have been described as proteasome inhibitors. These include aldehyde peptides (Vinitsky, A., Michaud, C, Powers, J. and Orlowski, M. 1992 Biochemistry 31, 9421-9428; Tsubuki, S., Hiroshi, K., Saito, Y., Miyashita, N ., Inomata, M. and Kawashima, S. 1993 Biochem. Biophys., Res. Commun., 196,1195-1201; Rock, K, I., Gramm, C, Rothstein, L, Clark, K., Stein, R. , Dick, L, Hwang, D. and Goldberg, AL (1994) Cell 78, 761-771) N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal (ALLN) and N-acetyl-L-leucinyl- 1-leucinyl-metional (LLM) with the most potent inhibitor of this type being N-carbobenzoxyl-1-L-leucinyl-L-leucinyl-L-norvalinal (MG115). Other reports have described a series of dipeptide inhibitors having IC 50 values in the range of 10 to 100 nM (Iqbal, M., Chatterjee S., Kauer, JC, Das, M., Messina, P., Freed, B., Biazzo, W and Siman, R. 1995. l-Med.Chem 38, 2276-2277). A series of α-ketocarbonyl and dipeptides derived from boronic ester (Iqbai, M., Chatterjee, S., Kauer, JC, Mallano, JP, Messina, PA, Reiboldt, A. and Siman, R. 1996. Bioorg. Med-Chem Lett 6, 287-290) and epoxyketones (Spattenstein, A., Leban, JJ., Huang JJ, Reinhardt, KR, Viveros, OH, Sigafoos, J. and Crouch, R. 1996. Tet.Lett.:37, 1434- 1346) has also been described as potent inhibitors of the proteasome. A different compound that inhibits specificity in inhibitory proteasome activity is Lactacystin (Fenteany, G., Standaert, RF, Lane, WS, Choi, S., Corey, EK and Schreiber, SL 1995 Science 268, 726-731) which is a metabolite Streptomyces. This molecule was originally discovered for its ability to induce a neurite result in a neuroblastoma cell line (Omura, S., Matsuzaki, K., Fujimoto, T., Kosuge, K., Furuya, T., Fujita, S. and Nakagawa, A. 1991 J. Antibiot. 44, 117-118) and was later shown to inhibit the proliferation of several cell types (Fenteany, G., Standaert, RF, Reichard, GA, Corey, EJ and Schreiber, SL 1994 Proc. Nat'l. Acad. Sci. USA 91, 3358-3362). It is now established that the proteasome is a major extralyosomal proteolytic system involved in the proteolytic pathways essential for various cellular functions such as cell division, antigen processing and the degradation of short-lived regulatory proteins such as oncogenic products, the factors of transcription and cyclins (Ciechanover, A. (1994) Cell 79, 13-21; Palombell, V.J., Rando, O.J., Goldberg, A.L. and Maniatis, T. 1994 Cell 78, 773-785). For example, the active form of NF-? B is a heterodimer consisting of a p65 subunit and a p50 subunit. The latter is present in the cytosol as an inactive precursor (p105). The proteolytic process of p105 to generate p50 occurs via the proteasome-ubiquitin pathway. Additionally, the processed p50 and p65 subunits are maintained in the cytosol as an inactive complex bond for the inhibitor protein L? B. Inflammatory stimuli such as LPS activate NF-? B by initiating the signaling pathway leading to the degradation of L? B. These signals also stimulate the processing of p105 in p50. Therefore, two proteolytic events are required, both governed by the ubiquitin-proteasome pathway for the activation of NF-αB induced signal. The observation that ubiquitin-mediated proteasomal proteolysis plays a critical role in the activation of NF-? B that could be exploited clinically by the use of inhibitors directed towards the proteasome. The abnormal activation of NF-? B followed by the stimulation of cytokine synthesis has been observed in several infectious and inflammatory diseases. The activation of NF-? B is also essential for angiogenesis and for the expression of the adhesion of molecules (CAMs and selection), therefore proteasome inhibitors may also have utility in the treatment of diseases associated with the vascular system. . It is well documented that the ubiquitin-proteasome pathway is critical for the regulated destruction of cyclins that govern the exit from mitosis and allow cells to progress to the next phase of the cell cycle (Glotzer, M., Murria, AW and Kirschner , MW (1991) Nature 349, 132-138). Therefore, inhibition of cyclin degradation by the use of proteasome inhibitors causes growth arrest. Therefore, another potential utility of proteasome inhibitors is their use in the treatment of diseases resulting from aberrant cell division. Many classes of peptide inhibitors of the 20S proteasome have been reported in recent literature. The α-ketoamide group has been used in protease inhibitors for numerous indications. Specifically, a series of α-ketocarbonyl and dipeptides derived from the boronic ester (Iqbal, M., Chatterjee, S., Kauer, J. C, Mallamo, JP, Messina, PA, Reiboldt, A, and Siman, R. 1996 Bioorg Med. Chem. Lett 6, 287-290) have been reported as potent inhibitors of 20S proteasomal function. The 3-indolopyruvic acid derivatives have been claimed as pharmaceutically active compounds for the treatment of disturbances of the central nervous system (De Luca, et al WO 88/09789) through a mechanism that modulates the levels of cinuric acid in the brain . Although several compositions have been discovered that inhibit cell proliferation to some degree, there remains a need for more potent compounds that inhibit cell proliferation via the 20S proteasome.
SUMMARY OF THE INVENTION It is an object of this invention to provide a method for inhibiting cell proliferation in mammals using a therapeutically effective amount of a composition hitherto unknown for its inhibitory properties of cell proliferation.
It is also an object of this invention to provide a method for the treatment of diseases that can be affected by the inhibition of proteasomal function. Furthermore, it is an object of this invention to provide a method for the treatment of proliferative diseases that operates by inhibiting proteasomal function. It is another object of this invention to use a therapeutically effective amount of the compositions described herein to inhibit cell proliferative disorders in humans. Yet another object of this invention is the use of a therapeutically effective amount of the compositions described herein to inhibit proteasomal function. In one embodiment, this invention is a composition having the formula:
wherein X2 is Ar or Ar-X3, wherein X3 is -C = O, or -CH2CO- and wherein A is phenyl, substituted phenyl, indole, substituted and any other heteroaryl; R1 and R2 are each individually selected from the side chains of the known natural a-amino acids and non-natural amino acids, hydrogen, branched and linear alkyl of 1-10 carbon atoms, branched and linear substituted alkyl of 1-10 carbon atoms. carbon, aryl, substituted aryl, branched and linear substituted aryl of 1-10 carbon atoms, alkoxyaryl, cycloalkyl of 3-8 carbon atoms, heterocycle, substituted heterocycle, heteroaryl and substituted heteroaryl; Xi is selected from hydroxide, monoalkylamino, dialkylamino, alkoxide, arylcoxide and
wherein X 4 is hydroxide, arylamino, monoalkylamino, dialkylamino, alkoxide or arylalkoxide and R 3 is selected from known natural a-amino acids, non-natural amino acids, hydrogen, branched and linear alkyl of 1-10 carbon atoms, branched and linear substituted alkyl of 1-10 carbon atoms, aryl, substituted aryl, branched and linear substituted aryl of 1-10 carbon atoms, alkoxyaryl, cycloalkyl of 3-8 carbon atoms, heterocycle, substituted heterocycle, heteroaryl and substituted heteroaryl.
In another embodiment, this invention is a method for the inhibition of proteasomal protease factor in mammals comprising the administration of a therapeutically effective amount of the composition described above to the mammal. In another embodiment, this invention is a pharmaceutical composition of the material comprising the composition according to claim 1 and one or more pharmaceutical excipients.
. DETAILED DESCRIPTION OF THE INVENTION This invention is a method for the inhibition of disorders of cell proliferation, infectious diseases and immunological diseases in mammals and especially in humans, using compositions having the following general formula:
where:
X2 is Ar or Ar-X3 wherein X3 is -C = O, -CH2CO- or (CH2) n where n = 0-2 and wherein Ar is phenyl, substituted phenyl, indole, substituted and any other heteroaryl. R1 and R2 are each independently selected from the side chains of known natural a-amino acids and non-natural amino acids; hydrogen, branched and linear alkyl of 1-10 carbon atoms, branched and linear substituted alkyl of 1-10 carbon atoms, aryl and substituted aryl, branched and linear substituted aryl of 1-10 carbon atoms, alkoxyaryl, cycloalkyl of 3 -8 carbon atoms, heterocycle and substituted heterocycle or heteroaryl and substituted heteroaryl. R2 is preferably biaryl or biphenyl. R1 is preferably isobutyl. X1 is selected from -OH, mono or dialkylamino, alkoxide, arylcoxide and
wherein: X4 is -OH, arylamino, mono or dialkylamino, alkoxy or arylalkoxide and preferably -OH R3 is selected from the side chains of known natural a-amino acids and non-natural amino acids, hydrogen, branched alkyl substituents and linear alkyl of 1-10 carbon atoms, branched and linear substituted alkyl of 1-10 carbon atoms, aryl and substituted aryl, branched and linear substituted aryl of 1-10 carbon atoms, alkoxyaryl , cycloalkyl of 3-8 carbon atoms, heterocycle and substituted heterocycle or heteroaryl and substituted heteroaryl R 3 is preferably CO 2 H, CH 2 CO 2 H, (CH 2) 2 CO 2 H, Arg, Lys, Asn, Gln, Asp, Glu, Phe and Nle. The following are definitions for certain terms used in this document. "Halogen" refers to fluorine, bromine, chlorine and iodine atoms. "Hydroxy" refers to the -OH group. "Tiol" or "mercapto" refers to the -SH group. "alkyl" refers to a long or branched chain cyclic alkyl group of one to ten carbon atoms. This term is further exemplified by such groups as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl (or 3-methylpropyl), cyclopropylmethyl, i-amyl, n-amyl, n -hexyl and the like. "Substituted alkyl" refers to lower alkyl as described including one or more groups such as hydroxyl, thiol, alkylthyl, halogen, alkoxy, amino, amido, carboxyl, cycloalkyl, substituted cycloalkyl, heterocycle, cycloheteroalkyl, substituted cycloheteroalkyl, acyl, carbocyl , aryl, substituted aryl, aryloxy, hetaryl, substituted hetaryl, aralkyl, heteroaralkyl, alkyl, alkenyl, alkyl, alkynyl, cycloalkyl, cycloheteroalkyl, cyano, said groups may be attached to any carbon atom of the middle part of the lower alkyl. "Aryloxy" denotes groups -Oar, where Ar is an aryl, substituted aryl, heteroaryl or a substituted heteroaryl group as defined below. '"Amino" denotes the group NRR', where R and R 'may independently be hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl or substituted hetaryl as defined below or acyl. "Amido" denotes the group -C (O) NRR ', where R and R' can be independently substituted by hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl as defined below. "Carboxyl" denotes the group -C (O) OR, where R can independently be hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl and the like as defined. "Aryl" or "Ar" refers to an aromatic carbocyclic group having at least one aromatic ring (e.g., phenyl or biphenyl) or condensed multiple rings in which at least one ring is aromatic (e.g., 1, 2, 3,4-tetrahydronaphthyl, naphthyl, anthryl or phenatryl). "Substituted aryl" refers to aryl optionally substituted by one or more functional groups, eg, halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl , nitro, cyano, thiol, sulfamido and the like. "Heterocycle" refers to a saturated or unsaturated aromatic carbocyclic group, having a single ring (eg, morpholino, pyridinyl or furyl) or multiple fused rings (eg, napthyridyl, quinoxalyl, quinolinyl, indolizinyl or benzo [b] thienyl) and having at least one heteroatom, such as N, O or S, within the ring, which may be optionally substituted and unsubstituted with, for example, halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido , carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like. "Heteroaryl" or "hetar" refers to a heterocycle in which at least one heterocyclic ring is aromatic. Preferred heteroaryls are phenyl, substituted phenyl, indole and substituted indoles. "Substituted heteroaryl" refers to a mono or poly heterocycle optionally substituted with one or more functional groups, eg, halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like. "Cycloalkyl" refers to a polycyclic or divalent cyclic alkyl group containing 3 to 15 carbon atoms. "Substituted cycloalkyl" refers to a cycloalkyl group comprising one or more substituents with, for example, halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano , thiol, sulfamido and the like. Examples of compounds that may be useful in the therapeutic methods of this invention and specifically useful as inhibitors of proteasomal function are identified in Table 1 below:
Table I. Compositions used to inhibit the proteasome
51
52 53 54
55 56 57 58 S9 60 I
118
119 20
162
163
164
165
67 68 69 70
187 ipdol
188 indole
189 Ipdol
190 Indole 91 Indole 92 Ipdol 93 i Ipdol 194
195
196
197
198
199
200
201
The compounds described above are useful in the treatment of diseases and disorders mediated by the 20S proteasome such as antiproliferative diseases, cancer, inflammation. It is preferred that the compositions of this invention be used to treat antiproliferative disorders and inflammation. It is more preferred that the compounds of this invention be used to treat inflammatory diseases. The compounds of the present invention are useful for treating disorders in mammals mediated by the 20S proteasome.
The compounds of this invention can be administered to mammals both prophylactically and therapeutically by any administration protocol that is capable of providing at least one compound of this invention to a 20S proteasome. Non-limiting examples of useful administration protocols include the oral, parenteral, cutaneous, transdermal, rectal, nasal or any other appropriate pharmaceutical protocol for administration of the composition that is within the knowledge of the person skilled in the art. The compositions of this invention can be administered in appropriate pharmaceutical dosage forms. The dosage dosage form will depend on the administration protocol used. The term "pharmaceutical dosage form" refers to articles such as tablets, capsules, liquids and powders, which comprise 20S proteasome inhibitors of this invention alone or in the presence of one or more pharmaceutical excipients. The selection of additives such as excipients and adjuvants will again depend on the chosen administration protocol. Those skilled in the pharmaceutical arts will recognize a wide variety of formulations and vehicles for administering the compositions of this invention. The chosen administration protocol for the compounds of this invention will ultimately dictate the final forms and composition of the pharmaceutical dosage forms comprising the 20S proteasome inhibitors of this invention. For example, the internal administration of the compounds of this invention is effected orally in the form of powders, tablets, capsules, pastes, beverages, granules or solutions, suspensions and emulsions that can be administered orally or in bolus, in medicinal food or in drinking water. Internal administration can also be completed using a gradual release formulation that includes additives such as surfactants or capsules coated with starch or using a rapid release formulation such as a lyophilized fast dissolving tablet. Cutaneous administration is effected, for example, in the form of transdermal patches, aerosol or creams and ointments. Parenteral administration is effected, for example, in the form of injections (intramuscular, subcutaneous, intravenous, intraperitoneally) or by implants. Appropriate pharmaceutical dosage forms incorporating the 20S proteasome inhibitors of this invention include but are not limited to solutions such as solutions for injection, oral solutions, concentrates for oral administration after dissolution, solutions for use on the skin or in the body cavities, formulations in ointments or ointments, gels, emulsions and suspension for cutaneous or oral administration and for injection, semi-solid prations, formulations in which the active compound is incorporated in a cream base or a base of emulsion of oil in water or water in oil, solid prations such as powders, premixes or concentrates, granules, pills, tablets, colds, capsules, aerosols and inhalants and shaped articles containing the active compound. The pharmaceutical dosage forms that are solutions can be administered by intravenous injection, intramuscularly and subcutaneously. Solutions for injection are prepared by dissolving the active compound in an appropriate solvent and, if appropriate, adding adjuvants such as solubilizers, acids, bases, stabilizing salts, antioxidants and preservatives. The solutions are removed and filtered in sterile form. Alternatively, the solutions including the compositions of this invention can be administered orally. The concentrates of the compositions of this invention are preferably orally administered only after diluting the concentrate to the concentration of the administration. Oral solutions and concentrates are prepared as described above in the case of solutions for injection. Solutions for use on the skin are applied by dripping, rubbing, rubbing, marking or spraying. These solutions are prepared as described above in the case of solutions for injection. The gels are applied to the skin or introduced into the body cavities. The gels are prepared by treatment solutions which have been prepared as described in the case of solutions for injection with such an amount of thickener that a clear substance of creamy consistency is formed or by any other means known to one skilled in the art. The paste or ointment formulations are applied to or sprayed on limited areas of the skin, the active compound penetrates the skin and acts systemically. The paste and ointment preparations are prepared by dissolving, suspending or emulsifying the active compound in appropriate solvents or solvent mixtures that are tolerated by the skin. If appropriate, other adjuvants such as dyes, resorption accelerators, antioxidants, light stabilizers and adhesives are added.
The emulsions can be administered orally, cutaneously or in the form of injections. The emulsions are of the water-in-oil type or the oil-in-water type. They are prepared by dissolving 20S proteasome inhibitors in the hydrophobic or hydrophilic phase and homogenizing the phase with a solvent of the opposite phase with the assistance of appropriate adjuvants such as emulsifiers, dyes, resorption accelerators, preservatives, antioxidants, light stabilizers and substances that increase the viscosity. The suspensions can be administered orally, cutaneously or in the form of injection. They are prepared by suspending the active compound in a suitable liquid with the addition of additional adjuvants such as wetting agents, dyes, resorption accelerators, preservatives, antioxidants and light stabilizers. The pharmaceutical compositions of this invention may include one or more additives in the form of pharmaceutically acceptable additives. Useful additives include solvents, solubilizers, preservatives, thickeners, wetting agents, dyes, resorption accelerators, antioxidants, light stabilizers, adhesives, viscosity-increasing substances, fillers, flavorings, lubricants and any other pharmaceutical composition of additives known to the person skilled in the art. The additive can be a solvent such as water, an alcohol such as ethanol, butanol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycols, N-methyl-pyrrolidone, alkanols, aromatic alcohols such as phenylethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as alkylene glycol, alkyl ethers such as dipropylene glycol mono-methyl ether, diethylene glycol mono-butyl ether, ketones such as acetone, methylethyl ketone , aliphatic and / or aromatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, 2,2-dimethyl-4-oxy-methylene-1,3-dioxolane. The following additives may be useful as solubilizers of the compositions of this invention: solvents that improve the solution of the active compound in the main solvent or prevent its precipitation. Examples thereof are polyvinylpyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters. Useful preservatives are, for example, benzyl alcohol, trichlorobutanol, p-hydroxybenzoic esters and n-butanol. Useful thickeners include inorganic thickeners such as bentonite, colloidal silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates. Other liquids that may be useful in the pharmaceutical dosage forms of this invention are for example, homogeneous solvents, solvent mixtures and wetting agents that are typically surfactants. Useful dyes are all dyes that are non-toxic and that can be dissolved or suspended. Useful accelerators of the reabsorption are DMSO, spraying oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols.
Useful antioxidants are sulphites or metabisulfites such as potassium metabilsufite, ascorbic acid, butylated hydroxytoluene, butylhydroxyanisole, tocopherol. A useful light stabilizer is novantisolic acid. Useful adhesives include cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin. Useful emulsifiers include nonionic surfactants such as polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, polyglycol alkylphenol ethers, ampholytic surfactants such as Di-Na N-lauryl-beta-iminodipropionate. or lecithin, anionic surfactants, such as Na-lauryl sulfate, fatty alcohol ether sulfates, the monoethanolamine salt of mono / dialkyl polyglycol ether orthophosphoric esters, cationic surfactants such as cetyltrimethylammonium chloride. Useful viscosity increase substances and substances that stabilize a therapeutic emulsion include carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, Arabica gum, polyvinylpyrrolidone, polyvinyl alcohol, methyl vinyl ether copolymers and maleic anhydride, polyethylene glycols, waxes, colloidal silica or mixtures of the substances mentioned. To prepare the solid dosage dosage forms, the active compound is mixed with appropriate additives, if appropriate, with the addition of adjuvants and the mixture is formulated if desired. Examples of physiologically acceptable solid inert additives include sodium chloride, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicas, clays, colloidal or precipitated silicone dioxide and phosphates. Examples of solid organic additives include sugars, cellulose, foods such as dehydrated milk, animal feeds, cereals and starches. Other suitable additives include lubricants and slip agents such as magnesium stearate, stearic acid, talc, bentonites, disintegrants such as starch or crosslinked polyvinylpyrrolidone.; binders such as linear starch, gelatin or polyvinylpyrrolidone and dry binders such as microcrystalline cellulose. In the pharmaceutical dosage forms described herein, the active compound can be presented in the form of a mixture with at least one of another 20S proteasome inhibitor. Alternatively, or in addition, the pharmaceutical dosage forms of the invention may, in addition to at least one 20S proteasome inhibitor, include any pharmaceutical compound that is capable of treating any known disease or disorder wherein the administration of both substances creates effects. Adverse not acceptable. Methods for the treatment of disorders and diseases mediated by the 20S proteasome comprise the administration of an effective amount of the selected compound or combinations thereof, preferably dispersed in a pharmaceutical dosage form. The ready-to-use pharmaceutical dosage forms of the invention contain the active compound in concentrations from 10 ppm to 20 percent by weight and preferably from 0.1 to 10 percent by weight. The pharmaceutical dosage forms of this invention that are diluted prior to administration preferably contain the active compound in concentrations from 0.5 to 90 weight percent and preferably from 5 to 50 weight percent. In general, it has proven advantageous to administer amounts of about 0.01 mg to about 100 mg of the active compound per kg of body weight per day to achieve effective results. The amount and frequency of administration of the pharmaceutical dosage forms comprise the 20S proteasome inhibitors of this invention which will be readily determined by one skilled in the art depending among other factors on the route of administration, the age and the condition of the patient. . These dose units can be administered one to ten times daily for a chronic or acute disease. Unacceptable toxicological effects are not expected when the compounds of the administration are administered in accordance with the present invention. The pharmaceutical dosage forms comprising the 20S proteasome inhibitors of this invention are made following the conventional techniques of the pharmaceutical involving grinding, mixing, granulation and compaction, when necessary for tabletting or grinding forms, mixing and filling for hard gelatin capsule forms. When a liquid additive is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Said liquid formulation can be administered directly or in a soft gelatin capsule. While the compositions described herein can be administered as described above, it is preferred that the method of this invention be achieved by oral administration of the compound described herein. When the route of oral administration is selected, a greater amount of the reactive agent will be required to produce the same effect as a smaller amount given for example parenterally. In accordance with good clinical practice, it is preferred to administer the compound according to this method at a concentration level that would produce effective therapeutic results without causing any harmful side effects. The compositions of this invention also have non-therapeutic utility. The compositions of this invention are useful as analytical standards for the testing of the 20S proteasome inhibitor.
Example 1 The compounds useful in the therapeutic method of this invention are prepared by conventional methods of organic chemistry. The references that can be found in the description of the synthesis technique of these compounds include Bodansky's "The Practice of Peptide Synthesis," Springer-Verlag, First Edition, 1984, "Protective Groups in Organic Synthesis," Second Edition, John Wiley and Sons, New York, 1991. All peptide bonds are achieved at room temperature with constant and gentle agitation. Peptide bonds and separations are monitored using the Kaiser test for amines. Xaa refers to any of the commercially available amino acids that can be purchased pre-added to the MBHA resin. Yaa and Zaa refer to any of the commercially available amino acids. The compounds of this invention can be prepared by solid phase peptide synthesis (SPPS) in the general procedure that follows: the Xaa-MBHA resin is weighed and transferred to an injection equipment with a sintered filter. The resin is pre-expanded in DMF and subsequently the N-terminal protection group is removed by treatment with 30% piperidine in DMF for 30 minutes. The separation solution is removed. The deprotected resin is washed five times with DMF, five times with MeOH and then five times with DMF. The amino acid Yaa can subsequently be bound to the deprotected resin using a solution of Yaa in DMF containing 3 equivalents, each of Yaa, carboxyimide coupling reagent and HOBT (hydroxy Benzotriazole). Successive couplings with Yaa solutions may be necessary to achieve coupling efficiencies that pass the Kaiser test. The non-protection of the N-terminal group and the Yaa coupling step can be repeated to couple a third Zaa amino acid. The final coupling stage uses a ketoacid, a carbodiimide and HOBT in DMF and this step is repeated until the coupling passes the Kaiser test. The complete sequence of peptides in the resin is dried under vacuum for at least six hours and then penetrates by treatment for 2.5 hours with 95/5 trifluoroacetic acid / water or a freshly prepared solution of 90% trifluoroacetic acid, 3% ethanedithiol , thioanisolaal 5% and anisole at 2%. Penetrated products are recovered by lyophilization from water or trituration of the diethylether. The purity of the product is estimated by TLC. The samples of selected peptides are verified by 1 H NMR to confirm the identity of the product.
Example 2 In this example the (3'-indolopyruvic acid) -N-biphenylalanine-D-Leu-Asp-OH was prepared according to the method of Example 1.
The resin F-moc-N-Asp (Ot-Bu) -MBH (20 mg) was weighed and transferred to a syringe equipped with a sintered filter. The resin was pre-expanded in 1 ml of DMF for 30 minutes. The Fmoc protection group (fluorenylmethyloxycarbonyl) was removed by treatment with 20% piperidine in DMF for 30 minutes. The deprotection solution was removed. The deprotected resin was washed five times with DMF, five times with MeOH and then five times with DMF. Fmoc-D-leu-OH was coupled to the deprotected resin (1 eq) using a solution of Fmoc-D-leu-OH (3 eq) in 1 ml of DMF containing carbodiimide (3 eq) and HOBT (hydroxy benzotriazole ) (3 eq). A second or third coupling with the Fmoc-D-Leu-OH solutions may be necessary to achieve the coupling efficiencies that pass the Kaiser test. The Fmoc deprotection and the amino acid coupling step was repeated to couple the Fmoc-N- (4,4-biphenyl) alanine. The final coupling step uses indolopyruvic acid (5 eq), düsopropylcarbodumide (5 eq) and HOBT (5 eq) in DMF and this step was repeated until the coupling passed the Kaiser test. The finished peptide sequence or resin was dried under vacuum for at least six hours and subsequently penetrated by treatment for 2.5 hours with 1 ml of 95/5 trifluoroacetic acid / water or a freshly prepared solution of 90% trifluoroacetic acid, 5% thioanisole , 3% ethanedithiol and 2% anisole. Penetrated products were recovered by lyophilization from water or trituration of diethylether. The purity of the product was estimated by TLC.
1 H NMR (400 MHz, d 6 -DMSO): d 6.5-7.7 (m, 14H), 4.5 (m, 1 H), 4.1 (m, 2H), 3.4 (m, 2H), 3 (m, H), 2.7 (m, 1 H), 1.1-1.5 (m, 3H), 0.5-0.9 (m, 6H).
Example 3
In this example, (3'-dino-pyrubic acid) -N-biphenylalanine-D-Leu-Asp-OH was prepared using the Chiron Mimotopes Needle Technology. The first residue of the amino acid Xaa was added to 4- (hydroxymethyl) phenoxyacetamide) resin needles (5.7 μmol / needle) by coupling each needle in 800 μL of the coupling solution (100 mM amino acid, 100 mM DIC, 10 mM DMAP,% DMF / CH2CI2) for two hours. The needles were subsequently rinsed with a DMF wash for 5 min, two washes of 5 min MeOH and 15 minutes air drying. The deprotection of the Fmoc group was carried out for 30 min with 800 μl of 20% piperidine in DMF. The washing of the needles was repeated (1 wash with DMF, 2 washes of MEOH, 15 minutes of air drying). The second amino acid residue Yaa (100 mM Yaa, 10 mM DIC, 100 mM HOBT and blue bromophenol indicator in DMF) was coupled until the blue color did not adhere any further to the surface of the needle. The coupling was repeated as necessary. Subsequently, the rinse cycle and the fmoc deprotection washings were also repeated. The next amino acid Zaa was coupled by repeating the washing and coupling procedures for the Yaa coupling, repeating the coupling if necessary. The last residue, the indolopirubic acid, was coupled with 15 eq, 100 mM, 15 eq DIC, 15 eq HOBT and blue bromophenol indicator in DMF. Repeating the coupling if necessary. After the last wash, the orange needles were removed from their supports and entered into individual 2 ml plastic centrifuge tubes with 1.5 ml of a freshly prepared solution of 90% trifluoroacetic acid, 5% thioanisole, 3% ethanedithiol and 2% anisole for 2.5 hours. The needles were removed from the tubes and the mixture was vented to near dryness under a stream of nitrogen. Grind with Et, 2? and turn down each tube. This stage was repeated three times per tube. The precipitated peptides were collected, lyophilized, weighed and used. The purity of the product was estimated by TLC. The initial products were co-encapsulated and compared against the authentic samples obtained in Example 1.
Example 4 The compounds of this invention prepared according to the method of Example 1 were tested as follows. The 20S catalytic subunit of the proteasome (also known as the multicatalytic proteinase complex) was purified to homogeneity from bovine brain in accordance with published methods (Wilk S. and Orlowski, M 1983, 40 842 J. Neurochem). The cimotryptic activity of the complex was measured by the increase in fluorescence followed by the penetration of the peptide substrate succinyl-leucine-leucine-valine-tyrosine-7-amino-4-methyl coumarin. Standard in vitro tests consist of 2 μg of 20S proteasome, 0.1-100 μg / ml of the proteasome inhibitor in 200 μl 50 mM HEPES, containing 0.1% sodium dodecyl sulfate, pH 7.5. The proteolytic reaction was initiated by adding 50 μM of the fluorogenic peptide substrate and letting it progress for 15 minutes at 37 ° C. The reaction was completed by the addition of 100 μL of 100 mM acetate stabilizer, pH 4.0. The rate of proteolysis is directly proportional to the amount of the aminomethylcoumarin released that was measured by fluorescent spectroscopy (EX 370 nm, EM 430 nm). The results of the 20S proteasome inhibitor tests are presented in Table II.
Table II IC 50 values for the inhibition of cimothyrosine as 20S proteasome activity
The compounds of this invention prepared according to the method of Example 1 were also tested as follows. The 20S catalytic subunit of the proteasome (also known as the multicatalytic proteinase complex) was purified to homogeneity from bovine brain in accordance with published methods (Wilk S. and Orlowski, M 1983, 40 842 J. Neurochem). The tryptic activity of the complex was measured by the increase in fluorescence followed by penetration of the peptide substrate CBZ-D-Ala-Leu- Arg- (7-amino-4-methyl-coumarin). The standard in vitro test consists of 2 μg of 20S proteasome, 0.1-100 μg / ml of the proteasome inhibitor in 200 ml of 50 mM HEPES, containing 0.1% sodium dodecyl sulfate, pH 7.5. The proteolytic reaction was initiated by the addition of 50 mM of flurogenic peptide substrate and allowed to progress for 15 minutes at 37 ° C. The reaction was completed by the addition of 100 μl of 100 mM acetate stabilizer, pH 4.0. The rate of proteolysis is directly proportional to the amount of the aminomethylcoumarin released that was measured by fluorescent spectroscopy (EX 370 nm, EM 430 nm). Compounds 1-207 were tested for inhibition of tryptic activity and active as inhibitors a >10 μg / ml.
Example 5 The compounds of this invention prepared according to the method of Example 1 were also tested as follows. The 20S catalytic subunit of the proteasome (also known as the multicatalytic proteinase complex) was purified to homogeneity from bovine brain in accordance with published methods (Wilk S. and Orlowski, M 1983, 40 842 J. Neurochem). The tryptic activity of the complex was measured by the increase in fluorescence followed by the penetration of the peptide substrate CBZ-D-Ala-Leu-Arg- (7-amino-4-methyl coumarin). The standard in vitro test consists of 20 μg of 20S proteasome, 0.1-100 μg / ml of the proteasome inhibitor in 200 μl of 50 mM HEPES, containing 0.1% sodium dodecyl sulfate, pH 7.5. The proteolytic reaction was initiated by the addition of 50 mM of flurogenic peptide substrate and allowed to progress for 15 minutes at 37 ° C. The reaction was completed by the addition of 100 μl of 100 mM acetate stabilizer, pH 4.0. The rate of proteolysis is directly proportional to the amount of the aminomethylcoumarin released that was measured by fluorescent spectroscopy (EX 370 nm, EM 430 nm). Compounds 1-207 were tested for inhibition of tryptic activity and active as inhibitors a > 10 μg / ml.
Example 6 The compounds of this invention prepared according to the method of Example 1 were also tested as follows. The 20S catalytic subunit of the proteasome (also known as the multicatalytic proteinase complex) was purified to homogeneity from bovine brain in accordance with published methods (Wilk S. and Orlowski, M 1983, 40 842 J. Neurochem). The tryptic activity of the complex was measured by the increase in fluorescence followed by the penetration of peptide substrate CBZ-D-Ala-Leu-Glu- (7-amino-4-methyl coumarin). The standard in vitro test consists of 2 μg of 20S proteasome, 0.1-100 μg / ml of the proteasome inhibitor in 200 ml of 50 mM HEPES, containing 0.1% sodium dodecyl sulfate, pH 7.5. The proteolytic reaction was initiated by the addition of 50 mM of fluorogenic peptide substrate and allowed to progress for 15 minutes at 37 ° C. The reaction was completed by the addition of - ml 100 mM acetate stabilizer, pH 4.0. The rate of proteolysis is directly proportional to the amount of the aminomethylcoumarin released that was measured by fluorescent spectroscopy (EX 370 nm, EM 430 nm). Compounds 1-207 were tested for inhibition of peptidylglutamyl activity at 10 μg / ml. Compound 190 was active at 5 μg / ml.
Claims (28)
1. A compound that has the formula: of: X2 is Ar or Ar-Xa, wherein X3 is -C = O, -CH2CO- or (CH2) n where n = 0-2 and wherein Ar is phenyl, substituted phenyl, indole, substituted indoles and any other heteroaryl; Ri and R2 are each individually selected from known natural α-amino acid side chains and non-natural amino acids, hydrogen, linear and branched alkyl of 1-10 carbon atoms, branched and linear substituted alkyl of 1-10 carbon atoms, aryl , substituted aryl, branched and linear substituted aryl of 1-10 carbon atoms, alkoxyaryl, cycloalkyl of 3-8 carbon atoms, heterocycle, substituted heterocycle, heteroaryl and substituted heteroaryl. Xi is selected from -OH, monoalkylamino, dialkylamino, alkoxide, arylcoxide and wherein: X4 is hydroxy, arylamino, monoalkylamino, dialkylamino, alkoxy or arylalkoxide; R3 is selected from the side chains of known natural a-amino acids, non-natural amino acids, hydrogen, branched and linear alkyl of 1-10 carbon atoms, branched and linear substituted alkyl of 1-10 carbon atoms, aryl, substituted aryl, branched and linear substituted aryl of 1-10 carbon atoms, alkoxyaryl, cycloalkyl of 3-8 carbon atoms, heterocycle, substituted heterocycle, heteroaryl and substituted heteroaryl.
2. The composition according to claim 1, wherein X1 is
3. The composition according to claim 2, wherein X 4 is -OH.
4. The composition according to claim 1, wherein X 4 is -OH.
5. The composition according to claim 4, wherein R 1 is selected from branched alkyl of 1-10 carbon atoms and unbranched alkyl substituents of 1-10 carbon atoms.
6. The composition according to claim 1, wherein X4 is -OH and R1 and R2 are each individually selected from the known natural a-amino acid side chains, non-natural amino acids and branched alkyl substituents and linear alkyl of 1-10 carbon atoms.
7. The composition according to claim 6, wherein X3 is selected from -C = O, CH2CO- and (-CH2) n where n = 0-2.
8. The composition according to claim 7, wherein R3 is selected from CO2H, CH2CO2H, (CH2) 2CO2H, Arg, Lys, Asn, Gln, Asp, Glu, Phe and NIc.
9. The composition according to claim 8, wherein Ar is selected from indole and substituted indole.
10. The compliance composition of claim 8, wherein Ar is selected from phenyl and substituted phenyl.
11. The composition according to claim 1, wherein X3 is CH2CO and R1 is isobutyl.
12. The composition according to claim 1, wherein X3 is -OH, R3 is H, X4 is H and Ar is selected from the group consisting of phenyl and indole.
13. The composition according to claim 11, wherein Ar is indole, Ri is D-Leu (isobutyl), X1 is H and X3 is -OH.
14. The composition according to claim 13, wherein R2 is 2-NAP and R3 is Asp.
15. The composition according to claim 13, wherein R2 is 4,4'-BPA and R3 is selected from the group consisting of NIe, Asp, Asn, β-Alanine, His and Arg.
16. The composition according to claim 1, wherein Ar is indole, X3 is selected from -C = O and CH2CO, R3 is selected from biaryl and substituted diphenyl, Ri is isobutane, R3 is CH2CO2H and X4 is -OH.
17. The composition according to claim 1, wherein Ar is selected from phenyl and substituted phenyl, X3 is selected from -C = O and -CH2CO, R2 is selected from biaryl and biphenyl, R1 is isobutyl, R3 is CH2CO2H and X4 is -OH
18. The composition according to claim 1, wherein Ar is indole, X3 is CH2CO, R2 is 4,4'-biphenyl, R1 is isobutyl, R3 is CH2CO2H and X4 is -OH.
19. A cationic salt of the composition according to claim 1.
20. An acid addition salt of the composition according to claim 1.
21. The use of an effective amount of the composition according to claim 1, for inhibiting cancer in a mammal.
22. The use of the composition according to claim 21, wherein the effective amount ranges from about 0.001 to about 100 mg / kg of mammalian weight.
23. The use of the composition according to claim 21, which is administered to a mammal suffering from autoimmune disorders selected from the group consisting of lupus, MS, ARD and arthritis.
24. The use of the composition according to claim 23, wherein the disorder is RA.
25. The use of the composition according to claim 21, wherein the mammal is a human.
26. A pharmaceutical composition comprising the composition according to claim 1 and one or more pharmaceutical excipients.
27. The pharmaceutical composition according to claim 26, wherein the pharmaceutical composition is in the form of a solution.
28. The pharmaceutical composition according to claim 26, wherein the pharmaceutical composition is in the form of a tablet.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09013365 | 1998-01-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA00007217A true MXPA00007217A (en) | 2001-07-03 |
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