Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin

Definitions

• compositions and methods of using such compositions to treat or prevent diseases or disorders associated with or mediated by JAMM proteins are disclosed.
• the methods and compositions are directed toward inhibition of the enzymatic activity of a JAMM domain, in particular the JAMM domain of the pnl l/Pohl/Psmdl4 subunit of the 26S proteasome, among other JAMM domains.
• This invention further relates to methods for measuring the activity of a putative inhibitor on Rpnl land other JAMM-containing proteins.
• the 26S proteasome comprises a complex arrangement of structural and enzymatic proteins that mediate binding of ubiquitiniated substrate proteins, their deubiquitination and eventual degradation to peptides.
• the subunits RPN11, Csn5, Brcc36, AMSH, AMSH-LP, a metalloprotease of the 26S proteasome and/or another JAMM-containing proteins act as cleavage enzymes for removal of ubiquitin from ubiquitin tagged proteins that are destined for degradation. This dynamic regulation of protein degradation is essential for maintenance of cellular integrity. Consequently, inhibition of proteasome activity such as that of the 26S proteasome will lead to apoptosis. See
• a target candidate for inhibition of the function of the 26S proteasome is any one of the JAMM proteases including such proteases as RPN11, Csn5, Brcc36, AMSH, AMSH-LP, a metalloprotease of the 26S proteasome or another JAMM- containing protein.
• the preferable JAMM protease is the metalloprotease Rpnl 1, that resides within the 19S regulatory particle, or cap, of the 26S proteasome.
• Rpnl 1 is responsible for the initial deubiquitination of target proteins (Eytan, et al. JBC 268(7):4668-4674 (1993); Verma, et al. Science 298:611-615 (2002)).
• the human homolog of this yeast protein is POH1.
• the present invention is directed to methods using compounds suitable for inhibition of JAMM protease activity and to methods for treatment of proliferative and metabolic disorders such as but not limited to neoplastic disease, autoimmune disease, and the like.
• Other classes of compounds useful in the methods of the invention display a cyclic structural scaffold based upon a pyrimidine, purine or quinoline base such as adenine, guanine, cystosine, uracil, thymine, pyrimidine, purine, saturated quinoline, saturated purine, saturated pyrimidine and unsaturated three membered rings such as benzoquinoline, thiophenoquinoline, phenazine, phenothiazine and similar scaffolds.
• Yet other classes of compounds of the invention include cinnamic acid derivatives such as phenyl cinnamate, N-methyl or N-phenyl cinnamamide and related compounds.
• the arrow indicates the location of the double bond to -CR 5 ;
• R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen, an aliphatic group, a heteroaliphatic group, an aryl group or a heteroaryl group;
• R 7 is hydrogen, an aliphatic group, a heteroaliphatic group, an aryl group, a heteroaryl group, a penicillin moiety or a cephalosporin moiety;
• R is hydrogen, halogen, cyano, an aliphatic group, a heteroaliphatic group, an aryl group or a heteroaryl group;
• R 9 is R 3 , Ar 2 , CHR 2 R 3 , COR 3 , CONHR 3 , NHAr 2 , CHR 2 COR 3 or
• R 10 , R 11 , R 12 and R 13 are each independently OR 3 , R 3 , NHAr 2 , NHCOAr 2 , Ar 2 ;
• X is O, S or NR 10 ;
• V is S or NR 11 ;
• W and T are each independently O or S;
• M is R 3 ;
• A is C or N
• Ar 1 and Ar 2 are each independently an aryl group or a heteroaryl group.
• R 1 ' R 2 , R 3 , R 4 , R 5 , R 6 and R 7 can be any number of aliphatic, substituted aliphatic, aryl, heteroaryl and similar groups as well as hydrogen.
• R 2 may also be halogen or cyano
• R 4 may also be CO(CH 2 ) n XR3 or an acyl group
• R 5 may be an acyl group, an amido group, an amine group, a methylene acyl group or amido group
• R 6 may be an oxo group, as well as an amino group or aminocarbonyl group (forming hydrazine or hydrazone groups with the N).
• R 7 may also be a penicillin or cephalosporin moiety.
• An especially preferred group of embodiments includes the compounds of following formulas V, VI, VII and VIII, the pharmaceutically acceptable salts thereof as well as their pharmaceutical compositions. These compounds, their salts and their pharmaceutical compositions are effective inhibitors of one or more JAMM proteases.
• the first and second embodiments of this especially preferred group are the compounds of formula V and VI, their pharmaceutically acceptable salts and their pharmaceutical compositions.
• R 1 and R 2 are each independently a Ci to C 6 alkyl or together form a 4-7 membered aliphatic ring.
• R 3 and R4 are each independently a Ci -C 3 straight or branched alkyl group, a Ci -C 3 alkoxy group, halogen, cyano or trifluoromethyl.
• R 5 and R6 are each independently hydrogen or a Ci -C 6 straight or branched alkyl group.
• Ar is an aryl or heteroaryl group or a substituted version thereof.
• R 14 and R 15 are each independently hydrogen, an aliphatic group or a heteroaryl group.
• N C(R 14 )-Ar.
• the third embodiment of this group includes the compound of formula VII, its pharmaceutically acceptable salts and it pharmaceutical composition.
• A is N or C 16 .
• B is N or CR 17 .
• R 16 and R 17 are each independently a Q to C 6 alkyl, aryl, heteroaryl group or a substituted aryl or heteroaryl group provided that R 16 and R 17 are not both methyl.
• Cy is an aryl, heteroaryl, or aliphatic group or a substituted version thereof with each Cy being independently selected.
• the compound of Formula VII is not any one of the compounds numbered 1 through 400 of Table lbelow or a pharmaceutically acceptable salt thereof; and, b) the compound of Formula VII is not:
• the fourth embodiment of this group includes the compound of Formula VIII, its pharmaceutically acceptable salts and its pharmaceutical composition.
• Ring A is a 5 or 6 membered aromatic ring with Wl, W2 and W3 being C, N, O or S and W4 being C or N or a bond between W 3 and the carbon to which W 4 is attached so as to make a 5 membered ring.
• X and Y are each independently C, N, O or S.
• Cy is an aryl or heteroaryl group or a substituted version thereof with each Cy being independently selected.
• Ri , R 2 , R 3 , R4 and R 5 are each independently an aliphatic group, an aryl group, a heteroaryl group or a substituted version thereof.
• Provisos apply to the compound of Formula VIII including those specifying that: a) the compound is not any one of the compounds numbered 1 through 400 of Table 1 below or a pharmaceutically acceptable salt thereof; and, b) the compound is not:
• Species of Formulas V and VI include the compounds of Formulas 1, 2 and 3, their pharmaceutically acceptable salts and their pharmaceutical compositions. These Formulas 1, 2 and 3 are the same as compound numbers 41, 30 and 134 of Table 1.
• the invention as well is directed to methods of treatment of human
• malconditions by disruption of the function of the 26S proteosome including reversible or irreversible inhibition of the JAMM protease including but not limited to pn 11 metalloprotease, Csn5, Brcc36, AMSH, AMSH-LP, a metalloprotease of the 26S proteasome or another JAMM-containing protein.
• Such malconditions include proliferative disorders and metabolic disorders.
• the invention as well is directed to pharmaceutical compositions containing any of the compounds described above as useful for inhibition of Rpn 11 metalloprotease bioactivity.
• the pharmaceutical compositions include a pharmaceutically acceptable carrier.
• Methods for treatment of disease concerning involvement of one or more JAMM proteases include methods for inhibition of the JAMM protease in vitro or in vivo. In particular, these methods include:
• a method for inhibition of JAMM protease comprising contacting a JAMM protease in vitro or in vivo with a compound of Formulas V, VI, VII or VIII or the pharmaceutical compositions thereof;
• a method for inhibition or amelioration of the JAMM protease activity in a patient comprising administering to the patient an effective amount of a compound of Formulas V, VI, VII or VIII or the
• a method of treating a proliferative or metabolic disorder of a patient comprising administering to the patient an effective amount of a compound of Formulas V, VI, VII or VIII or the pharmaceutical compositions thereof;
• the proliferative or metabolic disorder is a disease or malcondition including neoplastic disease or growth, cancer, autoimmune disease, metabolic abnormality or malcondition, angiogenesis, ischemia and reperfusion injury, multiple sclerosis, rheumatoid arthritis, neurodegenerative conditions, muscle wasting disease, renal failure, diabetes, hepatic failure, hyperproliferative conditions and infection by exogenous agents;
• a method for diagnosis of the susceptibility of candidate neoplastic cells to treatment by JAMM inhibition comprising combining the candidate neoplastic cells with a reporter substrate for a JAMM protease, observing the presence or absence of a cleaved reporter, adding a compound of Formulas V, VI, VII or VIII or the pharmaceutical compositions thereof and additional reporter substrate, and determining whether additional cleaved reporter is produced;
• the invention in addition is directed to compounds included in the foregoing generic descriptions that are not presented on Table 1 below.
• the invention includes these compounds per se (hereinafter novel compounds).
• Preferred embodiments of these novel compounds include those novel compounds that also meet the criteria set forth in the preceding text regarding "preferred embodiments of classes or groups of compounds.”
• an effective amount means that amount of a drug, pharmaceutical composition, or compound that will elicit the biological or medical response of a cell, tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
• therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
• the term also includes within its scope amounts effective to enhance normal physiological function.
• the term "optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s), which occur, and events that do not occur.
• substituted refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
• Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., Ci-Cio alkyl). Unless otherwise specifically designated, the term “Alkyl includes the numerical range of carbons "1 to 15" and that range refers to each integer in the given range; e.g., "1 to 15 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 15 carbon atoms. In some embodiments, the term alkyl means a C 1 -C4 alkyl group.
• Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, decyl, and the like.
• the alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), ⁇ -propyl, 1-methylethyl (z ' so-propyl), ft-butyl, ft-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.
• an alkyl group may be optionally substituted by one or more of substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -O a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a ,
• each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
• Alkylaryl refers to an -(alkyl)aryl radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
• Alkylheteroaryl refers to an -(alkyl)heteroaryl radical where heteroaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl
• Alkylheterocycloalkyl refers to an -(alkyl) heterocycyl radical where alkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for
• heterocycloalkyl and alkyl respectively.
• alkene refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
• an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
• the alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
• Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e. C 2 -C 10 alkenyl). Whenever it appears herein, a numerical range such as “2 to 10" refers to each integer in the given range; e.g., "2 to 10 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms.
• an alkenyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkenyl).
• the alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like.
• an alkenyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -O a , - SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a ,
• Alkenyl-cycloalkyl refers to an -(alkenyl)cycloalkyl radical where alkenyl and cyclo alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl respectively.
• Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (i.e. C 2 -Cio alkynyl).
• a numerical range such as “2 to 10” refers to each integer in the given range; e.g., "2 to 10 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
• an alkynyl comprises two to eight carbon atoms.
• an alkynyl has two to five carbon atoms (e.g., C 2 -C 5 alkynyl).
• alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
• an alkynyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,
• alkynyl includes cycloalkynyl.
• Alkynyl-cycloalkyl refers to refers to an -(alkynyl)cycloalkyl radical where alkynyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkynyl and cycloalkyl respectively.
• Aliphatic is an inclusive term referring to all of the foregoing and following nonaromatic terms including alkyl, cycloalkyl, alkenyl, cycloalkenyl, cycloalkyl- alkenyl, alkynyl, cycloalkynyl, alkynyl-cycloalkyl, alkenyl-cycloalkyl, and alkyl- heterocycloalkyl, cycloalkyl-heterocycloalkyl as well as the substituted versions thereof.
• Cyano refers to a -CN radical.
• Cycloalkyl refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (i.e. C 2 -Cio cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10" refers to each integer in the given range; e.g., "3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms. In some embodiments, it is a C3-C8 cycloalkyl radical.
• cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like.
• a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , - SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -N(R a )C(0)R a , -N(R a )C(0)OR a , -N(R a
• Cycloalkyl-alkenyl refers to a -(cycloalkyl) alkenyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and cycloalkyl respectively.
• Cycloalkyl-heterocycloalkyl refers to a -(cycloalkyl) heterocycyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and cycloalkyl respectively.
• Cycloalkyl-heteroaryl refers to a -(cycloalkyl) heteroaryl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and cycloalkyl respectively.
• alkoxy refers to the group -O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
• “Lower alkoxy” refers to alkoxy groups containing one to six carbons.
• C1-C4 alkyl is an alkyl group which encompasses both straight and branched chain alky Is of from 1 to 4 carbon atoms.
• alkoxy includes optionally substituted forms and refers to alkoxy wherein the alkyl constituent is substituted (i.e., -0-(substituted alkyl)).
• alkyl moiety of an alkoxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -O a , SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 ,
• R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
• a Ci-C 6 alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.
• Lower alkoxycarbonyl refers to an alkoxycarbonyl group wherein the alkoxy group is a lower alkoxy group.
• C 1 -C4 alkoxy is an alkoxy group which encompasses both straight and branched chain alkoxy groups of from 1 to 4 carbon atoms.
• alkoxycarbonyl includes substituted versions thereof such that it refers to the group (substituted alkyl)-O-C(O)- wherein the group is attached to the parent structure through the carbonyl functionality.
• alkyl moiety of an alkoxycarbonyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,
• heterocycloalkyl aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 ,
• Ci-Cio acyl radical refers to the total number of chain or ring atoms of the alkyl, aryl, heteroaryl or heterocycloalkyl portion of the acyloxy group plus the carbonyl carbon of acyl, i.e. three other ring or chain atoms plus carbonyl.
• the radical is heteroaryl or heterocycloalkyl
• the hetero ring or chain atoms contribute to the total number of chain or ring atoms.
• the "R" of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,
• each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
• R of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,
• R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
• Amino or “amine” refers to a -N(R a ) 2 radical group, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification.
• R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification.
• R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl, heteroaryl or heteroarylalky
• -N(R a ) 2 is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl.
• an amino group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 ,
• R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl and each of these moieties may be optionally substituted as defined herein.
• substituted amino also refers to N-oxides of the groups -NHR d , and NR d R d each as described above. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or
• Amide refers to a chemical moiety with formula -C(0)N(R) 2 or - NHC(0)R, where R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), each of which moiety may itself be optionally substituted. In some embodiments it is a C1-C4 amido or amide radical, which includes the amide carbonyl in the total number of carbons in the radical.
• the R 2 of - N(R) 2 of the amide may optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6-, or 7-membered ring.
• an amido group is optionally substituted independently by one or more of the substituents as described herein for alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
• An amide may be an amino acid or a peptide molecule attached to a compound of Formula (I), thereby forming a prodrug. Any amine, hydroxy, or carboxyl side chain on the compounds described herein can be amidified.
• Aromatic or aryl refers to an aromatic radical with six or ten ring atoms which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl).
• Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.
• Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
• the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups.
• an aryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 ,
• aryl also includes aliphatic-aryl and aryl-aliphatic.
• “Aralkyl” or “arylalkyl” refers to an (aryl)alkyl— radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
• Ester refers to a chemical radical of formula -COO , where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). Any amine, hydroxy, or carboxyl side chain on the compounds described herein can be esterified. The procedures and specific groups to make such esters are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety.
• an ester group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 ,
• R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
• Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
• the alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.
• Halo means fluoro, chloro, bromo or iodo.
• haloalkyl means fluoro, chloro, bromo or iodo.
• haloalkenyl means fluoro, chloro, bromo or iodo.
• haloalkynyl means alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
• fluoroalkyl and fluoroalkoxy include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
• Heteroalkyl “hetero alkenyl” and “heteroalkynyl” include optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
• a numerical range may be given, e.g. C 1 -C 4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long.
• a -CH 2 OCH 2 CH 3 radical is referred to as a "C 4 " heteroalkyl, which includes the heteroatom center in the atom chain length description.
• a heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,
• Heteroalkylaryl refers to an -(heteroalkyl)aryl radical where heteroalkyl and aryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and aryl respectively.
• Heteroalkylheteroaryl refers to an -(heteroalkyl)heteroaryl radical where heteroalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heteroaryl respectively.
• Heteroalkylheterocycloalkyl refers to an -(heteroalkyl)heterocycloalkyl radical where heteroalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heterocycloalkyl respectively.
• Heteroalkylcycloalkyl refers to an -(heteroalkyl) cycloalkyl radical where heteroalkyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and cycloalkyl respectively.
• Heteroaliphatic is an inclusive term covering all of the foregoing hetero alkyl, alkenyl, alkynyl terms including heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkylheteroaryl, heteroalkylheterocycloalkyl, heterocyclyl and heterocyclylalkyl as well as the substituted versions thereof.
• Heteroaryl or, alternatively, “heteroaromatic” refers to a 5, 6 or 10-membered aromatic radical (e.g., C5-C13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever it appears herein, a numerical range refers to each integer in the given range.
• An N- containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
• the polycyclic heteroaryl group may be fused or non- fused.
• heteroatom(s) in the heteroaryl radical is optionally oxidized.
• One or more nitrogen atoms, if present, are optionally quaternized.
• the heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
• heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,
• benzonaphthofuranyl benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,
• pyrido[3,2-d]pyrimidinyl pyrido[3,4-d]pyrimidinyl
• pyrazinyl pyrimidinyl
• pyridazinyl pyrrolyl
• quinazolinyl quinoxalinyl
• quinolinyl isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl
• a heteraryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -N(R a )C(0)OR a , -N(R a )C(0)R a , -N(R a )S(0) t R a (where t is 1 or 2),
• heteroaryl also includes ring systems substituted with one or more oxide (-0-) substituents, such as pyridinyl N-oxides.
• oxide (-0-) substituents such as pyridinyl N-oxides.
• heteroaryl includes aliphatic-heteroaryl and heteroaryl-aliphatic as well as the substituted versions thereof.
• Heterocyclyl refers to any monocyclic or polycyclic moiety comprising at least one heteroatom selected from nitrogen, oxygen and sulfur. As used herein, heterocyclyl moieties can be aromatic or nonaromatic.
• heterocyclyl moieties are optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -N(R a )C(0)OR a , -N(R a )C(0)R a ,
• R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.
• Heteroarylalkyl refers to a moiety having an aryl moiety, as described herein, connected to an alkylene moiety, as described herein, wherein the connection to the remainder of the molecule is through the alkylene group.
• Heterocyclylalkyl refers to a stable 5, 6 or 10-membered non-aromatic ring radical having from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the
• heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
• the heteroatoms in the heterocycloalkyl radical may be optionally oxidized.
• One or more nitrogen atoms, if present, are optionally quaternized.
• the heterocycloalkyl radical is partially or fully saturated.
• the heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s).
• heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,
• thiazolidinyl tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.
• a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,
• Heterocyclylalkyl also includes bicyclic ring systems wherein one
• non-aromatic ring usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.
• “Sulfanyl” refers to the groups: -S-(optionally substituted alkyl), -S-(optionally substituted aryl), -S -(optionally substituted heteroaryl), and -S-(optionally substituted heterocycloalkyl).
• “Sulfmyl” refers to the groups: -S(0)-H, -S(0)-(optionally substituted alkyl), -S(0)-(optionally substituted amino), -S(0)-(optionally substituted aryl),
• “Sulfonyl” refers to the groups: -S(0 2 )-H, -S(0 2 )-(optionally substituted alkyl), -S(0 2 )-(optionally substituted amino), -S(0 2 )-(optionally substituted aryl), -S(0 2 )-(optionally substituted heteroaryl), and -S(0 2 )-(optionally substituted heterocycloalkyl) .
• each R in sulfonamido contains 1 carbon, 2 carbons, 3 carbons, or 4 carbons total.
• a sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl respectively
• R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
• a sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl respectively.
• the compounds useful for treatment of proliferative and metabolic disorders according to the invention are described in the foregoing Summary of the Invention and include for example aryl vinyl compounds, aryl iminyl (Schiff base) compounds, aryl carboxamido compounds, pyrimidine and purine compounds as well as their heteroaryl and related derivatives. Examples of these compounds include those of the following formulas and generic characterizations ;
• Preferred, focused versions of the substituents of the compounds of Formulas V, VII and VIII include those wherein Ar, Ar and Cy are each independently phenyl, naphthyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, thiophenyl, pyrrolyl, thiazolyl, imidazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl or a substituted form thereof.
• These versions of Ar and Ar' are individually preferred so that each one can be separately and individually applied to the compound of Formula V. Any combination of these versions of Ar, Ar' and CY may also be applied to the compounds of Formula V VII and VIII.
• Further preferred versions of the substituents of compounds of Formulas V and VI include those in which R 14 and R 15 are both hydrogen. Further preferred versions of these substituents include the compounds of formula V wherein R 14 is hydrogen and R 15 is an aliphatic group
• substituents of the compound of Formula V, VII and Villi include those in which Ar, Ar' and Cy are each optionally and independently substituted with one or more substituents selected from the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a ,
• substituents for Ar', Ar' and Cy include one or more substituents wherein each substituent is independently selected from the group consisting of alkoxy, alkyl, cycloalkyl, phenyl, phenoxy, halogen, cyano, nitro, amino, imino, carboxyl, ester, amido, aminocarbonyl, sulfonamido, aminosulfonyl and morpholinyl wherein the moiety bonded to a divalent substituent selected from the group amino, imino, ester, amido, aminocarbonyl, sulfonamido and aminosulfonyl is hydrogen, alkyl, amino, alkyl amino, phenyl amino, substituted phenyl amino, phenyl or substituted phenyl wherein the substituent of the substituted phenyl in both instances is alkyl, alkoxy, halogen, nitro or cyano.
• Ar, Ar' and/or Cy include pyrrolyl, pyrazolyl, imidazolyl or triazolyl.
• the individual substituents can be separately and individually applied to the compounds of Formulas V, VII and VIII. Any combination of these preferred individual substituents may also be applied to the compounds of Formulas V, VII and VIII.
• Libraries of certain groups of these compounds are available from the Molecular Libraries Probe Production Centers Network (MLPCN) affiliated with National Institutes of Health (NIH), such as the Molecular Libraries Small Molecule Repository (MLSMR).
• MPCN Molecular Libraries Probe Production Centers Network
• NH National Institutes of Health
• MLSMR Molecular Libraries Small Molecule Repository
• the detailed information associated with such libraries provides identification of compound sources which in turn provide the methods for synthesis of the compounds in the libraries. That information is incorporated herein by reference as support for the processes to make the compounds recited by the foregoing Summary of the Invention.
• the libraries are available for purchase from MLSMR as 10 mM samples in DMSO stored on 96 microwell plates. The details of such libraries are posted on PubChem.
• the assay procedures for investigation of the MLSMR library of compounds follows the assay protocol set forth in U.S. Patent No. 7,741,432, (hereinafter the Parlati assay) the disclosure of which is incorporated herein by reference.
• a library of more than three hundred thirty thousand compounds was assayed for primary activity as JAMM protease inhibitors, as in particular as pn 11 inhibitors. Those compounds were then compared in secondary screens to ascertain selectivity. The results of the primary and secondary screens provided positive indications for 400 compounds. These compounds and the results of their assay in a) the primary Rpn 11 screen and b) in the secondary screens relative to the potency of thrombin and MMP2 are provided in Table 1.
• Candidate Compound Selection The results provided in Table 1 were analyzed and interpreted according to selectivity and potency factors as well as knowledge of molecular interactions with JAMM domains and several of the ubiquitin cleavage moieties associated with JAMM domains. This interpretive work produced the substructures presented in Table 2. These substructures provided guides and maps for delineating the scaffold structures disclosed in the foregoing Summary of the Invention as providing significant inhibitory activity as JAMM protease inhibitors, in particular, in the pn 1 1 assay and selectivity in the comparative thrombin and MMP2 assays.
• novel compounds While some of the compounds disclosed in the Summary of the Invention are available in the MLP library, others are novel analogs and/or novel derivatives (hereinafter novel compounds).
• novel compounds recited by the generic disclosure presented in the foregoing Summary of the Invention are also aspects of the invention. These novel compounds are suitable for inhibition of pn 11 metalloprotease. These novel compounds per se constitute an additional aspect of the invention. These novel compounds are those included in the generic disclosure of the Summary that are not listed on Table 1.
• compositions A therapeutically effective amount of a compound used in the methods of the present invention will depend upon a number of factors including, for example, the age and weight of the subject being treated, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian.
• a pharmaceutical composition comprises a pharmaceutically acceptable carrier and an amount of a compound of any foregoing embodiments under the Summary section effective to inhibit the protease activity of a JAMM protease.
• an effective amount of a compound to be used in the methods of the invention for the treatment of diseases or conditions associated with inappropriate JAMM activity will generally be in the range of 0.1 mg to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 mg to 10 mg/kg body weight per day. This amount may be given in a single dose per day or in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
• An effective amount of a salt or solvate, thereof, may be determined as a proportion of the effective amount of the compound to be used in the methods of the invention per se.
• the compounds to be used in the methods of the present invention and in the pharmaceutical compositions of the invention may be in the form of and/or may be administered as pharmaceutically acceptable salts, N-oxide derivatives, protected derivatives (i.e. prodrugs), and individual isomers and mixture of isomers thereof.
• the salts of the present invention are
• pharmaceutically acceptable salts refer to non-toxic salts of the compounds to be used in the methods of this invention. Suitable pharmaceutically acceptable salts can include acid or base additions salts.
• a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound to be used in the methods of the invention with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamaic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic, or hexanoic acid), optionally in a suitable solvent such as water or an organic solvent, to give the salt which is usually isolated for example by crystallization and filtration.
• a suitable inorganic or organic acid such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fuma
• a pharmaceutically acceptable acid addition salt of a compound can comprise, for example, a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate, or hexanoate salt.
• a pharmaceutically acceptable base addition salt may, where there is a suitable acidic group, be formed by reaction of a compound with a suitable inorganic or organic base (e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine), optionally in a suitable solvent such as water or an organic solvent, to give the base addition salt which is usually isolated for example by crystallization and filtration.
• a suitable inorganic or organic base e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine
• a suitable solvent such as water or an organic solvent
• suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as sodium, potassium, calcium or magnesium salts.
• suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as sodium, potassium, calcium or magnesium salts.
• Other salts e.g. oxalates or trifluoroacetates, may be used, for example in the isolation of compounds to be used in the methods of the invention, and are included within the scope of this invention.
• the invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the compounds to be used in the methods of the invention.
• the invention further provides a pharmaceutical composition, which comprises a compound to be used in the methods of the invention and salts or solvates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
• a pharmaceutical composition which comprises a compound to be used in the methods of the invention and salts or solvates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
• the compounds and salts or solvates thereof, are as described above.
• the carriers, diluents, or excipients must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• a process for the preparation of a pharmaceutical composition including admixing a compound disclosed above, or salts, solvates and physiological functional derivatives thereof (i.e., prodrugs), with one or more pharmaceutically acceptable carriers, diluents or excipients.
• compositions comprising compounds to be used in the methods of the invention may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
• a unit may contain, for example, 5 mg to 1 g, 1 mg to 700 mg, or 5 mg to 100 mg, of a compound to be used in the methods of the invention depending on the condition being treated, the route of administration and the age, weight and condition of the patient.
• unit doses may therefore be administered more than once a day.
• unit dosage compositions are those containing a daily dose or sub-dose (for administration more than once a day), as herein above recited, or an appropriate fraction thereof, of an active ingredient.
• such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.
• compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, inhaled, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
• Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with one or more carriers or excipients.
• compositions adapted for oral administration may be presented as discrete units such as pills, capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil- in-water liquid emulsions or water-in-oil liquid emulsions.
• the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
• Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
• Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
• Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
• a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
• suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
• Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
• Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
• Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
• a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
• a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone
• a solution retardant such as paraffin
• a resorption accelerator such as a quaternary salt
• an absorption agent such as bentonite, kaolin or dicalcium phosphate.
• the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, or solutions of cellulosic or polymeric materials and forcing through a screen.
• the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
• the lubricated mixture is then compressed into tablets.
• the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
• a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided.
• Dyestuffs can be added to these coatings to distinguish different unit dosages.
• Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
• Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
• Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
• Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
• dosage unit compositions for oral administration can be microencapsulated.
• the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
• the compounds to be used in the methods of the invention and salts and thereof, may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
• Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
• the disclosed compounds may be coupled with soluble polymers as targetable drug carriers.
• Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol,
• compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
• the active ingredient may be delivered from the patch by iontophoresis as generally described in Remington: The Science and Practice of Pharmacy, 21 s Edition, hereby incorporated by reference in its entirety.
• compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
• compositions are preferably applied as a topical ointment or cream.
• the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
• the active ingredient may be formulated in a cream with an oil-in- water cream base or a water-in-oil base.
• Pharmaceutical compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
• compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
• compositions adapted for rectal administration may be presented as suppositories or as enemas.
• Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
• compositions for nasal or inhaled administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered by rapid inhalation through the nasal passage from a container of the power held close up to the nose.
• compositions adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurised aerosols, nebulizers or insufflators.
• suitable compositions wherein the carrier is a liquid for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
• compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
• the compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried
• sterile liquid carrier for example water for injections, immediately prior to use.
• sterile liquid carrier for example water for injections
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
• compositions may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
• the compounds to be used in the methods of the present invention and their salts and solvates, thereof, may be employed alone or in combination with other therapeutic agents for the treatment of the diseases or conditions associated with inappropriate JAMM activity, for instance cancer.
• Combination therapies according to the present invention thus comprise the administration of at least one compound to be used in the methods of the invention or a pharmaceutically acceptable salt or solvate thereof, and the use of at least one other cancer treatment method.
• combination therapies according to the present invention comprise the administration of at least one compound to be used in the methods of the invention or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and at least one other pharmaceutically active agent, for example an anti-neoplastic agent.
• pharmaceutically active agents may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order and by any convenient route.
• the amounts of the compound to be used in the methods of the invention and the other pharmaceutically active agents and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
• another anti-cancer therapy is at least one additional chemotherapeutic therapy.
• chemotherapeutic therapy may include one or more of the following categories of anti-cancer agents:
• antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea;
• alkylating agents for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas
• antimetabolites for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxy
• antitumour antibiotics for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin- C, dactinomycin and mithramycin
• antimitotic agents for example vinca alkaloids like vincristrine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere
• topoisomerase inhibitors for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptochecin
• cytostatic agents such as antio estrogens (for example tamoxifen, toremifine, raloxifine, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LH H agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate) aromatase inhibitors (for example as anastrozole, letrozole, vorazole and
• agents which inhibit cancer cell invasion for example metalloproteinase inhibitors and inhibitors of urokinase plasminogen activator receptor function;
• inhibitors of growth factor function include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab (HerceptinTM) and the anti-erbbl antibody cetuximab (C225), farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine-threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGF family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl-7- methoxy-6-(3-morpholinoproproxy)quinazolin-4-amine (gefitinib, AZD 1839), N-3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4- amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4- fluoroph
• gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
• GDEPT gene-directed enzyme pro-drug therapy
• immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenecity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell energy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine- transfected tumour cell lines and approaches using anti-idiotypic antibodies.
• cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
• compositions of the invention are used in combination with the proteasome inhibitor MG132 ⁇ see Banerjee and Liefshitz (2001), Potential of the proteasome inhibitor MG-132 as an anticancer agent, alone and in combination. Anticancer Res . 21 3941).
• pharmaceutical compositions of the invention are used in combination with TRAIL or a TRAIL receptor agonist, for instance with MD5- 1.
• the compositions of the invention are used in combination with bortezomib, or other proteasome inhibitors.
• the dose of each compound may differ from that when the compound is used alone.
• synergistic combinations are envisioned.
• the compounds to be used in the methods of the present invention and their salts and solvates, thereof, may be employed alone or in combination with other therapeutic agents for the treatment of the diseases or conditions associated with inappropriate JAMM activity.
• Neoplastic growth may include cancer.
• the present invention relates to a method for treating or lessening the severity of a cancer selected from: brain (gliomas), glioblastomas, breast, Wilm's tumor, Ewing's sarcoma,
• lymphoblastic T cell leukemia chronic myelogenous leukemia, chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lympho
• the cancer is selected from brain cancer (gliomas), glioblastomas, breast cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma and thyroid cancer.
• brain cancer gliomas
• glioblastomas breast cancer, colon cancer, head and neck cancer
• kidney cancer lung cancer
• liver cancer melanoma
• ovarian cancer pancreatic cancer
• prostate cancer sarcoma and thyroid cancer.
• the cancer to be treated is associated with the proteasome. See Voorhees et al., The Proteasome as a Target for Cancer Therapy, Clinical Cancer Research, vol. 9, 6316-6325, December 2003, incorporated by reference in its entirety.
• the cancer is associated with a particular target, such as NFkB, p44/42 MAPK, P-gp, Topi, TopIIalpha.
• the cancer is a solid tumor.
• the cancer is selected from multiple myeloma, metastatic breast cancer, non- small cell lung cancer, prostate cancer, advanced colorectal cancer, ovarian or primary peritoneal carcinoma, hormone refractory prostate cancer, squamous cell carcinoma of the head and neck,metastatic pancreatic adenocarcinoma,gastroesophageal junction or stomach, or non-Hodgkin's lymphoma.
• This disorder can include cancer or immune disorders characterized by excessive cell proliferation or cellular signaling.
• this includes human cancers that overexpress c-Myc or express an oncogenic form of the K-Ras protein.
• Neurodegenerative diseases and conditions may include without limitation stroke, ischemic damage to the nervous system, neural trauma (e.g., percussive brain damage, spinal cord injury, and traumatic damage to the nervous system), multiple sclerosis and other immune-mediated neuropathies (e.g., Guillain-Barre syndrome and its variants, acute motor axonal neuropathy, acute inflammatory demyelinating polyneuropathy, and Fisher Syndrome), HIV/ AIDS dementia complex, axonomy, diabetic neuropathy, Parkinson's disease, Huntington's disease, ALS, multiple sclerosis, bacterial, parasitic, fungal, and viral meningitis, encephalitis, vascular dementia, multi-infarct dementia, Lewy body dementia, frontal lobe dementia such as Pick's disease, subcortical dementias (such as Huntington or progressive supranuclear palsy), focal cortical atrophy syndromes (such as primary aphasia), metabolic-toxic dementias (such as chronic hypothyroidism or B
• Compounds to be used in the methods of the invention may be used to treat cachexia and muscle-wasting diseases.
• Compounds to be used in the methods of the invention may be used to treat such conditions wherein the condition is related to cancer, chronic infectious diseases, fever, muscle disuse (atrophy) and denervation, nerve injury, fasting, renal failure associated with acidosis, diabetes, and hepatic failure.
• Compounds to be used in the methods of the invention can be used to treat hyperproliferative conditions such as diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, IgA nephropathy, cirrhosis, biliary atresia, congestive heart failure, scleroderma, radiation-induced fibrosis, and lung fibrosis (idiopathic pulmonary fibrosis, collagen vascular disease, sarcoidosis, interstitial lung diseases and extrinsic lung disorders).
• the treatment of burn victims is often hampered by fibrosis, thus, an additional embodiment of the application is the topical or systemic administration of the inhibitors to treat burns. Wound closure following surgery is often associated with disfiguring scars, which may be prevented by inhibition of fibrosis.
• the application relates to a method for the prevention or reduction of scarring.
• Compounds to be used in the methods of the invention can be used to treat ischemic conditions or reperfusion injury for example acute coronary syndrome (vulnerable plaques), arterial occlusive disease (cardiac, cerebral, peripheral arterial and vascular occlusions), atherosclerosis (coronary sclerosis, coronary artery disease), infarctions, heart failure, pancreatitis, myocardial hypertrophy, stenosis, and restenosis.
• acute coronary syndrome vulnerable plaques
• arterial occlusive disease cardiac, cerebral, peripheral arterial and vascular occlusions
• atherosclerosis coronary sclerosis, coronary artery disease
• infarctions heart failure
• pancreatitis myocardial hypertrophy
• stenosis stenosis
• restenosis for example acute coronary syndrome (vulnerable plaques), arterial occlusive disease (cardiac, cerebral, peripheral arterial and vascular occlusions), atherosclerosis (coronary s
• Compounds to be used in the methods of the invention can be used for the inhibition of TNF alpha to prevent and/or treat septic shock.
• Compounds to be used in the methods of the invention can be used for inhibiting antigen presentation in a cell, including exposing the cell to an agent described herein.
• a compound of the invention may be used to treat immune-related conditions such as allergy, asthma, organ/tissue rejection (graft-versus-host disease), and auto-immune diseases, including, but not limited to, lupus, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel diseases (such as ulcerative colitis and Crohn's disease).
• a further embodiment is a method for moedulating the immune system of a subject (e.g., inhibiting transplant rejection, allergies, auto-immune diseases, and asthma), including administering to the subject an effective amount of a compound of the invention.
• Compounds to be used in the methods of the invention can be used in methods for altering the repertoire of antigenic peptides produced by the proteasome or other protein assembly with multicatalytic activity.
• Compounds to be used in the methods of the invention can be used in methods for inhibiting IKB-alpha degradation, including contacting the cell with an agent identified herein.
• a further embodiment is a method for reducing the cellular content of NF-KB in a cell, muscle, organ, or subject, including contacting the cell, muscle, organ, or subject with a compound of the invention.
• Compounds to be used in the methods of the invention can be used in methods for affecting cyclin-dependent eukaryotic cell cycles.
• Compounds of the invention can be used in methods for treating a proliferative disease in a subject (e.g., cancer, psoriasis, or restenosis).
• Compounds to be used in the methods of the invention can be used for treating cyclin-related inflammation in a subject.
• One embodiment is a method for treating p53-related apoptosis, including administering to a subject an effective amount of a compound of the invention.
• the compounds to be used in the methods of the present application are useful for the treatment of a parasitic infection, such as infections caused by protozoan parasites.
• the agents are useful for the treatment of parasitic infections in humans caused by a protozoan parasite selected from Plasmodium sps., Trypanosoma sps., Leishmania sps., Pneumocystis carinii, Toxoplasma gondii, Entamoeba histolytica, Entamoeba invadens, and Giardia lamblia.
• the agents are useful for the treatment of parasitic infections in animals and livestock caused by a protozoan parasite selected from Plasmodium hermani, Cryptosporidium sps., Echinococcus granulosus, Eimeria tenella, Sarcocystis neurona, and Neurospora crassa.
• a protozoan parasite selected from Plasmodium hermani, Cryptosporidium sps., Echinococcus granulosus, Eimeria tenella, Sarcocystis neurona, and Neurospora crassa.
• Other compounds useful as proteasome inhibitors in the treatment of parasitic diseases are described in WO 98/10779, which is incorporated herein in its entirety.
• the methods of treatment include inhibiting, arresting,
• a human disorder characterized by abnormal regulatory peptide degradation resulting in excessive cell proliferation or cell signaling includes a cancer or immune disorder, a cancer resulting from overexpression of c-Myc or expression of an oncogenic form of the K- as protein.
• the methods also include inhibition or amelioration of JAMM metalloprotease domain activity in a human patient suffering from abnormal JAMM metalloprotease domain activity on ubiquitin modified proteins. As described above, these methods involve administering to the patient an effective amount of a compound or pharmaceutical formulation disclosed above so that the abnormal JAMM metalloprotease domain activity is ameliorated, reduced or inhibited.
• compositions identified herein can also be useful as diagnostic agents (e.g., in diagnostic kits or for use in clinical laboratories) for screening for proteins (e.g., enzymes, transcription factors) processed by Ntn hydrolases, including the proteasome.
• the agents are also useful as research reagents for specifically binding the X/MB 1 subunit or alpha-chain and inhibiting the proteolytic activities associated with it. For example, the activity of (and specific inhibitors of) other subunits of the proteasome can be determined.
• Inhibitors identified herein can be used to determine whether a cellular, developmental, or physiological process or output is regulated by proteolytic activity.
• One such method includes obtaining an organism, an intact cell preparation, or a cell extract; exposing the organism, cell preparation, or cell extract to an agent identified herein; exposing the agent-exposed organism, cell preparation, or cell extract to a signal, and monitoring the process or output. See, for example, US patent 7,741,432.
• the compounds to be used in the methods of this invention may be used as a part of a diagnostic assay. For instance cells from a patient may be obtained and an assay may be performed to determine whether the compounds to be used in the methods of the invention are likely to be effective therapeutic compounds for that patient.
• the cells obtained from the patient can be for instance cancerous cells from a tumor.
• the cells can be cultured and compounds to be used in the methods of the invention can be applied to determine how the cancerous cells respond.
• the Diagnostics aspect of the invention also includes an assay for the determination of inhibition of JAMM metalloprotease domain activity.
• the assay involves combining a JAMM enzymatic material with a protein substrate and determining whether a potential inhibitory candidate will function in this assay to lessen the enzymatic activity.
• the JAMM enzymatic material is either a standard or taken from a patient's cells.
• the protein substrate similarly is either standard or taken from a patient's cells.
• the a JAMM enzymatic material selected from the group consisting of a JAMM domain containing protein, a signalosome complex and a 26S proteasome complex containing the JAMM protein that can be isolated from a patient's cells.
• the protein substrate is selected from the group consisting of a protein modified by a ubiquitin, a protein modified by a ubiquitin-like modifier and a protein modified by a ubiquitin chain that can be isolated from a patient's cells.
• the combination of the JAMM enzymatic material and the protein substrate produces an enzymatic medium.
• the protein substrate is modified with a tag that is detectable by measurement of molecular weight, spectroscopic interaction or chromatographic R f determination, Following the isolation and tagging, the enzymatic medium is manipulated to conduct a first measurement of the enzymatic medium relative to the protein substrate alone wherein the first measurement is made by a detection of the tag.
• a potential inhibitory candidate is combined with the tagged protein substrate and the JAMM enzymatic material is added to produce a candidate medium.
• the candidate medium is manipulated to conduct a second measurement of the candidate medium relative to the protein substrate alone wherein the second measurement is made by detection of the tag.
• the ability of the inhibitory candidate to be effective treatment for the patient in need is assessed by comparing the first and second measurements to identify a candidate that demonstrates at least about a 50 % inhibition at a concentration of no more than 500 micromolar in the candidate medium, the difference between the first and second measurements being at least about 50% with the second measurement being greater than the first measurement.

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