Classifications

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  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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  • C07C233/00—Carboxylic acid amides
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  • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
  • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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  • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
  • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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  • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
  • C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
  • C07C275/16—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by carboxyl groups
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  • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
  • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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  • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
  • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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  • C07C327/00—Thiocarboxylic acids
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  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/24—Oxygen or sulfur atoms
  • C07D207/26—2-Pyrrolidones
  • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
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  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/24—Oxygen or sulfur atoms
  • C07D207/26—2-Pyrrolidones
  • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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  • C07D209/04—Indoles; Hydrogenated indoles
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  • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
  • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
  • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
  • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

• This invention relates to compounds that are inhibitors of interleukin-l ⁇ converting enzyme.
• This invention also relates to a method of treatment of stroke, reperfusion injury, Alzheimer's disease, shigellosis, inflammatory diseases, and to a pharmaceutically acceptable composition that contains a compound that is an inhibitor of interleukin-l ⁇ converting enzyme.
• the compounds of the present invention are inhibitors of interleukin- 1 ⁇ converting enzyme (ICE; Caspase-1) and are useful in treating diseases in which interleukin- 1 plays a role.
• ICE interleukin- 1 ⁇ converting enzyme
• ICE acts on pro-interleukin-l ⁇ (pro-IL-l ⁇ ) to produce interleukin-l ⁇ (IL-l ⁇ ), which is an inflammatory cytokine.
• ICE (Caspase-1) regulates at least four cytokines.
• diseases are associated with interleukin- 1 activity. Examples of diseases in which interleukin- 1 is involved include, but are not limited to, inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, neuroinflammatory disorders such as stroke. Other diseases include septic shock, reperfusion injury, Alzheimer's disease, and shigellosis.
• IL-l ⁇ activity has been shown to have beneficial in vivo effects.
• compounds that are interleukin- 1 receptor antagonists have been shown to inhibit ischaemic and excitotoxic damage in rat brains. See, for example, Relton J.K., et al., Brain Research Bulletin.
• the compounds of the present invention are also inhibitors of other cysteine proteases in the ICE family. Many of these proteases have only recently been described in the literature. While the nomenclature is still unresolved, the following proteases are representative members of this class of enzymes; Ich-2 (also called Tx or ICErel-II), ICErel-III, Ich-I (also called Nedd-2), CPP-32 (also called apopain and yama), Mch-2, Mch-3 (also called ICE-lap3, CMH-1), and Ced-3. See Henkart P.A., Immunity. 1996;4:195-201.
• Caspase-4 can activate IL-l ⁇ and IL-18. It has been shown that a murine homolog of Caspase-4 can activate ICE. Thus, inhibition of Caspase-4 will act to inhibit ICE. See Thornberry N.A., et al., Perspectives in Drug Discovery and Design. 1994;2:389-399.
• ICE In addition to its effects on IL-l ⁇ production, ICE has been shown to play a role in the production of the inflammatory mediator interferon- ⁇ (Ghayur, et al., Nature. 1997;386(6625):619-623). ICE processes the inactive proform of interferon- ⁇ inducing factor (IGIF; Interleukin- 18) to active IGIF, a protein which induces production of interferon- ⁇ by T-cells and natural killer cells. Interferon- ⁇ has been implicated in the pathogenesis of diseases such as inflammatory disorders and septic shock. Therefore, ICE inhibitors would be expected to have beneficial effects in such disease states by effects on interferon- ⁇ .
• IGIF interferon- ⁇ inducing factor
• cysteine proteases in the ICE family (also known as caspases with ICE being known as Caspase-1) has been further defined.
• the following proteases are representative members of this class of enzymes using the nomenclature described in Alnemri, et al, Cell.
• Caspase-2 also known as Ich-1
• Caspase-3 also known as CPP32, Yama, and apopain
• Caspase-4 also known as TX, Ich-2, and ICE rel-II
• Caspase-5 also known as ICE rel-III
• Caspase-6 also known as Mch2
• Caspase-7 also known as Mch3
• Caspase-8 also known as FLICE and Mch5
• Caspase-9 also known as ICE-LAP6 and Mch6
• Caspase-10 also known as Mch4
• the present invention provides compounds of the Formula I
• R 1 is R 3 OC-, R 3 CO-, R 3 SO 2 -, Ra
• each R a is independently hydrogen, Ci -C6 alkyl, or -(CH2) n aryl;
• R 2 is -(CRR) n -aryl, -(CRR) n -X-aryl,
• each R is independently hydrogen, Ci -Cg alkyl, halogen or hydroxy
• X is O or S
• R 3 is Ci-Cs alkyl, aryl, heteroaryl,
• each R' is independently Ci -C ⁇ alkyl
• Ci -Cg alkylaryl, aryl, or hydrogen; each J is independently
• each R b is independently hydrogen, Cj-Cg alkyl, aryl, substituted aryl; arylalkyl, heteroarylalkyl, substituted arylalkyl, or substituted heteroarylalkyl;
• R4 is hydrogen
• R 5 is C1-C6 alkyl-CO-, -(CH 2 ) n aryl,
• R ⁇ is O
• Rl is phenyl-SO2-.
• R 1 is CH3-OC-.
• R 1 is phenyl-CH CH 2 -CO-.
• R 1 is phenyl-CH2-CO-.
• R a is hydrogen
• R 2 is -(CH2) n -phenyl.
• R 2 is -(CH2) n -naphthyl.
• R 2 is -(CH 2 ) n -O-phenyl.
• R 2 is -(CH2) n -O-naphthyl.
• R 2 is -(CH 2 ) n -S-phenyl.
• R 2 is-(CH 2 )n-CH(phenyl) 2 .
• R 2 is-(CH 2 )n-CH(phenyl) 2 .
• R a is hydrogen; Ri is benzyloxycarbonyl; R 2 is aryl-X(CRR) n -, aryl-(CRR) n -, heteroaryl-(CRR) n -, or cycloalkyl-(CRR) n -; n is 1, 2, or 3; X is O or S; and R is hydrogen, methyl, or benzyl.
• R a is hydrogen
• Ri is benzyloxycarbonyl
• R 2 is -(CH 2 ) n -naphthyl
• R a is hydrogen; i is benzyloxycarbonyl; and
• R 2 is -CH2-naphthyl.
• R a is hydrogen; R 2 is benzyloxycarbonyl,
• Also provided is a method of inhibiting interleukin-l ⁇ converting enzyme comprising administering to a patient in need of inhibition of interleukin-l ⁇ converting enzyme a therapeutically effective amount of a compound of Formula I.
• the inflammatory disease is arthritis. In a preferred embodiment of the treatment of inflammatory diseases, the inflammatory disease inflammatory bowel disease.
• Also provided is a method of treating reperfusion injury the method of comprising administering to a patient having reperfusion injury a therapeutically effective amount of a compound of Formula I.
• composition that contains a compound of Formula I.
• each n is independently 0 to 3, and the pharmaceutically acceptable, salts, esters, amides, and prodrugs thereof.
• alkyl means a straight or branched chain hydrocarbon. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl.
• alkoxy means an alkyl group attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.
• halogen includes chlorine, fluorine, bromine and iodine.
• aryl means an aromatic hydrocarbon. Representative examples of aryl groups include phenyl and naphthyl.
• heteroatom includes oxygen, nitrogen, sulfur, and phosphorus.
• heteroaryl means an aryl group wherein one or more carbon atom of the aromatic hydrocarbon has been replaced with a heteroatom. Examples of heteroaryl groups include furan, thiophene, pyrrole, thiazole, pyridine, pyrimidine, pyrazine, benzofuran, indole, coumarin, quinoline, isoquinoline, and naphthyridine.
• the aryl or heteroaryl groups may be substituted with one or more substituents, which can be the same or different.
• substituents include alkyl, alkoxy, thioalkoxy, hydroxy, halogen, trifluoromethyl, amino, alkylamino, dialkylamino, -NO 2 , -CN, -CO H, -CO 2 alkyl, -SO 3 H, -CHO,
• n 1 to 5 and R is hydrogen or alkyl.
• cycloalkyl means a cyclic alkyl group.
• examples of cycloalkyl groups include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
• heterocycle means a cycloalkyl group on which one or more carbon atom has been replaced with a heteroatom.
• heterocycles include piperazine, morpholino, and piperidine.
• aryl, heteroaryl, cycloalkyl, and heterocycle as used herein include substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycle.
• the compounds of Formula I can be administered to a patient either alone or as part of a pharmaceutically acceptable composition.
• the compositions can be administered to patients such as humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
• compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
• suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
• Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
• compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
• adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
• Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
• isotonic agents for example sugars, sodium chloride, and the like.
• Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or, (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid;
• binders as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia;
• humectants as for example, glycerol
• disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
• absorption accelerators as for example, quaternary ammonium compounds
• the dosage forms may also comprise buffering agents.
• wetting agents as for example, cetyl alcohol, and glycerol monostearate
• adsorbents as for example, kaolin and bentonite
• lubricants as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.
• the dosage forms may also comprise buffering agents.
• compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
• Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan or mixtures of these substances, and the like.
• inert diluents commonly used in the art, such as water or other solvents, solub
• the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, macrocrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
• compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
• suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
• Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.
• the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
• the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg/kg of body weight per day is preferable.
• the specific dosage used can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.
• salts refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
• salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention.
• salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
• Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
• alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
• nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.
• ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like See, for example, Berge S.M., et al., "Pharmaceutical Salts.” J. Pharm. Sci.. 1977;66:1-19, which is incorporated herein by reference).
• esters of the compounds of this invention examples include Ci -C6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. Ci -C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
• Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary Cj-Cg alkyl amines and secondary Ci -C ⁇ dialkyl amines wherein the alkyl groups are straight or branched chain.
• the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom.
• Amides derived from ammonia, Ci -C3 alkyl primary amines and Ci -C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
• prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
• a thorough discussion is provided in Higuchi T. and Stella V., "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
• the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
• each asymmetric carbon can have either the R or S configuration. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of this invention.
• the compounds of the present invention are administered to a patient in need of ICE or Caspase-4 inhibition.
• Caspase-4 inhibition are those patients having a disease or condition in which ICE or Caspase-4 plays a role.
• diseases include, but are not limited to, inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, neuroinflammatory disorders such as stroke, and septic shock.
• Other diseases include reperfusion injury, Alzheimer's disease, and shigellosis.
• a “therapeutically effective amount” is an amount of a compound of Formula I that when administered to a patient having a disease that can be treated with a compound of Formula I ameliorates a symptom of the disease.
• a therapeutically effective amount of a compound of Formula I is readily determined by one skilled in the art by administering a compound of Formula I to a patient and observing the results.
• 3-Benzyloxycarbonylamino-5-bromo-4-oxo-pentozoic acid tert-butyl ester also known as Z-Asp(OtBu)-bromomethyl ketone
• Z-Asp(OtBu)-bromomethyl ketone can be purchased commercially or prepared according to the procedure of Dolle, et al., J. Med. Chem., 1994;37:563-564.
• This methylbromo ketone is treated with an appropriately substituted carboxylic acid and a base such as potassium fluoride.
• bases such as potassium carbonate, cesium carbonate, or potassium t-butoxide could be used.
• the reagents should be mixed in dimethyl formamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), acetonitrile or other appropriate solvent and stirred at room temperature for 8 to 24 hours.
• the t-butyl ester protecting group can be removed in acidic media ,preferably trifluoroacetic acid, to produce the carbobenzoxy aspartyl esters shown in Scheme 1.
• a mixture of an appropriately substituted acyloxymethyl ketone of a carbobenzoxy aspartyl t-butyl ester was hydrogenated with an equivalent of hydrochloric or other acid in the presence of a catalyst such as palladium on carbon to yield the amine salt.
• the salt can be acylated with an appropriately substituted isocyanate, sulfonyl chloride, chloroformate or phenylpropionyl chloride to afford the N-substituted derivatives.
• isocyantes, sulfonyl chlorides, or chloro formates can be purchased commercially or synthesized by methods described in the chemical literature.
• the t-butyl ester protecting group can be removed in the final step using acidic media, preferably trifluoroacetic acid, to produce the acyloxy methylketone derivatives shown in Scheme 2.
• the amine salt of the acyloxymethyl ketone of Z-Asp(Ot-Bu)OH was synthesized and treated with an appropriately substituted carboxylic acid and coupling reagent.
• the coupling agent may be, but is not limited to, such reagents as 1,3-dicyclohexylcarbodiimide (DCC), 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), l, -carbonyldiimidazole (CDI), l, -carbonylbis(3-methylimidazolium) triflate (CBMIT), isobutylchloroformate, benzotriazol- 1 -yloxytris(dimethylamino)- phosphonium hexafluorophosphate (BOP), 2-(3,4-dihydro-4-oxo- 1,2,3- benzotriazin-3-yl)
• DCC 1,
• 1-Hydroxybenzotriazole hydrate should be added to the reaction to improve yield and limit isomerization and base, preferably an amine such as trimethyl amine or methyl morpholine should be added as an acid scavenger.
• the resulting amide product was treated with acidic media, preferably trifluoroacetic acid, to remove the t-butyl ester and produce the final products as described in Scheme 3.
• the amine salt of the acyloxymethyl ketone of Cbz-Asp(OtBu)OH was synthesized and treated with an appropriately substituted acid chloride or acid fluoride to generate an amide product.
• the acid chlorides were purchased commercially or were prepared by treating carboxylic acids with agents such as thionyl chloride, phosphorous tribromide, or oxalyl chloide/DMF.
• the acid fluorides were prepared by treating a carboxylic acid with cyanuric fluoride.
• the penultimate amide product was treated with acidic media preferably trifluoroacetic acid to remove the t-butyl ester and afford the final products as described in Scheme 4.
• Step B Step C Formation of the RCO 2 H, KF, 1 bromo methyl ketone DMF
• the hydrochloride salt of H-Asp(OtBu)OMe was treated with an appropriately substituted carboxylic acid and coupling reagent.
• the coupling agent may be but is not limited to such reagents described in Example 3.
• 1-Hydroxybenzotriazole hydrate should be added to the reaction to improve yield and limit isomerization and base, preferably an amine such as trimethyl amine or methyl morpholine should be added as an acid scavenger.
• the resulting amide product was treated with an alkaline reagent such as sodium hydroxide to hydrolyze the methyl ester to the carboxylic acid.
• the hydrochloride salt of H-Asp(OtBu)OMe was treated with an appropriately protected amino acid and coupling reagent.
• the coupling agent may be, but is not limited to, such reagents as described in Example 3.
• 1-Hydroxybenzotriazole hydrate should be added to the reaction to improve yield and limit isomerization and base, preferably an amine such as trimethyl amine or methyl morpholine should be added as an acid scavenger.
• the resulting amide product was treated with an alkaline reagent such as sodium hydroxide to hydrolyze the methyl ester to the carboxylic acid.
• the Cbz-amine protecting group was removed using standard catalytic hydrogenation conditions and coupling of another protected amino acid can proceed as described above. This process was repeated until the peptide was the desired length.
• the resulting peptide product was treated with an alkaline reagent such as sodium hydroxide to hydrolyze the methyl ester to the carboxylic acid.
• the appropriately substituted acyloxymethyl ketone of a protected amino acid was synthesized as described in Example 7.
• the Cbz-amine protecting group was removed using standard catalytic hydrogenation conditions, and the amine product was treated with an appropriately substituted carboxylic acid and a coupling reagent.
• the coupling agent may be, but is not limited to, such reagents described in Example 3.
• 1-Hydroxybenzotriazole hydrate should be added to the reaction to improve yield and limit isomerization and base, preferably an amine such as trimethyl amine or methyl morpholine should be added as an acid scavenger.
• the penultimate amide product was treated with acidic media preferably trifluoroacetic acid to remove the t-butyl ester and afford the final products as described in Scheme 7.
• Trans- 1 ,2-cyclohexanedicarboxylic anhydride was treated with the amine salt of an appropriately substituted acyloxymethyl ketone of aspartyl t-butyl ester in the presence of pyridine and 4-dimethylaminopyridine (DMAP) to yield the amide product.
• the carboxylic acid can be functionalized with appropriately substituted amines or alcohols and standard coupling reagents as described in Example 3 to afford amide and ester products.
• the penultimate product was treated with acidic media, preferably trifluoroacetic acid, to remove the t-butyl ester and afford the final products as described in Scheme 8.
• Methyl methacrylate was treated with the anion of an appropriately substituted sulfide to afford the Michael adduct which was hydrolyzed in basic media such as sodium hydroxide to produce the carboxylic acid.
• the amide intermediate is treated with an oxidizing agent which may be, but is not limited to, m-chloroperbenzoic acid, potassium monoperoxysulfate, or sodium perborate to obtain the desired oxidized product.
• an oxidizing agent which may be, but is not limited to, m-chloroperbenzoic acid, potassium monoperoxysulfate, or sodium perborate.
• the t-butyl ester of the penultimate intermediate was deprotected in acidic media, preferably trifluoroacetic acid, to afford the final compounds as described in Scheme 9.
• a 4-substituted-2-oxazolidinone chiral auxiliary as described by Evans, et al., J. Org. Chem., 1985;50:1830 was mixed with a base, such as but not limited to, n-butyl lithium followed by treatment with an appropriately substituted acid chloride or other activated carboxylic acid to afford the N-acylated product.
• a base such as, but not limited to, sodium bis(trimethylsilyl)amide and t-butyl bromoacetate to produce the alkylated chiral product.
• the chiral auxiliary was removed using lithium hydroxide and hydrogen peroxide to obtain the chiral acid.
• Treatment of the acid with the amine salt of H-Asp(OBz)O-allyl and a coupling reagent as described in Example 3 afforded the succinyl amide product.
• the product can be elaborated in one of two ways.
• the allyl ester was removed with phenylsilane and tetrakis(triphenyl-phosphine)palladium or other Pd(0) catalyst to obtain the carboxylic acid, and the acid was converted to the methylbromo ketone and subsequently to the acyloxymethyl ketone as described in Example 5.
• the penultimate intermediate was subjected to catalytic hydrogenation to remove the benzyl ester and afford the final amide products as described in Scheme 10.
• the allyl ester is removed using phenylsilane and tetrakistetrakis(triphenylphosphine)palladium or other Pd(0) catalyst to obtain the carboxylic acid.
• This acid is converted to the methylbromo ketone and subsequently to the acyloxymethyl ketone as described in Example 5.
• Removal of the t-butyl ester of the acyloxymethyl ketone with trifluoroacidic acid and subsequent conversion of the resulting carboxylic acid to the ester resulted in a new ester product.
• the esterification can be accomplished using a variety of literature techniques which includes but is not limited to treatment of the carboxylic acid with an appropriately substituted alcohol in the presence of a coupling reagent.
• the penultimate intermediate was subjected to catalytic hydrogenation to remove the benzyl ester and afford the final ester products as described in Scheme 10.
• the appropriately substituted S-acetyl mercapto carboxylic acid was treated with benzyl bromide and l,8-diazobicyclo[5.4.0]undec-7-ene (DBU) to produce the benzyl ester which was subsequently reacted with chlorine gas to yield the sulfonyl chloride.
• the sulfonyl chloride was treated with N,N-bis(p- methoxybenzyl)amine to afford the sulfonamide which was subjected to catalytic hydrogenation to obtain the intermediate carboxylic acid.
• the acid was activated using cyuranic fluoride which was then mixed with the amine salt of H-Asp(Ot-
• Z is carbobenzoxy, also known as cbz, Asp is aspartic acid and tBu is tert-butyl
• Z is carbobenzoxy, also known as cbz, Asp is aspartic acid and tBu is tert-butyl
• 1-naphthylacetic acid (1.00 g, 5.37 mmol
• potassium fluoride (0.74 g, 12.74 mmol) in 10 mL of dimethylformamide (DMF) was stirred at room temperature for 12 hours.
• DMF dimethylformamide
• Step A A mixture of 3-benzyloxycarbonylamino-5-(naphthalen- 1 -yl-acetoxy)-4- oxo-pentanoic acid tert-butyl ester (1.495 g, 2.956 mmol, Example 1, Step A),
• Example 2 In a process analogous to Example 2, using the appropriately substituted isocyantes, appropriately substituted sulfonyl chlorides, appropriately substituted chloroformates, or appropriately substituted acid chlorides with 3-amino- 5-(naphthalen-l-yl-acetoxy)-4-oxo-pentanoic acid, tert-butyl ester hydrochloride (Example 2, Step A), the corresponding compounds were prepared as follows: EXAMPLE 2a 3-Methoxycarbonylamino-5-(naphthalene- 1 -yl-acetoxy)-4-oxo-pentanoic acid, as off-white solid. Analysis calculated for C19H19HO7 (373.366): C, 61.12; H, 5.13; N, 3.75.
• EXAMPLE 3a 5 -(Naphthalen- 1 -yl-acetoxy)- 4-oxo-3 - [(thiophene-3 -carbonvD-amino] -pentanoic acid, as a foamy off-white solid.
• Diastereomer A or B was reacted with trifluoroacetic acid as described for Example 4 to yield 3-[(2-carbamoyl-cyclopentanecarbonyl)-amino]-5-(naphthalen- l-yl-acetoxy)-4-oxo-pentanoic acid 4b (diastereomer A), mp 171-185°C and 3 - [(2-carbamoyl-cyclopentanecarbonyl)-amino] -5 -(naphthalen- 1 -yl-acetoxy)-4- oxo-pentanoic acid 4c (diastereomer B), mp 208-210°C.
• Example 2 (407 mg, 1.0 mmol) in a single portion. The mixture allowed to stir at room temperature for 16 hours. The solution was diluted with ethyl acetate and washed with saturated NaHCO3, saturated KHPO4 and brine solution, dried (MgSO4), filtered, and concentrated.
• N-(l,2,3,4-tetrahydro-l-oxo-isoquinoline-2-yl)-acetyl aspartic acid 4-tert-butyl ester (2.8 g, 7.4 mMol) in tetrahydrofuran (40 mL) at -15°C was added N-methylmorpholine (0.75 mL, 8 mMol) followed by dropwise addition of ethyl chloroformate (0.79 mL, 8 mMol). After 15 minutes at -10°C 50 mL of a 0.2N solution of diazomethane in ether was added dropwise.
• EXAMPLE 5z 3-[2-(3-Acetylamino-2-oxo-2H-pyridin-l-v ⁇ -acetylamino]-5-(3,3-diphenyl- propionyloxyV4-oxo-pentanoic acid as a course pink powder.
• the starting acid was prepared as described in Bioorganic & Medicinal Chemistry Letters. 1997;7:1337-1342. Analysis calculated for C29H29N3O O.585 CF3CO2H (614.274):
• EXAMPLE 5aa 3-[2-(3-Acetylamino-2-oxo-2H-pyridin-l-yl)-acetylamino]-5-(2-benzyl-3-phenyl- propionyloxy)-4-oxo-pentanoic acid as a fine brown powder.
• the starting acid was prepared as described in Bioorganic & Medicinal Chemistry Letters. 1997;7:1337- 1342.

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