WO2001079167A2 - Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis - Google Patents
Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis Download PDFInfo
- Publication number
- WO2001079167A2 WO2001079167A2 PCT/US2001/012333 US0112333W WO0179167A2 WO 2001079167 A2 WO2001079167 A2 WO 2001079167A2 US 0112333 W US0112333 W US 0112333W WO 0179167 A2 WO0179167 A2 WO 0179167A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- substituted
- group
- unsubstituted
- aryl
- Prior art date
Links
- 0 *C(C(*)C(N(*)C(*)C=C(*)*)=O)C(c1c(*)c(*)c(*)[n]1*)=O Chemical compound *C(C(*)C(N(*)C(*)C=C(*)*)=O)C(c1c(*)c(*)c(*)[n]1*)=O 0.000 description 14
- IDXLALZVWZGIDG-GORDUTHDSA-N C/C=C(\CCO1)/C1=O Chemical compound C/C=C(\CCO1)/C1=O IDXLALZVWZGIDG-GORDUTHDSA-N 0.000 description 3
- LCMMCVCTOCSEBU-GSUHWGLPSA-N O=C(CC(Cc(cc1)ccc1F)C(N[C@@H](C[C@H](CCN1)C1=O)/C=C(\CCO1)/C1=O)=O)c1ccc[nH]1 Chemical compound O=C(CC(Cc(cc1)ccc1F)C(N[C@@H](C[C@H](CCN1)C1=O)/C=C(\CCO1)/C1=O)=O)c1ccc[nH]1 LCMMCVCTOCSEBU-GSUHWGLPSA-N 0.000 description 2
- IGCNNRCGQHUMDX-SQVIKHKRSA-N C=C/C=C(\C=C/CC[C@H](CC(c1ccc(-c2c(cccc3)c3ccc2)[nH]1)=O)C(N[C@@H](C[C@H](CCN1)C1=O)/C=C(\CCO1)/C1=O)=O)/F Chemical compound C=C/C=C(\C=C/CC[C@H](CC(c1ccc(-c2c(cccc3)c3ccc2)[nH]1)=O)C(N[C@@H](C[C@H](CCN1)C1=O)/C=C(\CCO1)/C1=O)=O)/F IGCNNRCGQHUMDX-SQVIKHKRSA-N 0.000 description 1
- SWPKOMKSOOCZSM-JCGZTPGGSA-N CC1C(F)=CC=C(C[C@@H](C(N[C@@H](C[C@H](CCN2)C2=O)/C=C(\CCO2)/C2=O)=O)NC(c2ccc(-c3cccc4c3cccc4)[nH]2)=O)C1 Chemical compound CC1C(F)=CC=C(C[C@@H](C(N[C@@H](C[C@H](CCN2)C2=O)/C=C(\CCO2)/C2=O)=O)NC(c2ccc(-c3cccc4c3cccc4)[nH]2)=O)C1 SWPKOMKSOOCZSM-JCGZTPGGSA-N 0.000 description 1
- ONLWPHANFDORGA-UHFFFAOYSA-N CCC(CC)C(NC)=O Chemical compound CCC(CC)C(NC)=O ONLWPHANFDORGA-UHFFFAOYSA-N 0.000 description 1
- JSDUOUVZQRZOOY-UHFFFAOYSA-N CCCC1OCCO1 Chemical compound CCCC1OCCO1 JSDUOUVZQRZOOY-UHFFFAOYSA-N 0.000 description 1
- RINPFTMJWDOZAZ-SECBINFHSA-N CCCCN([C@H](CO1)C(C)C)C1=O Chemical compound CCCCN([C@H](CO1)C(C)C)C1=O RINPFTMJWDOZAZ-SECBINFHSA-N 0.000 description 1
- UQIGPPFRDZOZEE-VNKNIMTOSA-N CCOC(/C=C/[C@H](CCC(N)=O)NC([C@H](Cc1ccccc1)NC(c1ccc(-c2cccc(C(C)C)c2)[nH]1)=O)=O)=O Chemical compound CCOC(/C=C/[C@H](CCC(N)=O)NC([C@H](Cc1ccccc1)NC(c1ccc(-c2cccc(C(C)C)c2)[nH]1)=O)=O)=O UQIGPPFRDZOZEE-VNKNIMTOSA-N 0.000 description 1
- SKYIUKKNKOZAQZ-YHBGTCLZSA-N CCOC(/C=C/[C@H](CCC(N)=O)NC([C@H](Cc1ccccc1)NC(c1ccc(-c2cncc3c2cccc3)[nH]1)=O)=O)=O Chemical compound CCOC(/C=C/[C@H](CCC(N)=O)NC([C@H](Cc1ccccc1)NC(c1ccc(-c2cncc3c2cccc3)[nH]1)=O)=O)=O SKYIUKKNKOZAQZ-YHBGTCLZSA-N 0.000 description 1
- AVXCZVUIYCXOAU-KCECPYSNSA-N CCOC(/C=C/[C@H](C[C@H](CCN1)C1=O)NC(CCC(C)O)=O)=O Chemical compound CCOC(/C=C/[C@H](C[C@H](CCN1)C1=O)NC(CCC(C)O)=O)=O AVXCZVUIYCXOAU-KCECPYSNSA-N 0.000 description 1
- SNQZSQTZYZWORZ-FNMZJVBZSA-N CCOC(/C=C/[C@H](C[C@H](CCN1)C1=O)NC([C@@H](CC(c([nH]1)ccc1[IH]COC(/C=C/[C@H](C[C@H](CCN1)C1=O)NC([C@H](CC#C)NC(c1ccc(-c2c(C(F)(F)F)cccc2)[nH]1)=O)=O)=O)=O)Cc1ccccc1)=O)=O Chemical compound CCOC(/C=C/[C@H](C[C@H](CCN1)C1=O)NC([C@@H](CC(c([nH]1)ccc1[IH]COC(/C=C/[C@H](C[C@H](CCN1)C1=O)NC([C@H](CC#C)NC(c1ccc(-c2c(C(F)(F)F)cccc2)[nH]1)=O)=O)=O)=O)Cc1ccccc1)=O)=O SNQZSQTZYZWORZ-FNMZJVBZSA-N 0.000 description 1
- OVRREKBUSHLLCO-KNXLSDOESA-N CCOC(/C=C/[C@H](C[C@H](CCN1)C1=O)NC([C@H](Cc1ccccc1)NC(c1ccc(-c(cc2)c(C(F)(F)F)cc2/[O]=C2\OCC/C2=C\[C@H](C[C@H](CCN2)C2=O)NC([C@H](Cc(cc2)ccc2F)NC(c2ccc(-c3ccccc3)[nH]2)=O)=O)[nH]1)=O)=O)=O Chemical compound CCOC(/C=C/[C@H](C[C@H](CCN1)C1=O)NC([C@H](Cc1ccccc1)NC(c1ccc(-c(cc2)c(C(F)(F)F)cc2/[O]=C2\OCC/C2=C\[C@H](C[C@H](CCN2)C2=O)NC([C@H](Cc(cc2)ccc2F)NC(c2ccc(-c3ccccc3)[nH]2)=O)=O)[nH]1)=O)=O)=O OVRREKBUSHLLCO-KNXLSDOESA-N 0.000 description 1
- ZYBOXSDTMZRWBC-UHFFFAOYSA-N COC(c([nH]1)ccc1Br)=O Chemical compound COC(c([nH]1)ccc1Br)=O ZYBOXSDTMZRWBC-UHFFFAOYSA-N 0.000 description 1
- VONGYFFEWFJHNP-UHFFFAOYSA-N COC(c1ccc[nH]1)=O Chemical compound COC(c1ccc[nH]1)=O VONGYFFEWFJHNP-UHFFFAOYSA-N 0.000 description 1
- GMIDLMBYUVTJND-NMRJBTAYSA-N C[C@H]([C@@H](CC(c1ccc(-c2cccc3c2cccc3)[nH]1)=O)C(N[C@@H](C[C@H](CCN1)C1=O)/C=C(\CCO1)/C1=O)=O)c(cc1)ccc1F Chemical compound C[C@H]([C@@H](CC(c1ccc(-c2cccc3c2cccc3)[nH]1)=O)C(N[C@@H](C[C@H](CCN1)C1=O)/C=C(\CCO1)/C1=O)=O)c(cc1)ccc1F GMIDLMBYUVTJND-NMRJBTAYSA-N 0.000 description 1
- YREDEURSMORFGC-REZCGKABSA-N O=C(CC(CC(CC1)=CC=C1F)C(N[C@@H](C[C@H](CCN1)C1=O)/C=C(\CCO1)/C1=O)=O)c1ccc(-c2cccc3c2cccc3)[nH]1 Chemical compound O=C(CC(CC(CC1)=CC=C1F)C(N[C@@H](C[C@H](CCN1)C1=O)/C=C(\CCO1)/C1=O)=O)c1ccc(-c2cccc3c2cccc3)[nH]1 YREDEURSMORFGC-REZCGKABSA-N 0.000 description 1
- PBWIZQOMWNDOIE-IOMMGAHLSA-N O=C([C@H](CC(CC1)=CC=C1F)NC(c1ccc(-c2c(cccc3)c3c(CCOC(/C=C/[C@H](C[C@H](CCN3)C3=O)NC([C@H](Cc3ccccc3)NC(c3ccc(-c4c(cccc5)c5ccc4)[nH]3)=O)=O)=O)cc2)[nH]1)=O)N[C@@H](C[C@H](CCN1)C1=O)/C=C(\CCO1)/C1=O Chemical compound O=C([C@H](CC(CC1)=CC=C1F)NC(c1ccc(-c2c(cccc3)c3c(CCOC(/C=C/[C@H](C[C@H](CCN3)C3=O)NC([C@H](Cc3ccccc3)NC(c3ccc(-c4c(cccc5)c5ccc4)[nH]3)=O)=O)=O)cc2)[nH]1)=O)N[C@@H](C[C@H](CCN1)C1=O)/C=C(\CCO1)/C1=O PBWIZQOMWNDOIE-IOMMGAHLSA-N 0.000 description 1
- UBQCDQPYCIQFNT-VHQOIORISA-N OC1OCC/C1=C\[C@H](C[C@H](CCN1)C1=O)NC(C(CC(c1ccc(-c2ccccc2)[nH]1)=O)Cc(cc1)ccc1F)=O Chemical compound OC1OCC/C1=C\[C@H](C[C@H](CCN1)C1=O)NC(C(CC(c1ccc(-c2ccccc2)[nH]1)=O)Cc(cc1)ccc1F)=O UBQCDQPYCIQFNT-VHQOIORISA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—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
- 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
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/32—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/34—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 two double bonds between ring members or between ring members and non-ring members 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07K5/0205—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)3-C(=0)-, e.g. statine or derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the invention relates to pyrrole-containing peptidomimetic compounds that inhibit the enzymatic activity of picomaviral 3C proteases, especially rhinovirus 3C proteases (RVPs), and that retard viral growth in cell culture.
- the invention also relates to the use of these compounds in pharmaceutical compositions, methods of treatment of rhino viral infections using these compounds and compositions, and processes for the synthesis of these compounds and compounds useful in the syntheses thereof.
- the picornaviruses are a family of tiny non-enveloped positive-stranded RNA-containing viruses that infect humans and other animals. These viruses include the human rhinoviruses, human polioviruses, human coxsackieviruses. human echoviruses, human and bovine enteroviruses, encephalomyocarditis viruses, meningitis virus, foot and mouth viruses, hepatitis A virus, and others. The human rhinoviruses are a major cause ofthe common cold. To date, there are no effective therapies on the market that cure the common cold, only treatments that relieve the symptoms. Picomaviral infections may be treated by inhibiting the proteolytic picomaviral 3C enzymes.
- These enzymes are required for the natural maturation of the picomaviruses. They are responsible for the autocatalytic cleavage ofthe genomic, large polyprotein into the essential viral proteins.
- Members ofthe 3C protease family are cysteine proteases, where the sulfhydryl group most often cleaves the glutamine-glycine amide bond. Inhibition of 3C proteases is believed to block proteolytic cleavage ofthe viral polyprotein, which in rum can retard the maturation and replication ofthe viruses by interfering with viral particle production. Therefore, inhibiting the processing of this cysteine protease with selective small molecules that are specifically recognized should represent an important and useful approach to treat and cure viral infections of this nature and, in particular, the common cold.
- This invention relates to compounds useful for inhibiting the activity of picomaviral 3C proteases having the general Formula I:
- R is an alkylcarbonylalkyl, cycloalkylcarbonylalkyl, arylcarbonylalkyl, heteroarylcarbonylalkyl, alkylcarbonylaminoalkyl, cycloalkylcarbonylaminoalkyl, heterocycloalkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, heteroarylcarbonylaminoalkyl, alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, heterocycloalkylaminocarbonylalkyl, arylaminocarbonylalkyl, heteroarylaminocarbonylalkyl group, where each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl moiety thereof is unsubstituted or substituted with one or more suitable substituents;
- R is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents
- R d is H, halo, hydroxyl, or an alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy or alkylthio group is unsubstituted or substituted with one or more suitable substituents;
- R c is a moiety having the formula:
- R e and R are each independently H or a lower alkyl group; m is 0 or 1, provided that when m is 1, R a is not an amino-substituted alkylcarbonylalkyl or amino-substituted alkylcarbonylaminoalkyl group, and when m is 0, R a is selected from an alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, heterocycloalkylaminocarbonylalkyl, arylaminocarbonylalkyl, heteroarylaminocarbonylalkyl and heteroarylcarbonylaminoalkyl group, provided that R a is not substituted indolecarbonylaminoalkyl; p is an integer of from 0 to 5;
- A is CH or N; when p is 1, 2, 3, 4, or 5, A 2 is C(R 8 )(R h ), N(R f ), S, S(O), S(O) 2 , or O, and when p is 0, A 2 is C(R g )(R h )(R i ), ⁇ R 6 ) ⁇ ), S ⁇ 8 ), S O) ⁇ 8 ), S(O) 2 (R ), or O Et 8 ), where each R 8 , R h and R 1 is independently H or a lower alkyl group; each A 3 present is each independently C(R 8 )(R h ), N(R f ), S, S(O), S(O) 2 , or
- R 1 , R m , R n and R° are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two ofthe R 1 , R m , R and R°, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which may be optionally substituted, or Z and R d , together with the atoms to wliich they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and R d are as defined above except for moieties that cannot
- a 2 is C(R g )(R h ), N(R), S, S(O), S(O) 2 , or O, where each R , R h and R f is independently H or a lower alkyl group; each A 3 present is independently C(R ⁇ )(R h ), N(R), S, S(O), S(O) 2 , or O, where each R g , R h and R 1 is independently H or a lower alkyl group; when p is 1 , 2, 3 , 4, or 5 , A 4 is N(R j ), C(R g )(R h ), or O, and when p is 0, A 4 is
- each R g , R h and R 1 is independently H or a lower alkyl group
- each R J is H, an alkyl, aryl, or acyl group
- Z and Z 1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, -0(0) ⁇ , -CO ⁇ 1 , -CN, -C(O)NR 1 R m , -C(O)NR 1 OR m , -C ⁇ R 1 , -C(S)NR 1 R m , -NO 2 , -SOR m , -SO a R 1 , -SO 2 NR 1 R m , -SO 2 (NR 1 )(OR m ), -SONR 1 , -SO 3 R 1 , -PO(OR') 2 , -PO OR'XOR" 1 ) , -PO NR ⁇ XOR 11 ) , -PO
- One embodiment of this invention relates to compounds useful for inhibiting the activity of picomaviral 3C proteases having the following general Formula II:
- R a' is an alkyl, cycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents
- n is 1, 2 or 3
- m is 1
- R x and R y are each independently selected from H and an alkyl group, unsubstituted or substituted with one or more suitable substituents
- R b , R°, R d , Z and Z 1 are as defined above, provided that R a ' is not an amino-substituted alkyl group.
- Another embodiment of this invention relates to compounds useful for inhibiting the activity of picomaviral 3C proteases having the following general Formula HI:
- R a ' is an alkyl, cycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents
- n is 1, 2 or 3
- m is 1
- R x and R y are each independently selected from H and an alkyl group, unsubstituted or substituted with one or more suitable substituents
- R b , R c , R d , Z and Z 1 are as defined above, provided that R a ' is not an amino-substituted alkyl group.
- This invention also relates to compounds useful for inhibiting the activity of picomaviral 3C proteases having the following general Formula IV:
- R a' is an alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group, where the alkyl, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group is unsubstituted or substituted with one or more suitable substituents
- n is 1, 2 or 3
- R x and R y are each independently selected from H and an alkyl group, unsubstituted or substituted with one or more suitable substituents
- R b , R°, R d , Z and Z 1 are as defined above.
- This invention relates to compounds useful for inhibiting the activity of picomaviral 3C proteases having the general Formula V:
- W is CH orN
- R 1 is H, halo or an alkoxy, alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group, where the alkoxy, alkyl, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group is unsubstituted or substituted with one or more suitable substituents;
- R 2 and R 3 are each independently H, halo or an alkoxy or lower alkyl group, where the alkoxy or lower alkyl group is unsubstituted or substituted with a suitable substituent; or R 1 together with R 2 form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is unsubstituted or substituted with a suitable substituent;
- R 4 and R 6 are each independently H or a lower alkyl group, unsubstituted or substituted with a suitable substituent
- R 5 is H or an alkyl group, unsubstituted or substituted with a suitable substituent
- R 7 is a moiety having the formula:
- R 8 and R 9 are each independently H or a lower alkyl group; m is 0 or 1, provided that when W is N, m is 0 and R 1 together with R 2 form an aryl ring, the aryl ring is unsubstituted (e.g., R 1 together with R 2 and the pyrrole to which they are bound do not form a substituted indole); p is an integer of from 0 to 5;
- A is CH orN; when p is 1, 2, 3, 4, or 5, A 2 is C(R 10 )(R n ), N(R 12 ), S, S(O), S(O) 2 , or O, and when p is 0, A 2 is C(R 10 )(R ⁇ )(R 12 ), N(R 10 )(R 12 ), S(R 10 ), S(O)(R 10 ), S(O) 2 (R 10 ), or O(R 10 ) where each R 10 , R 11 and R 12 is independently H or a lower alkyl group; each A 3 present is independently C(R 10 )(R ⁇ ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R 10 , R ⁇ and R 12 is independently H or a lower alkyl group; when p is 1, 2, 3, 4, or 5, A 4 is N(R 13 ), C(R 10 )(R n ), or O, and when p is 0, A 4 is N(
- a 2 is C(R 10 )(R ⁇ ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R 10 , R" and R 12 is independently H or a lower alkyl group; each A 3 present is independently C(R 10 )(R n ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R'°, R 11 and R 12 is independently H or a lower alkyl group; when p is 1, 2, 3, 4, or 5, A 4 is N(R 13 ), C(R 10 )(R n ), or O, and when p is 0, A 4 is N(R 13 )(R 14 ), C(R 10 )(R U )(R 12 ), and O(R 14 ), where each R 10 , R n and R 12 is independently H or a lower alkyl group, each R 13 is H or an alkyl, aryl, or acyl group, and each R 14 is H or an al
- Z and Z 1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, -C(O)R 15 , -CO 2 R 15 , -CN, -C(O)NR 15 R 16 , -C(O)NR 15 OR 16 , -C(S)R 15 , -C(S)NR 15 R 16 , -NO 2 , -SOR 16 , -SO 2 R 15 , -SO 2 NR 15 R 16 , -SO 2 (NR 15 )(OR 16 ), -SONR 15 , -SO 3 R 15 , -PO(OR 15 ) 2 , -PO(OR 15 )(OR 16 ) ; -PO(NR 15 R 16 )(OR 17
- R c and R 7 are defined to provide structures where m is 1 and p is 1 -5 (i.e., both A 2 and A 3 are present), m is 0 and p is 0 (i.e, both A 2 and A 3 are absent), m is 0 and p is 1-5 (i.e, A 2 is absent and A 3 is present) and m is 1 and p is 0 (i.e, A 2 is present and A 3 is absent). Accordingly, one of ordinary skill in the are will recognize that when both A 2 and A 3 are present (m is 1 and p is 1-5), the dotted line between A !
- a 2 represents a bond and the dotted line between A 2 , and A 3 represents a bond.
- the dotted line between Aj and A 2 represents a hydrogen and the dotted line between A 2 and A 3 represents a hydrogen (e.g., Aj is CH 2 or NH and A 3 is CH(R S )(R h ), NH(R), SH, S(O)H, S(O) 2 H, or OH or
- a 2 is CH(R 10 )(R n ), NH(R 12 ), SH, S(O)H, S(O) 2 H, or OH.
- m is 1 and p is 1 or 2 or m is 0 and p is 0 or m is 1 and p is 0. More preferably, when m is 1 and p is 1 or 2, A 2 and A 3 are both C(R s )(R h ) or C(R 10 )(R U ), respectively. More preferably, m is 1 and p is 1.
- antipicornaviral agents ofthe invention include prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts and solvates of such compounds.
- alkyl represents a straight- or branched-chain saturated or unsaturated hydrocarbon, containing 1 to 10 carbon atoms which may be unsubstituted or substituted by one or more ofthe substituents described below.
- a C r C 6 alkyl represents an alkyl substituent containing 1 to 6 carbon atoms.
- alkyl substituents include, but are not limited to methyl (Me), ethyl (Et), propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, propenyl, butenyl, pentenyl, ethynyl, butynyl, propynyl (propargyl, isopropynyl), pentynyl, hexynyl and the like.
- the term "lower alkyl” refers to an alkyl group containing from 1 to 4 carbon atoms.
- Cycloalkyl represents a group comprising a non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon contaimng from 3 to 14 carbon atoms which maybe unsubstituted or substituted by one or more ofthe substituents described below and may be saturated or unsaturated.
- exemplary cycloalkyls include monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl- cyclohexyl, cycloheptyl and the like, that may be fully saturated or partially unsaturated.
- Illustrative examples of cycloalkyl groups include the following:
- Heterocycloalkyl represents a group comprising a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or partially unsaturated, containing 3 to 18 ring atoms, which includes 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more ofthe substituents described below.
- heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-l,4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, azabicyclo[4.3.0]nonyl, oxabicyclo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like.
- heterocycloalkyl groups include, but are
- Aryl represents a group comprising an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing from 6 to 18 carbon ring atoms, which may be unsubstituted or substituted by one or more ofthe substituents described below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
- aryl groups include the following moieties:
- Heteroaryl represents a group comprising an aromatic monovalent monocyclic, bicyclic, or tricyclic radical, containing 5 to 18 ring atoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more ofthe substituents described below.
- the term “heteroaryl” is also intended to encompass the N-oxide derivative (or N-oxide derivatives, if the heteroaryl group contains more than one nitrogen such that more than one N-oxide derivative maybe formed) ofthe nitrogen-containing heteroaryl groups described herein.
- heteroaryl groups include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3-b]tbianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, t
- N-oxide derivatives of heteroaryl groups include, but are not limited to, pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, triazinyl N-oxide, isoquinolyl N-oxide, and quinolyl N-oxide.
- heteroaryl groups include the following moieties:
- R is H, alkyl or hydroxyl
- suitable substituent represents a substituent that is optionally present on any ofthe above alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl groups, described herein, and is selected from alkyl (except for alkyl) haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, nitro, amino, hydroxamino, cyano, halo, hydroxyl, alkoxy, aUcylenedioxy, aryloxy, cycloalkoxy, heterocycloalkoxy, heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkylcarbon
- Preferred "suitable substituents" include alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, halo, hydroxyl, alkoxy, aUcylenedioxy, aryloxy, cycloaUcoxy, heteroaryloxy, and carboxyl.
- alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties of any ofthe above substituents maybe optionally substituted by one or more of alkyl (except for alkyl), halo, haloalkyl, aryl or heteroaryl, where the aryl or heteroaryl is unsubstituted or substituted with one or more subsituents, (e.g., haloaryl), independently selected from alkyl, haloalkyl, aUcylenedioxy, nitro, amino, hydroxamino, alkylamino, dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio or arylthio groups.
- alkyl except for alkyl
- aryl or heteroaryl is unsubstit
- halogen and halo represent chloro, fluoro, bromo or iodo substituents.
- Heterocycle is intended to mean a heteroaryl or heterocycloalkyl group.
- Acyl is intended to mean a -C(O)-R radical, wherein R is an alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group.
- Acyloxy is intended to mean an -OC(O)-R radical, wherein R is an alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group.
- Thioacyl is intended to mean a -C(S)-R radical, wherein R is an alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group.
- Sulfonyl is intended to mean an -SO 2 - biradical.
- Sulfenyl is intended to mean an -SO- biradical.
- Sulfo is intended to mean an -SO 2 H radical.
- Sulfoxide is intended to mean a -SO 3 ⁇ radical
- “Hydroxy” is intended to mean the radical -OH.
- Amine or “amino” is intended to mean the radical -NH 2 .
- NUylamino is intended to mean the radical - ⁇ H-Pv, wherein R,. is an alkyl group.
- Dialkylamino is intended to mean the radical - ⁇ R a R,-, wherein
- R a and R b are each independently an alkyl group, and is intended to include heterocycloalkyl groups, wherein R ⁇ and R b , taken together, form a heterocyclic ring that includes the amine nitrogen.
- "Hydroxamino” is intended to mean the radical -N-OH.
- Alkoxy is intended to mean the radical -OR-., wherein R j , is an alkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, and the like.
- “Lower alkoxy” groups have alkyl moieties having from 1 to 4 carbons.
- AUcylenedioxy is intended to mean the divalent radical -OR-.O- which is bonded to adjacent atoms on an aryl or heteroaryl moiety (e.g., adjacent atoms on a phenyl or naphthyl ring) , wherein R a is a lower alkyl group.
- Alkoxycarbonyl is intended to mean the radical -C(O)OR., wherein R,. is an alkyl group.
- Alkylsulfonyl is intended to mean the radical -SO ⁇ , wherein ⁇ is an alkyl group.
- Alkylaminocarbonyl is intended to mean the radical -C(O)NHR a , wherein R_.
- Dialkylaminocarbonyl is intended to mean the radical -C(O)NR a R b , wherein R a and R b are each independently an alkyl group.
- Mercapto is intended to mean the radical -SH.
- Alkylthio is intended to mean the radical -SR a , wherein R a is an alkyl group.
- Carboxyl is intended to mean the radical -C(O)OH.
- Carbamoyl is intended to mean the radical -C(O)NH 2 .
- Cycloalkylalkyi is intended to mean the radical -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined as above, and is exemplified by the bonding arrangement present in the groups -CH 2 -cyclohexane or -CH 2 -cyclohexene.
- Arylalkyl is intended to mean the radical -alkylaryl, wherein alkyl and aryl are defined as above, and is exemplified by the bonding arrangement present in a benzyl group.
- Aminocarbonylalkyl is intended to mean the radical -alkylC(O) NH 2 and is exemplified by the bonding arrangement present in the group -CH 2 CH 2 C(O)NH 2 .
- Alkylaminocarbonylalkyl is intended to mean the radical -alkylC(O)NHR a , wherein a is an alkyl group and is exemplified by the bonding arrangement present in the group -CH 2 CH 2 C(O)NHCH 3 .
- Alkylcarbonylaminoalkyl is intended to mean the radical and is exemplified by the bonding arrangement present in the group -CH 2 NHC(O)CH 3 .
- Dialkylaminocarbonylalkyl is intended to mean the radical -aUcylC(O)NR a R b , wherein R ⁇ and R b are each independently an alkyl group.
- Aryloxy is intended to mean the radical -OR c , wherein R c is an aryl group.
- Heteroaryloxy is intended to mean the radical -ORj, wherein R d is a heteroaryl group.
- Arylthio is intended to mean the radical -SR,., wherein R c is an aryl group.
- Heteroarylthio is intended to mean the radical -SR d , wherein R d is a heteroaryl group.
- alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups and the substituents containing these groups, as defined hereinabove, may be optionally substituted by at least one other substituent.
- the term "optionally substituted” is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more suitable substituents. Various groups may be unsubstituted or substituted (i.e., they are optionally substituted) as indicated. If the substituents themselves are not compatible with the synthetic methods of this invention, the substituent maybe protected with a suitable protecting group that is stable to the reaction conditions used in these methods.
- the protecting group may be removed at a suitable point in the reaction sequence ofthe method to provide a desired intermediate or target compound.
- suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety, some instances, a substituent may be specifically selected to be reactive under the reaction conditions used in the methods of this invention. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful in an intermediate compound in the methods of this invention or is a desired substituent in a target compound.
- Particular embodiments of this invention comprise the compounds of Formulas H and UI, wherein n is 2 or 1, respectively, depicted by the formula:
- W is CH orN
- R a' is an alkyl, cycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, aryl, and heteroaryl group is unsubstituted or substituted with one or more suitable substituents, provided that R a' is not an amino-substituted alkyl group;
- R 4 and R 6 are each independently H or a lower alkyl group
- R 5 is H or an alkyl group
- R 7 is a substituent having the formula:
- R 8 and R 9 are each independently H or lower alkyl; p is an integer of from 1 to 5; A j is CH orN; when p is 1, 2, 3, 4, or 5, A 2 is C(R 10 )(R U ), N(R 12 ), S, S(O), S(O) 2 , or O, and when p is 0, A 2 is C(R 10 )(R 1 ] )(R 12 ), N(R 10 )(R 12 ), S(R 10 ), S(O)(R 10 ), S(O) 2 (R 10 ), or O(R 10 ) where each R 10 , R 11 and R 12 is independently H or a lower alkyl group; each A 3 present is independently C(R 10 )(R n ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R 10 , R ⁇ and R 12 is independently H or a lower alkyl group; when p is 1, 2, 3, 4, or 5, A 4 is N(R 13
- preferred embodiments of Formula VI of this invention comprise the compounds depicted by the formula:
- R a ', R 4 , R 5 , R 6 , R 7 , Z and Z 1 are as defined above.
- this invention comprises the compounds depicted by the formula:
- R 1 is H, halo or an alkoxy, alkyl, aryl, cycloaUcyl, heterocycloalkyl or heteroaryl group, where the alkoxy, alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group is unsubstituted or substituted with one or more suitable substituents;
- R 2 and R 3 are each independently H, halo or an alkoxy or lower alkyl group, where the alkoxy or lower alkyl group is unsubstituted or substituted with one or more suitable substituents; or R 1 together with R 2 form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, where the cycloaUcyl, heterocycloalkyl, aryl or heteroaryl ring is unsubstituted or substituted with one or more suitable substituents;
- R 4 and R 6 are each independently H or a lower alkyl group, unsubstituted or substituted with one or more suitable substituents;
- R s is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents;
- R 7 is a moiety having the formula:
- R 8 and R 9 are each each independently H or a lower alkyl group; m is O or l; p is an integer of from 0 to 5; A ⁇ s CH orN; when p is 1, 2, 3, 4, or 5, A 2 is C(R 10 )(R n ), N(R 12 ), S, S(O), S(O) 2 , or O, and when p is 0, A 2 is C(R 10 )(R U )(R 12 ), N(R 10 )(R 12 ), S(R 10 ), S(O)(R 10 ), S(O) 2 (R 10 ), or O(R !0 ) where each R 10 , R ⁇ and R 12 is independently H or a lower alkyl group; each A 3 present is independently C(R 10 )(R n ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R 10 , R 11 and R 12 is independently H or a lower alkyl group; when p is
- R 15 , R 16 , R 17 and R 18 are each independently H or an alkyl, cycloaUcyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two ofthe R 15 , R 16 , R 17 and R 18 , taken together with the atom
- R 1 is H, halo or an alkoxy, alkyl, aryl, cycloaUcyl, heterocycloalkyl, or heteroaryl group, where the alkoxy, alkyl, aryl, cycloaUcyl, heterocycloalkyl, or heteroaryl group is unsubstituted or substituted with one or more suitable substituents;
- R 2 and R 3 are each independently H, halo or an alkoxy or lower alkyl group, where the alkoxy or lower alkyl group is unsubstituted or substituted with one or more suitable substituents; or R 1 together with R 2 form a cycloaUcyl, heterocycloalkyl, aryl or heteroaryl ring, where the cycloaUcyl, heterocycloalkyl, aryl or heteroaryl ring is unsubstituted or substituted with one or more suitable substituents;
- R 4 and R 6 are each independently H or lower alkyl, unsubstituted or substituted with one or more suitable substituents;
- R 5 is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents;
- R 7 is a moiety having the formula:
- R 8 and R 9 are each independently H or a lower alkyl group; m is 0 or 1, provided that when m is 0 and R 1 together with R 2 form an aryl ring, the aryl ring is unsubstituted (e.g., R 1 together with R 2 and the pyrrole to which they are bound do not form a substituted indole); p is an integer of from 0 to 5; when p is 1, 2, 3, 4, or 5, A 2 is C(R 10 )(R n ), N(R 12 ), S, S(O), S(O) 2 , or O, and when p is 0, A 2 is C(R 10 )(R ⁇ )(R 12 ), N(R 10 )(R 12 ), S(R 10 ), S(O)(R ]0 ), S(O) 2 (R 10 ), or O(R 10 ) where each R 10 , R 11 and R 12 is independently H or a lower alkyl group; each A 3 present is
- a 2 is C(R 10 )(R U ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R 10 , R u and R 12 is independently H or a lower alkyl group; each A 3 present is independently C(R 10 )(R U ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R 10 , R 11 and R 12 is independently H or a lower alkyl group; when p is 1, 2, 3, 4, or 5, A 4 is N(R 13 ), C(R 10 )(R n ), or O, and when p is 0,
- Z and Z 1 are each independently H, F, an alkyl, cycloaUcyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, aryl, cycloaUcyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, -C(O)R 15 , -CO 2 R 15 , -CN, -C(O)NR 15 R 16 , -C(O)NR ,5 OR 16 , -C(S)R 15 , -C(S)NR 15 R 16 , -NO 2 , -SOR 16 , -SO 2 R 15 , -SO 2 NR 15 R 16 , -SO 2 (NR ls )(OR 16 ), -SONR 15 , -SO 3 R 15 , -PO(OR 15 ) 2 , -PO(OR 15 )(OR 16 ) ,
- R 1 maybe selected from H and a lower alkyl, phenyl, naphthyl, pyridyl, quinoyl, isoquinoyl or isoxazoyl group, where the lower alkyl, phenyl, naphthyl, pyridyl, quinoyl, isoquinoyl or isoxazoyl group is unsubstituted or substituted with one or more substituents selected from alkyl (but not as a substituent for alkyl), hydroxy, halo, haloalkyl, alkoxy, haloalkoxy and aUcylenedioxy moiety.
- R 1 groups include, but are not limited to H, phenyl, ⁇ -naphthyl, ⁇ -naphthyl, 2-chlorophenyl, 2- ⁇ , ⁇ , ⁇ -trifluoromethylphenyl, 3-chloro-6- methoxyphenyl, 2,3-dichlorophenyl, 4-isoquinoyl, 3-iso-propylphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 2-methylphenyl (o-tolyl), 2-bromophenyl, 3-pyridyl, 4-pyridyl, 3-methyl-isoxazol-5-yl, 3,3,3-trifluoroprop-l-yl, and
- R 2 and R 3 may be each independently selected from H, halo, alkoxy, unsubstituted lower alkyl, haloalkyl, and lower alkoxyalkyl.
- R 4 and R 6 may be each independently selected from H, unsubstituted lower alkyl, haloalkyl and lower alkoxyalkyl.
- Yet another preferred embodiment of this invention comprises the compounds depicted by the formula:
- each R z is H or a suitable substituent and n z is an integer from 1 to 4; R 7 is a moiety having the formula:
- R 8 and R 9 are each independently H or a lower alkyl group; p is an integer of from 1 to 5; when p is 1, 2, 3, 4, or 5, A 2 is C(R 10 )(R n ), N(R 12 ), S, S(O), S(O) 2 , or O, and when p is 0, A 2 is C ⁇ 10 ) ⁇ 1 l )(R 12 ), N(R I0 )(R 12 ), S(R 10 ), S(O)(R 10 ), S(O) 2 (R 10 ), or O(R 10 ) where each R 10 , R 11 and R 12 is independently H or a lower alkyl group; each A 3 present is independently C(R 10 )(R ⁇ ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R 10 , R 11 and R 12 is independently H or a lower alkyl group;
- each R z is independently selected from H, halo, alkoxy, unsubstituted lower alkyl, haloalkyl, and lower alkoxyalkyl.
- R 3 may be independently selected from H, halo, alkoxy, unsubstituted lower alkyl, haloalkyl and lower alkoxyalkyl and
- R 4 and R 6 may be each independently selected from H, unsubstituted lower alkyl, haloalkyl and lower alkoxyalkyl.
- Another preferred embodiment of this invention comprise the compounds of Formula JV, wherein n is 1, depicted by the formula:
- R a' is an alkyl, aryl, cycloaUcyl, heterocycloalkyl or heteroaryl, where the alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group is unsubstituted or substituted with one or more suitable substituents;
- R 5 is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents,; each R 6 is independently H or a lower alkyl group, unsubstituted or substituted with one or more suitable substituents,; R 7 is a moiety having the formula:
- R 8 and R 9 are each independently H or a lower alkyl group; m is O or 1; p is an integer of from 0 to 5;
- a j is CH orN; when p is 1, 2, 3, 4, or 5, A 2 is C(R 10 )(R n ), N(R 12 ), S, S(O), S(O) 2 , or O, and when p is 0, A 2 is C(R 10 )(R n )(R 12 ), N(R 10 )(R 12 ), S(R 10 ), S(O)(R 10 ), S(O) 2 (R 10 ), or O(R 10 ) where each R 10 , R" and R 12 is independently H or a lower alkyl group; each A 3 present is independently C(R I0 )(R n ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R 10 , R 11 and R 12 is independently H or a lower alkyl group; when p is 1, 2, 3, 4, or 5, A 4 is N(R 13 ), C(R 10 )(R n ), or O, and when p is 0, A 4 is
- Z and Z 1 are each independently H, F, an alkyl, cycloaUcyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, -C(O)R 15 , -CO 2 R 15 , -CN, -C(O)NR I5 R 16 , -C(O)NR 15 OR 16 , -C(S)R 15 , -C(S)NR 15 R 16 , -NO 2 , -SOR 16 , -SO 2 R 15 , -SO 2 NR 15 R 16 , -SO 2 (NR 15 )(OR 16 ), -SONR 15 , -SO 3 R 15 , -PO(OR 15 ) 2 , -PO(OR I5 )(OR 16 )
- R a' may be selected from H, lower alkyl, phenyl, naphthyl, pyridyl, quinoyl, isoquinoyl and isoxazoyl, each of which may be substituted by alkyl (but not as a substituent for alkyl), hydroxy, halo, haloalkyl, alkoxy, haloaUcoxy and aUcylenedioxy.
- Each R 6 may be independently selected from H, unsubstituted lower alkyl, haloalkyl and loweralkoxyalkyl.
- a desired salt may be prepared by any suitable method known in the art, including treatment ofthe free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
- an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid,
- a desired salt may be prepared by any suitable method known to the art, including treatment ofthe free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like.
- suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines, such as piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
- All compounds of this invention contain at least one chiral center and may exist as single stereoisomers (e.g., single enantiomers or diastereomers), any mixture of stereosisomers (e.g., any mixture of enantiomers or diastereomers) or racemic mixtures thereof. All such single stereoisomers, mixtures and racemates are intended to be encompassed within the broad scope ofthe present invention. Where the stereochemistry of the chiral carbons present in the chemical structures illustrated herein is not specified, the chemical structure is intended to encompass compounds containing either stereoisomer of each chiral carbon. When used describe a particular compound, the term "optically pure" is used herein to indicate that the compound is substantially enantiomerically or diastereomerically pure.
- Compounds that are substantially enatiomerically pure contain at least 90% of a single isomer and preferably contain at least 95% of a single isomer.
- Compounds that are substantially diastereomerically pure contain at least 90% of a single isomer of each chiral carbon center present in the diastereomer, and preferably contain at least 95% of a single isomer of each chiral carbon. More preferably, when an optically active compound is desired, it contains at least 97.5% of a single isomer and, most preferably, at least 99% ofthe single isomer.
- Compounds identified herein as single stereoisomers are meant to describe compounds that are present in a form that contains at least 90% of a single isomer.
- racemic or “racemic mixture” refers to a mixture of equal amounts of enantiomeric compounds, which encompasses mixtures of enantiomers and mixtures of enantiomeric diastereomers.
- the compounds of this invention may be obtained in stereochemically (e.g., enantiomerically or diastereomerically ) pure or substantially stereochemically pure form. Such compounds may be obtained synthetically, according to the procedures described herein using optically pure or substantially optically pure materials. Alternatively, these compounds may be obtained by resolution/separation of a mixture of stereoisomers, including racemic mixtures, using conventional procedures.
- Exemplary methods that may be useful for the resolution/separation of stereoisomeric mixtures include chromatography and crystallization/re-crystallization. Other useful methods may be found in "Enantiomers, Racemates, and Resolutions," J. Jacques et al., 1981, John Wiley and Sons, New York, NY. Preferred stereoisomers ofthe compounds of this invention are described herein.
- R 5 is H or an unsubstituted alkyl group or an optionally substituted lower alkyl group, where these groups are comprised of a straight- or branched-chain saturated hydrocarbon group, a straight- or branched-chain substituted saturated hydrocarbon group, or group comprised of a straight- or branched-chain saturated hydrocarbon moiety and an unsaturated hydrocarbon moiety.
- R 5 or R x /R y is a substituted alkyl group
- the point of attachment of R 5 or R x R y is via a saturated hydrocarbon moiety.
- the saturated hydrocarbon group may be optionally substituted with a cycloaUcyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an alkoxy group, an aryloxy group, an alkylthio group, an arylthio group, where each alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl moiety thereof maybe optionally substituted.
- R 5 or R x /R y is comprised of a saturated hydrocarbon moiety and an unsaturated hydrocarbon moiety
- the saturated hydrocarbon moiety may be bound to an unsaturated hydrocarbon moiety containing one or more double-bonds or triple-bonds, the terminal positions of which may be substituted by the substituents described above, or may contain additional straight- or branched-chain saturated hydrocarbon moieties.
- the unsaturated hydrocarbon moiety contains one double-bond or one triple-bond, the terminal position(s) of which may optionally contain a straight- or branched-chain saturated hydrocarbon moiety.
- both terminal positions ofthe double bond contain a straight- or branched-chain saturated hydrocarbon moiety.
- R 5 or R x /R y is H or a lower alkyl, arylalkyl, heteroarylalkyl, cycloaUcylaUcyl group, or a group comprised of a straight-chain saturated hydrocarbon moiety and an unsaturated hydrocarbon moiety, where the alkyl, arylalkyl, heteroarylalkyl, cycloaUcylaUcyl group is unsubstituted or substituted with one or more suitable substituents.
- R 5 or R x /R y is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-l-yl, 2-propen-2-yl, 2-propyn-l-yl, 3-methyl-3-buten-l-yl, -methylcyclohexyl, substituted or unsubstituted -methylthienyl or substituted or unsubstituted benzyl, where the methyl, ethyl, propyl, propenyl, butenyl or cyclohexyl moiety thereof is optionally substituted with one or more substituents independently selected from lower alkoxy, hydroxy, amino, aUcylamino or diaUcylamino and halogen, the phenyl moiety ofthe substituted benzyl is substituted by one or more substituents independently
- R 5 or R7R y When R 5 or R7R y is substituted methyl, the methyl (methylene) moiety may be substituted with an alkoxy group, an aryloxy group, an alkylthio group or an arylthio group.
- R 5 or R7R y is H, ethyl, 2-propyn-l-yl, -methylcyclohexyl, or substituted or unsubstituted benzyl, where the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy and halogen.
- R 5 (or R x or R y in Formulas H, JJJ and VI) is selected from H and:
- R' may be H or alkyl and each R" may be H or independently selected from lower alkyl, lower alkoxy, hydroxy, amino, aUcylamino or diaUcylamino, and halogen.
- R 7 (or R c in Formulas I, H, HI and VI) is selected from -CH 2 CH 2 C(O)NH 2 ; -CH 2 CH 2 C(O)NH-aUcyl; -CH 2 NHC(O)CH 3 ; and , where n is 1
- R 7 is
- Z and Z 1 are each independently H, alkyl, where the alkyl is unsubstituted or substituted with one or more suitable substituents, -CO 2 R 15 (in Formulas V to XH) or -CO ⁇ 1 (in Formulas I to VI), where R 1 and R 15 are as defined above, or Z and 7), taken together with the atom to which they are attached, form a heterocycloalkyl group, as defined above, which may be optionally substituted.
- Z and/or Z 1 maybe -C(S)OR n or -C(S)OR 19 , where R n and R 19 are as defined above.
- heterocycloalkyl group may optionally contain O, N, S and/or P and may be substituted by one or more of oxo (keto) or thioketo.
- Z and Z 1 are each independently selected from H, lower alkyl which is unsubstituted or substituted with one or more suitable substituents, -CO 2 H, -CO 2 -alkyl and -CO 2 -cycloalkyl, or taken together with the atom to which they are attached form a heterocycloalkyl group , which is optionally substituted with one or more of keto or thioketo.
- Z and Z 1 are not both H.
- Z 1 is H or lower alkyl and Z is a -CO 2 H, -CO 2 -alkyl, -CO 2 -alkylaryl, -CO 2 -aUcylheteroaryl, -CO 2 -cycloaUcyl group, where the lower alkyl, -alkyl, -cycloalkyl, -alkylaryl and -alkylheteroaryl moieties thereof are unsubstituted or substituted with one or more suitable substituents, or Z 1 and Z taken together with the atom to which they are attached form a heterocycloalkyl group, which may be optionally substituted.
- Exemplary Z groups include, but are not limited to: substituted and unsubstituted -CO 2 -aUcyl groups, which include straight- and branched-chain aUcyl groups such as ethoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl and (2,2-dimethylpropyl)-oxycarbonyl, where the ethoxy, t-butoxy, isopropoxy, and (2,2-dimethylpropyl)-oxy moieties thereof are unsubstituted or substituted with one or more suitable substituents; and include substituted and unsubstituted straight and branched-chain arylalkyl and heteroarylalkyl groups, such as benzyloxycarbonyl and pyridylmethyleneoxycarbonyl, where the benzyl and pyridylmethylene moieties thereof are unsubstituted or substituted with one or more suitable substituents; and include substituted and unsubstituted
- 7) is H and Z is -CO 2 CH 2 CH 3 , -CO 2 (CH(CH 3 ) 2 ), -CO 2 (C(CH 3 ) 3 ), -CO 2 CH 2 (C(CH 3 ) 3 ), -CO 2 (cyclo-C 5 H 9 ) or Z 1 and Z taken together with the atom to which they are attached form
- Z 1 is H and Z is selected from ethoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, (2,2-dimethylpropyl)- oxycarbonyl, benzyloxycarbonyl, pyridylmethyleneoxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and cycloheptyloxycarbonyl, or Z 1 and Z taken together with the atom to which they are attached form
- R c and R 7 are defined to provide structures where m is 1 and p is 1 -5 (i.e., both A 2 and A 3 are present), m is 0 and p is 0 (i.e, both A 2 and A 3 are absent), m is 0 and p is 1-5 (i.e, A 2 is absent and A 3 is present) and m is 1 and p is 0 (i.e, A 2 is present and A 3 is absent).
- the dotted line between A x and A 2 represents a hydrogen and the dotted line between A 2 and A 3 represents a hydrogen (e.g., Aj is CH 2 or NH and A 3 is CH(R £ )(R h ), NH(R), SH, S(O)H, S(O) 2 H, or OH or CH(R 10 )(R n ), NH(R 12 ), SH, S(O)H, S(O) 2 H, or OH); and when A 2 is present and A 3 is • absent (m is 1 and p is 0), the dotted line between A ⁇ and A 2 represents a bond and A 2 is C(R g )(R h )(R i ), N ⁇ R 1 ), S(R S ), S(0)(R ), S(O) 2 (R g ), or €>( *) or A 2 is C(R 10 )
- m is 1 and p is 1 or 2 or m is 0 and p is 0 or m is 1 and p is 0. More preferably, when m is 1 and p is 1 or 2, A 2 and A 3 are both C(R s )(R h ) or C(R 10 )(R n ), respectively. More preferably, m is 1 and p is 1.
- R d and each R are preferably H
- each R 4 and R 6 are preferably H and in the compounds of Formula XHI, each R 6 is preferably H.
- R a is (C r C 4 )alkylcarbonyl-(C r C 4 )alkyl, (C 3 -C 8 )cycloaUcylcarbonyl-(C 1 -C 4 )alkyl, heteroarylcarbonyl-(C 1 -C 4 )aUcyl, ( -C ⁇ alkylcarbonylamino- ⁇ -C ⁇ alkyl, (C 3 -C 8 ) cycloaUcylcarbonylamino-(C 1 -C 4 )aUcyl, heterocycloalkylcarbonylamino- ⁇ C aUcyl, arylcarbonylamino-(C 1 -C 4 )aUcyl, heteroarylcarbonylamino-(C r C 4 )aUcyl, (C,-C 4 aUcylaminocarbonyl-(C 1 -C 4 )aUcyl, (C 3 -C 8
- R a is (C j -C ⁇ alkylcarbonyl ⁇ C j -C ⁇ alkyl, phenylcarbonyl- ⁇ j -C aUcyl, naphthylcarbonyl-(C r C 4 )aUcyl, pyrrolylcarbonyl-(C 1 -
- R b and R d are each independently H or C,-C 4 alkyl; preferably R b and R d are each H; R c is selected from -CH 2 CH 2 C(O)NH 2 ; -CH 2 CH 2 C(O)NH-alkyl;
- n 1 or 2;
- Z 1 is H or C r C 4 alkyl and Z is -CO 2 -alkyl, -CO 2 -cycloaUcyl, -CO 2 -aUcylaryl or -CO 2 -alkylheterocycloaryl, or Z 1 and Z taken together with the atom to which they are
- Z 1 is H and Z is -CO 2 CH 2 CH 3 ,
- Z 1 is H and Z is -CO 2 CH 2 CH 3 or
- R c is , where n is 1 or 2, when
- R a is an indolylcarbonylamino- ⁇ -C alkyl group where the indolyl moiety thereof is substituted with one or more suitable substituents or R a is is not an amino-substituted (C r C 4 )alkylcarbonylamino-(C r C 4 )alkyl or R a is is not an amino-substituted (C 1 -C 4 )aUcylcarbonyl-(C 1 -C 4 )alkyl; and R c is selected from -CH 2 CH 2 C(O)NH 2 ; -CH 2 CH 2 C(O)NH-alkyl; -CH 2 NHC(O)CH 3 ; and
- n is 1 or 2
- R a is an indolylcarbonylamino-(C r C 4 )alkyl group where the indolyl moiety thereof is unsubstituted or R a is a (C C 4 ) (C 3 -C 8 )cycloaUcylaminocarbonyl-(C 1 -C 4 )aUcyl, heterocycloaUcylaminocarbonyl- heteroarylaminocarbonyl-(C ⁇ -C 4 )alkyl, or heteroarylcarbonylamino-(C 1 -C 4 )aUcyl group, wherein each (C ⁇ C 4 )alkyl, (C 3 -C 8 )cycloaUcyl, heterocycloaUcyl, aryl and heteroaryl moiety thereof is unsubstituted or substituted with one or more suitable substituents; or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or
- R c is , where n is 1, when
- R a is an indolylcarbonylamino-(C 1 -C 4 )alkyl group where the indolyl moiety thereof is substituted with one or two substituents independently selected from halo, - alkoxy, unsubstituted C r C 4 alkyl and - haloalkyl, C C 4 haloalkoxy, methylenedioxy, aryl, heterocycloaUcyl, and heteroaryl where the aryl, heterocycloaUcyl and heteroaryl is unsubstituted or substituted by one ore more substituents independently selected from halo, C]-C 4 alkyl, Cj-Q, haloalkyl, C r C 4 alkoxy, C r C 4 haloalkoxy and methylenedioxy; and R c is selected from -CH 2 CH 2 C(O)NH 2 ; -CH 2 CH 2 C(O)NH-alkyl; -CH 2 NHC(
- R a is (C r C 4 )alkylcarbonyl-(C r C 4 )aUcyl, (C 5 -C 6 )cycloalkyl carbonyl-(Cj-C 4 )alkyl, arylcarbonyl-(C r C 4 )aUcyl, heteroarylcarbonyl-(C 1 -C 4 )aUcyl,
- R is an indolylcarbonylamino-(C 1 -C 4 )alkyl group where the indolyl moiety thereof is substituted with one or two substituents independently selected from halo, C C 4 alkoxy, unsubstituted C r C 4 alkyl and C C 4 haloalkyl; and and R c is -CH 2 CH 2 C(O)NH 2 or when
- R a is (C 1 -C 4 )aUcylcarbonyl-(C r C 4 )aUcyl, phenylcarbonyl-(C ⁇ -C 4 )alkyl, naphthylcarbonyl-(C 1 -C 4 )aUcyl, pyrrolylcarbonyl-(C 1 -C 4 )aUcyl, indolylcarbonyl-(C C 4 )aUcyl, (C r C 4 )aUcylcarbonylamino-(C r C 4 )aUcyl, pyrrolylcarbonylamino-(C j -C 4 )aUcyl, indolylcarbonylamino-(C , -C 4 )alkyl, phenylcarbonylarnino-(C r C 4 )aUcyl, naphthylcarbonylamino- ⁇ C ⁇ aUcyl
- R a ' is a (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, aryl or heteroaryl group, wherein the (C,-C 4 )alkyl, (C 3 -C 8 )cycloalkyl, aryl and heteroaryl group is unsubstituted or substituted with one or more substituents independently selected from (C ⁇ -C 4 )alkyl, aryl, (C 3 -C 8 )cycloalkyl, heterocycloaUcyl, heteroaryl, halo, hydroxyl, (C ⁇ -C 4 )alkoxy, aUcylenedioxy (as a substituent for aryl or heteroaryl), aryloxy, (C 3 -C 8 )cycloalkoxy, heteroaryloxy, and carboxyl where the (C r C 4 )alkyl, aryl, (C 3 -C 8 )cycloalkyl,
- R c is , where n is 1 or 2; preferably R c is
- R , R d , Z and Z 1 are defined as in Formula I, above.
- R ' is a (C r C 4 )alkyl, (C 3 -C 8 )cycloalkyl, aryl or heteroaryl group, wherein the
- R a ' is not an amino- substituted ( -C ⁇ alkyl group; preferably, R a ' is a (Cj-C alkyl, phenyl, naphthyl, pyrrolyl or indolyl group, where the (C j -C 4 )alkyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C r C 4 alkoxy or C r C 4 haloalkoxy and the phenyl, naphthyl, pyrrolyl or indolyl group is unsubstituted or substituted with one or more substituents independently selected from halo, Cj-C 4 alkyl, C C 4 haloalkyl, C
- n 1, 2 or 3; preferably n is 1 ;
- R x is H and R y is H, C r C 4 alkyl, C r C 4 haloaUcyl or an arylalkyl, heteroarylalkyl, cycloaUcylaUcyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloaUcylaUcyl group is unsubstituted or substituted with one or more suitable substituents; preferably, R x is H and
- R c is and R b , R d , Z and Z 1 are defined as in Formula I, above.
- R a ' is a (C j -C alkyl, (C 3 -C 8 )cycloaUcyl, heterocycloalkyl, aryl or heteroaryl group, wherein the (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, heterocycloaUcyl, aryl and heteroaryl group is unsubstituted or substituted with one or more suitable substituents; preferably, R ' is a (C r C 4 )alkyl, phenyl or naphthyl group, where the (C r C 4 )alkyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C C 4 alkoxy or C C 4 haloaUcoxy and the phenyl or naphthyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C r C 4 alkyl, C
- W is CH orN;
- R a ' is a C C 4 alkyl, C 3 -C 8 cycloaUcyl, aryl or heteroaryl group, where the C C 4 alkyl, C 3 -C 8 cycloaUcyl, aryl, and heteroaryl group is unsubstituted or substituted with one or more suitable substituents, provided that R a ' is not an amino-substituted alkyl group; preferably, R a' is a C r C 4 alkyl, C 5 -C 6 cycloaUcyl, phenyl, naphthyl or heteroaryl group; where the phenyl, naphthyl or heteroaryl group is unsubstituted or substituted with one or more substituents independently selected from halo, C C 4 alkyl, Cj- haloaUcyl, C r C 4 alkoxy, C r C 4 haloaUcoxy,
- R 4 and R 6 are each independently H or C r C 4 alkyl; preferably R 4 and R 6 are eachH;
- R 5 is H, C C 4 alkyl, C,-C 4 haloaUcyl or an arylalkyl, heteroarylalkyl, cycloaUcylaUcyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloaUcylaUcyl group is unsubstituted or substituted with one or more suitable substituents; preferably, R 5 is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-l-yl, 2- ⁇ ro ⁇ en-2-yl, 2-propyn-l-yl, 3-methyl-3-buten-l-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl
- R 7 is , where n is 1 or 2; preferably, R 7 is
- R 7 is and
- Z 1 is H or C r C 4 alkyl and Z is -CO 2 -alkyl, -CO 2 -cycloalkyl, -CO 2 -alkylaryl or -CO 2 -aUcylheterocycloaryl, or Z 1 and Z taken together with
- Z 1 is H and Z is -CO 2 CH 2 CH 3 , -CO 2 (CH(CH 3 ) 2 ), -CO 2 (C(CH 3 ) 3 ), -CO 2 CH 2 (C(CH 3 ) 3 ), -CO 2 (cyclo-C 5 H 9 ) or Z 1 and Z taken together with the atom to which they are attached form
- Z 1 is H and Z is -CO 2 CH 2 CH 3 or Z 1 and Z taken together
- R a' , R 4 , R 3 , R 6 , R 7 , Z and Z 1 are as defined above.
- specific embodiments of this invention comprise the compounds depicted by the formula:
- R 1 is H, halo, C r C 4 alkyl, C r C 4 haloalkyl, or an aryl or heteroaryl group, where the aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents; preferably, R 1 is H, halo, Cj-C 4 alkyl, Cj-C 4 haloalkyl or a phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group, where the phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group is unsubstituted or substituted with one or more substituents independently selected from: halo, C,-C 4 alkyl, C r C 4 haloaUcyl, C r C 4 alkoxy, C r C 4 haloaUcoxy and methylenedi
- R 2 and R 3 are each independently H or Cj-C 4 aUcyl; preferably R 2 and R 3 are each H; or
- R 1 together with R 2 form a cycloaUcyl, heterocycloaUcyl, aryl or heteroaryl ring, where the cycloaUcyl, heterocycloaUcyl, aryl or heteroaryl ring is unsubstituted or substituted with one or more suitable substituents; or preferably, R 1 together with R 2 form a phenyl ring, which is unsubstituted or substituted with one or more suitable substituents and R 3 is H;
- R 4 and R 6 are each independently H or Cj-C 4 alkyl; preferably R 4 and R 6 are each H; R 5 is H, C r C 4 aUcyl, C -C 4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloaUcylaUcyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloaUcylaUcyl group is unsubstituted or substituted with one or more suitable substituents; preferably, R 5 is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-l-yl, 2-propen-2-yl, 2-propyn-l-yl, 3-methyl-3-buten-l-yl
- R 7 is selected from -CH 2 CH 2 C(O)NH 2 ; -CH 2 CH 2 C(O)NH-alkyl;
- n 1 or 2;
- R 7 is -CH 2 CH 2 C(O)NH 2 where n is i; most preferably, R 7 is -CH 2 CH 2 C(O)NH 2 or and
- Z 1 is H or C C 4 alkyl and Z is -CO 2 -alkyl, -CO 2 -cycloaUcyl, -CO 2 -alkylaryl or -CO 2 -alkylheterocycloaryl, or Z 1 and Z taken together with the atom to which
- Z 1 is H
- Z is -CO 2 CH 2 CH 3 , -CO 2 (CH(CH 3 ) 2 ), -CO 2 (C(CH 3 ) 3 ), -CO 2 CH 2 (C(CH 3 ) 3 ), -CO 2 (cyclo-C 5 H 9 ) or Z 1 and Z taken together with the atom to which they
- Z 1 is H and Z is -CO 2 CH 2 CH 3 or Z 1 and Z taken together with the
- Another specific embodiment of this invention comprises the compounds depicted by the formula:
- R 1 is H, halo, C r C 4 alkyl, C r C 4 haloaUcyl, or an aryl or heteroaryl group, where the aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents; preferably, R 1 is H, halo, C r C 4 alkyl, -Q, haloaUcyl or a phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group, where the phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group is unsubstituted or substituted with one or more substituents independently selected from: halo, C C 4 alkyl, C r C 4 haloaUcyl, C r C 4 alkoxy, Cj- haloalkoxy and methylenedioxy;
- R 2 and R 3 are each independently H or C r C 4 alkyl; preferably R 2 and R 3 are each H; or
- R 1 together with R 2 form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, where the cycloaUcyl, heterocycloaUcyl, aryl or heteroaryl ring is unsubstituted or substituted with one or more suitable substituents; or preferably, R 1 together with R 2 form an unsubstituted phenyl ring and R 3 is H;
- R 4 and R 6 are each independently H or C r C 4 alkyl; preferably R 4 and R 6 are each H;
- R 5 is H, C r C 4 alkyl, C r C 4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloaUcylaUcyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloaUcylaUcyl group is unsubstituted or substituted with one or more suitable substituents; preferably, R 5 is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-l-yl, 2-propen-2-yl, 2-propyn-l-yl, 3-methyl-3-buten-l-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, e
- R 5 is H, ethyl, 2-propyn-l-yl, methylcyclohexyl or benzyl
- R 7 is selected from -CH 2 CH 2 C(O)NH 2 ; -CH 2 CH 2 C(O)NH-aUcyl;
- R 7 is -CH 2 CH 2 C(O)NH 2 or
- R 7 is selected from here n is 1 or 2,
- n i, or
- Z 1 is H or C r C 4 alkyl and Z is -CO 2 -alkyl, -CO 2 -cycloalkyl, -CO 2 -aUcylaryl or -CO 2 -alkylheterocycloaryl, or Z 1 and Z taken together with the atom to which
- Z 1 is H
- Z is -CO 2 CH 2 CH 3 , -CO 2 (CH(CH 3 ) 2 ), -CO 2 (C(CH 3 ) 3 ), -CO 2 CH 2 (C(CH 3 ) 3 ), -CO 2 (cyclo-C 5 H 9 ) or Z 1 and Z taken together with the atom to wliich they are
- Z 1 is H
- Z is -CO 2 CH 2 CH 3 or Z 1 and Z taken together with the atom to which they are attached form or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
- each R z is independently selected from halo and a C ⁇ -C 4 alkoxy, - alkyl, aryl, heterocycloaUcyl or heteroaryl group where the C C 4 alkoxy or C r C 4 alkyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C r C 4 alkoxy or C r C 4 haloalkoxy and the aryl, heterocycloaUcyl or heteroaryl group is unsubstituted or substituted by one ore more substituents independently selected from halo, C r C 4 alkyl, C r C 4 haloaUcyl, C r C 4 alkoxy, Cj- haloaUcoxy and methylenedioxy and n z is an integer from 1 to 4; preferably, each R z is independently selected from halo, C r C 4 alkoxy, unsubstituted C r C
- R 3 is H, halo, C r C 4 alkoxy, unsubstituted C r C 4 alkyl, C r C 4 haloaUcyl and Cj-Q, alkoxyalkyl; preferably, R 3 is H or C r C 4 alkyl; more preferably, R 3 is H ; R 4 and each R 6 are independently selected from H, unsubstituted lower alkyl, haloalkyl and lower alkoxyalkyl, preferably, R 4 and each R 6 are independently H or C r C 4 alkyl; more preferably R 4 and R 6 are each H;
- R 5 is H, C ] -C 4 aUcyl, C,-C 4 haloaUcyl or an arylalkyl, heteroarylalkyl, cycloaUcylaUcyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloaUcylaUcyl group is unsubstituted or substituted with one or more suitable substituents; preferably, R 5 is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-l-yl, 2-propen-2-yl, 2-propyn-l-yl, 3 -methyl-3 -buten- 1 -yl, -methylcyclohexyl, -methylthienyl or benzy
- R s is H, ethyl, 2-propyn-l-yl, methylcyclohexyl or benzyl;
- Z 1 is H or C r C 4 alkyl and Z is -CO 2 -alkyl, -CO 2 -cycloaUcyl, -CO 2 -aUcylaryl or -CO 2 -alkylheterocycloaryl, or Z 1 and Z taken together with
- Z 1 is H and Z is -CO 2 CH 2 CH 3 , -CO 2 (CH(CH 3 ) 2 ), -CO 2 (C(CH 3 ) 3 ), -CO 2 CH 2 (C(CH 3 ) 3 ), -CO 2 (cyclo-C 5 H 9 ) or Z 1 and Z taken together with the atom
- Z 1 is H and Z is -CO 2 CH 2 CH 3 or Z 1 and Z taken together with
- Another preferred embodiment of this invention comprises the compounds of Formula XH, depicted by the formula:
- R a' is a C r C 4 alkyl, aryl, C 3 -C 7 cycloaUcyl, heterocycloaUcyl or heteroaryl group, where the C r C 4 alkyl, aryl, C 3 -C 7 cycloaUcyl, heterocycloaUcyl or heteroaryl group is unsubstituted or substituted with one or more substituents independently selected from alkyl, haloalkyl, aUcylenedioxy (as a substituent for aryl or heteroaryl), nitro, amino, hydroxamino, aUcylamino, dialkylamino, halo, hydroxyl, alkoxy, haloaUcoxy, aryloxy, mercapto, alkylthio or arylthio, aryl or heteroaryl, where the aryl or heteroaryl group is unsubstituted or substituted with one or more substituents independently selected from
- R 7 is selected from -CH 2 CH 2 C(O)NH 2 ; -CH 2 CH 2 C(O)NH-alkyl;
- n 1 or 2;
- R 7 is -CH 2 CH 2 C(O)NH 2 or , where n is 1;
- R 7 is -CH 2 CH 2 C(O)NH 2 or ;
- Z 1 is H or C r C 4 alkyl and Z is -CO 2 -alkyl, -CO 2 -cycloaUcyl, -CO 2 -aUcylaryl or -CO 2 -alkylheterocycloaryl, or Z 1 and Z taken together with the atom to which they are attached form , preferably, Z 1 is H and Z is -CO 2 CH 2 CH 3 , -CO 2 (CH(CH 3 ) 2 ), -CO 2 (C(CH 3 ) 3 ), -CO 2 CH 2 (C(CH 3 ) 3 ), -CO 2 (cyclo-C 5 H 9 ) or Z 1 and Z taken together with the atom to which they are
- Z 1 is H and Z is -CO 2 CH 2 CH 3 or Z 1 and Z taken together with
- R a ' is an alkyl, cycloaUcyl, aryl or heteroaryl group, where said alkyl, cycloaUcyl, aryl, and heteroaryl group is unsubstituted or substituted with one or more suitable substituents, and each W, R 4 , R 5 , R 6 , R 7 , Z and Z 1 are as defined in VI above, provided that R ' is not amino-substituted alkyl.
- Particularly preferred embodiments ofthe compounds of Formula Vl-a comprise the compounds depicted by the formula:
- R a ' is an alkyl, cycloaUcyl, aryl or heteroaryl group, where said alkyl, cycloalkyl, aryl, and heteroaryl group is unsubstituted or substituted with one or more suitable substituents, and each R 4 , R 5 , R 6 , R 7 , Z and Z 1 are as defined above, provided that R a' is not amino-substituted alkyl.
- R a ' is an alkyl, cycloalkyl, aryl or heteroaryl group, where said alkyl, cycloaUcyl, aryl, and heteroaryl group is unsubstituted or substituted with one or more suitable substituents, and each R 4 , R 5 , R 6 , R 7 , Z and Z 1 are as defined above, provided that R a' is not amino-substituted alkyl.
- the compounds of this invention have the formula:
- R 1 is an alkyl, cycloaUcyl, heterocycloaUcyl, aryl or heteroaryl group, where the alkyl, cycloaUcyl, heterocycloaUcyl, aryl, and heteroaryl group is unsubstituted or substituted with one or more suitable substituents, and each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Z and Z 1 are as defined above for IX.
- the compounds of this invention have the formula:
- R 5 is H and the invention comprises the compounds depicted by the formula:
- each R a , R 6 , R 7 , Z and Z 1 are as defined above.
- R 6 is preferably H. In the compounds of Formulas Vl-a to XH-b, R 6 is preferably H.
- Preferred specific compounds include those of any ofthe Examples below, especially:
- the invention is also directed to intermediate compounds of Formula XIH which are useful in the synthesis of certain compounds of Formulas I-XH:
- R 5 ' is a lower alkyl or aryl group, where the lower alkyl or aryl group is unsubstituted or substituted with one or more suitable substituents, (where -CH 2 -R 5 ' represents R 5 as defined above) and R E is H or an alkyl or aryl group, where the alkyl or aryl group is unsubstituted or substituted with one or more suitable substituents.
- the invention is also directed to pharmaceutically acceptable salts ofthe compounds of Formulas XIH.
- Preferred examples ofthe compounds of Formula XHI include the following:
- R E groups include, but are not limited to, H, methyl, tert-butyl, allyl, and benzyl, as illustrated in the following:
- the antipicornaviral compounds of this invention include prodrags, the pharmaceutically active metabolites, and the pharmaceutically acceptable salts and solvates thereof.
- the compounds of Formulas I to XH, prodrugs, pharmaceutically acceptable salts, and pharmaceutically active metabolites and solvates thereof have an antipicornaviral activity, more preferably antirbino viral activity, corresponding to an EC 50 less than or equal to 100 ⁇ M in the Hl-HeLa cell culture assay.
- a "prodrug” is intended to mean a compound that is converted under physiological conditions or by solvolysis or metabolically to a specified compound that is pharmaceutically active.
- a prodrug containing such a moiety may be prepared according to conventional procedures by treatment of a compound of this invention containing, for example, an amido, carboxylic acid, or hydroxyl moiety with a suitable reagent.
- a "pharmaceutically active metabolite" is intended to mean a pharmacologically active compound produced through metabolism in the body of a specified compound.
- Prodrugs and active metabolites of compounds of this invention ofthe above-described Formulas may be determined using techniques known in the art, for example, through metabolic studies. See, e.g., “Design of Prodrugs,” (Bundgaard, ed.), 1985, Elsevier Publishers B.V., Amsterdam, The Netherlands.
- a "pharmaceutically acceptable salt” is intended to mean a salt that retains the biological effectiveness ofthe free acids and bases of a specified compound and that is not biologically or otherwise undesirable.
- Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulf ⁇ tes, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates,
- a “solvate” is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound.
- solvates include compounds ofthe invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
- inventive compounds, salts, and solvates may exist in different crystal forms, all of which are intended to be within the scope of the present invention and specified formulas.
- the present invention is also directed to a method of inhibiting picomaviral 3C protease activity, comprising contacting the protease with an effective amount of a compound of Formulas I to XH, or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof.
- picomaviral 3C protease activity may be inhibited in mammalian tissue by administering a compound of Formulas I to XH or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof. More preferably, the present method is directed at inhibiting rhinoviral protease activity.
- Treating” or “treatment” is intended to mean at least the mitigation of a disease condition in a mammal, such as a human, that is alleviated by the inhibition ofthe activity of one or more picomaviral 3C proteases, including, but not limited to human rhinoviruses, human poliovirus, human coxsackievimses, encephalomyocarditis virases, meningitis viras, and hepatitis A viras.
- the methods of treatment for mitigation of a disease condition include the use ofthe compounds in this invention in any conventionally acceptable manner, for example, as a prophylactic.
- the activity ofthe inventive compounds as inhibitors of picomaviral 3C protease activity may be measured by any ofthe suitable methods known to those skilled in the art, including in vivo and in vitro assays.
- An example of a suitable assay for activity measurements is the antiviral Hl-HeLa cell culture assay described herein.
- Administration ofthe compounds ofthe Formulas I to XH and their pharmaceutically acceptable prodrags, salts, active metabolites, and solvates may be performed according to any ofthe generally accepted modes of administration available to those skilled in the art.
- suitable modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal.
- An inventive compound of Formulas I to XH or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof may be administered as a pharmaceutical composition in any pharmaceutical form recognizable to the skilled artisan as being suitable.
- Suitable pharmaceutical forms include solid, semisolid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols.
- Pharmaceutical compositions ofthe invention may also include suitable excipients, diluents, vehicles, and carriers, as well as other pharmaceutically active agents, depending upon the intended use or mode of administration.
- the inventive pharmaceutical compositions are delivered orally, or intranasally in the form of suspensions.
- Acceptable methods of preparing suitable pharmaceutical forms ofthe pharmaceutical compositions maybe routinely determined by those skilled in the art.
- pharmaceutical preparations may be prepared following conventional techniques ofthe pharmaceutical chemist involving steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural, and/or rectal administration.
- the compounds (active ingredients) may be formulated into solid oral dosage forms which may contain, but are not limited to, the following inactive ingredients: diluents (i.e., lactose, com starch, microcrystalline cellulose), binders (i.e., povidone, hydroxypropyl methylcellulose), disintegrants (i.e., crospovidone, croscarmellose sodium), lubricants (i.e., magnesium stearate, stearic acid), and colorants (FD&C lakes or dyes).
- the compounds may be formulated into other oral dosage forms including liquids, suspensions, emulsions, or soft gelatin capsules, with each dosage form having a unique set of ingredients.
- Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles, or excipients may be employed in the pharmaceutical compositions.
- Illustrative solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesium stearate, and stearic acid.
- Hlustrative liquid carriers include syrup, peanut oil, olive oil, saline solution, and water.
- the carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
- the preparation when a liquid carrier is used, the preparation maybe in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g., solution), or a nonaqueous or aqueous liquid suspension.
- a dose ofthe pharmaceutical composition contains at least a therapeutically effective amount ofthe active compound (i.e., a compound of Formulas I to XH or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof), and preferably is made up of one or more pharmaceutical dosage units.
- the selected dose maybe administered to a mammal, for example, a human patient, in need of treatment mediated by inhibition of picomaviral 3C protease activity, by any known or suitable method of administering the dose, including: topically, for example, as an ointment or cream; orally; rectally, for example, as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural, or intraocular infusion.
- a “therapeutically effective amount” is intended to mean the amount of an inventive agent that, when administered to a mammal in need thereof, is sufficient to effect treatment for disease conditions alleviated by the inhibition of the activity of one or more picomaviral 3C proteases, such as human rhinoviruses, human poliovirus, human coxsackievimses, encephalomyocarditis virases, menigoviras, and hepatitis A virus.
- the amount of a given compound ofthe invention that will be therapeutically effective will vary depending upon factors such as the particular compound, the disease condition and the severity thereof, the identity ofthe mammal in need thereof, which amount may be routinely determined by artisans.
- compounds ofthe general formulas are prepared by the methods of the present invention, including the General Methods below, where the R 1 , R 4 , R 5 , R 6 , Z and Z 1 substituents present in the compounds illustrated in the General and Specific Methods are as defined above.
- Abbreviations used herein include: DCC (1,3- dicyclohexylcarbodiimide), HOBT (1-hydroxybenzotriazole hydrate), HATU (O-(7- - tetramethyluromum hexafluorophosphate), IBX (2- iodoxybenzoic acid), FMOC (9-fluorenylmethoxycarbonyl), Boc (t-butoxycarbonyl), DIEA (diisopropylethylamme), DMSO (dimethylsulfoxide), TMSOTf (trimethylsilyl trifluoromethanesulfonate), TFA (trifluoroacetic acid), LiHMDS (lithium bis(trimethylsilyl)amide) .
- a sidechain protected (P) compound 1 (Dragovich, et al., J. ⁇ cf. C7*em. 1998, 41, 2819), is coupled using standard peptide coupling methods, to another amino acid with a different protecting group (P') on the alpha-nitrogen, to give di-peptide compound 2.
- the sidechain- protecting group P is then removed to give 4.
- 2,5-disubstituted pyrroles are prepared by bromination of pyrrole-2-carboxylic acid ester 10, where R is an alkyl or aryl group, which is unsubstituted or substituted with one or more suitable substituents, to give 11, followed by a transition-metal mediated carbon-carbon bond forming reaction (for example, using Pd° with an appropriate ligand such as triphenylphosine or triphenylarsine) with an organometallic species, R ! M (for example, an organoboronic acid or an organotin compound) to give 12.
- R is an alkyl or aryl group, which is unsubstituted or substituted with one or more suitable substituents
- General Method 5 depicts another method used to make 2,5-disubstituted pyrroles, analogous to the method described by Kruse, et al., Heterocycles, 1987, 26, 3141.
- the aldehyde is deprotected to give 16, then is condensed with an ammonia equivalent such as ammonium chloride, to provide pyrrole 17.
- This pyrrole is then reacted with a phosgene-type equivalent such as trichloroacetyl chloride (analogous to the method described by Bailey, et al., Org. Synth., 1971, 51, 100), to provide the 2,5-disubstituted pyrrole 18.
- a phosgene-type equivalent such as trichloroacetyl chloride
- General Method 6 shows an alternate method to make 2,5-disubstituted pyrroles.
- Aldehyde 19 is reacted with a micleophilic organometallic compound containing a protected aldehyde to provide alcohol 20.
- the alcohol is then oxidized to ketone 15 using standard methodology such as a Swem oxidation.
- Ketone 15 is carried on to pyrrole 18 using the same method as shown in General Method 5.
- General Method 7 shows an alternate method to make 2,5-disubstituted pyrroles.
- Aldehyde 19 is reacted with a micleophilic organometallic compound containing a protected aldehyde to provide alcohol 20.
- the alcohol is then oxidized to ketone 15 using standard methodology such as a Swem oxidation.
- Ketone 15 is carried on to pyrrole 18 using the same method as shown in General Method 5.
- General Method 7 shows an alternate method to make 2,5-disubstitute
- General Method 7 depicts the preparation of a pyrrole containing the keto- methylene moiety, 27, analogous to the method described by Gonzalez-Muniz et. al. (Gonzalez-Muniz, et al., Tetrahedron, 1992, 48, 5191; Garcia-Lopez, et al., Tetrahedron Lett., 1988, 29, 1577; Garcia-Lopez, et al, Tetrahedron, 1988, 44, 5138).
- R 4 M organometallic reagent
- This compound is deprotonated by treatment with a strong base, then reacted with an electrophile (R 5 -X 3 ) to give 26. Decarboxylation of compound 26 gives product 27.
- General Method 8
- R' ester of 31 is selectively removed, and the resulting acid is converted to the disubstituted amide 32, by coupling to a secondary amine.
- Compound 32 is reacted with pyrrole 17, under typical Vilsmeier reaction conditions (Silverstein, et al., Org. Synth., 1963, Coll. Vol. IV, 831) to give pyrrole 33.
- R 1 , R" and R" are each independently lower alkyl, which is unsubstituted or substituted with one or more suitable substituents, .
- NH present in pyrrole-carboxylic acid 34 may also be protected with a suitable protecting group which may be removed at any time during the synthesis of 38.
- the methodology for converting pyrrole-carboxylic acid 34 to intermediate 38 is generally described in: Hoffman, R. V.; Tao, J. Tetrahedron 1991, 53, 7119-7126.
- Specific Method 1 describes the preparation of compounds containing a glutamine residue in the P-1 position.
- FMOC-4-amino-hept-2(trans)-enedioic acid -1 ethyl ester 42 (Dragovich, et al., J Med. Chem. 1998, 41, 2819) was coupled to Rink polystyrene utilizing HATU as a coupling reagent to get 43.
- the FMOC protecting group was removed with piperidine, and the liberated amine was then coupled to an FMOC-protected amino acid 44 to get compound 45.
- the FMOC of 45 was again removed with piperidine, and the free amine was acylated with a 5-substituted-2- pyrrole carboxylic acid chloride 46 (prepared as described in Specific Methods 4,5, and
- Specific Method 2 describes the synthesis of compounds containing the oxo- pyrrolidine sidechain in the P-1 position.
- Boc-protected 4S-amino-5-(2-oxo-pyrrolidin- 3S-yl)-pent-2(trans)-enoic acid ethyl ester 49 (prepared by a method analogous to that described in Tian, et al., U.S. Provisional Patent Application No. 60/150,358, filed August 24, 1999 and also Baldwin et al., J. Org. Chem., 1971, 36, 1441) was deprotected with HCl, then coupled using HATU to a Boc-protected amino acid 50.
- the Boc -protected product 51 was treated with HCl, then coupled to a 5-substituted- pyrrole-2-carboxylic acid chloride 46 (prepared as described in Specific Methods 4, 5, and 6), to produce product 52.
- Specific Method 3 describes the preparation of compounds containing the pyrrole-ketomethylene moiety. Boc-protected 4S-amino-5-(2-oxo-pyrrolidin-3S-y ⁇ )- pent-2(trans)-enoic acid ethyl ester 49 was deprotected with HCl, then coupled to acid 53 (prepared as described in Specific Method 7 and 8), using HATU, to provide compound 54.
- Carboxylic acid 59 was converted to an acid chloride using oxalyl chloride, then converted to the N-methoxy-N-methyl amide with O,N-dimethyl hydroxylamine. This amide 60 was reacted with Grignard reagent 61 to give ketone 62. The dioxolane- protecting group was converted to the corresponding aldehyde with aqueous HCl, then condensed with ammonium chloride to give pyrrole 63.
- Specific Method 6 describes an alternate method of pyrrole synthesis.
- Aldehyde 65 was reacted with Grignard reagent 61 to give alcohol 66.
- This alcohol was subjected to Swem oxidation conditions to provide ketone 62, which was converted to the acid chloride 46 according to Specific Method 5.
- Specific Method 7 describes the synthesis of a racemic pyrrole-ketomethylene compound.
- 5-Substituted-pyrrole-2-carboxylic acid 67 (prepared as described in Specific Methods 4, 5 and 6) was converted to the Weinreb amide 68 using standard conditions, then treated with methyllithium to give pyrrole-acetone 69.
- This ketone was converted to its silyl-enol ether with trimethylsilyl inflate, then brorninated with N- bromosuccinimide to give bromide 70.
- the bromide was displaced with sodium diethylmalonate to give malonate 71.
- the sodium enolate of this compound was alkylated to give 72, which was then de-esterified and de-carboxylated to give carboxylic acid 53.
- Specific Method 8 describes the synthesis of a racemic pyrrole-ketomethylene compound.
- H-D-propargyl glycine (80) (or a suitable salt thereof) is treated with sodium nitrite under mildly acidic aqueous conditions to provide hydroxy acid 81 in good yield.
- This material is esterified by exposure to acidic methanol to give hydroxy ester 82.
- Boc-D-3,4-difluorophenylalanine 83 is deprotected by treatment with trifluoroacetic acid in CH 2 C1 2 to afford amino acid TFA salt 84.
- This intermediate is treated with sodium nitrite under mildly acidic aqueous conditions to provide hydroxy acid 85 in good yield.
- Compound 85 is esterified by exposure to either methanol or benzyl alcohol under acidic conditions to give hydroxy esters 86 and 87, respectively.
- Flash column chromatography was conducted using Silica gel 60 (Merck Art 9385).
- Analytical thin layer chromatography (TLC) was conducted using precoated sheets of Silica 60 F254 (Merck Art 5719). Melting points were determined on a Mel-Temp apparatus and are uncorrected. All reactions were conducted in septum-sealed flasks under a slight positive pressure of argon unless otherwise noted. All commercial reagents were used as received from their respective suppliers with the following exceptions. Tetrahydrofuran (THF) was distilled from sodium-benzophenone ketyl prior to use.
- THF Tetrahydrofuran
- Dichloromethane (CH2CI2) was distilled from calcium hydride prior to use.
- the abbreviations used herein include: Et2 ⁇ (diethyl ether), DMF (N,N-dimethylformamide), DMSO (dimethylsulfoxide), MTBE (tert-butyl methyl ether), CH3OH (methanol), EtOH (ethanol), EtOAc (ethyl acetate), DME (ethylene glycol dimethyl ether) Ac (acetyl), Me (methyl), Ph (phenyl), Tr (triphenylmethyl), Cbz
- the resin was then treated with a solution of Fmoc-4-amino-hept-2(trans)-enedioic acid- 1 -ethyl ester la - b (2.37 mmol, 1.00 g), DIEA (4.74 mmol, 0.82 ml), and HATU (2.37 mmol, 0.90 g) in DMF (25 ml). The resulting mixture was agitated for 1 h, then washed with
- the resulting mixture was agitated for 1 h, then washed with DMF (3x25 ml).
- the Fmoc was removed by treatment with a solution of 20% piperidine-DMF (25 ml), then agitation for 10 min.
- the resin was washed with DMF (3x10 ml), MeOH (3x10 ml), and CH 2 C1 2 (3x10 ml).
- the resin was then dried in a vacuum desiccator. (The resin at this stage will be hereafter referred to as Phe-Gln-resin) .
- Argon gas was bubbled 15 min through a solution of 5-bromo-lH-pyrrole-2- carboxylic acid methyl ester (10.0 mmol, 2.04 g), 1-naphthylboronic acid (30.0 mmol, 5.16 g), 2M aqueous sodium carbonate (20 ml), and DMF (150 ml).
- the mixture was then treated with tris(dibenzylidienacetone)dipalladium (0) (0.50 mmol, 0.46 g), and triphenylarsine (2.0 mmol, 0.61 g), then heated to reflux under argon for 12 h.
- the mixture was partitioned between ethyl acetate (500 ml) and water (150 ml).
- 5-Naphthalen-l-yl-lH-pyrrole-2-carboxylic acid methyl ester was diluted with 1:1 dioxane-water (30 ml), and treated with lithium hydroxide hydrate (24.4 mmol, 1.02 g), then heated to reflux for 15 min.
- the solution was acidified with 20% aqueous citric acid (30 ml), then extracted with ethyl acetate (75 ml). The organics were washed with brine (2x20 ml), then concentrated under reduced pressure.
- the residue was diluted with CH 2 C1 2 , (30 ml), and treated with oxalyl chloride (24.0 mmol, 2.10 ml), and DMF (one drop), then heated to reflux for 30 min.
- the solution was concentrated under reduced pressure to provide 1.95 g of 5-naphthalen-l-yl-lH-pyrrole-2-carboxylic acid chloride.
- Oxalyl chloride (115.0 mmol, 10.0 ml) in CH 2 C1 2 (200 ml) was cooled to -78 °C under an argon atmosphere.
- DMSO 240.0 mmol, 17.0 ml was then added slowly, keeping the internal temperature below -50 °C. After completing the addition, the solution was held 20 minutes at -78 °C.
- EXAMPLE 8 6-Carbamoyl-4S-(2S- ⁇ [5-(2,5-dimethoxy-phenyl)-lH-pyrrole-2-carbonyl]-amino ⁇ -3- phenyl-propionylamino)-hex-2-enoic acid ethyl ester. (Compound 7)
- 5-Pyridin-3-yl-lH-pyrrole-2-carboxylic acid chloride was prepared according to the procedure described in Method 5 of Example 12, starting with 3-pyridine carboxylic acid. This material was coupled to Phe-Gln resin, and converted to the title compound according to the procedure described in Method 1 of Example 2. !
- 5-Pyridin-4-yl-lH-pyrrole-2-carboxylic acid chloride was prepared according to the procedure described in Method 5 of Example 12, starting with 4-pyridine carboxylic acid. This material was coupled to Phe-Gln resin, and converted to the title compound according to the procedure described in Method 1 of Example 2. !
- Gln-resin was coupled with Fmoc-leucine, deprotected, then coupled to 5-(2- trifluoromethyl-phenyl)-lH-pyrrole-2-carboxylic acid chloride (prepared according to the procedure described in Method 6 of Example 4), following Method 1 of Example 2.
- Gln-resin was coupled with Fmoc-norvaline, deprotected, then coupled to 5-(2- trifluoromethyl-phenyl)-lH-pyrrole-2-carboxylic acid chloride (prepared according to the procedure described in Method 6 of Example 4), following Method 1 of Example 2.
- Gln-resin was coupled with Fmoc-norleucine, deprotected, then coupled to 5-(2- trifluoroniethyl-phenyl)-lH-pyrrole-2-carboxylic acid chloride (prepared according to the procedure described in Method 6 of Example 4), following Method 1 of Example 2.
- Gln-resin was coupled with Fmoc-glycine, deprotected, then coupled to 5-(2- trifluoromethyl-phenyl)-lH-pyrrole-2-carboxylic acid chloride (prepared according to the procedure described in Method 6 of Example 4), following Method 1 of Example 2.
- the product was diluted with DMF (10 ml), treated with Boc-4-fluoro-phenylalanine (3.40 mmol, 0.96 g), DIEA (10.2 mmol, 1.8 ml), and HATU (3.40 mmol, 1.29 g), then held at room temperature for lh.
- the resulting solution was diluted with in ethyl acetate (75 ml), washed with brine (3x20 ml), then concentrated under reduced pressure.
- CH 2 C1 2 (5 ml) was treated with HCl (4.8 mmol, 1.2 ml of 4M in dioxane), and held 1 h, then concentrated under reduced pressure.
- the product was diluted with CH 2 C1 2 (5 ml) and collidine (2.89 mmol, 0.38 ml), and treated with 5-naphthalene-l-yl-lH-pyrrole-2- carboxylic acid chloride (prepared according to the procedure described in Method 4 of Example 2, starting with 1-naphthalene boronic acid, 0.96 mmol, 0.25 g), then held at room temperature for 1 h.
- Gln-resin was coupled with Fmoc-N-methyl-phenylalanine, according to the procedure described in Method 1 of Example 2, then deprotected and coupled with 5- (2-trifluoromethyl-phenyl)-lH-pyrrole-2-carboxylic acid (prepared according to the procedure described in Method 6 of Example 4), according to the procedure described in Method 1 of Example 2.
- 2R-Benzyl-N,N-dimethyl-succinamic acid was prepared according to the procedure described in Example 8, starting with hydrocinnamic acid. This material was reacted with 2-(2-trifluoromethyl-phenyl)-lH-pyrrole (prepared according to the procedure described in Example 6), then demethylated to give 2R-benzyl-4-oxo-4-[5- (2-trifluoromethyl-phenyl)-lH-pyrrol-2-yl] -butyric acid (all following Method 8).
- 2R-Ethyl-N,N-dimethyl-succinamic acid methyl ester was prepared according to the procedure described in Example 8, starting with butyric acid. This was reacted with 2-(2-trifluoromethyl-phenyl)-lH-pyrrole (prepared according to the procedure described in Example 6), then demethylated to give 2R-ethyl-4-oxo-4-[5-(2-trifluoromethyl- phenyl)- lH-pyrrol-2-yl] -butyric acid (all following Method 8).
- 2R-Dimethylcarbamoylmethyl-pent-4-ynoic acid methyl ester was prepared according to the procedure described in Example 8, starting with 4-pentynoic acid. This material was reacted with 2-(2-chloro-phenyl)-lH-pyrrole (prepared according to the procedure described in Example 6, starting with 2-chlorobenzaldehyde).
- Recombinant rhinovirus 3C proteases (see Birch et al., "Purification of recombinant human rhinovirus 14 3C protease expressed in Escherichia coli," Protein Expr. Pur. (1995), vol. 6(5), 609-618) from serotypes 14, 16, and 2 were prepared by the following standard chromatographic procedures: (1) ion exchange using Q Sepharose Fast Flow from Pharmacia; (2) affinity chromatography using Affi-Gel Blue from Biorad; and (3) sizing using Sephadex G- 100 from
- Each assay sample contained 2% DMSO, 50 mM tris pH 7.6, 1 mM EDTA, a test compound at the indicated concentration, approximately 1 ⁇ M substrate, and 50-100 nM protease.
- the k D bs/I values were obtained from reactions initiated by addition of enzyme rather than substrate. RVP activity was measured in the fluorescence resonance energy transfer assay.
- the substrate was (N-terminal)
- Antirhino viral Hl-HeLa Cell Culture Assay In this cell protection assay, the ability of compounds to protect cells against
- HRV infection was measured by the XTT dye reduction method, which is described in Weislow et al., J. Natl. Cancer hist. (1989), vol. 81, 577-586.
- Hl-HeLa cells were infected with HRV-14 at a multiplicity of infection (m.o.i.) of 0.13 (viras particles/cell) or mock-infected with medium only. Infected or mock-infected cells were resuspended at 8 x 10 ⁇ cells per ml, and incubated with appropriate concentrations ofthe compounds to be tested. Two days later, XTT/PMS was added to test plates and the amount of formazan produced was quantified spectrophotometrically at 450/650 nm.
- the EC50 value was calculated as the concentration of compound that increased the percentage of formazan production in compound-treated, viras-infected cells to 50% of that produced by compound-free, mock-infected cells.
- the 50% cytotoxic dose (CC50) was calculated as the concentration of compound that decreased the percentage of formazan produced in compound-treated, mock-infected cells to 50% of that produced by compound-free, mock-infected cells.
- the therapeutic index (TI) was calculated by dividing the CC50 value by the EC50 value.
- HRV human rhinovirus
- HRV stocks were propagated and viral assays were performed in Hl-HeLa cells (ATCC). Cells were grown in minimal essential medium with 10% fetal bovine serum, available from Life Technologies (Gaithersburg, MD). Test results for the HRV assay are shown in the table below.
- Coxsackievirus types A-21 (CAV-21) and B3 (CVB3) were purchased from American Type Culture Collection (ATCC, Rockville, MD). Viras stocks were propagated and antiviral assays were performed in Hl-HeLa cells (ATCC). Cells were grown in minimal essential medium with 10% fetal bovine serum (Life Technologies, Gaithersburg, MD). The ability ofthe compounds of this invention to protect cells against either CAV-21 or CVB3 infection was measured by the XTT dye reduction method. This method is described in Weislow et al., J. Natl. Cancer List. (1989), vol. 81, 577-586.
- Hl-HeLa cells were infected with CAV-21 or CVB3 at a multiplicity of infection (m.o.i.) of 0.025 or 0.075, respectively, or mock-infected with medium only.
- Hl-HeLa cells were plated at 4 x 10 ⁇ cells per well in a 96-well plate and incubated with appropriate concentrations ofthe test compound.
- the EC50 was calculated as the concentration of compound that increased the formazan production in compound-treated, virus-infected cells to 50% of that produced by compound-free, uninfected cells.
- the 50% cytotoxic dose (CC50) was calculated as the concentration of compound that decreased formazan production in compound-treated, uninfected cells to 50% of that produced in compound-free, uninfected cells.
- the therapeutic index (TI) was calculated by dividing the CC50 by the EC50.
- Echovirus type 11 was purchased from ATCC (Rockville, MD). Viras stocks were propagated and antiviral assays were performed in MRC-5 cells (ATCC). Cells were grown in minimal essential medium with 10% fetal bovine serum (Life Technologies, Gaithersburg, MD). The ability ofthe compounds of this invention to protect cells against ECHO 11 infection was measured by the XTT dye reduction method (Weislow et al., J. Natl. Cancer hist. (1989), vol. 81, 577-586). MRC-5 cells were infected with ECHO 11 at an m.o.i. of 0.003 or 0.004, respectively, or mock-infected with medium only.
- Infected or uninfected cells were added at 1 x 10 ⁇ cells per well and incubated with appropriate concentrations of compound. Four days later, XTT/PMS was added to test plates, and the amount of formazan produced was quantified spectrophotometrically at 450/650 nm.
- the EC50 was calculated as the concentration of compound that increased the formazan production in compound-treated, viras-infected cells to 50% of that produced by compound-free, uninfected cells.
- the 50% cytotoxic dose (CC50) was calculated as the concentration of compound that decreased formazan production in compound-treated, uninfected cells to 50% of that produced in compound-free, uninfected cells.
- the therapeutic index (TI) was calculated by dividing the CC50 by the EC50.
- Activity ofthe compounds against enterovirus type 70 (EV 70) may be measured by the same assay as described above in this section. Enterovirus type 70 (EV 70) may be obtained from the American Type
- Antiviral data obtained for the test compounds are shown in the table below.
- the designation "ND” indicates that a value was not determined for that compound, and the designation "NA” means not applicable. *. > U-> t t o o Ux o u> Ux
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Crystallography & Structural Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyrrole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01925037A EP1274682A2 (en) | 2000-04-14 | 2001-04-12 | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis |
JP2001576769A JP2003531139A (en) | 2000-04-14 | 2001-04-12 | Anti-picornaviral compounds and compositions, their pharmaceutical use, and their synthetic substances |
BR0110077-7A BR0110077A (en) | 2000-04-14 | 2001-04-12 | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis |
CA002406475A CA2406475A1 (en) | 2000-04-14 | 2001-04-12 | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis |
AU2001251639A AU2001251639A1 (en) | 2000-04-14 | 2001-04-12 | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis |
MXPA02010195A MXPA02010195A (en) | 2000-04-14 | 2001-04-12 | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis. |
IL15224301A IL152243A0 (en) | 2000-04-14 | 2001-04-12 | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis |
PL01365198A PL365198A1 (en) | 2000-04-14 | 2001-04-12 | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis |
HU0300928A HUP0300928A3 (en) | 2000-04-14 | 2001-04-12 | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US19779600P | 2000-04-14 | 2000-04-14 | |
US60/197,796 | 2000-04-14 | ||
US19849700P | 2000-04-18 | 2000-04-18 | |
US60/198,497 | 2000-04-18 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2001079167A2 true WO2001079167A2 (en) | 2001-10-25 |
WO2001079167A3 WO2001079167A3 (en) | 2002-02-28 |
Family
ID=26893177
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2001/012333 WO2001079167A2 (en) | 2000-04-14 | 2001-04-12 | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis |
Country Status (19)
Country | Link |
---|---|
US (3) | US6610730B2 (en) |
EP (1) | EP1274682A2 (en) |
JP (1) | JP2003531139A (en) |
KR (1) | KR20030019350A (en) |
CN (1) | CN1431995A (en) |
AR (1) | AR028338A1 (en) |
AU (1) | AU2001251639A1 (en) |
BR (1) | BR0110077A (en) |
CA (1) | CA2406475A1 (en) |
HU (1) | HUP0300928A3 (en) |
IL (1) | IL152243A0 (en) |
MX (1) | MXPA02010195A (en) |
PA (1) | PA8515201A1 (en) |
PE (1) | PE20011277A1 (en) |
PL (1) | PL365198A1 (en) |
SV (1) | SV2001000379A (en) |
UY (1) | UY26666A1 (en) |
WO (1) | WO2001079167A2 (en) |
ZA (1) | ZA200208257B (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005030794A3 (en) * | 2003-09-22 | 2005-08-18 | Eisai Co Ltd | Hemiasterlin derivatives and uses thereof |
US7192972B2 (en) | 2002-03-22 | 2007-03-20 | Eisai Co., Ltd. | Hemiasterlin derivatives and uses thereof |
WO2009148599A1 (en) * | 2008-06-04 | 2009-12-10 | Synta Pharmaceuticals Corp. | Pyrrole compunds that modulate hsp90 activity |
EP2347652A1 (en) | 2008-01-25 | 2011-07-27 | Rhodia Opérations | Esteramides, their preparation and their use |
WO2021252491A1 (en) * | 2020-06-10 | 2021-12-16 | Aligos Therapeutics, Inc. | Anti-viral compounds for treating coronavirus, picornavirus, and norovirus infections |
EP3733672B1 (en) | 2017-12-25 | 2023-03-22 | Sumitomo Chemical Company, Limited | Heterocyclic compounds and noxious arthropod control agent containing same |
US12065428B2 (en) | 2021-09-17 | 2024-08-20 | Aligos Therapeutics, Inc. | Anti-viral compounds |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7462594B2 (en) * | 2003-12-31 | 2008-12-09 | Taigen Biotechnology Co., Ltd. | Peptide-like compounds that inhibit coronaviral 3CL and flaviviridae viral proteases |
AU2004312547A1 (en) * | 2003-12-31 | 2005-07-21 | Taigen Biotechnology | Protease inhibitors |
KR100891699B1 (en) | 2007-04-10 | 2009-04-03 | 광주과학기술원 | 7-amino-4-S-3-4-fluorophenyl-2-R-3-methyl-2-5-methylisoxazole-3-carboxamidobutanamidopropanamido-7-oxo-2-heptenoate derivatives, preparation method thereof, and a phamaceutical compositions for the prevention and treatment of the viral diseases as an active ingredient |
WO2022156692A1 (en) * | 2021-01-22 | 2022-07-28 | 中国人民解放军军事科学院军事医学研究院 | Cyclic peptide viral protease inhibitor, preparation method therefor, and application thereof in antiviral drugs |
PE20240775A1 (en) | 2021-07-09 | 2024-04-17 | Aligos Therapeutics Inc | ANTIVIRAL COMPOUNDS |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996009822A1 (en) * | 1994-09-27 | 1996-04-04 | Sanofi Winthrop, Inc. | Antipicornaviral agents |
WO1996030395A2 (en) * | 1995-03-31 | 1996-10-03 | Takeda Chemical Industries, Ltd. | Cysteine protease inhibitor |
WO1997043305A1 (en) * | 1996-05-14 | 1997-11-20 | Agouron Pharmaceuticals, Inc. | Inhibitors of picornavirus 3c proteases and methods for their use and preparation |
WO1998004524A1 (en) * | 1996-07-25 | 1998-02-05 | Pharmacia & Upjohn S.P.A. | Acryloyl substituted distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents |
WO1998043950A1 (en) * | 1997-03-28 | 1998-10-08 | Agouron Pharmaceuticals, Inc. | Antipicornaviral compouds, compositions containing them, and methods for their use |
WO1999031122A1 (en) * | 1997-12-16 | 1999-06-24 | Agouron Pharmaceuticals, Inc. | Antipicornaviral compounds and methods for their use and preparation |
WO1999057135A1 (en) * | 1998-04-30 | 1999-11-11 | Agouron Pharmaceuticals, Inc. | Antipicornaviral compounds, their preparation and use |
WO2001010894A2 (en) * | 1999-08-04 | 2001-02-15 | Agouron Pharmaceuticals, Inc. | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5374623A (en) | 1992-08-20 | 1994-12-20 | Prototek, Inc. | Cysteine protease inhibitors effective for in vivo use |
US5486623A (en) | 1993-12-08 | 1996-01-23 | Prototek, Inc. | Cysteine protease inhibitors containing heterocyclic leaving groups |
IL112759A0 (en) | 1994-02-25 | 1995-05-26 | Khepri Pharmaceuticals Inc | Novel cysteine protease inhibitors |
IT1269511B (en) | 1994-05-17 | 1997-04-01 | Univ Degli Studi Milano | AMINO-SULPHONIC ACID DERIVATIVES, THEIR USE IN THE SYNTHESIS OF PSEUDOPEPTIDES AND PROCEDURE FOR THEIR PREPARATION |
US5498616A (en) | 1994-11-04 | 1996-03-12 | Cephalon, Inc. | Cysteine protease and serine protease inhibitors |
US5856530A (en) | 1996-05-14 | 1999-01-05 | Agouron Pharmaceuticals, Inc. | Antipicornaviral compounds and methods for their use and preparation |
WO1997049668A1 (en) | 1996-06-13 | 1997-12-31 | Smithkline Beecham Corporation | Inhibitiors of cysteine protease |
US6020371A (en) | 1997-03-28 | 2000-02-01 | Agouron Pharmaceuticals, Inc. | Antipicornaviral compounds compositions containing them and methods for their use |
US6331554B1 (en) * | 1997-03-28 | 2001-12-18 | Agouron Pharmaceuticals, Inc. | Antipicornaviral compounds, compositions containing them, and methods for their use |
US6369226B1 (en) | 1999-06-21 | 2002-04-09 | Agouron Pharmaceuticals, Inc. | Substituted benzamide inhibitors of rhinovirus 3C protease |
AU778062B2 (en) | 1999-08-24 | 2004-11-11 | Agouron Pharmaceuticals, Inc. | Process and intermediates for the preparation of isoxazolecaroxamides and analogues |
PE20010517A1 (en) | 1999-08-24 | 2001-05-16 | Agouron Pharma | THE EFFICIENT SYNTHETIC ROUTES FOR THE PREPARATION OF RINOVIRUS PROTEASE INHIBITORS AND KEY INTERMEDIATES |
PE20020157A1 (en) | 1999-12-03 | 2002-02-22 | Agouron Pharma | PYRIDONE DERIVED COMPOUNDS AS PICORNAVIRAL 3C PROTEASE INHIBITORS, COMPOSITIONS, THEIR PHARMACEUTICAL USES AND MATERIALS FOR THEIR SYNTHESIS |
CN1525957A (en) * | 2000-06-14 | 2004-09-01 | ������ҩ������˾ | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis |
-
2001
- 2001-04-11 PE PE2001000336A patent/PE20011277A1/en not_active Application Discontinuation
- 2001-04-11 PA PA20018515201A patent/PA8515201A1/en unknown
- 2001-04-12 WO PCT/US2001/012333 patent/WO2001079167A2/en not_active Application Discontinuation
- 2001-04-12 IL IL15224301A patent/IL152243A0/en unknown
- 2001-04-12 EP EP01925037A patent/EP1274682A2/en not_active Withdrawn
- 2001-04-12 AU AU2001251639A patent/AU2001251639A1/en not_active Abandoned
- 2001-04-12 CA CA002406475A patent/CA2406475A1/en not_active Abandoned
- 2001-04-12 CN CN01810359A patent/CN1431995A/en active Pending
- 2001-04-12 BR BR0110077-7A patent/BR0110077A/en not_active IP Right Cessation
- 2001-04-12 HU HU0300928A patent/HUP0300928A3/en unknown
- 2001-04-12 PL PL01365198A patent/PL365198A1/en not_active Application Discontinuation
- 2001-04-12 MX MXPA02010195A patent/MXPA02010195A/en unknown
- 2001-04-12 JP JP2001576769A patent/JP2003531139A/en active Pending
- 2001-04-12 KR KR1020027013804A patent/KR20030019350A/en not_active Application Discontinuation
- 2001-04-12 US US09/834,783 patent/US6610730B2/en not_active Expired - Fee Related
- 2001-04-16 UY UY26666A patent/UY26666A1/en unknown
- 2001-04-17 SV SV2001000379A patent/SV2001000379A/en not_active Application Discontinuation
- 2001-04-17 AR ARP010101775A patent/AR028338A1/en not_active Application Discontinuation
-
2002
- 2002-10-14 ZA ZA200208257A patent/ZA200208257B/en unknown
-
2003
- 2003-05-12 US US10/435,082 patent/US6872745B2/en not_active Expired - Fee Related
-
2004
- 2004-11-12 US US10/986,109 patent/US20050101651A1/en not_active Abandoned
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996009822A1 (en) * | 1994-09-27 | 1996-04-04 | Sanofi Winthrop, Inc. | Antipicornaviral agents |
WO1996030395A2 (en) * | 1995-03-31 | 1996-10-03 | Takeda Chemical Industries, Ltd. | Cysteine protease inhibitor |
WO1997043305A1 (en) * | 1996-05-14 | 1997-11-20 | Agouron Pharmaceuticals, Inc. | Inhibitors of picornavirus 3c proteases and methods for their use and preparation |
WO1998004524A1 (en) * | 1996-07-25 | 1998-02-05 | Pharmacia & Upjohn S.P.A. | Acryloyl substituted distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents |
WO1998043950A1 (en) * | 1997-03-28 | 1998-10-08 | Agouron Pharmaceuticals, Inc. | Antipicornaviral compouds, compositions containing them, and methods for their use |
WO1999031122A1 (en) * | 1997-12-16 | 1999-06-24 | Agouron Pharmaceuticals, Inc. | Antipicornaviral compounds and methods for their use and preparation |
WO1999057135A1 (en) * | 1998-04-30 | 1999-11-11 | Agouron Pharmaceuticals, Inc. | Antipicornaviral compounds, their preparation and use |
WO2001010894A2 (en) * | 1999-08-04 | 2001-02-15 | Agouron Pharmaceuticals, Inc. | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis |
Non-Patent Citations (6)
Title |
---|
DRAGOVICH P S ET AL: "SOLID-PHASE SYNTHESIS OF IRREVERISBLE HUMAN RHINOVIRUS 3C PROTEASE INHIBITORS. PART 1: OPTIMIZATION OF TRIPEPTIDES INCORPORATING N-TERMINAL AMIDES" BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 7, no. 4, 1999, pages 589-598, XP000885728 ISSN: 0968-0896 cited in the application * |
DRAGOVICH P S ET AL: "Structure-based design of irreversible, tripeptidyl human rhinovirus 3C protease inhibitors containing N-methyl amino acids" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 9, no. 15, 2 August 1999 (1999-08-02), pages 2189-2194, XP004174157 ISSN: 0960-894X * |
DRAGOVICH P S ET AL: "Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 2. Peptide structure-activity studies" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 41, no. 15, 16 July 1998 (1998-07-16), pages 2819-2834, XP002100727 ISSN: 0022-2623 * |
DRAGOVICH P S ET AL: "Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 42, no. 7, 8 April 1999 (1999-04-08), pages 1203-1212, XP002153927 ISSN: 0022-2623 cited in the application * |
DRAGOVICH P S ET AL: "STRUCTURE-BASED DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF IRREVERSIBLE HUMAN RHINOVIRUS 3C PROTEASE INHIBITORS. 4. INCORPORATION OF P1 LACTAM MOIEITES AS L-GLUTAMINE REPLACEMENTS" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 42, no. 7, 8 April 1999 (1999-04-08), pages 1213-1224, XP002153221 ISSN: 0022-2623 cited in the application * |
MOSS N ET AL: "PEPTIDOMIMETIC INHIBITORS OF HERPES SIMPLEX VIRUS RIBONUCLEOTIDE REDUCTASE WITH IMPROVED IN VIVO ANTIVIRAL ACTIVITY" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 39, no. 21, 11 October 1996 (1996-10-11), pages 4173-4180, XP002072015 ISSN: 0022-2623 * |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8129407B2 (en) | 2002-03-22 | 2012-03-06 | Eisai Inc. | Hemiasterlin derivatives and uses thereof in the treatment of cancer |
US7064211B2 (en) | 2002-03-22 | 2006-06-20 | Eisai Co., Ltd. | Hemiasterlin derivatives and uses thereof |
US7192972B2 (en) | 2002-03-22 | 2007-03-20 | Eisai Co., Ltd. | Hemiasterlin derivatives and uses thereof |
US7528152B2 (en) | 2002-03-22 | 2009-05-05 | Eisai Co., Ltd. | Hemiasterlin derivatives and uses thereof in the treatment of cancer |
US7585976B2 (en) | 2002-03-22 | 2009-09-08 | Eisai Co., Ltd. | Hemiasterlin derivatives and uses thereof |
US8633224B2 (en) | 2002-03-22 | 2014-01-21 | Eisai Co., Ltd. | Hemiasterlin derivatives and uses thereof in the treatment of cancer |
WO2005030794A3 (en) * | 2003-09-22 | 2005-08-18 | Eisai Co Ltd | Hemiasterlin derivatives and uses thereof |
US9392785B2 (en) | 2008-01-25 | 2016-07-19 | Rhodia Operations | Use of esteramides as solvents, novel esteramides and process for preparing esteramides |
EP2347652A1 (en) | 2008-01-25 | 2011-07-27 | Rhodia Opérations | Esteramides, their preparation and their use |
US8450500B2 (en) | 2008-06-04 | 2013-05-28 | Synta Pharmaceuticals Corp. | Pyrrole compounds that modulate HSP90 activity |
US8785658B2 (en) | 2008-06-04 | 2014-07-22 | Synta Pharmaceuticals Corp. | Pyrrole compounds that modulate HSP90 activity |
US9067884B2 (en) | 2008-06-04 | 2015-06-30 | Synta Pharmaceuticals Corp. | Pyrrole compounds that modulate HSP90 activity |
WO2009148599A1 (en) * | 2008-06-04 | 2009-12-10 | Synta Pharmaceuticals Corp. | Pyrrole compunds that modulate hsp90 activity |
EP3733672B1 (en) | 2017-12-25 | 2023-03-22 | Sumitomo Chemical Company, Limited | Heterocyclic compounds and noxious arthropod control agent containing same |
WO2021252491A1 (en) * | 2020-06-10 | 2021-12-16 | Aligos Therapeutics, Inc. | Anti-viral compounds for treating coronavirus, picornavirus, and norovirus infections |
US11952365B2 (en) | 2020-06-10 | 2024-04-09 | Aligos Therapeutics, Inc. | Anti-viral compounds |
US12065428B2 (en) | 2021-09-17 | 2024-08-20 | Aligos Therapeutics, Inc. | Anti-viral compounds |
Also Published As
Publication number | Publication date |
---|---|
US6610730B2 (en) | 2003-08-26 |
MXPA02010195A (en) | 2003-04-25 |
US20050101651A1 (en) | 2005-05-12 |
PL365198A1 (en) | 2004-12-27 |
SV2001000379A (en) | 2001-10-16 |
IL152243A0 (en) | 2003-05-29 |
HUP0300928A2 (en) | 2003-08-28 |
PE20011277A1 (en) | 2002-01-07 |
WO2001079167A3 (en) | 2002-02-28 |
HUP0300928A3 (en) | 2005-08-29 |
ZA200208257B (en) | 2003-07-25 |
BR0110077A (en) | 2003-06-17 |
KR20030019350A (en) | 2003-03-06 |
EP1274682A2 (en) | 2003-01-15 |
US20020006943A1 (en) | 2002-01-17 |
CA2406475A1 (en) | 2001-10-25 |
PA8515201A1 (en) | 2002-10-24 |
AR028338A1 (en) | 2003-05-07 |
US20030225042A1 (en) | 2003-12-04 |
JP2003531139A (en) | 2003-10-21 |
US6872745B2 (en) | 2005-03-29 |
AU2001251639A1 (en) | 2001-10-30 |
CN1431995A (en) | 2003-07-23 |
UY26666A1 (en) | 2001-11-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6514997B2 (en) | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis | |
EP1073672B1 (en) | Antipicornaviral compounds, their preparation and use | |
AU779321B2 (en) | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis | |
US6610730B2 (en) | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis | |
JP2002508389A (en) | Anti-picornavirus compounds and methods for their use and production | |
CN107001358A (en) | Adjust the new pyridine hepyramine compound of istone lysine demethylase (KDM) catalytic activity | |
CN101641341A (en) | Amide compounds and their use as antitumor agents | |
US6632825B2 (en) | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis | |
EP1329457B1 (en) | Antipicornaviral compounds, their preparation and use | |
AU2023204968A1 (en) | Novel isoindolinone derivative compounds as caspase inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
WWE | Wipo information: entry into national phase |
Ref document number: 521876 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 152243 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2406475 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002/08257 Country of ref document: ZA Ref document number: PA/a/2002/010195 Country of ref document: MX Ref document number: 2001251639 Country of ref document: AU Ref document number: 1020027013804 Country of ref document: KR Ref document number: 200208257 Country of ref document: ZA |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 2001 576769 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2001925037 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 018103596 Country of ref document: CN |
|
WWP | Wipo information: published in national office |
Ref document number: 2001925037 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1020027013804 Country of ref document: KR |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2001925037 Country of ref document: EP |