WO2001021160A2 - Derives de carboxamide, inhibiteurs selectifs d'agents pathogenes - Google Patents
Derives de carboxamide, inhibiteurs selectifs d'agents pathogenes Download PDFInfo
- Publication number
- WO2001021160A2 WO2001021160A2 PCT/EP2000/009306 EP0009306W WO0121160A2 WO 2001021160 A2 WO2001021160 A2 WO 2001021160A2 EP 0009306 W EP0009306 W EP 0009306W WO 0121160 A2 WO0121160 A2 WO 0121160A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- use according
- virus
- compounds
- alkyl
- substituents
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
-
- 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
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/66—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/80—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/40—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
- C07D333/66—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention relates to the use of carboxamide compounds as selective inhibitors of pathogens, particularly viruses and, more particularly, herpesviridae. Surprisingly, these compounds show reduced side effects in comparison with previous antiviral compounds. Thus, a novel method for 10 preventing or treating infections by pathogens, particularly herpesviridae is provided.
- HCMV Human Cytomegalqvirus
- Allograft recipients (20,000 allograft transplantations per year in US) are often infected (or superinfected) by virus from the transplanted organ.
- Clinical symptoms in the postransplant period include prolonged fever, 5 leukopenia, thrombocytopenia, atypical lymphocytosis, elevated hepatic transaminases and decreased graft survival.
- HCMV infection has been associated with high mortality rates (80-90% for untreated HCMV pneumonia), which have been reduced by newer antiviral agents to 1 0-20% (reviewed in Britt J.B. and Alford C.A., 0 1 996, Cytomegaloviruses, pp.2494-2523.
- B.N the Best Fit for HCMV pneumonia
- Ganciclovir is available for intravenous and oral administration and as an implant in the case of retinitis. Toxicities include leukopenia and thrombocytopenia. Foscarnet (phosphonoformic acid) exhibits considerable renal toxicity and is only available in intravenous form, which is also true for Cidofovir.
- Leflunomide an immunomodulatory drug used in rheumatoid arthritis, was previously found to inhibit HCMV replication in cell culture.
- the antiinflammatory and immunosuppressive properties of Leflunomide have been demonstrated in animal models of autoimmune disease and organ transplant rejection (Reviewed in J. Rheumatology (1998) 25:20, Agents Actions (1991) 32:10) and it was recently approved for use in rheumatoid arthritis in the US (Scrip (1998) (2370):22).
- the proposed basis for the antiproliferative action of Leflunomide for example, in mitogen-stimulated human T-lymphocytes (JBC (1998) 273:21682), is the suppression of the de novo pathway of pyrimidine synthesis.
- the active metabolite of Leflunomide is a noncompetitive inhibitor of Dihydroorotate dehydrogenase ( D H O D H ) ( Bioc h em . Ph a rma co l . ( 1 995 ) 5_0_: 861 ; J. Pharmacol. Exper.ther. (1995) 275:1043; JBC (1995) 270:22467. Eur.J. Biochem. (1996) 240:292; Biochemistry (1996) 35:1270), a mitochondrial enzyme which catalyzes the rate-limiting step in this biosynthetic pathway.
- D H O D H Dihydroorotate dehydrogenase
- carboxamide derivatives can selectively inhibit kinases from pathogens, particularly from herpesviridae such as HCMV, without significantly inhibiting DHODH.
- pathogens particularly from herpesviridae such as HCMV
- these compounds show a pronounced reduction in HCMV replication but do not inhibit purified recombinant human DHODH in an in vitro assay.
- This surprising uncoupling of antipathogen efficacy and inhibition of the de novo pyrimidine synthesis suggests that the subject carboxamide derivatives are free of the side effects associated with the antiproliferative and immunosuppressive properties of prior art medicaments such as Leflunomide.
- the present invention refers to the use of compounds of the general formulae (la) , (lb), (lc) or (Id) : (la) (lb)
- X and Z are substituents comprising an aromatic or heteroaromatic ring system for the manufacture of an agent against infectious diseases.
- X and/or Z may be an aromatic radical, preferably a phenyl radical which is unsubstituted or which carries at least one substituent, e.g. 1 -4 substituents which may be selected from hydroxy, cyano, nitro, halo, e.g.
- X and/or Z is an aromatic or heteroaromatic radical, e.g . a phenyl radical having at least one, particularly one, two or three C ⁇ -C 4 haloalkyl substituents, e.g . C, haloalkyl substituents such as -CF 3 , -CHF 2 and -CH 2 F.
- X and/or Z may be selected from radicals represented by formulae (lla-c) :
- Y is preferably hydrogen or C ⁇ alkyl, more preferably hydrogen.
- X and/or Z comprises a heterocyclic ring which may contain one or several heteroatoms such as oxygen, nitrogen and/or sulfur, preferably a 5-membered heterocyclic ring which may be selected from pyrrole, pyrazole, imidazole, 1 ,2,3-triazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole, 1 ,2,4-thiadiazole, 1 ,3,4-thiadiazole, thiophene, furan, indole and 3-thiaindole, a 6-membered heterocyclic ring which may be selected from pyridine, pyran, pyrimidine, pyridazine, pyrimidine and pyrazine, or a bi- or polycyclic heteroaromatic ring such as indazole, imidazole, chinoline or isochinoline.
- the heterocyclic ring can be mono, di,
- R is at least one substituent, e.g. one or two substituents selected from halo, C ⁇ Cg alkyl, ⁇ 3 alkoxy or aryl, e.g . phenyl.
- the aromatic and/or heteroaromatic ring of X an Z may be directly linked to the central structural element of the compounds (la-d), i.e. by a covalent bond .
- the linkage may comprise an alkylene-group, preferably a C C 4 alkylene group, e.g. a C ⁇ or C 2 alkylene group.
- compounds (la), (lb), (lc) and (Id) have a selectivity for kinases from pathogens compared with the cellular enzyme DHODH .
- the compounds are suitable for the preparation of an agent against infectious diseases, particularly viral infections, more particularly, against infections by herpesviruses.
- the herpesviruses may be selected from human herpesviruses and herpesviruses from other mammals, such as bovine, equine, porcine and pongine herpesviruses.
- Suitable herpesviruses are selected from ⁇ -herpesviruses, e.g.
- herpesvirus such as herpes simplex virus 1 , herpes simplex virus 2, bovine herpesvirus 2, cercopithecine herpesvirus 1 or varicellaviruses such as varicella zoster virus, porcine herpesvirus 1 (pseudorabiesvirus) bovine herpesvirus 1 and equine herpesvirus 1 (equine abortion virus) .
- the herpesvirus may be selected from ⁇ -herpesviruses, e.g. cytomegaloviruses such as human cytomegalovirus and from roseoloviruses, such as human herpesvirus 6, human herpesvirus 7 or aotine herpesviruses 1 and 3.
- the herpesviruses may be selected from ⁇ -herpesviruses, e.g. from lymphocryptoviruses such as Epstein-Barr virus, cercopithecine herpesvirus 2 or porcine herpesvirus 1 , or from rhadinoviruses such as human herpesvirus 8, ateline herpesvirus 2 or saimudine herpesvirus 1 , or preferably, the virus is selected from human herpesvirus 1 (HSV-1 ), varicella zoster virus (VZV) or human cytomegalovirus (HCMV) .
- HSV-1 human herpesvirus 1
- VZV varicella zoster virus
- HCMV human cytomegalovirus
- the compounds are active against Foscarnet-resistant HCMV strains. Thus, they are likely to have a mode of action which is different from the HCMV drugs on the market, making them valuable tools for combination therapy approaches, e.g. for combination therapies together with viral DNA polymerase inhibitors. Furthermore, it was found that the compounds are potent inhibitors of ganciclovir-resistant virus strains, particularly ganciclovir-resistant HCMV strains.
- the compounds of the formula I are suitable for the manufacture of an agent for the prophylaxis and/or treatment of a viral infection.
- This prophylaxis or treatment comprises administering a pharmaceutical composition containing as an active agent a pharmaceutically effective amount of a compound of the general formula I to a subject, preferably a human, in need thereof, e.g. a subject suffering from a herpesvirus infection or a subject which is in need of a prophylactic administration to avoid the outbreak of a herpesvirus infection.
- the pharmaceutical composition may contain suitable diluents, carriers and auxiliary agents. Further, the composition may also contain other pharmaceutically active agents, e.g. antiviral agents.
- the pharmaceutical composition may be suitable for oral, parenteral, e.g . intradermal, intravenous or intramuscular, rectal, nasal and topical applications.
- the composition may be an injectable solution, ointment, cream or spray. Further, the composition may have retardation properties, i.e. showing a delayed release of the active agent.
- the dosage of the active agent depends on the specific compound being administered, the type and the severity of the viral infection. For example, a dosage from 0.01 mg to 100 mg per day and per kg/body weight for the active agent is suitable.
- the efficacy of the compounds of formulae (la), (lb), (Ic) and (Id) against enzymes from pathogens, e.g. viral kinases, may be determined in an in vitro enzyme inhibition test.
- the anti-viral effect can also be determined directly in a cell culture assay.
- a preferred and new cell culture assay is described in Example 2.2 and comprises the use of cells infected with a recombinant human cytomegalovirus carrying a reporter gene, e.g . the GFP-gene.
- the reporter gene is preferably inserted into the viral genome in a manner that viral replication is still possible.
- the reporter gene may be inserted into the HCMV gene region encoding the open reading frames US9 and US1 0.
- a further embodiment of the present invention refers to the use of compounds of the general formula (IV) :
- X and Y are defined as for the compounds (la-d) and R' is selected from C -C alkyl and C 3 -C 4 cycloalkyl, particularly CH 3 , for the preparation of an agent against ganciclovir-resistant virus strains.
- the compounds may be present in the form of a physiologically acceptable salt, e.g. an alkali metal, amonium or substituted amonium salt, particularly the sodium salt or the salt of a basic amino acid such as lysine.
- the compounds of formula (IV) may be classified as leflunomides. Surprisingly, these leflunomides are potent inhibitors of ganciclovir-resistant virus strains, particularly ganciclovir-resistant herpes virus strains and more particularly ganciclovir- resistant HCMV strains.
- the compounds of the formula (IV) are suitable for the manufacture of an agent for the prophylaxis and/or treatment of a viral infection.
- This prophylaxis or treatment may be carried out as described above for compounds of the formulae (la) and (lb) .
- Fig. 1 is a list of compounds of the present invention having anti-viral activity.
- Fig. 2 is a diagram showing the efficacy of compounds of the present invention against a ganciclovir-resistant virus strain.
- the aromatic rings can be mono, di, tri, or tetrasubstituted with e.g. alkyl, substituted alkyl, aryl, hydroxy, halogen, nitro, carboxy, thiomethyl groups.
- the heterocyclic ring can be mono, di, tri, or tetrasubstituted with e.g. alkyl, substituted alkyl, aryl, hydroxy, oxo, halogen, nitro, thiomethyl groups.
- the cDNA for human DHODH (accession number M94065) was obtained via PCR with EST clone AA173225 (from RZPD in Berlin) and oligonucleotides 5'-CTG AAT TCA AAT TAC CGT GGA GAC ACC TGC
- the assay was basically performed as described by Copeland et al. ("NBT assay", Arch. Biochem. Biophys.323:79, 1 995) with slight modifications: 20 ⁇ of a 5x ubiquinone mixture ( 1 mM Ubiquinone Q1 0, 0.5 % Triton X100, 500 mM Tris pH 7.5), 2 ⁇ of 1 0 mM NBT (nitroblue tetrazolium), 2-1 0 ⁇ of DHODH-GST (depending on the batch of 1 -liter bacterial preparation), 91 - 83 ⁇ of water and 5 ⁇ of compound or DSMO were added to each well of a 96-well microtiter plate.
- HFF Human foreskin fibroblasts
- pBlueScribe vector pBS + (Stratagene) : the first contained restriction sites for Nhel, Spel, Pad and Bgll followed by a loxP sequence (ATAACTTCGTATAGCATACATTATACGAAGTTAT) and was introduced into Pstl/Xbal sites of the vector; the second contained another loxP sequence followed by restriction sites Hpal, Clal and Pmel and was introduced into BamHI/Asp71 8 sites.
- a gene cassette comprising of a "humanized” version of the ORF coding for GFP (gfp-h) under the control of the HCMV enhancer/promoter and the Ptk/PY441 enhancer-driven neoR selection marker was excised from plasmid pUF5 (Zolotukhin et al., 1 996, J .Virol.70, 4646-4654) and inserted into the recombination vector via Bglll sites.
- HCMV sequences with homology to the gene region containing the open reading frames US9 and US1 0 were inserted.
- viral sequences were amplified from template pCM49 (Fleckenstein et al., 1 982, Gene 1 8, 39-46) via PCR in a 35-cycle program (denaturation 45 sec at 95°C, annealing 45 sec at 55 °C and elongation 2 min at 72 °C) by the use of Vent DNA polymerase (New England Biolabs) .
- a US 1 0-specific sequence of 1 983 bp in length was generated using primers US 1 0[200900]Spel (GCTCACTAGTGGCCTAGCCTGGCTCATGGCC) and US1 0[ 1 9891 8]Pacl (GTCCTTAATTAAGACGTGGTTGTGGTCACCGAA) and inserted at the vector 5' cloning position via Spel/Pacl restriction sites (see bold-print) .
- a US9-specific sequence of 201 0 bp was generated using primers US9- 3'Pmel (CTCGGTTTAAACGACGTGAGGCGCTCCGTCACC) and US-5' Clal (TTGCATCGATACGGTGTGAGATACCACGATG) inserted at the vector 3' cloning position via Pmel/Clal restriction sites.
- the resulting construct pHM673 was linearized by the use of restriction enzyme Nhel and transfected into HEF cells via the electroporation method using a Gene Pulser (Bio-rad; 280 V, 960 ⁇ F, 400 ⁇ ) .
- a Gene Pulser Bio-rad; 280 V, 960 ⁇ F, 400 ⁇
- cells were used for infection with 1 PFU/ml of HCMV strain AD 1 69.
- Selection with 200 ⁇ g/ml G41 8 was started 24 h post infection. Following 3 weeks of passage in the presence of G41 8, GFP fluorescence could be detected in most of the infected cells.
- Plaque assays were performed with infectuous culture supernatant on HFF cells and single virus plaques were grown by transfer to fresh HFF cells cultured in 48-well plates.
- DNA was isolated from cells of 32 fluorescence-positive wells and confirmed for the presence of recombinant virus by PCR.
- HFF cells were cultivated in 1 2-well plates to 90-100% confluency and used for infection with dilutions of virus-positive cell culture supernatants. Virus inoculation was performed for 90 min at 37 °C under occasional shaking before virus was removed and the cell layers were rinsed with PBS. Overlays of MEM 5 % (v/v) fetal calf serum and 0.3% (w/v) agarose were added to each well and all samples were incubated at 37°C in a 5 % CO 2 atmosphere for approximately 1 2 days. Finally, overlays were removed and the formation of foci was visualized by staining with 1 % crystal violet in 20% ethanol for 1 min.
- plaque assays After repeated rinsing with PBS, plates were air- dried at room temperature and plaque numbers were counted with a light microscope.
- quantification of plaque assays could also be performed without crystal violet staining by a direct counting of the amount of green fluorescent plaques using fluorescence microscopy.
- Antiviral compounds The reference compounds used for antiviral studies, ganciclovir (GCV, Cymeven), foscarnet sodium (FOS, Foscavir) and cidofovir (CDV, Vistide) were purchased from Syntex Arzneistoff (Aachen, Germany), Sigma- Aldrich (Germany) and Pharmacia & Upjohn S.A. (Luxembourg), respectively. Stocks were prepared in aequeous solution and stored at -20 °C. The test compounds were dissolved in DMSO and aliquots were stored at -20°C.
- HFF cells were cultivated in 1 2-well plates to 90-1 00% confluency and used for infection with 0,5xTCID 50 of AD1 69-GFP virus. Virus inoculation was performed for 90 min at 37 °C with occasional shaking before virus was removed and the cell layers were rinsed with PBS. Infected cell layers were incubated with 2 ml of MEM containing 5% (v/v) fetal calf serum and optionally of the respective test substances or DMSO as control. Infected cells were incubated at 37 °C in a 5% CO 2 atmosphere for 7 days and harvested by trypsination and centrifugation.
- lysis buffer 25 mM Tris pH 7.8, 2 mM DTT, 2 mM trans-1 ,2-diaminocyclohexane-N,N,N',N'- tetraacetic acid, 1 % Triton X-1 00, 10% glycerol
- lysis buffer 25 mM Tris pH 7.8, 2 mM DTT, 2 mM trans-1 ,2-diaminocyclohexane-N,N,N',N'- tetraacetic acid, 1 % Triton X-1 00, 10% glycerol
- Cells were either grown on Lab-Tek Permanox slides (Nunc) or harvested from 6-well plates, spotted onto glass slides with marked rings (Medco) and fixed by a 1 5-min treatment with 3% formaldehyde in PBS followed by permeabilization for 1 5 min in 0.1 % Triton X-1 00 in PBS at room temperature. Blocking was achieved by incubation with Cohn Fraction ll/lll of human gamma-globulin (Sigma; 2 mg/ml) for 30 min at 37 °C.
- the IE 1 /IE2-specific primary antibody MAb81 0 (Chemicon International, Inc.
- Table 1 shows the compounds and lists which percentage of DHODH activity is inhibited at a concentration of 20 ⁇ M. Values are averages of duplicate measurements from two different experiments. Percentage of HCMV inhibition at 20 ⁇ M and 1 00 /vM (two different experiments) of the substances are also shown. Values are averages of duplicate measurements. Table 1
- the compounds shown in Fig. 1 also have significant anti-viral activity in the assay system as described above.
- a series of laboratory variants of AD 1 69-GFP virus with resistance against ganciclovir (GCV) was generated.
- HFF cells were infected in 1 2-well plates with MOI 0.002 and incubated with 1 ⁇ M of GCV.
- GFP-expression in infected cells was monitored microscopically and the supernatants of positive wells were transferred to fresh cells weekly. Thereby GCV concentrations were increased stepwise ( 1 -//M increase in each step) up to the point where the total virus replication became critical and resistant virus grew out in individual wells. Using supernatants of these wells, two rounds of plaque purifications were performed on HFF cells.
- GCV-resistant viral clones e.g. AD1 69-GFP31 4
- HFF cells were cultivated in 1 2-well plates to 90-1 00% confluency and used for infection with dilutions of virus stocks (i.e. AD 1 69-GFP or AD1 69- GFP31 4) .
- virus inoculation was performed for 90 minutes at 37 °C under occasional shaking before virus was removed and the cell layers were rinsed with PBS.
- Overlays of MEM containing 5% (v/v) fetal calf serum and 0.3% (w/v) agarose were added to each well. The plates were incubated at 37°C in a 5 % CO 2 atmosphere for 8-1 2 d.
- plaque purification of GFP- expressing viruses plates were used for fluorescence microscopy, GFP- positive plaques were picked from the overlays and transferred to fresh cells for virus multiplication.
- plaque reduction assays antiviral compounds were incubated in the overlays after infection. Overlays were removed and plaque formation was visualized by staining with 1 % cristal violet in 20% ethanol for 1 min. After repeated rinsing with PBS, plates were air-dried at room temperature and plaque numbers were counted with a light microscope.
- quantification of plaque reduction assays could be performed alternatively, without cristal violet staining, by a direct counting of the numbers of green fluorescent plaques using fluorescence microscopy.
- HFF cells were cultivated in 1 2-well plates (250,000 cells/well) and used for infection with 0.5xTCID 50 -GFP of AD1 69-GFP or AD 1 69-GFP31 4 virus. Virus inoculation was performed as described above. [TCID 50 -GFP was defined as the dilution of the virus inoculum producing 50% of the maximal GFP signal in HFF cells] . Then, infected cell layers were incubated with 2,5 ml of MEM containing 5 % (v/v) fetal calf serum and optionally a dilution of one of the respective test compounds. Infected cells were incubated at 37 °C in a 5 % CO 2 atmosphere for 7 d.
- lysis buffer 25 mM Tris pH 7.8 2 mM DTT, 2 mM trans- 1 ,2-diaminocyclohexane-N,N,N',N'- tetraacetic acid, 1 % Triton X-100, 1 0% glycerol
- lysis buffer 25 mM Tris pH 7.8 2 mM DTT, 2 mM trans- 1 ,2-diaminocyclohexane-N,N,N',N'- tetraacetic acid, 1 % Triton X-100, 1 0% glycerol
- GCV-resistant HCMV is sensitive to compound ( 1 ) or compound (6) .
- HFF cells were cultivated in 1 2-well plates and infected with the indicated concentrations of GFP-expressing variants of HCMV, AD1 69-GFP (parental) or AD1 69-GFP314 (GCV-resistant) .
- the following chemical compounds were added to the culture media: DMSO 0.07% (A), 0.1 4% (B), ganciclovir (GCV) 1 0 M (A and B), compound (6) 35 ⁇ M (A) and 70 M (B), and compound ( 1 ) 35 ⁇ M (A) and 70 ⁇ M (B) .
- Seven days postinfection infected cells were harvested and used for GFP quantification.
- the results for parental virus AD 1 69-GFP and a GCV- resistant virus mutant (AD 1 69-GFP314) are shown in Fig. 2a and 2b, respectively.
Abstract
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/EP2000/009306 WO2001021160A2 (fr) | 1999-09-23 | 2000-09-22 | Derives de carboxamide, inhibiteurs selectifs d'agents pathogenes |
AU79064/00A AU7906400A (en) | 1999-09-23 | 2000-09-22 | Carboxamide derivatives as selective inhibitors of pathogens |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99118802.0 | 1999-09-23 | ||
EP99118802 | 1999-09-23 | ||
EP00115240.4 | 2000-07-13 | ||
EP00115240 | 2000-07-13 | ||
PCT/EP2000/009306 WO2001021160A2 (fr) | 1999-09-23 | 2000-09-22 | Derives de carboxamide, inhibiteurs selectifs d'agents pathogenes |
Publications (3)
Publication Number | Publication Date |
---|---|
WO2001021160A2 true WO2001021160A2 (fr) | 2001-03-29 |
WO2001021160A3 WO2001021160A3 (fr) | 2002-01-31 |
WO2001021160B1 WO2001021160B1 (fr) | 2002-05-30 |
Family
ID=27222599
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2000/009306 WO2001021160A2 (fr) | 1999-09-23 | 2000-09-22 | Derives de carboxamide, inhibiteurs selectifs d'agents pathogenes |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2001021160A2 (fr) |
Cited By (64)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004056797A1 (fr) * | 2002-12-23 | 2004-07-08 | 4Sc Ag | Aromatic compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
DE10304374A1 (de) * | 2003-02-04 | 2004-08-05 | Aventis Pharma Deutschland Gmbh | Neue substituierte 2-Aminoimidazole, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
DE10304294A1 (de) * | 2003-02-04 | 2004-08-12 | Aventis Pharma Deutschland Gmbh | N-Substituierte(Benzoimidazol-2-yl)-phenyl, Verfahren zu ihrer Herstellung , ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
WO2005004864A1 (fr) * | 2003-07-11 | 2005-01-20 | Merck Patent Gmbh | Derives de benzimidazoles utilises comme inhibiteurs de kinase raf |
US7049333B2 (en) | 2002-06-04 | 2006-05-23 | Sanofi-Aventis Deutschland Gmbh | Substituted thiophenes: compositions, processes of making, and uses in disease treatment and diagnosis |
US7071355B2 (en) | 2002-12-23 | 2006-07-04 | 4 Sc Ag | Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
WO2006136580A2 (fr) * | 2005-06-21 | 2006-12-28 | Neurosearch A/S | Nouveaux derives de 2-(phenylamino)benzimidazole et utilisation de ceux-ci en tant que modulateurs de canaux de potassium actives par le calcium a faible conductance |
JP2007518765A (ja) * | 2004-01-21 | 2007-07-12 | ノバルティス アクチエンゲゼルシャフト | 有機化合物 |
US7247736B2 (en) | 2002-12-23 | 2007-07-24 | 4Sc Ag | Method of identifying inhibitors of DHODH |
US7365094B2 (en) | 2002-12-23 | 2008-04-29 | 4Sc Ag | Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
US7432281B2 (en) | 2003-10-07 | 2008-10-07 | Renovis, Inc. | Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same |
US7514583B2 (en) | 2002-05-31 | 2009-04-07 | Proteotech, Inc. | Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer's disease, type 2 diabetes, and parkinson's disease |
US7521470B2 (en) | 2004-06-18 | 2009-04-21 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
US7576099B2 (en) | 2005-02-28 | 2009-08-18 | Renovis, Inc. | Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same |
WO2009110542A1 (fr) * | 2008-03-07 | 2009-09-11 | 住友化学株式会社 | Composé anilide et son utilisation |
US20100056515A1 (en) * | 2006-10-25 | 2010-03-04 | Kazuyoshi Aso | Benzimidazole compounds |
US20100076078A1 (en) * | 2006-09-11 | 2010-03-25 | Syngenta Corp Protection, Inc. | Insecticidal compounds |
US7696352B2 (en) | 2004-06-18 | 2010-04-13 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
US7763608B2 (en) | 2006-05-05 | 2010-07-27 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
US7812176B2 (en) | 2004-03-23 | 2010-10-12 | Arena Pharmaceuticals, Inc. | Processes for preparing substituted N-aryl-N′-[3-(1H-pyrazol-5-YL) phenyl] ureas and intermediates thereof |
US7884101B2 (en) | 2004-11-19 | 2011-02-08 | Arena Pharmaceuticals, Inc. | 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US8067614B2 (en) | 2003-02-04 | 2011-11-29 | Sanofi-Aventis Deutschland Gmbh | N-substituted (benzoimidazol-2-yl)phenylamines, processes for their preparation, their use as a medicament or diagnostic aid, and a medicament comprising them |
CN102285979A (zh) * | 2011-07-26 | 2011-12-21 | 贵州大学 | N-(2-(取代苯并噻唑-2-氨基甲酰基)-苯基)-取代吡唑甲酰胺类化合物及其制备方法和用途 |
US8088806B2 (en) | 2005-05-09 | 2012-01-03 | Achillion Pharmaceuticals, Inc. | Thiazole compounds and methods of use |
US8106209B2 (en) | 2008-06-06 | 2012-01-31 | Achillion Pharmaceuticals, Inc. | Substituted aminothiazole prodrugs of compounds with anti-HCV activity |
US8148417B2 (en) | 2006-05-18 | 2012-04-03 | Arena Pharmaceuticals, Inc. | Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US8148418B2 (en) | 2006-05-18 | 2012-04-03 | Arena Pharmaceuticals, Inc. | Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US8163935B2 (en) | 2005-04-27 | 2012-04-24 | Takeda Pharmaceutical Company Limited | Fused heterocyclic compounds |
US8183263B2 (en) | 2007-05-22 | 2012-05-22 | Achillion Pharmaceuticals, Inc. | Heteroaryl substituted thiazoles |
CN102603729A (zh) * | 2012-01-12 | 2012-07-25 | 贵州大学 | N-(2-(取代苯并噻唑-2-氨基甲酰基)-取代苯基)吡啶甲酰胺类衍生物 |
US20120277185A1 (en) * | 2009-07-24 | 2012-11-01 | Bayer Cropsciende Ag | Pesticidal Carboxamides |
US8318752B2 (en) | 2003-09-19 | 2012-11-27 | Astrazeneca Ab | 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-methylcarbamoyl-methyl)piperidin-4-yl]oxy}quinazoline, its pharmaceutically acceptable salts, and pharmaceutical compositions comprising the same |
EP2591354A1 (fr) * | 2010-07-07 | 2013-05-15 | Ardelyx, Inc. | Composés et procédés pour l'inhibition du transport de phosphate |
US8481535B2 (en) | 2006-05-18 | 2013-07-09 | Arena Pharmaceuticals, Inc. | Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor |
US8530501B2 (en) | 2009-12-17 | 2013-09-10 | Millennium Pharmaceuticals, Inc. | Salts and crystalline forms of a factor Xa inhibitor |
US8742120B2 (en) | 2009-12-17 | 2014-06-03 | Millennium Pharmaceuticals, Inc. | Methods of preparing factor xa inhibitors and salts thereof |
US8754133B2 (en) | 2001-11-02 | 2014-06-17 | Proteotech, Inc. | Compounds, compositions and methods for the treatment of inflammatory diseases |
US8754238B2 (en) | 2003-07-22 | 2014-06-17 | Arena Pharmaceuticals, Inc. | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto |
US8809339B2 (en) | 2010-07-07 | 2014-08-19 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US8815908B2 (en) | 2010-07-07 | 2014-08-26 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US8815910B2 (en) | 2010-07-07 | 2014-08-26 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US8916569B2 (en) | 2010-07-07 | 2014-12-23 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US8980891B2 (en) | 2009-12-18 | 2015-03-17 | Arena Pharmaceuticals, Inc. | Crystalline forms of certain 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US9034911B2 (en) | 2008-10-28 | 2015-05-19 | Arena Pharmaceuticals, Inc. | Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto |
US9078899B2 (en) | 2013-01-10 | 2015-07-14 | Gruenenthal Gmbh | Pyrazolyl-based carboxamides II |
US9126946B2 (en) | 2008-10-28 | 2015-09-08 | Arena Pharmaceuticals, Inc. | Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea and crystalline forms related thereto |
US9206136B2 (en) | 2013-01-10 | 2015-12-08 | Grünenthal GmbH | Pyrazolyl-based carboxamides I |
US9216982B2 (en) | 2008-01-04 | 2015-12-22 | Intellikine Llc | Certain chemical entities, compositions and methods |
US9434692B2 (en) | 2006-10-03 | 2016-09-06 | Arena Pharmaceuticals, Inc. | Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
WO2016202935A1 (fr) | 2015-06-19 | 2016-12-22 | Bayer Pharma Aktiengesellschaft | Inhibiteurs de transport du glucose |
US9556149B2 (en) | 2008-04-02 | 2017-01-31 | Arena Pharmaceuticals, Inc. | Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor |
US9567327B2 (en) | 2007-08-15 | 2017-02-14 | Arena Pharmaceuticals, Inc. | Imidazo[1,2-a]pyridine derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US9604965B2 (en) | 2010-04-23 | 2017-03-28 | Cytokinetics, Inc. | Substituted pyridazines as skeletal muscle modulators |
US9663483B2 (en) | 2010-06-07 | 2017-05-30 | Novomedix, Llc | Furanyl compounds and the use thereof |
US9730886B2 (en) | 2010-04-23 | 2017-08-15 | Cytokinetics, Inc. | Amino-pyrimidine skeletal muscle modulators |
US9822131B2 (en) | 2008-01-04 | 2017-11-21 | Intellikine Llc | Certain chemical entities, compositions and methods |
USRE46621E1 (en) | 2011-01-10 | 2017-12-05 | Infinity Pharmaceuticals, Inc. | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
US9994528B2 (en) | 2010-04-23 | 2018-06-12 | Cytokinetics, Inc. | Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use |
US10022355B2 (en) | 2015-06-12 | 2018-07-17 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder |
US10034859B2 (en) | 2015-07-15 | 2018-07-31 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease |
US11110096B2 (en) | 2014-04-16 | 2021-09-07 | Infinity Pharmaceuticals, Inc. | Combination therapies |
US11147818B2 (en) | 2016-06-24 | 2021-10-19 | Infinity Pharmaceuticals, Inc. | Combination therapies |
CN114763346A (zh) * | 2021-01-15 | 2022-07-19 | 华东师范大学 | 一类用于诱导软骨形成的化合物及其应用 |
WO2024028893A1 (fr) * | 2022-08-01 | 2024-02-08 | Council Of Scientific And Industrial Research An Indian Registered Body Incorporated Under The Regn. Of Soc. Act (Act Xxi Of 1860) | Benzimidazoles substitués pour le traitement de maladies virales |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8759380B2 (en) | 2011-04-22 | 2014-06-24 | Cytokinetics, Inc. | Certain heterocycles, compositions thereof, and methods for their use |
US8828998B2 (en) | 2012-06-25 | 2014-09-09 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3303201A (en) * | 1964-02-24 | 1967-02-07 | Herbert C Stecker | Halogenated anilides of thiophene carboxylic acids |
WO1995019169A2 (fr) * | 1994-01-07 | 1995-07-20 | Sugen, Inc. | Traitement de troubles lies au facteur mitogenique plaquettaire tels que les cancers a l'aide d'inhibiteurs du recepteur de facteur mitogenique plaquettaire |
WO1996016675A2 (fr) * | 1994-11-30 | 1996-06-06 | Rega Institute | Composition de prevention et de traitement d'une infection a vih-1 comprenant au moins deux inhibiteurs differents de la transcriptase inverse vih-1 |
EP0821952A1 (fr) * | 1996-07-31 | 1998-02-04 | Hoechst Aktiengesellschaft | L'usage des dérivés d'isoxazole et d'amide d'acide crotonique pour la modulation de l'apoptose |
WO1998040381A1 (fr) * | 1997-03-14 | 1998-09-17 | Vertex Pharmaceuticals Incorporated | Inhibiteurs de l'enzyme impdh |
WO2000040242A2 (fr) * | 1998-12-30 | 2000-07-13 | Axxima Pharmaceuticals Ag | Preparation d'un agent servant a lutter contre le virus de l'hepatite b, le vih, le paramyxovirus et l'orthomyxovirus |
-
2000
- 2000-09-22 WO PCT/EP2000/009306 patent/WO2001021160A2/fr active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3303201A (en) * | 1964-02-24 | 1967-02-07 | Herbert C Stecker | Halogenated anilides of thiophene carboxylic acids |
WO1995019169A2 (fr) * | 1994-01-07 | 1995-07-20 | Sugen, Inc. | Traitement de troubles lies au facteur mitogenique plaquettaire tels que les cancers a l'aide d'inhibiteurs du recepteur de facteur mitogenique plaquettaire |
WO1996016675A2 (fr) * | 1994-11-30 | 1996-06-06 | Rega Institute | Composition de prevention et de traitement d'une infection a vih-1 comprenant au moins deux inhibiteurs differents de la transcriptase inverse vih-1 |
EP0821952A1 (fr) * | 1996-07-31 | 1998-02-04 | Hoechst Aktiengesellschaft | L'usage des dérivés d'isoxazole et d'amide d'acide crotonique pour la modulation de l'apoptose |
WO1998040381A1 (fr) * | 1997-03-14 | 1998-09-17 | Vertex Pharmaceuticals Incorporated | Inhibiteurs de l'enzyme impdh |
WO2000040242A2 (fr) * | 1998-12-30 | 2000-07-13 | Axxima Pharmaceuticals Ag | Preparation d'un agent servant a lutter contre le virus de l'hepatite b, le vih, le paramyxovirus et l'orthomyxovirus |
Cited By (127)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8754133B2 (en) | 2001-11-02 | 2014-06-17 | Proteotech, Inc. | Compounds, compositions and methods for the treatment of inflammatory diseases |
US8163957B2 (en) | 2002-05-31 | 2012-04-24 | Proteotech, Inc. | Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer's disease, type 2 diabetes and parkinson's disease |
US7514583B2 (en) | 2002-05-31 | 2009-04-07 | Proteotech, Inc. | Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer's disease, type 2 diabetes, and parkinson's disease |
US7317033B2 (en) | 2002-06-04 | 2008-01-08 | Sanofi-Aventis Deutschland Gmbh | Substituted thiophenes: compositions, processes of making, and uses in disease treatment and diagnosis |
US7763643B2 (en) | 2002-06-04 | 2010-07-27 | Sanofi-Aventis Deutschland Gmbh | Substituted thiophenes: compositions, processes of making, and uses in disease treatment and diagnosis |
US7049333B2 (en) | 2002-06-04 | 2006-05-23 | Sanofi-Aventis Deutschland Gmbh | Substituted thiophenes: compositions, processes of making, and uses in disease treatment and diagnosis |
US7488746B2 (en) | 2002-06-04 | 2009-02-10 | Sanofi-Aventis Deutschland Gmbh | Substituted thiophenes: compositions, processes of making, and uses in disease treatment and diagnosis |
US7071355B2 (en) | 2002-12-23 | 2006-07-04 | 4 Sc Ag | Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
JP2006514023A (ja) * | 2002-12-23 | 2006-04-27 | 4エスシー エージー | 抗炎症剤、免疫調節剤及び増殖抑制剤としての芳香族化合物 |
EP2283898A1 (fr) * | 2002-12-23 | 2011-02-16 | 4Sc Ag | Composés cycloalkyles utilisés comme agents anti-inflammatoires, immunomodulateurs et anti-proliferatifs |
JP2010215655A (ja) * | 2002-12-23 | 2010-09-30 | 4Sc Ag | 抗炎症剤、免疫調節剤及び増殖抑制剤としての芳香族化合物 |
US7247736B2 (en) | 2002-12-23 | 2007-07-24 | 4Sc Ag | Method of identifying inhibitors of DHODH |
WO2004056797A1 (fr) * | 2002-12-23 | 2004-07-08 | 4Sc Ag | Aromatic compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
US7365094B2 (en) | 2002-12-23 | 2008-04-29 | 4Sc Ag | Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
US8067614B2 (en) | 2003-02-04 | 2011-11-29 | Sanofi-Aventis Deutschland Gmbh | N-substituted (benzoimidazol-2-yl)phenylamines, processes for their preparation, their use as a medicament or diagnostic aid, and a medicament comprising them |
US7442717B2 (en) | 2003-02-04 | 2008-10-28 | Sanofi-Aventis Deutschland Gmbh | Substituted 2-aminoimidazoles, process for their preparation, their use as medicament or diagnostic aid |
DE10304294A1 (de) * | 2003-02-04 | 2004-08-12 | Aventis Pharma Deutschland Gmbh | N-Substituierte(Benzoimidazol-2-yl)-phenyl, Verfahren zu ihrer Herstellung , ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
DE10304374A1 (de) * | 2003-02-04 | 2004-08-05 | Aventis Pharma Deutschland Gmbh | Neue substituierte 2-Aminoimidazole, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
JP4823903B2 (ja) * | 2003-07-11 | 2011-11-24 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | ベンズイミダゾール誘導体 |
US7691886B2 (en) | 2003-07-11 | 2010-04-06 | Merck Patent Gmbh | Benzimidazole derivatives as raf kinase inhibitors |
JP2007513054A (ja) * | 2003-07-11 | 2007-05-24 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | ベンズイミダゾール誘導体 |
WO2005004864A1 (fr) * | 2003-07-11 | 2005-01-20 | Merck Patent Gmbh | Derives de benzimidazoles utilises comme inhibiteurs de kinase raf |
US9775829B2 (en) | 2003-07-22 | 2017-10-03 | Arena Pharmaceuticals, Inc. | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto |
US9273035B2 (en) | 2003-07-22 | 2016-03-01 | Arena Pharmaceuticals, Inc. | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto |
US8871797B2 (en) | 2003-07-22 | 2014-10-28 | Arena Pharmaceuticals, Inc. | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto |
US8754238B2 (en) | 2003-07-22 | 2014-06-17 | Arena Pharmaceuticals, Inc. | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto |
US8318752B2 (en) | 2003-09-19 | 2012-11-27 | Astrazeneca Ab | 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-methylcarbamoyl-methyl)piperidin-4-yl]oxy}quinazoline, its pharmaceutically acceptable salts, and pharmaceutical compositions comprising the same |
US7432281B2 (en) | 2003-10-07 | 2008-10-07 | Renovis, Inc. | Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same |
JP2007518765A (ja) * | 2004-01-21 | 2007-07-12 | ノバルティス アクチエンゲゼルシャフト | 有機化合物 |
US7812176B2 (en) | 2004-03-23 | 2010-10-12 | Arena Pharmaceuticals, Inc. | Processes for preparing substituted N-aryl-N′-[3-(1H-pyrazol-5-YL) phenyl] ureas and intermediates thereof |
US8377974B2 (en) | 2004-06-18 | 2013-02-19 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
US7696352B2 (en) | 2004-06-18 | 2010-04-13 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
US7521470B2 (en) | 2004-06-18 | 2009-04-21 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
US8153670B2 (en) | 2004-06-18 | 2012-04-10 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
US10781180B2 (en) | 2004-11-19 | 2020-09-22 | Arena Pharmaceuticals, Inc. | 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US8785441B2 (en) | 2004-11-19 | 2014-07-22 | Arena Pharmaceuticals, Inc. | 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US7884101B2 (en) | 2004-11-19 | 2011-02-08 | Arena Pharmaceuticals, Inc. | 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US7576099B2 (en) | 2005-02-28 | 2009-08-18 | Renovis, Inc. | Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same |
US8163935B2 (en) | 2005-04-27 | 2012-04-24 | Takeda Pharmaceutical Company Limited | Fused heterocyclic compounds |
US8088806B2 (en) | 2005-05-09 | 2012-01-03 | Achillion Pharmaceuticals, Inc. | Thiazole compounds and methods of use |
WO2006136580A3 (fr) * | 2005-06-21 | 2007-04-12 | Neurosearch As | Nouveaux derives de 2-(phenylamino)benzimidazole et utilisation de ceux-ci en tant que modulateurs de canaux de potassium actives par le calcium a faible conductance |
WO2006136580A2 (fr) * | 2005-06-21 | 2006-12-28 | Neurosearch A/S | Nouveaux derives de 2-(phenylamino)benzimidazole et utilisation de ceux-ci en tant que modulateurs de canaux de potassium actives par le calcium a faible conductance |
US7960561B2 (en) | 2005-06-21 | 2011-06-14 | Neurosearch A/S | 2-(phenylamino) benzimidazole derivatives and their use as modulators of small-conductance calcium-activated potassium channels |
US7763608B2 (en) | 2006-05-05 | 2010-07-27 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
US7767697B2 (en) | 2006-05-05 | 2010-08-03 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
US8063077B2 (en) | 2006-05-05 | 2011-11-22 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
US8349873B2 (en) | 2006-05-05 | 2013-01-08 | Millennium Pharmaceuticals, Inc. | Factor XA inhibitors |
US9987252B2 (en) | 2006-05-18 | 2018-06-05 | Arena Pharmaceuticals, Inc. | Primary amines and derivitves thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
USRE45337E1 (en) | 2006-05-18 | 2015-01-13 | Arena Pharmaceuticals, Inc. | Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US9221755B2 (en) | 2006-05-18 | 2015-12-29 | Arena Pharmaceuticals, Inc. | Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US8148418B2 (en) | 2006-05-18 | 2012-04-03 | Arena Pharmaceuticals, Inc. | Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US10450276B2 (en) | 2006-05-18 | 2019-10-22 | Arena Pharmaceuticals, Inc. | Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US9328107B2 (en) | 2006-05-18 | 2016-05-03 | Arena Pharmaceuticals, Inc. | Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US8481535B2 (en) | 2006-05-18 | 2013-07-09 | Arena Pharmaceuticals, Inc. | Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor |
US9199940B2 (en) | 2006-05-18 | 2015-12-01 | Arena Pharmaceuticals, Inc. | Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor |
US8664258B2 (en) | 2006-05-18 | 2014-03-04 | Arena Pharmaceuticals, Inc. | Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US8680119B2 (en) | 2006-05-18 | 2014-03-25 | Arena Pharmaceuticals, Inc. | Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
USRE45336E1 (en) | 2006-05-18 | 2015-01-13 | Arena Pharmaceuticals, Inc. | Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US8148417B2 (en) | 2006-05-18 | 2012-04-03 | Arena Pharmaceuticals, Inc. | Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US9783502B2 (en) | 2006-05-18 | 2017-10-10 | Arena Pharmaceuticals, Inc. | Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor |
US20100076078A1 (en) * | 2006-09-11 | 2010-03-25 | Syngenta Corp Protection, Inc. | Insecticidal compounds |
US8466180B2 (en) * | 2006-09-11 | 2013-06-18 | Syngenta Crop Protection Llc | Insecticidal compounds |
US9434692B2 (en) | 2006-10-03 | 2016-09-06 | Arena Pharmaceuticals, Inc. | Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US10351531B2 (en) | 2006-10-03 | 2019-07-16 | Arena Pharmaceuticals, Inc. | Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US9732039B2 (en) | 2006-10-03 | 2017-08-15 | Arena Pharmeceuticals, Inc. | Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
JP2010507664A (ja) * | 2006-10-25 | 2010-03-11 | 武田薬品工業株式会社 | ベンズイミダゾール化合物 |
US20100056515A1 (en) * | 2006-10-25 | 2010-03-04 | Kazuyoshi Aso | Benzimidazole compounds |
US8183263B2 (en) | 2007-05-22 | 2012-05-22 | Achillion Pharmaceuticals, Inc. | Heteroaryl substituted thiazoles |
US10058549B2 (en) | 2007-08-15 | 2018-08-28 | Arena Pharmaceuticals, Inc. | Imidazo[1,2-α]pyridine derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US9567327B2 (en) | 2007-08-15 | 2017-02-14 | Arena Pharmaceuticals, Inc. | Imidazo[1,2-a]pyridine derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US9655892B2 (en) | 2008-01-04 | 2017-05-23 | Intellikine Llc | Certain chemical entities, compositions and methods |
US11433065B2 (en) | 2008-01-04 | 2022-09-06 | Intellikine Llc | Certain chemical entities, compositions and methods |
US9216982B2 (en) | 2008-01-04 | 2015-12-22 | Intellikine Llc | Certain chemical entities, compositions and methods |
US9822131B2 (en) | 2008-01-04 | 2017-11-21 | Intellikine Llc | Certain chemical entities, compositions and methods |
WO2009110542A1 (fr) * | 2008-03-07 | 2009-09-11 | 住友化学株式会社 | Composé anilide et son utilisation |
US10787437B2 (en) | 2008-04-02 | 2020-09-29 | Arena Pharmaceuticals, Inc. | Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor |
US9556149B2 (en) | 2008-04-02 | 2017-01-31 | Arena Pharmaceuticals, Inc. | Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor |
US8106209B2 (en) | 2008-06-06 | 2012-01-31 | Achillion Pharmaceuticals, Inc. | Substituted aminothiazole prodrugs of compounds with anti-HCV activity |
US9745270B2 (en) | 2008-10-28 | 2017-08-29 | Arena Pharmaceuticals, Inc. | Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto |
US9034911B2 (en) | 2008-10-28 | 2015-05-19 | Arena Pharmaceuticals, Inc. | Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto |
US9801856B2 (en) | 2008-10-28 | 2017-10-31 | Arena Pharmaceuticals, Inc. | Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto |
US10071075B2 (en) | 2008-10-28 | 2018-09-11 | Arena Pharmaceuticals, Inc. | Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto |
US10117851B2 (en) | 2008-10-28 | 2018-11-06 | Arena Pharmaceuticals, Inc. | Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto |
US10583122B2 (en) | 2008-10-28 | 2020-03-10 | Arena Pharmaceuticals, Inc. | Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto |
US9353064B2 (en) | 2008-10-28 | 2016-05-31 | Arena Pharmaceuticals, Inc. | Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto |
US9126946B2 (en) | 2008-10-28 | 2015-09-08 | Arena Pharmaceuticals, Inc. | Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea and crystalline forms related thereto |
US10543193B2 (en) | 2008-10-28 | 2020-01-28 | Arena Pharmaceuticals, Inc. | Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto |
US8822691B2 (en) * | 2009-07-24 | 2014-09-02 | Bayer Cropscience Ag | Pesticidal carboxamides |
US20120277185A1 (en) * | 2009-07-24 | 2012-11-01 | Bayer Cropsciende Ag | Pesticidal Carboxamides |
US8530501B2 (en) | 2009-12-17 | 2013-09-10 | Millennium Pharmaceuticals, Inc. | Salts and crystalline forms of a factor Xa inhibitor |
US8742120B2 (en) | 2009-12-17 | 2014-06-03 | Millennium Pharmaceuticals, Inc. | Methods of preparing factor xa inhibitors and salts thereof |
US8980891B2 (en) | 2009-12-18 | 2015-03-17 | Arena Pharmaceuticals, Inc. | Crystalline forms of certain 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto |
US9604965B2 (en) | 2010-04-23 | 2017-03-28 | Cytokinetics, Inc. | Substituted pyridazines as skeletal muscle modulators |
US10272030B2 (en) | 2010-04-23 | 2019-04-30 | Cytokinetics, Inc. | Amino-pyrimidine skeletal muscle modulators |
US9730886B2 (en) | 2010-04-23 | 2017-08-15 | Cytokinetics, Inc. | Amino-pyrimidine skeletal muscle modulators |
US10765624B2 (en) | 2010-04-23 | 2020-09-08 | Cytokinetics, Inc. | Amino-pyrimidine skeletal muscle modulators |
US10076519B2 (en) | 2010-04-23 | 2018-09-18 | Cytokinetics, Inc. | Substituted pyridazines as skeletal muscle modulators |
US11369565B2 (en) | 2010-04-23 | 2022-06-28 | Cytokinetics, Inc. | Amino-pyrimidine skeletal muscle modulators |
US9994528B2 (en) | 2010-04-23 | 2018-06-12 | Cytokinetics, Inc. | Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use |
US9663483B2 (en) | 2010-06-07 | 2017-05-30 | Novomedix, Llc | Furanyl compounds and the use thereof |
US8916569B2 (en) | 2010-07-07 | 2014-12-23 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US8809339B2 (en) | 2010-07-07 | 2014-08-19 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US9278102B2 (en) | 2010-07-07 | 2016-03-08 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US9289429B2 (en) | 2010-07-07 | 2016-03-22 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US9289430B2 (en) | 2010-07-07 | 2016-03-22 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
EP2591354A4 (fr) * | 2010-07-07 | 2014-05-14 | Ardelyx Inc | Composés et procédés pour l'inhibition du transport de phosphate |
US8815908B2 (en) | 2010-07-07 | 2014-08-26 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US8815910B2 (en) | 2010-07-07 | 2014-08-26 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US9301951B2 (en) | 2010-07-07 | 2016-04-05 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
EP2591354A1 (fr) * | 2010-07-07 | 2013-05-15 | Ardelyx, Inc. | Composés et procédés pour l'inhibition du transport de phosphate |
USRE46621E1 (en) | 2011-01-10 | 2017-12-05 | Infinity Pharmaceuticals, Inc. | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
US11312718B2 (en) | 2011-01-10 | 2022-04-26 | Infinity Pharmaceuticals, Inc. | Formulations of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one |
US10550122B2 (en) | 2011-01-10 | 2020-02-04 | Infinity Pharmaceuticals, Inc. | Solid forms of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one and methods of use thereof |
US9840505B2 (en) | 2011-01-10 | 2017-12-12 | Infinity Pharmaceuticals, Inc. | Solid forms of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1 (2H)-one and methods of use thereof |
CN102285979A (zh) * | 2011-07-26 | 2011-12-21 | 贵州大学 | N-(2-(取代苯并噻唑-2-氨基甲酰基)-苯基)-取代吡唑甲酰胺类化合物及其制备方法和用途 |
CN102603729A (zh) * | 2012-01-12 | 2012-07-25 | 贵州大学 | N-(2-(取代苯并噻唑-2-氨基甲酰基)-取代苯基)吡啶甲酰胺类衍生物 |
US9206136B2 (en) | 2013-01-10 | 2015-12-08 | Grünenthal GmbH | Pyrazolyl-based carboxamides I |
US9078899B2 (en) | 2013-01-10 | 2015-07-14 | Gruenenthal Gmbh | Pyrazolyl-based carboxamides II |
US11110096B2 (en) | 2014-04-16 | 2021-09-07 | Infinity Pharmaceuticals, Inc. | Combination therapies |
US11944631B2 (en) | 2014-04-16 | 2024-04-02 | Infinity Pharmaceuticals, Inc. | Combination therapies |
US10022355B2 (en) | 2015-06-12 | 2018-07-17 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder |
WO2016202935A1 (fr) | 2015-06-19 | 2016-12-22 | Bayer Pharma Aktiengesellschaft | Inhibiteurs de transport du glucose |
US11304932B2 (en) | 2015-07-15 | 2022-04-19 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease |
US10034859B2 (en) | 2015-07-15 | 2018-07-31 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease |
US11147818B2 (en) | 2016-06-24 | 2021-10-19 | Infinity Pharmaceuticals, Inc. | Combination therapies |
CN114763346A (zh) * | 2021-01-15 | 2022-07-19 | 华东师范大学 | 一类用于诱导软骨形成的化合物及其应用 |
WO2024028893A1 (fr) * | 2022-08-01 | 2024-02-08 | Council Of Scientific And Industrial Research An Indian Registered Body Incorporated Under The Regn. Of Soc. Act (Act Xxi Of 1860) | Benzimidazoles substitués pour le traitement de maladies virales |
Also Published As
Publication number | Publication date |
---|---|
WO2001021160A3 (fr) | 2002-01-31 |
WO2001021160B1 (fr) | 2002-05-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2001021160A2 (fr) | Derives de carboxamide, inhibiteurs selectifs d'agents pathogenes | |
US10556904B2 (en) | Derivatives and methods of treating hepatitis B infections | |
US11352328B2 (en) | Heterocyclic compounds for the treatment of arenavirus | |
US5124327A (en) | HIV reverse transcriptase | |
US8563562B2 (en) | Compounds having antiviral properties | |
CZ20021020A3 (cs) | Sloučeniny pro léčení ischemie | |
TW200406392A (en) | Thiazolidinones, their production and use as pharmaceutical agents | |
US20030199503A1 (en) | Compounds and methods for the treatment of prevention of flavivirus infections | |
KR20050059294A (ko) | 11-베타-하이드록시 스테로이드 데하이드로게나제 형태 1및 형태 2의 억제제 | |
JP2011502984A (ja) | サーチュインモジュレーターとしてのアミド誘導体 | |
US11505539B2 (en) | Deuterated compounds as inhibitors of the BCL6 BTB domain protein-protein interaction and/or as BCL6 degraders | |
TW202035412A (zh) | 雜芳基二氫嘧啶衍生物和治療b型肝炎感染之方法 | |
US20040176374A1 (en) | Arylsulfonamides as antiviral agents | |
WO2013036749A1 (fr) | Inhibiteurs de l'hélicase du vhc et leurs procédés d'utilisation | |
JP4928444B2 (ja) | 抗ウイルス作用を有する置換アザキナゾリン化合物 | |
KR20030088509A (ko) | 항바이러스제로서의 신규한 아릴술폰아미드 | |
JP2012502881A (ja) | ベンズイミダゾールnf−カッパb阻害剤 | |
JP2015524835A (ja) | トリ(ヘテロ)アリールピラゾール及びその使用 | |
US7115636B2 (en) | Hetrocyclic aryl sulphonamides | |
KR20020079963A (ko) | 바이러스 질병용 약제 | |
US20090048310A1 (en) | Agent for prevention/treatment of disease caused by acyclovir-resistant herpesvirus | |
AU2020321067A1 (en) | Dihydropyrimidine derivatives and uses thereof in the treatment of HBV infection or of HBV-induced diseases | |
KR20000053122A (ko) | Hiv 프로테아제 억제제로 유용한 1-(3-아미노인다졸-5-일)-3-페닐메틸-시클릭 우레아 | |
JP2005521669A (ja) | 抗ウイルス剤として使用するための5員ヘテロ環 | |
KR20220005549A (ko) | Hbv 감염 또는 hbv-유도성 질환의 치료에 유용한 아미드 유도체 |
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 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 US 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 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 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 US 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 BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
WPC | Withdrawal of priority claims after completion of the technical preparations for international publication | ||
AK | Designated states |
Kind code of ref document: B1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN 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 US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: B1 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 BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase in: |
Ref country code: JP |