WO2000034268A1 - Thio-urees inhibitrices des virus de l'herpes - Google Patents

Thio-urees inhibitrices des virus de l'herpes Download PDF

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Publication number
WO2000034268A1
WO2000034268A1 PCT/US1999/028838 US9928838W WO0034268A1 WO 2000034268 A1 WO2000034268 A1 WO 2000034268A1 US 9928838 W US9928838 W US 9928838W WO 0034268 A1 WO0034268 A1 WO 0034268A1
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Prior art keywords
phenyl
thioureido
chloro
amide
carboxylic acid
Prior art date
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PCT/US1999/028838
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English (en)
Inventor
Jonathan David Bloom
Martin Joseph Digrandi
Russell George Dushin
Stanley Albert Lang
Bryan Mark O'hara
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American Home Products Corporation
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Publication date
Priority to HU0104611A priority Critical patent/HUP0104611A3/hu
Priority to KR1020017007115A priority patent/KR20010086090A/ko
Priority to CA002350996A priority patent/CA2350996A1/fr
Priority to EA200100635A priority patent/EA200100635A1/ru
Priority to BR9915993-7A priority patent/BR9915993A/pt
Priority to PL99349043A priority patent/PL349043A1/xx
Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Priority to EP99965131A priority patent/EP1137647A1/fr
Priority to JP2000586715A priority patent/JP2002531557A/ja
Priority to AU31111/00A priority patent/AU3111100A/en
Priority to IL14326199A priority patent/IL143261A0/xx
Publication of WO2000034268A1 publication Critical patent/WO2000034268A1/fr
Priority to NO20012837A priority patent/NO20012837L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
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    • 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
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings 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
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/06—1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
    • 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
    • C07D307/38—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • 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
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • 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
    • C07D405/12—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 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

Definitions

  • viruses have been identified which are members of the family Herpesviridae (reviewed in Roizman, B. 1996. Herpesviridae, p. 2221-2230. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott- Raven Publishers, Philadelphia, PA).
  • Each member of this family is characterized by an enveloped virus containing proteinaceous tegument and nucleocapsid, the latter of which houses the viruses' relatively large double-stranded DNA genome (i.e. approximately 80-250 kilobases).
  • HSV-1 and HSV-2 herpes simplex virus type 1
  • HSV-2 herpes simplex virus type 2
  • VZV varicella- zoster virus
  • the human betaherpesviruses are cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7).
  • the gammaherpesviruses are lymphotropic and include Epstein-Barr virus (EBV) and Kaposi's herpesvirus (HHV-8). Each of these herpesviruses is causally- related to human disease, including herpes labialis and herpes genitalis (HSV-1 and HSV-2 [Whitley, R.J. 1996.
  • Herpes Simplex Viruses p. 2297-2342.
  • B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA] chicken pox and shingles (VZV [Arvin, A. 1996. Varicella-Zoster Virus, p. 2547-2585.
  • infectious mononucleosis EBV [Rickinson, A. B.
  • HCMV Kaposi's sarcoma
  • reactivated virus can be transmitted to infants during birth, causing either skin or eye infection, central nervous system infection, or disseminated infection (i.e. multiple organs or systems). Shingles is the clinical manifestation of VZV reactivation.
  • Treatment of HSV and VZV is generally with antiviral drugs such as acyclovir (Glaxo Wellcome), ganciclovir (Roche) and foscarnet (Asta) which target viral encoded DNA polymerase.
  • HCMV is a ubiquitous opportunistic pathogen infecting 50-90% of the adult population (Britt, W. J., and Alford, C. A. 1996. Cytomegalovirus, p. 2493-2523. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.).
  • Primary infection with HCMV is usually asymptomatic, although heterophile negative mononucleosis has been observed. The virus is horizontally transmitted by sexual contact, breast milk, and saliva. Intrauterine transmission of HCMV from the pregnant mother to the fetus occurs and is often the cause of serious clinical consequences.
  • HCMV remains in a latent state within the infected person for the remainder of his/her life.
  • Cell-mediated immunity plays a central role in controlling reactivation from latency. Impaired cellular immunity leads to reactivation of latent HCMV in seropositive persons.
  • HCMV disease is associated with deficient or immature cellular immunity.
  • HCMV is one of the two most common pathogens causing clinical disease (the other is Pneumocystis).
  • the most common manifestation of HCMV in AIDS is retinitis, although infection of other organs including the adrenal glands, lungs, GI tract, and central nervous system are also reported frequently.
  • 90% of AIDs patients have active HCMV infection; 25- 40% (-85,000 patients in the United States) have life- or sight-threatening HCMV disease.
  • HCMV is the cause of death in 10% of persons with AIDs.
  • HCMV reactivation or reinfection is common amongst kidney, liver, heart, and allogeneic bone marrow transplant patients. Pneumonia is the most common HCMV disease in these patients, occurring in up to 70% of these transplant patients.
  • Congenital infection due to HCMV occurs in 1% of all births, about 40K per year. Up to 25% of these infants are symptomatic for HCMV disease between ages 0-3 years. HCMV disease is progressive, causing mental retardation and neurological abnormalities, in children. Recent studies suggest that treatment with anti-HCMV drugs may reduce morbidity in these children.
  • ganciclovir a nucleoside analog with hemopoietic cell toxicity
  • foscarnet Astra
  • a pyrophosphate analog with nephrotoxicity Astra
  • cidofovir, Gilead a nucleoside phosphonate with acute nephrotoxicity.
  • Each of these drugs target the viral-encoded DNA polymerase are typically administered intravenously due to their low bioavailability, and, as noted above, are the source of significant toxicity.
  • Ganciclovir-resistant mutants which arise clinically are often cross-resistant with cidofovir. Hence, there is a need for safer (i.e. less toxic), orally bioavailable antiviral drugs which are directed against novel viral targets.
  • Phenyl thioureas are disclosed for use in a variety of pharmaceutical applications. Armistead, et al., WO 97/40028, teaches phenyl ureas and thioureas as inhibitors of the inosine monophosphate dehydrogenase (IMPDH) enzyme which is taught to play a role in viral replication diseases such herpes.
  • IMPDH inosine monophosphate dehydrogenase
  • Widdowson, et al., WO 96/25157 teaches phenyl urea and thiourea compounds of the below formula for treating diseases mediated by the chemokine, interieukin- 8.
  • herpes viruses including human cytomegalovirus, herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus, human herpesviruses-6 and -7, and Kaposi herpesvirus.
  • A is heteroaryl
  • R 9 -R 12 are independently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, or R 9 and R 10 or R perpetrat and R I2 may be taken together to form aryl of 5 to 7 carbon atoms; W is O, NR 6 , or is absent; G is aryl or heteroaryl;
  • X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; and
  • J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6; or a pharmaceutical salt thereof.
  • A is a 5 or 10 membered mono or bicyclic heteroaryl having 1 or 2 heteroatoms. More preferably, A is pyridyl, furyl, imidazolyl, pyrrolyl, thienyl, or indanyl. Still more preferably, A is 3-pyridyl.
  • A is substituted with one or more substitutents selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, -CN, -NO 2 , -CO 2 R 6 , -COR 6 , -OR 6 , -SR 6 , -SOR 6 , -SO 2 R 6 , -CONR ⁇ , -NR 6 N(R 7 R 8 ), -N(R 7 R 8 ) or W-Y-(CH 2 ) n -Z wherein R 6 and R.
  • R g is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or
  • R- and R 8 taken together may form a 3 to 7 membered heterocycloalkyl
  • W is O, NR 6 , or is absent
  • Y is -(CO)- or -(CO 2 )-, or is absent;
  • Z is alkyl of 1 to 4 carbon atoms, -CN, -CO 2 R 6 , COR 6 , -CONR ⁇ , -OCOR 6 , -NR 6 COR-, -OCONR 6 , -OR 6 , -SR 6 , -SOR 6 , -SO 2 R 6 , SR 6 N(R_R 8 ), -N(R_R 8 ) or phenyl; and n is 1 to 6.
  • A is substituted with one or more substitutents selected from halogen or alkyl of 1-6 carbon atoms.
  • At least 1 of R 9 -R 12 is not hydrogen.
  • one of R 9 -R 12 is not hydrogen, one or more of R 9 -R 12 are selected from halogen, methyl, methoxy, and cyano. More preferably each of R 9 -R, 2 is hydrogen.
  • G is preferably a 5 or 6 membered heteroaryl having 1 or 2 heteroatoms. More preferably, G is furyl or thiadiazole and in still more preferred embodiments, G is 1,2,3 thiadiazolyl or 2-furyl. Alternatively, G may be alkyl of 1 to 6 carbon atoms which optionally may be substituted, preferably by a halogen.
  • X is preferably a bond or straight chain lower alkyl group.
  • X is a lower alkyl group it is preferred that X is methyl or ethyl.
  • Preferred compounds of the present invention are the following compounds which include pharmaceutical salts thereof.
  • Furan-2-carboxylic acid [4-(3-pyridin-2-yl-thioureido)-phenyl]-amide;
  • Furan-2-carboxylic acid [4-(3-pyridin-4-yl-thioureido)-phenyl] -amide;
  • Furan-2-carboxylic acid [4-(3-pyridin-3-yl-thioureido)-phenyl]-amide; [l,2,3]Thiadiazole-4-carboxylic acid ⁇ 4-[3-(6-chloro-pyridin-3-yl)-thioureido]- phenyl ⁇ -amide;
  • Furan-2-carboxylic acid [4-(3-pyrimidin-4-yl-thioureido)-phenyl]-amide;
  • Furan-2-carboxylic acid [4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-amide;
  • [l,2,3]Thiadiazole-4-carboxylic acid [4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]- amide;
  • Furan-2-carboxylic acid [4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-amide; [l,2,3]Thiadiazole-4-carboxylic acid [4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]- amide;
  • Alkyl as used herein refers to straight or branched chain lower alkyl of 1 to 6 carbon atoms.
  • exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
  • Alkenyl as used herein refers to straight or branched chain lower alkyl of 2 to 6 carbon atoms containing at least one carbon-carbon double bond. Alkenyl includes vinyl groups.
  • Alkynyl refers to straight or branched chain lower alkyl of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond.
  • Alkyl, alkenyl and alkynyl groups of the present invention may be substituted or unsubstituted.
  • Cycloalkyl refers to a saturated mono or bicyclic ring system of 3 to 10 carbon atoms.
  • Exemplary cycloalkyl groups include cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl groups of the present invention may be substituted or unsubstituted.
  • Heterocycloalkyl refers to a saturated mono or bicyclic ring system of 3 to 10 members having 1 to 3 heteroatoms selected from N, S and O, including, but not limited to aziridinyl, azetidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrazolidinyl, piperidinyl, and pyrrolidinyl. Heterocycloalkyl groups of the present invention may be substituted or unsubstituted.
  • Aryl refers to an aromatic mono or bicyclic ring of 5 to 10 carbon atoms.
  • exemplary aryl groups include phenyl, naphthyl, and biphenyl.
  • Aryl groups of the present invention may be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic mono or bicyclic ring of 5 to 10 members having 1 to 3 heteroatoms selected from N, S or O including, but not limited to thiazolyl, thiadiazolyl, oxazolyl, furyl, indolyl, benzothiazolyl, benzotriazolyl, benzodioxyl, indazolyl, and benzofuryl.
  • Preferred heteroaryls include quinolyl, isoquinolyl, napthalenyl, benzofuranyl, benzothienyl, indolyl, pyridyl, pyrazinyl, thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, isofhiazolyl, thiazolyl, pyrazolyl, triazolyl, thiadiazolyl, and imidazolyl.
  • Heteroaryl groups of the present invention may be substituted or unsubstituted.
  • Perhaloalkyl refers to an alkyl group of 1 to 6 carbon atoms in which three or more hydrogens are substituted with halogen.
  • Phenyl as used herein refers to a 6 membered aromatic ring.
  • Halogen as used herein refers to chlorine, bromine, iodine and fluorine.
  • substitutents are unsubstituted and may include alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, heterocycloalkyl of 1 to 6 members, perhaloalkyl of 1 to 6 carbon atoms, alkylamino, dialkylamino, aryl or heteroaryl.
  • Carbon number refers to the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituents such as an alkyl or alkoxy substituents.
  • alkylcycloalkyl is an alkyl-cycloalkyl group in which alkyl and cycloalkyl are as previously described.
  • Pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
  • a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
  • the compounds of this invention contain a chiral center, providing for various seteroisomeric forms of the compounds such as racemic mixtures as well as the individual optical isomers.
  • the compounds of the present invention are substantially pure optical isomers.
  • substantially pure is meant the composition contains greater than 75% of the desired isomer and may include no more than 25% of the undesired isomer.
  • the pure optical isomer is greater than 90% of the desired isomer.
  • the (S) isomer is preferred.
  • the individual isomers can be prepared directly or by asymmetric or stereospecific synthesis or by conventional separation of optical isomers from the racemic mixture.
  • novel compounds of the present invention are prepared according to the following reaction schemes.
  • appropriately substituted thioureas 1 can be prepared as described by Methods 32 and 33 by reacting amines 2 and 5 in the presence of either one molar equivalent of 1,1 '-thiocarbonyl diimidazole in an appropriate solvent such as dichloro-methane and tetrahydrofuran or mixtures thereof or one molar equivalent of l,l'-thiocarbonyl-di-(l,2,4)-triazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof at room temperature.
  • an appropriate solvent such as dichloro-methane and tetrahydrofuran or mixtures thereof
  • l,l'-thiocarbonyl-di-(l,2,4)-triazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof at room temperature.
  • Thioureas 1 wherein A comprises at least one substituent which is 1- hydroxyethoxy or carboxy-methoxy, R 9 -R 12 and G are defined as above and X equals a bond, may be prepared from the corresponding alkyl esters by alkaline hydrolysis with aqueous sodium or potassium hydroxide in a suitable solvent such as methanol, tetrahydrofuran or mixtures thereof at room temperature in accordance with Methods 35 and 36.
  • Thioureas 1 wherein A comprisese at least one substituent which is 1- acyloxyethoxy or methansulfonoxyethoxy, R 9 -R 12 and G are defined as above and X equals a bond, may be prepared from the corresponding 1-hydroxyethoxy derivative by acylation with appropriate acylating agents such as benzoic acid chloride or methanesulfonic acid chloride in the presence of a suitable tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane or the like at room temperature in accordance with Methods 37 and 38.
  • acylating agents such as benzoic acid chloride or methanesulfonic acid chloride in the presence of a suitable tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane or the like at room temperature in accordance with Methods 37 and 38.
  • Thioureas 1 wherein A comprises at least one substituent which is 1-amino- ethoxy, R 9 -R 12 and G are defined as above and X equals a bond, may be prepared from the corresponding 1-methanesulfonoxy-ethoxy derivative by reaction with an appropriate secondary amine such as dimethylamine in a suitable solvent mixture such as tetrahydrofuran and water or the like at room temperature in accordance with Method 39.
  • Thioureas 1 wherein A comprises at least one substituent which is 1-amino- alkyl, R 9 -R 12 and G are defined as above and X equals a bond, may be prepared from the corresponding 1-azidoalkyl derivative by reaction with stannous chloride in a suitable solvent such as methanol, ethanol or the like at room temperature in accordance with Method 40.
  • the intermediates 2 and 5 may be prepared according to the following protocols:
  • amines 2, wherein A is defined above and X is defined above and amines 5, wherein R 9 -R 12 are defined above may be prepared by reduction of the appropriately substituted nitrobenzenes and corresponding heteroaryls according to a variety of procedures known to those skilled in the art and described in R. J. Lindsay, Comprehensive Organic Chemistry (ed. Sutherland), Volume 2, Chapter 6.3.1, Aromatic Amines, 1979.
  • Such procedures include the reduction of nitrobenzenes to form anilines upon exposure to: a) iron powder and a strong acid, such as hydrochloric acid (Methods 1 A) either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; b) iron powder and glacial acetic acid (Method IB), either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; c) iron powder and aqueous ammonium chloride (Method IC), either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; d) tin and a strong mineral acid, such as hydrochloric acid (Method ID), either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; e) when substitute
  • amines 2, wherein A is defined above and X is defined above and anilines 5, wherein R 9 -R 12 are defined above may be prepared by the cleavage of the aniline nitrogen-carbon bond of amide and carbamate derivatives of these anilines according to a variety of procedures known to those skilled in the art and described in Greene, Protective Groups in Organic Synthesis volume 2, Chapter 7, 1991, and references therein. Such procedures include:
  • amines 2, wherein A is defined above, and X equals a bond and at least one substituent of A is vinyl may be prepared by the palladium catalyzed coupling of a vinyl trialkyltin reagent, such as tributylvinyltin, with an appropriately substituted bromo- or iodo-aniline, for example 3-chloro-4- iodo-aniline, employing a palladium catalyst, such as tris(dibenzylidineacetone)- bipalladium, and a ligand, such as triphenylarsine, in a suitable solvent such as tetrahydrofuran or N-methylpyrrolidinone, at temperatures ranging from room temperature to the reflux temperature of the solvent, essentially according to the procedures of V. Farina and G.P. Roth in Advances in Metal-Organic Chemistry. Vol. 5, 1-53, 1996 and references therein.
  • amines 2, wherein A is defined above and X is defined above and at least one substituent of A is defined as dialkylamino may be prepared by the palladium catalyzed amination of an appropriately substituted 3- or 5-bromo- or iodo-aniline, by secondary amines under conditions which employ a palladium catalyst, such as bis(dibenzylidineacetone)palladium, and a ligand, such as tri-o-tolylphosphine, and at least two molar equivalents of a strong base, such as lithium bis- (trimethylsilyl) amide in a sealed tube, in a suitable solvent such as tetrahydrofuran or toluene, at temperatures ranging from room temperature to 100°C, essentially according to the procedures of J.F. Hartwig and J. Louie Tetrahedron Letters 36 (21), 3609 (1995).
  • a palladium catalyst such as bis(dibenzylidineacetone)palladium
  • amines 2, wherein A is defined above and X is defined above and at least one substituent of A is defined as alkyl may be prepared by the palladium catalyzed alkylation of an appropriately substituted 3- or 5-bromo-or iodo-aniline, by alkenes under condiditons which employ a palladium catalyst such as [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) chloride- dichloromethane complex and in the presence of 9-borabicyclo[3.3.1]nonane and a suitable base such as aqueous sodium hydroxide in a suitable solvent such as tetrahydrofuran or the like at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • a palladium catalyst such as [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) chloride- dichloromethane complex
  • a suitable base such as aqueous sodium
  • acyl and carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C may be prepared by the derivatization of the corresponding amines as described in Methods 2A-2G according to a variety of procedures known to those skilled in the art and described in Greene, Protective Groups in Organic Synthesis volume 2, Chapter 7, 1991, and references therein.
  • Such procedures include: a) the reaction of an appropriately substituted amine with di-tert-butyl-dicarbonate (Method 2A) in the presence or absence of one or more molar equivalents of a tertiary amine such as triethylamine or N,N-diisopropylethylamine in a suitable solvent such as acetone, tetrahydrofuran, dimethylformamide, dichloromethane, and the like, at temperatures ranging from room temperature to the reflux temperature of the solvent to produce the corresponding arylamino-tert-butyl- carbamate, or; b) the reaction of an appropriately substituted aniline with l-[2-a tert-butyl-dicarbonate (Method 2A) in the presence or absence of one or more molar equivalents of a tertiary amine such as triethylamine or N,N-diisopropylethylamine in a suitable solvent such as
  • Nitrobenzene intermediates that are ultimately converted to amines 2 and 5 by methods shown above in Methods 1A-1G may be prepared in accordance with Methods 4A, 4C, 4E-4F.
  • the nitrobenzene intermediates which are ultimately converted into amines 2, where A comprises substituent defined as alkoxy, thioalkoxy, alkylsulfenyl, alkylsulfinyl, and dialkylamino may be prepared by the nucleophilic displacement of appropriately substituted 2-, 4-, and/or 6-fluoro-, chloro-, bromo-, iodo-, trifluoromethylsulfonyl-, or (4-methylphenyl)sulfonyl- substituted nitrobenzenes or corresponding heteroaryls by methods which include the following: a) reaction of alcohols with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes, benzonitriles or corresponding heteroaryls (Method 4A) either neat or in an appropriate solvent such as tetrahydrofuran, dioxane, aceton
  • the nitrobenzene intermediates and corresponding heteroaryls which are ultimately converted into amines 2, wherein at least one substitutent of A is defined as alkoxy may be prepared from the corresponding substituted hydroxy-nitrobenzenes and corresponding heteroaryls by methods which include the following: a) reaction of the hydroxy-nitrobenzene with an alkyl halide or dialkyl sulfonate ester (Method 5C) in the presence of a base, such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride, or sodium hydride, in an appropriate solvent such as acetone, N,N-dimethylformamide, tetrahydrofuran or dimethylsulfoxide at temperatures ranging from room temperature to the reflux temperature of the solvent, or; b) reaction of the hydroxy-nitrobenzene or corresponding heteroaryl with an alkyl alcohol, triphenylphosphine, and a dialky
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent of A is defined as alkoxy may be prepared the corresponding substituted hydroxy aryl- or heteroarylamino-tert-butyl-carbamate by reaction with alkyl halides, trifluormethane-sulfonates, 4- methylbenzenesulfonates, dialkylsulfonate, ethylene carbonate and the like in the presence of a suitable base such as potassium carbonate in an appropriate solvent such as acetone, toluene, or N,N-dimethyl-formamide at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • a suitable base such as potassium carbonate
  • an appropriate solvent such as acetone, toluene, or N,N-dimethyl-formamide
  • the nitrobenzene and corresponding heteroaryls which are ultimately converted into amines 2, comprising at least one alkoxy at least one halogen, and X equals a bond may be prepared by standard halogenation reactions which include the following: a) reaction of a 2- or 4- hydroxy-nitrobenzene or corresponding heteroaryl with aqueous sodium hypochlorite (Methods 7A and 7B), at room temperature or; b) reaction of a 2-hydroxy-4-methoxy or 2,4-dimethoxynitrobenzene or corresponding heteroaryl (Method 7C and 7D) with bromine in suitable solvent such as chloroform, dichlormethane, glacial acetic acid or the like in the presence or the absence of silver trifluoroacetate at room temperature, or; c) reaction of a 2,4-dimethoxynitrobenzene or corresponding heteroaryl (Method 7E) with benzyltrimethylam
  • the nitrobenzene intermediates or corresponding heteroaryl which are ultimately converted into amines 2, wherein A is substituted by CF 3 and X equals a bond may be prepared from the corresponding substituted 4-iodo- nitrobenzenes or corresponding heteroaryl by reaction with trimethyl(trifluoromethyl)silane in the presence of cuprous iodide and potassium fluoride in a suitable solvent such as N,N- dimethyl-form amide or the like at a temperature ranging from room temperature to the reflux temperature of the solvent in a sealed reaction vessel.
  • a suitable solvent such as N,N- dimethyl-form amide or the like
  • the nitrobenzene intermediates which are ultimately converted into amines 2, wherein A comprises a substituent defined as - HNCOC ⁇ NR ⁇ or -HNCOCH 2 SR 6 , and X equals a bond may be prepared from the corresponding substituted 4-(N-chloroacetyl)-nitroaniline by reaction with either a suitable secondary amine such as dimethylamine, morpholine or the like in a suitable solvent such as tetrahydrofuran and/or water mixtures at temperatures ranging from room temperature to the reflux temperature of the solvent or by reaction with an appropriate thiol in the presence of a suitable base such as sodium or potassium carbonate or the like in a suitable solvent such as tetrahydrofuran, 1,4-dioxane or the like at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • a suitable secondary amine such as dimethylamine, morpholine or the like
  • a suitable solvent such as tetrahydrofuran and/or water mixtures at
  • the nitrobenzene intermediates or corresponding heteroaryl which are ultimately converted into amines 2, wherein at least one substituent of A is defined as triflate and X equals a bond may be prepared from the corresponding phenol by reaction with trifluoromethane sulfonic anhydride in the presence of a tertiary amines such as triethylamine or diisopropyl-ethylamine or the like in a suitable solvent such as dichloromethane at temperatures ranging from 0°C to room temperature.
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent A is defined as either alkylsulfenyl or alkylsulfinyl may be prepared by reaction of the appropriate 4-alkylthio acylarylamino or acylheteroarylamino or carbamoylarylamino or carbamoylheteroarylamino derivative with an appropriate oxidizing agent such as dimethyloxirane or sodium periodate in a suitable solvent mixture such as acetone and dichloromethane or water at room temperature.
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein a substituent of A is defined as 1 -hydroxyethyl and X equals a bond may be prepared by reacting the corresponding 4- vinyl carbamoyl aniline with sodium borohydride in the presence of mercuric acetate in a suitable solvent such as tetrahydrofuran, 1 ,4- dioxane or the like and water at room temperature.
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein a substituent of A is defined as 2-hydroxyethyl and X equals a bond, may be prepared by reacting the corresponding 4- vinyl carbamoyl aniline with sodium borohydride in the presence of glacial acetic acid in a suitable solvent such as tetrahydrofuran, 1,4- dioxane or the like at temperatures ranging from 0°C to room temperature.
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein a substituent of A is defined as 1-azidoethyl and and X is defined above, may be prepared by reacting the corresponding 4-(l -hydroxyethyl) carbamoyl aniline with hydrazoic acid in the presence of a dialkylazodicarboxylate such as diethylazodicarboxylate and triphenylphosphine in a suitable solvent mixture such as tetrahydrofuran and dichloromethane at temperatures ranging from 0°C to room temperature.
  • a dialkylazodicarboxylate such as diethylazodicarboxylate and triphenylphosphine
  • a suitable solvent mixture such as tetrahydrofuran and dichloromethane
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein a substituent of A is defined as 3-dimethylaminoprop-l-ynyl and X is defined above, may be prepared by reacting the corresponding 4-iodocarbamoyl aniline with 1- dimethylamino-2-propyne in a suitable tertiary amine solvent such as triethylamine or diisopropylethylamine in the presence of bis(triphenylphosphine)palladium(II) chloride and cuprous iodide at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • a suitable tertiary amine solvent such as triethylamine or diisopropylethylamine
  • bis(triphenylphosphine)palladium(II) chloride and cuprous iodide at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein a substituent of A is defined as 3-dimethylaminoacryloyl and X equals a bond, may be prepared by reacting the corresponding 4-(3-dimethylaminoprop-l-ynyl)carbamoyl aniline with a suitable peracid such as 3-chloroperoxybenzoic acid in a suitable solvent mixture such as dichloromethane and methanol at temperatures ranging from 0°C to room temperature.
  • a suitable peracid such as 3-chloroperoxybenzoic acid
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein a substituent of A is defined as either 4-isoxazol-5-yl or 4-(lH-pyrazol-3-yl) and X equals a bond, may be prepared by reacting the corresponding 4- (3- dimethylamino-acryloyl)carbamoyl aniline with either hydroxylamine hydrochloride or hydrazine hydrate in a suitable solvent such as 1,4-dioxane or ethanol and the like at room temperature.
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein a substituent of A is defined as -HNCO 2 Z, Z is defined above and X equals a bond, may be prepared by reacting the corresponding 4-aminocarbamoyl aniline with 1,1- carbonyl-di-(l,2,4)-triazole and an appropriately substituted alcohol in a suitable solvent mixture such as tetrahydrofuran and dichloromethane and the like at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • a suitable solvent mixture such as tetrahydrofuran and dichloromethane and the like
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent of A is defined as dialkylamino and X is defined above may be prepared by reaction of appropriately substituted aldehydes in the presence of either sodium cyanoboro-hydride or hydrogen gas and 10 % palladium on carbon in a suitable solvent such as water, methanol, tetrahydrofuran mixtures or toluene or the like at room temperature.
  • amines 2 wherein at least one substituent of A is defined as hydroxy and X is defined above can be prepared by reaction of the corresponding ester such as acetate with an appropriate base such as sodium bicarbonate or sodium hydroxide in a suitable solvent mixture such as methanol- water mixtures at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • amines 2 wherein at least one substituent of A is defined as 2-hydroxybenzamido and X is defined above can be prepared by reaction of the corresponding N-(4-aminophenyl)phthalimide with lithium borohydride in an appropriate solvent such as tetrahydrofuran, diethyl ether, or the like at room temperature.
  • the intermediate amines 2 wherein X equals either -CH 2 - or -(CH 2 ) 2 - can be prepared by the following procedures: a) reduction of an appropriately substituted benzo- phenyl- or corresponding heteroarylacetonitrile with borane-dimethylsulfide complex in a suitable solvent such as ethylene glycol dimethyl ether, tetrahydrofuran or the like a temperatures ranging from room temperature to the reflux temperature of the solvent.
  • a suitable solvent such as ethylene glycol dimethyl ether, tetrahydrofuran or the like
  • Method 44 b) reduction under one or more atmospheres of hydrogen in the presence of a suitable catalyst such as 5 % or 10 % palladium on carbon and an acid such as 4-methyl-benzenesulfonic acid, hydrochloric acid or the like in a suitable solvent such as ethylene glycol monomethyl ether, ethyl acetate, ethanol or the like at room temperature.
  • a suitable catalyst such as 5 % or 10 % palladium on carbon and an acid such as 4-methyl-benzenesulfonic acid, hydrochloric acid or the like
  • a suitable solvent such as ethylene glycol monomethyl ether, ethyl acetate, ethanol or the like at room temperature.
  • Method 50 c) reduction with lithium aluminum hydride in a suitable solvent such as tetrahydrofuran or diethyl ether at temperatures ranging from 0°C to room temperature.
  • Method 51 and are ultimately converted to amines 2 wherein X equals -(CH 2 ) 2 - can be prepared by reaction of an appropriately substituted benzaldehyde or corresponding heteroaryl with nitro-methane in the presence of ammonium acetate in a suitable solvent such as acetic acid at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • a suitable solvent such as acetic acid at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • the benzaldehydes or corresponding heteroaryls, utilized as starting materials in Method 53 can be prepared by diisobutylaluminum hydride reduction of an appropriately substituted benzonitrile or corresponding heteroaryl.
  • Method 52 The substituted benzonitriles or corresponding heteroaryls, utilized as starting materials in Method 52, can be prepared from the corresponding aryl or heteroaryl bromide by reaction with copper cyanide in a suitable solvent such as N,N-dimethylformamide at temperatures ranging from room temperatture to the reflux temperature of the solvent.
  • a suitable solvent such as N,N-dimethylformamide
  • nitrile precursors may be prepared by reaction of an appropriately substituted phenol, thiophenol or corresponding heteroaryl with bromoacetonitrile in the presence of a suitable base such as potassium carbonate in an appropriate solvent such as acetone at room temperature according to Method 49.
  • a suitable base such as potassium carbonate
  • the nitrile precursors can be prepared essentially according to the procedure of Wilk, B. Synthetic Comm.
  • intermediate amines 2 wherein X equals -(CH(CH 3 ))- can be prepared by acid or base catalyzed hydrolysis of the corresponding formamide using an appropriate acid catalyst such as 6N hydrochloric acid or a suitable base catalyst such as 5N sodium or potassium hydroxide in an appropriate solvent mixture such as water and methanol or water and ethanol at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • an appropriate acid catalyst such as 6N hydrochloric acid or a suitable base catalyst such as 5N sodium or potassium hydroxide
  • an appropriate solvent mixture such as water and methanol or water and ethanol at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • the formamide precursors utilized as starting materials in Method 46 and which are ultimately converted into amines 2, are prepared according to Method 45 by treatment of an appropriately substituted acetophenone with ammonium formate, formic acid and formamide at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • amines 2 wherein X equals -(CH(CH 3 ))- can be prepared by reduction of an appropriately substituted O-methyl oxime in the presence of sodium borohydride and zirconium tetrachloride in a suitable solvent such as tetrahydrofuran or diethyl ether at room temperature
  • Method 48 essentially according to the procedure of Itsuno, S., Sakurai, Y., Ito, K. Synthesis 1988, 995.
  • the requisite O- methyl oximes can be prepared from the corresponding acetophenone by reaction with methoxylamine hydrochloride and pyridine in a suitable solvent such as ethanol or methanol at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • a suitable solvent such as ethanol or methanol at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • Amines 2 for which X equals -CH(J)- where J is defined as above can be prepared by reduction of the appropriately substituted ketone by the methods described above (Methods 45, 47, and 48).
  • ketones when not commercially available, can be prepared by reaction of a suitably substituted benzaldehyde with an appropriate organometallic reagent such as phenyllithium, isopropylmagnesium bromide or ethylmagnesium bromide or the like in a suitable solvent such as diethyl ether or tetrahydrofuran at temperatures ranging from -78 °C to 0°C.
  • organometallic reagent such as phenyllithium, isopropylmagnesium bromide or ethylmagnesium bromide or the like
  • a suitable solvent such as diethyl ether or tetrahydrofuran
  • the intermediate anilines 5 may be prepared as previously described Method 3A.
  • Method 3A treating phenyl carbamic acid tert-butyl ester 6, wherein G is described as above, with neat trifluoroacetic acid at room temperature followed by neutralization with aqueous sodium hydroxide affords the desired anilines 5.
  • carbamic acid esters 6, wherein R 9 -R 12 and G are described as above, are prepared as shown in Method 2E by reaction of substituted carboxylic acids 8a, wherein G is described as above, and an appropriately substituted 4- aminophenyl carbamic acid tert-butyl esters 7 in the presence of a suitable coupling agent such as benzotriazole-l-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate, 2-(lH-benzotriazole-l-yloxy)-l,l,3,3-tetramethyluronium hexafluoro- phosphage, dicyclo-hexyl carbodiimide or the like and in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane, dimethylformamide and the like, at room temperature to produce the corresponding arylamino
  • Carboxylic acids 8a are either commercially available or are prepared according to literature methods.
  • G is a substituted thiadiazole
  • the acid is available from the corresponding carboxylic acid ester by reaction with an appropriate base such as sodium or potassium hydroxide in a suitable solvent mixture such as methanol or ethanol and water at room temperature.
  • the corresponding carboxylic acid 8a is available from the corresponding ethyl or methyl ester by reaction with an appropriate base such as sodium or potassium hydroxide in a suitable solvent mixture such as methanol or ethanol and water at room temperature.
  • Tbese esters are either commercially available or can be prepared according to literature methods. When the carboxylic acid ester precursors which are ultimately converted to acids 8a are not commmercially available, they may be prepared by methods known in the literature.
  • 5-substituted-l,2,3-thiadiazole-4 carboxylic acid esters may be prepared essentially according to the procedure of Caron, M J. Org. Chem. 51, 4075 (1986) and Taber, D. F., Ruckle, R. E. /. Amer. Chem. Soc. 108, 7686
  • a solution of this compound in a suitable solvent such as tetrahydrofuran is treated with gaseous hydrogen sulfide in the presence of a suitable tertiary amine base such as triethylamine or diiso-propylethylamine or the like at room temperature to give the corresponding 4-carboethoxy-thiazole.
  • a suitable solvent such as tetrahydrofuran
  • gaseous hydrogen sulfide in the presence of a suitable tertiary amine base such as triethylamine or diiso-propylethylamine or the like at room temperature to give the corresponding 4-carboethoxy-thiazole.
  • Additional appropriately substituted thiazoles may be prepared essentially according to the procedure of Bredenkamp, M. W., Holzafel, C. W., van Zyl, W. J. Synthetic Comm. 20, 2235 (1990).
  • Appropriate unsaturated oxazoles are prepared essentially according to the procedure of Henneke, K. H., Sch ⁇ llkopf, U., Neudecker, T. Liebigs Ann. Chem. 1979 (1979).
  • Substituted oxazoles may be prepared essentially according to the procedures of Galeotti, N., Montagne, C, Poncet, J., Jouin, P. Tetrahedron Lett. 33, 2807, (1992) and Shin, C, Okumura, K., Ito, A., Nakamura, Y. Chemistry Lett. 1305, (1994).
  • N-(4-Nitro-phenyl)-isobutyrlamide 2.0 g
  • ethylene glycol monomethyl ether 100 mL
  • 10% palladium on carbon 275 mg
  • the mixture is hydrogenated for 2 hours at room temperature under 30 psi of hydrogen on a Parr hydrogenation apparatus.
  • the catalyst is then removed by filtration through diatomaceous earth and the filtrate is evaporated to dryness under reduced pressure by azeotroping three times with heptane. Trituration of the residue with heptane provides the desired product as a white solid.
  • Furan-2-carboxylic acid (4-amino-2-phenylcarbamoyl-phenyl)amide
  • the solution is then cooled, concentrated under reduced pressure, diluted with ethyl acetate, and washed successively three times with 5% aqueous hydrochloric acid then once with saturated aqueous sodium chloride.
  • the solution is dried over anhydrous sodium sulfate then concentrated under reduced pressure to provide the desired crude product as a brown oil. Crystallization is induced by addition of hexanes, and the collected solid material is recrystallized from hexanes to give the desired product as a white solid.
  • Trifluoroacetic acid (5 mL) is added to solid (3,5-dichloro-4-ethoxy-phenyl)- carbamic acid tert-butyl ester (0.97 g) and the mixture is stirred for approximately 45 minutes at room temperature. Water is then added, and the mixture is cooled in an ice bath and basified with solid potassium carbonate. The solution is extracted three times with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium chloride then dried over anhydrous sodium sulfate. Concentration under reduced pressure and recrystallization from hexanes provides the desired product as a pale yellow crystalline solid.
  • N- (4- Amino-pheny ll))-2-methyl-benzamide Acetic acid 2-(4-am ⁇ iino-phenylcarbamoyl)-phenyl ester N- (4- Amino-pheny ll))-4-fluoro-benzamide N- (4- Amino-pheny ll))-3-fluoro-benzamide N- (4- Amino-pheny ll))-2-fluoro-benzamide N-(4- Amino-pheny ll))-2-methoxy-benzamide N- (4- Amino-pheny ll))-3-methoxy-benzamide N- (4- Amino-pheny ll))-4-methoxy-benzamide N- (4- Amino-pheny ll))-2-phenyl-acetamide N-(4- Amino-pheny ll))-2,2-dimethyl-propionamide N- (4- Amino-pheny ll))-2,2,2-trifluoro-
  • Potassium carbonate (5.0 g) is added to a solution of N-[3-cyano-4-(2,2,2- trifluoroacetyl-amino)-phenyl]-2-fluoro-benzamide (2.5 g) in methanol (270 mL) and water (16 mL) and the mixture is refluxed overnight. After removing the solvent under reduced pressure, the residue is suspended in water and extracted with dichloromethane. The organic extracts are pooled, washed with water and then saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide the desired compound as a white solid.
  • the organic layer is then dried over anhydrous magnesium sulfate, the solvent is removed under reduced pressure, and the resulting oil is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an orange solid.
  • n-Butyl lithium (12.3 mL of a 2.5 M solution in hexanes) is added dropwise to a solution of N-methyl aniline (3.0 g) in tetrahydrofuran (75 mL) at 0°C.
  • the mixture is allowed to warm slowly to room temperature and is then re-cooled to 0°C and added by cannula to a solution of 3-chloro-4-fluoronitrobenzene (4.9 g) in tetrahydrofuran (35 mL) that is kept at -78 °C.
  • reaction mixture is permitted to warm to room temperature over the course of 1 hour, and is then concentrated under reduced pressure, quenched by addition of saturated aqueous ammonium chloride, and extracted three times with ethyl acetate.
  • the pooled organic layers are washed three times with 5% aqueous hydrochloric acid, once with water, once with saturated aqueous sodium bicarbonate, once with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate.
  • the residue is chromatographed over silica gel (5% diethyl ether in hexanes is used as the eluant) to provide the desired product as a clear colorless oil.
  • the solvent is then removed by evaporation under reduced pressure and the resulting residue is chromatographed over silica gel (30% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white foam.
  • the solvent is removed under reduced pressure and the residue is chromatographed over silica gel (1% diethyl ether in hexanes followed by 10% ethyl acetate in hexanes is used as the eluant) to provided the desired product as a colorless oil.
  • aqueous acidic extracts are then basified with solid potassium carbonate and extracted three times with ethyl acetate.
  • These pooled organic extracts are then washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent is removed under reduced pressure. The resulting residue is chromatographed over silica gel (hexanes and then 10% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an amber oil.
  • the solvent is removed by evaporation under reduced pressure and the resulting residue is chromatographed over silica gel (33% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a colorless solid.
  • the resulting oil is purified by chromatography over silica gel (30% diethyl ether in petroleum ether is used as the eluant) and then recrystallized from hexanes to give the desired product as pale yellow needles.
  • Ethyl benzoylacetate (5.0 g) is dissolved in methanol (10 mL) and added rapidly to a hot solution of semicarbazide hydrochloride (29 g) in water (130 mL). To this is added pyridine (4.1 g) and after heating to reflux for 5 minutes, the reaction mixture is cooled to -20 °C overnight. The resulting solid semicarbazone is collected by filtration, washed with water and then diethyl ether to give the desired product as white crystals.
  • furan-2-carboxylic acid (4- ⁇ 3-[4-(l-azido-ethyl)-3-chloro-phenyl]-thioureido)- phenyl)-amide (0.22 g) and the solution is stirred for approximately 15 hours at room temperature.
  • the solution is then diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate then saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate.
  • the product is extracted three times into 5% aqueous hydrochloric acid, and pooled acidic extracts are then basified with cooling by addition of 5N aqueous sodium hydroxide.
  • This basic solution is then extracted with ethyl acetate, and these pooled organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure.
  • the resulting residue is chromatographed over silica gel (20-30% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a slightly tinted solid.
  • the mixture is then cooled to room temperature, diluted with hexanes, washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
  • the resulting oil is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white powder.
  • Methoxylamine hydrochloride (2.33 g) is added to a solution of 3'-(trifluoromethyl)- acetophenone (1.5 g) in ethanol (20 mL) and pyridine (2 mL). The solution is heated at reflux for 45 minutes. The reaction mixture is then cooled, concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the desired product as a colorless oil (1.61 g).
  • the aqueous (acid) layer is basified with sodium hydroxide and extracted twice with ethyl acetate.
  • the organic layer is then washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate.
  • the solvent is removed under reduced pressure to provide the desired product as a yellow oil (0.20 g).
  • Diisobutylaluminum hydride (10 mL of a IM solution in methylene chloride) is added dropwise to a solution of 3-dimethylamino-5-trifluoromethylbenzonitrile (1.06 g) in methylene chloride (25 mL) at 0 °C and the mixture stirred for 2 hours. While still at 0 °C a saturated aqueous solution of sodium potassium tartrate (8 mL) is slowly added and the solution is stirred for 1.5 hours. The reaction mixture is then extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide the desired product as a yellow solid (0.97 g).
  • Nitromethane (0.473 g) is added to a solution of 3-dimethylamino-5-trifluoromethyl- benzaldehyde (0.885 g) and ammonium acetate (0.339 g) in acetic acid (3.4 mL) and the solution is heated at 110 °C for 6 hours. The reaction mixture is cooled to 0 °C and a solid forms which is filtered and washed with 1 : 1 water-acetic acid. This solid is recrystallized from ethanol to provide the desired product as a red solid (0.39 g).
  • Diethylazodicarboxylate (5.2 g) is added dropwise to a solution of 4-bromo- phenethylalcohol (2.01 g), and triphenylphosphine (7.9 g) in diethyl ether (16 mL) at 0 °C.
  • the reaction mixture is stirred for 10 minutes and a solution of acetone cyanohydrin (2.6 g) in diethyl ether (10 mL) is added.
  • the clear orange solution is stirred for 5 minutes at 0 °C and then at 25 °C for 12 hours.
  • the reaction mixture is then filtered, and washed with diethyl ether.
  • the filtrate is concentrated under reduced pressure and chromatographed over silica gel (10% ethyl acetate-hexanes is used as the eluant) to provide the desired product as a pale yellow oil (2.04 g).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Oncology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Furan Compounds (AREA)

Abstract

La présente invention concerne des composés représentés par la formule générale (I) ou l'un de ses sels pharmaceutiques. Dans cette formule, A est hétéroaryle; R9-R12 sont indépendamment hydrogène, C1-C4 alkyle, C1-C4 perhaloalkyle, halogène, C1-C4 alcoxy, ou cyano, ou R9 pris avec R10 ou R11 pris avec R12 peuvent former un C5-C7 aryle; W est O, NR6, ou est absent; G est aryle ou hétéroaryle; et X est une liaison, -NH, C1-C6 alkyle, C1-C6 alcényle, C1-C6 alcoxy, C1-C6 thioalkyle, C1-C6 alkylamino, ou (CH)J; et J est C1-C6 alkyle, C3-C7 cycloalkyle, phényle ou benzyle; et n est un entier de 1 à 6. Ces composés conviennent au traitement d'affections associées au virus de l'herpès, y-compris le cytomégalovirus humain, les herpèsvirus simplex, le virus d'Epstein-Barr, le virus de la varicelle-zona, les herpèsvirus -6 et -7 humains, et l'herpèsvirus de Kaposi.
PCT/US1999/028838 1998-12-09 1999-12-06 Thio-urees inhibitrices des virus de l'herpes WO2000034268A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
KR1020017007115A KR20010086090A (ko) 1998-12-09 1999-12-06 헤르페스 바이러스의 티오우레아 억제제
CA002350996A CA2350996A1 (fr) 1998-12-09 1999-12-06 Thio-urees inhibitrices des virus de l'herpes
EA200100635A EA200100635A1 (ru) 1998-12-09 1999-12-06 Производные тиомочевины в качестве ингибиторов вирусов герпеса
BR9915993-7A BR9915993A (pt) 1998-12-09 1999-12-06 Composto, composição farmacêutica, processo para inibir a replicação de um vìrus herpes, e, processo para tratar um paciente sofrendo de uma infecção de vìrus herpes
PL99349043A PL349043A1 (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses
HU0104611A HUP0104611A3 (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses and medicaments containing them
EP99965131A EP1137647A1 (fr) 1998-12-09 1999-12-06 Thio-urees inhibitrices des virus de l'herpes
JP2000586715A JP2002531557A (ja) 1998-12-09 1999-12-06 ヘルペスウイルスのチオ尿素インヒビター
AU31111/00A AU3111100A (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses
IL14326199A IL143261A0 (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses
NO20012837A NO20012837L (no) 1998-12-09 2001-06-08 Tiourea-inhibitorer for herpesvirus

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US20796198A 1998-12-09 1998-12-09
US09/207,961 1998-12-09

Publications (1)

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WO2000034268A1 true WO2000034268A1 (fr) 2000-06-15

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JP (1) JP2002531557A (fr)
KR (1) KR20010086090A (fr)
CN (1) CN1333769A (fr)
AU (1) AU3111100A (fr)
BR (1) BR9915993A (fr)
CA (1) CA2350996A1 (fr)
CZ (1) CZ20012057A3 (fr)
EA (1) EA200100635A1 (fr)
HU (1) HUP0104611A3 (fr)
IL (1) IL143261A0 (fr)
NO (1) NO20012837L (fr)
PL (1) PL349043A1 (fr)
WO (1) WO2000034268A1 (fr)
ZA (1) ZA200104318B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6376515B2 (en) 2000-02-29 2002-04-23 Cor Therapeutics, Inc. Benzamides and related inhibitors of factor Xa
US6844367B1 (en) 1999-09-17 2005-01-18 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
WO2006019955A2 (fr) * 2004-07-14 2006-02-23 President And Fellows Of Harvard College Methodes et compositions antivirales
US8524907B2 (en) 2006-11-02 2013-09-03 Millennium Pharmaceuticals, Inc. Methods of synthesizing pharmaceutical salts of a factor Xa inhibitor

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7718671B2 (en) * 2003-07-10 2010-05-18 Achillion Pharmaceuticals, Inc. Substituted arylthiourea derivatives useful as inhibitors of viral replication
KR101013183B1 (ko) * 2006-04-14 2011-02-10 남명숙 달관측판

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998045259A2 (fr) * 1997-04-10 1998-10-15 Pharmacia & Upjohn Company Compositions antivirales polyaromatiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998045259A2 (fr) * 1997-04-10 1998-10-15 Pharmacia & Upjohn Company Compositions antivirales polyaromatiques

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6844367B1 (en) 1999-09-17 2005-01-18 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US7285565B2 (en) 1999-09-17 2007-10-23 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US8518977B2 (en) 2000-02-29 2013-08-27 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor XA
US8063036B2 (en) 2000-02-29 2011-11-22 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US10179124B2 (en) 2000-02-29 2019-01-15 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US6835739B2 (en) 2000-02-29 2004-12-28 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US7314874B2 (en) 2000-02-29 2008-01-01 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US7342013B2 (en) 2000-02-29 2008-03-11 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US7727982B2 (en) 2000-02-29 2010-06-01 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US7727981B2 (en) 2000-02-29 2010-06-01 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US9629831B2 (en) 2000-02-29 2017-04-25 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor XA
US9108922B2 (en) 2000-02-29 2015-08-18 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US6376515B2 (en) 2000-02-29 2002-04-23 Cor Therapeutics, Inc. Benzamides and related inhibitors of factor Xa
US8691847B2 (en) 2000-02-29 2014-04-08 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
WO2006019955A2 (fr) * 2004-07-14 2006-02-23 President And Fellows Of Harvard College Methodes et compositions antivirales
US7893108B2 (en) 2004-07-14 2011-02-22 President And Fellows Of Harvard College Antiviral methods and compositions
WO2006019955A3 (fr) * 2004-07-14 2006-08-24 Harvard College Methodes et compositions antivirales
US8524907B2 (en) 2006-11-02 2013-09-03 Millennium Pharmaceuticals, Inc. Methods of synthesizing pharmaceutical salts of a factor Xa inhibitor
US9221758B2 (en) 2006-11-02 2015-12-29 Millennium Pharmaceuticals, Inc. Methods of synthesizing pharmaceutical salts of a factor Xa inhibitor

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HUP0104611A2 (hu) 2002-04-29
EA200100635A1 (ru) 2001-12-24
CZ20012057A3 (cs) 2001-11-14
HUP0104611A3 (en) 2002-10-28
AU3111100A (en) 2000-06-26
BR9915993A (pt) 2001-09-04
CA2350996A1 (fr) 2000-06-15
IL143261A0 (en) 2002-04-21
KR20010086090A (ko) 2001-09-07
ZA200104318B (en) 2002-08-26
CN1333769A (zh) 2002-01-30
PL349043A1 (en) 2002-07-01
NO20012837D0 (no) 2001-06-08
JP2002531557A (ja) 2002-09-24
EP1137647A1 (fr) 2001-10-04
NO20012837L (no) 2001-07-19

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