WO2000034269A1 - Inhibiteurs de thio-uree des virus de l'herpes - Google Patents

Inhibiteurs de thio-uree des virus de l'herpes Download PDF

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Publication number
WO2000034269A1
WO2000034269A1 PCT/US1999/028892 US9928892W WO0034269A1 WO 2000034269 A1 WO2000034269 A1 WO 2000034269A1 US 9928892 W US9928892 W US 9928892W WO 0034269 A1 WO0034269 A1 WO 0034269A1
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Prior art keywords
phenyl
thioureido
chloro
carbon atoms
amino
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PCT/US1999/028892
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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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Priority claimed from US09/444,782 external-priority patent/US6166028A/en
Priority to KR1020017007051A priority Critical patent/KR20010086082A/ko
Priority to EP99965143A priority patent/EP1140913A1/fr
Priority to PL99348177A priority patent/PL348177A1/xx
Priority to EA200100637A priority patent/EA200100637A1/ru
Priority to HU0104758A priority patent/HUP0104758A3/hu
Priority to AU31122/00A priority patent/AU756043B2/en
Priority to BR9916042-0A priority patent/BR9916042A/pt
Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Priority to IL14320399A priority patent/IL143203A0/xx
Priority to CA002351390A priority patent/CA2351390A1/fr
Priority to JP2000586716A priority patent/JP2002531558A/ja
Priority to SK769-2001A priority patent/SK7692001A3/sk
Publication of WO2000034269A1 publication Critical patent/WO2000034269A1/fr
Priority to NO20012836A priority patent/NO20012836L/no
Priority to BG105580A priority patent/BG105580A/bg

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • 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

  • 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
  • NZN varicella-zoster virus
  • the human betaherpesviruses are cytomegalovirus (HCMV), human herpesvirus 6 (HHN-6) and human herpesvirus 7 (HHV-7).
  • the gammaherpesviruses are lymphotropic and include Epstein-Barr virus (EBN) and Kaposi's herpesvirus (HHV-8).
  • EBN Epstein-Barr virus
  • HHV-8 Kaposi's herpesvirus
  • 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. ⁇ . 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 HCMV is one of the two most common pathogens causing clinical disease (the other is Pneumocystis).
  • HCMV ulcerative colitis
  • 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 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
  • foscamet 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. Widdowson, et al, WO 96/25157, teaches phenyl urea and thiourea compounds of the below formula for treating diseases mediated by the chemokine, interleukin-8.
  • IMPDH inosine monophosphate dehydrogenase
  • herpes viruses including human cytomegalovirus, herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus, human herpesviruses-6 and -7, and Kaposi herpesvirus.
  • R,-R 5 are independently selected from hydrogen, 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-R 8 , -NR 6 N(R-R 8 ), -N(R_R 8 ) or W-Y-(CH 2 ) n -Z; or R 2 and R 3 or R 3 and R 4 , taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R 6 and R- are independently hydrogen
  • A is heteroaryl; 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_R g , -OCOR 6 , - NR 6 COR-, -OCONR 6 , -OR 6 , -SR 6 , -SOR 6 , -SO 2 R 6 , SR6N(R7R8), -
  • 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;
  • 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.
  • R R 5 is not hydrogen, and preferably one to three of R,-R 5 is not hydrogen.
  • R,- R 5 is selected from hydrogen, alkoxy of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, and halogen.
  • X is (CH)J where J is alkyl of 1 to 6 carbon atoms. More preferably, J is an alkyl of 1 to 3 carbon atoms and most preferably J is methyl.
  • A may be substituted with at least one of 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.
  • A is most preferably unsubstituted.
  • G is preferably a 5 or 6 membered heteroaryl having 1 or 2 heteroatoms.
  • G is oxazoly, furyl, thiazolyl or thiadiazolyl and in more preferred embodiments, G is 1,2,3 thiadiazolyl, 1,3 thiazolyl, or 2-furyl. G is most preferably thiazolyl, and in particular 1,3 thiazolyl.
  • Preferred compounds of the present invention are the following compounds which include pharmaceutical salts thereof:
  • 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, benzo thiazolyl, benzotriazolyl, benzodioxyl, indazolyl, and benzofuryl.
  • Preferred heteroaryls include quinolyl, isoquinolyl, napthalenyl, benzofuranyl, benzothienyl, indolyl, pyridyl, pyrazinyl, thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, 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. Unless otherwise limited substitutents are unsubstituted 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 target is VZV
  • 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, wherein R,-R 5 , A and G are described as above, in the presence of either one molar equivalent of 1,1 '- thiocarbonyl-diimidazole in an appropriate solvent such as dichloromethane 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.
  • Thioureas 1 wherein at least one substituent of R,-R 5 is 1-hydroxyethoxy or carboxy-methoxy, A 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 at least one substituent of R,-R 5 is 1-acyloxyethoxy or methansulfonoxyethoxy, A 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 at least one substituent of R R 5 is 1-aminoethoxy, A 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 at least one substituent of R,-R 5 is 1-aminoalkyl, A 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 intermediate isothiocyanates 3 and 4 shown above in Methods 31 and 34 are prepared in accordance with Method 41 (below) essentially according to the procedures of Staab, H.A. and Walther, G. Justus Liebigs Ann. Chem. 657, 104 (1962)) by reacting appropriately substituted amines 5 or 2, respectively, wherein R,- R 5 , A and G are described above and X is defined above, with one molar equivalent of l,l'-thiocarbonyldiimidazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof.
  • the intermediates 2 and 5 may be prepared according to the following protocols:
  • amines 2, wherein R,-R 5 and X are defined above and amines 5, wherein A is defined above may be prepared by reduction of the appropriately substituted nitrobenzenes 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 R
  • amines 2, wherein R ⁇ R,, are defined above and X is defined as above and anilines 5, wherein A is 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 Svnthesis volume 2, Chapter 7, 1991, and references therein.
  • Such procedures include: a) the exposure of appropriately substituted arylamino-tert-butyl-carbamates to a strong acid such as trifluoroacetic acid (Method 3A)either neat or in an appropriate solvent such as dichloromethane at temperatures between 0°C and room temperature, or; b) the exposure of appropriately substituted arylamino-(2-trimethylsilylethyl)- carbamates to a fluoride ion source such as tetrabutylammonium fluoride or potassium fluoride (Method 3B) in aqueous acetonitrile or tetrahydrofuran or mixtures thereof at temperatures ranging from room temperature to the reflux temperature of the solvent, or; c) the exposure of appropriately substituted arylamino-trifluoroacetamides to a strong base such as sodium or potassium hydroxide or sodium or potassium carbonate in an alcohol solvent such as methanol or ethanol (Method 3C) at temperatures ranging
  • amines 2, wherein R,-R 5 are defined above, and X equals a bond and at least one substituent of R,-R 5 is defined as 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 R,-R 5 are defined above and X is defined as above and at least one substituent of R 2 or R 4 is defined as dialkylamino may be prepared by the palladium catalyzed amination of an appropriately substituted 3- or 5-bromo- or iodo-aniline, for example 3-amino-5- bromobenzotrifluoride, 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.
  • a palladium catalyst such as bis(dibenzylidineacetone)pal
  • amines 2, wherein R ⁇ R j are defined above and X is defined as above and at least one substituent of R 2 or R 4 is defined as alkyl may be prepared by the palladium catalyzed alkylation of an appropriately substituted 3- or 5-bromo-or iodo-aniline, for example 3-amino-5- bromobenzotrifluoride 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.
  • acyl such as [l,l'-bis(diphenylphosphino)ferrocene]palladium(II
  • 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, R 2 and R 4 are defined above and R R 3 , and/or R 5 are 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 by methods which include the following: a) reaction of alcohols with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes or benzonitriles (Method 4 A) either neat or in an appropriate solvent such as tetrahydrofuran, dioxane,
  • the nitrobenzene intermediates which are ultimately converted into amines 2, wherein at least one substitutent R,-R 5 is defined as alkoxy may be prepared from the corresponding substituted hydroxy- nitrobenzenes 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 with an alkyl alcohol, triphenylphosphine, and a dialkylazadicarboxylate reagent (Method 6
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent R,-R 5 is defined as alkoxy may be prepared the corresponding substituted hydroxy arylamino-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 intermediates which are ultimately converted into amines 2, R j and/or R 3 is alkoxy, and R, and/or R 4 is a 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 with aqueous sodium hypochlorite (Methods 7A and 7B), at room temperature or; b) reaction of a 2-hydroxy-4-methoxy or 2,4-dimethoxynitrobenzene (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 (Method 7E) with benzyltrimethylammonium dichloroiodate in the
  • a suitable solvent such as N,N-dimethyl- formamide or the like
  • a suitable secondary amine such as dimethylamine, morpholine or the like
  • a suitable solvent
  • the nitrobenzene intermediates which are ultimately converted into amines 2, wherein at least one substituent of R,-R 5 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 R -R 5 is defined as either alkylsulfenyl or alkylsulfinyl may be prepared by reaction of the appropriate 4-alkylthio acyl- arylamino or carbamoyl arylamino 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 R 4 is defined as 1-hydroxyethyl and R,-R 3 and R 5 are defined as above 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 R 4 is defined as 2-hydroxyethyl and R,-R 3 and R 3 are defined as above 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 R 4 is defined as 1-azidoethyl and R. R ; , and R 5 are defined as above and X is defined as 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 R 4 is defined as 3-dimethylaminoprop-l-ynyl and R,-R 3 and R 5 are defined as above and X is defined as above, may be prepared by reacting the corresponding 4- iodocarbamoyl aniline with l-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
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R 4 is defined as 3-dimethylaminoacryloyl and R,-R 3 and R 5 are defined as above 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 R 4 is defined as either 4-isoxazol-5-yl or 4-(lH-pyrazol-3-yl) and R ⁇ -R 3 and R 5 are defined as above 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.
  • 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 R ⁇ R ; is defined as dialkylamino and X is defined as 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.
  • a suitable solvent such as water, methanol, tetrahydrofuran mixtures or toluene or the like at room temperature.
  • R,-R 5 is defined as hydroxy and X is defined as 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.
  • an appropriate base such as sodium bicarbonate or sodium hydroxide
  • a suitable solvent mixture such as methanol- water mixtures
  • amines 2 wherein at least one substituent of R,-R 5 is defined as 2-hydroxybenzamido and X is defined as 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 R,-R 5 are defined as above and X equals either -CH 2 - or -(CH 2 ) 2 - can be prepared by the following procedures: a) reduction of an appropriately substituted benzo- or phenylacetonitrile 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.
  • the unsaturated nitro precursors which are utilized as starting materials in Method 51 and are ultimately converted to amines 2 wherein R,-R 5 are defined as above and X equals -(CH 2 ) 2 - can be prepared by reaction of an appropriately substituted benzaldehyde 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. (Method 53);
  • the benzaldehydes, utilized as starting materials in Method 53 can be prepared by diisobutylaluminum hydride reduction of an appropriately substituted benzonitrile.
  • Method 52 The substituted benzonitriles, utilized as starting materials in Method 52, can be prepared from the corresponding aryl 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. (Method 59)
  • the requisite nitrile precursors may be prepared by reaction of an appropriately substituted phenol or thiophenol 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.
  • the nitrile precursors can be prepared essentially according to the procedure of Wilk, B. Synthetic Comm. 23, 2481 (1993), by reaction of an appropriately substituted phenethanol with acetone cyanohydrin and triphenylphosphine in the presence of a suitable azodicarboxylate such as diethyl azodicarboxylate in an appropriate solvent such as diethyl ether or tetrahydro-furan or the like at temperatures ranging from 0°C to room temperature. (Method 54)
  • intermediate amines 2 wherein R,-R 5 are defined as above and 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. (Method 46)
  • 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 R,-R 5 are defined as above and 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. (Method 47)
  • Amines 2 for which R,-R 5 are defined as above and 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.
  • the intermediate anilines 5 may be prepared as previously described Method 3A.
  • carbamic acid esters 6, wherein A and G are described as above are prepared as shown in Method 2C by reaction of substituted acid chlorides, 8, where G is described as above, and 4-aminophenyl-carbamic acid tert-butyl esters 7 or the corresponding heteroaryl, wherein A is described above, in the presence of triethylamine in an appropriate solvent such as dichloromethane, dimethylsulfoxide, or dimethylformamide or mixturestthereof.
  • Carboxylic acid chlorides 8 are either commercially available or prepared from the corresponding carboxylic acid by reaction with oxalyl chloride in a suitable solvent such as dichloromethane at room temperature.
  • amines 5 may be prepared as previously described by methods 1 A- IG.
  • treating 2-amino-5-nitropyridine (7) with heterocyclic acid chlorides 8 or other activated acid derivatives as described in Methods 2C-2E affords the nitro amide 6, where G is described as above.
  • Subsequent reduction by procedures described in Methods 1A-1G affords amines 5.
  • carbamic acid esters 6, wherein A 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 or the corresponding heteroaryl in the presence of a suitable coupling agent such as benzotriazole-1-yloxy-tris- (dimethylamino)-phosphonium hexafluorophosphate, 2-(lH-benzotriazole-l-yloxy)- 1,1,3,3-tetra-methyluronium hexafluorophosphate, dicyclohexyl 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 heteroaryl or 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.
  • an appropriate base such as sodium or potassium hydroxide
  • a suitable solvent mixture such as methanol or ethanol and water at room temperature.
  • 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. J. Amer. Chem. Soc. 108, 7686
  • 4- substituted- 1,2,3-thiadiazole -5-carboxylic acid esters may be prepared essentially according to the procedure of Shafiee, A., Lalezari, I., Yazdani, S., Shahbazian, F. M., Partovi, T. J. Pharmaceutical Sci. 65, 304 (1976).
  • a suitable alcoholic solvent such as methanol or ethanol
  • an aqueous solution semicarbazide hydrochloride at temperatures ranging from room temperature to the reflux temperature of the solvent in the presence of a suitable base such as pyridine gives corresponding semicarbazone derivative.
  • 4-carboalkoxythiazoles are prepared essentially according to the procedure of Sch ⁇ llkopf, U., Porsch, P., Lau, H. LiebigsAnn. Chem. 1444 (1979).
  • a suitable alcoholic solvent such as ethanol at room temperature gives the corresponding 3-dimethylamino-2-isocyano-acrylic acid ethyl ester.
  • 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.
  • 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.
  • 3,4,5-Trichloronitrobenzene (14.86 g) is added to a solution of potassium phenoxide (8.66 g) in diethylene glycol (66 mL) and the mixture is heated to 160°C for approximately 15 hours.
  • the resulting dark brown solution is cooled to room temperature, poured onto 100 mL cold water, and extracted twice with diethyl ether.
  • the pooled organic extracts are washed with water, 10% aqueous sodium hydroxide, and then dried over anhydrous magnesium sulfate. Following removal of the solvent under reduced pressure the resulting oil is distilled in a Kugelrohr apparatus to provide a yellow oil that solidifies on standing. Recrystallization from ethanol-water provides the desired product as a pale yellow solid.
  • 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 residue is treated successively three times with small portions of methanol (ca. 50 ml) followed by evaporation to near dryness under reduced pressure, and the volume of the solution is adjusted to 250 mL by addition of methanol.
  • the methanolic solution of the N-oxide is then heated to reflux for approximately 15 hours, then cooled, and the solvent is evaporated to dryness under reduced pressure.
  • the residue is purified by chromatography over silica gel (80% ethyl acetate in hexanes is used as the eluant) to give the desired product as a pale yellow solid.
  • 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.
  • N-(chloroacetyl)-2-chloro-4-nitroaniline (3.80 g) in tetrahydrofuran (50 mL) is added thiomorpholine (10 mL) and the solution allowed to stand for 1 hour.
  • This reaction mixture is poured into water a pale yellow solid is collected and then recrystallized from hot 2-propanol to give a pale yellow crystalline solid.
  • N-(chloroacetyl)-2-chloro-4-nitroaniline (3.01 g) in N,N- dimethylformamide (100 mL) is added powdered sodium carbonate (6.0 g) and 2- dimethylaminoethanethiol hydrochloride (6.0 g).
  • the mixture is stirred for 1 hour at 25° C, poured into water and extracted into ethyl acetate.
  • the ethyl acetate solution is dried over anhydrous potassium carbonate and concentrated under reduced pressure to give an oil.
  • the oil is crystallized from toluene- hexanes (3:1) to yield a pale yellow crystalline 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.
  • 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).

Abstract

11invention concerne des composés de formule (1), dans laquelle R1-R5 sont indépendamment choisis parmi hydrogène, alkyle avec 1 à 6 atomes de carbone, alkényle avec 2 à 6 atomes de carbone, alkynyle avec 2 à 6 atomes de carbone, perhaloalkyle avec 1 à 6 atomes de carbone, cycloalkyle avec 3 à 10 atomes de carbone, hétérocycloalkyle avec 3 à 10 éléments carbonés, aryle, hétéroaryle, halogène, -CN, -NO2, -CO2R6, -COR6, -OR6, -SR6, -SOR6, -SO2R6, -CONR7R8, NR6N(R7R8), -N(R7R8) ou W-Y-(CH2)n-Z; ou R2 et R3 ou R3 et R4 forment ensemble un hétérocycloalkyle avec 3 à 7 chaînons ou un hétéroaryle avec 3 à 7 chaînons; R6 and R7 désignent indépendamment hydrogène, alkyle avec 1 à 6 atomes de carbone, perhaloalkyl avec 1 à 6 atomes de carbone, ou aryle; R8 représente hydrogène, alkyle avec 1 à 6 atomes de carbone, perhaloalkyle avec 1 à 6 atomes de carbone, cycloalkyle avec 3 à 10 atomes de carbone, hétérocycloalkyle avec 3 à 10 éléments, aryle or hétéroaryle; ou R7 and R8 peuvent former ensemble un hétérocycloalkyle avec 3 à 7 chaînons; A désigne hétéroaryle; W représente O, NR6, ou est absent; Y symbolise -(CO)- ou -(CO2)-, ou est absent; Z désigne alkyle avec 1 à 4 atomes de carbone, -CN, -CO2R6, -COR6, -CONR7R8, -OCOR6, -NR6COR7, -OCONR6, -OR6, -SR6, -SOR6, -SO2R6, SR6N(R7R8), -N(R7R8) ou phényle; G représente aryle or hétéroaryle; X désigne une liaison,NH, alkyle avec 1 à 6 atomes de carbone, alkényle avec 1 à 6 atomes de carbone, alkoxy avec 1 à 6 atomes de carbone, thioalkyle avec 1 à 6 atomes de carbone, alkylamino avec 1 à 6 atomes de carbone, ou (CH)J; J symbolise alkyle avec 1 à 6 atomes de carbone, cycloalkyle avec 3 à 7 atomes de carbone, phényle, ou benzyle; et n est un nombre entier variant entre 1 et 6. Ces composés sont utiles pour le traitement de maladies liées aux virus de l'herpès, notamment les maladies des inclusions cytomégaliques humaines, l'herpès simplex virus, le virus d'Epstein-Barr, le virus varicelle-zona, les virus de l'herpès humain type 6 et 7, et le virus de l'herpès de Kaposi.
PCT/US1999/028892 1998-12-09 1999-12-06 Inhibiteurs de thio-uree des virus de l'herpes WO2000034269A1 (fr)

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SK769-2001A SK7692001A3 (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses
BR9916042-0A BR9916042A (pt) 1998-12-09 1999-12-06 Composto, composição farmacêutica, e, processospara inibir a replicação de um vìrus herpes, e detratamento de um paciente que sofra de umainfecção do vìrus herpes
PL99348177A PL348177A1 (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses
EA200100637A EA200100637A1 (ru) 1998-12-09 1999-12-06 Ингибиторы вирусов герпеса на основе тиомочевины
HU0104758A HUP0104758A3 (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses and pharmaceutical compositions containing them
AU31122/00A AU756043B2 (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses
IL14320399A IL143203A0 (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses
KR1020017007051A KR20010086082A (ko) 1998-12-09 1999-12-06 허피스 바이러스의 티오우레아 억제제
EP99965143A EP1140913A1 (fr) 1998-12-09 1999-12-06 Inhibiteurs de thio-uree des virus de l'herpes
CA002351390A CA2351390A1 (fr) 1998-12-09 1999-12-06 Inhibiteurs de thio-uree des virus de l'herpes
JP2000586716A JP2002531558A (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
BG105580A BG105580A (bg) 1998-12-09 2001-06-08 Тиоуреа като инхибитор на херпес вирус
NO20012836A NO20012836L (no) 1998-12-09 2001-06-08 Tiourea-inhibitorer for herpes virus

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US6376515B2 (en) 2000-02-29 2002-04-23 Cor Therapeutics, Inc. Benzamides and related inhibitors of factor Xa
EP1402887A1 (fr) * 2002-09-18 2004-03-31 Jerini AG Nouvelles composés pour inhibiter la prolifération non-désirée des cellules, et leurs utilisation
US6844367B1 (en) 1999-09-17 2005-01-18 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
WO2007113644A2 (fr) * 2006-04-05 2007-10-11 Orchid Research Laboratories Limited Nouveaux inhibiteurs d'hdac
US7507860B2 (en) 2004-04-13 2009-03-24 Pfizer Inc. Androgen modulators
US7576128B2 (en) 2004-02-13 2009-08-18 Pfizer Inc. Androgen receptor modulators
US7674819B2 (en) 2005-05-05 2010-03-09 Warner-Lambert Company Llc Androgen modulators
US8524907B2 (en) 2006-11-02 2013-09-03 Millennium Pharmaceuticals, Inc. Methods of synthesizing pharmaceutical salts of a factor Xa inhibitor

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WO1999021835A1 (fr) * 1997-09-03 1999-05-06 Fujisawa Pharmaceutical Co., Ltd. DERIVES DE QUINOLINE UTILISES COMME INHIBITEURS DE H+ATPase ET COMME INHIBITEURS DE RESORPTION OSSEUSE

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WO1998045259A2 (fr) * 1997-04-10 1998-10-15 Pharmacia & Upjohn Company Compositions antivirales polyaromatiques
WO1999021835A1 (fr) * 1997-09-03 1999-05-06 Fujisawa Pharmaceutical Co., Ltd. DERIVES DE QUINOLINE UTILISES COMME INHIBITEURS DE H+ATPase ET COMME INHIBITEURS DE RESORPTION OSSEUSE

Cited By (25)

* 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
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
US6835739B2 (en) 2000-02-29 2004-12-28 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
US10179124B2 (en) 2000-02-29 2019-01-15 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
US8063036B2 (en) 2000-02-29 2011-11-22 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
WO2004030664A3 (fr) * 2002-09-18 2004-08-12 Jerini Ag Nouveaux composes pouvant inhiber une proliferation de cellules non desiree et leur utilisation
EP1402887A1 (fr) * 2002-09-18 2004-03-31 Jerini AG Nouvelles composés pour inhibiter la prolifération non-désirée des cellules, et leurs utilisation
WO2004030664A2 (fr) * 2002-09-18 2004-04-15 Jerini Ag Nouveaux composes pouvant inhiber une proliferation de cellules non desiree et leur utilisation
US7576128B2 (en) 2004-02-13 2009-08-18 Pfizer Inc. Androgen receptor modulators
US7507860B2 (en) 2004-04-13 2009-03-24 Pfizer Inc. Androgen modulators
US7799823B2 (en) 2005-05-05 2010-09-21 Warner-Lambert Company Llc Androgen modulators
US7674819B2 (en) 2005-05-05 2010-03-09 Warner-Lambert Company Llc Androgen modulators
WO2007113644A3 (fr) * 2006-04-05 2009-06-04 Orchid Res Lab Ltd Nouveaux inhibiteurs d'hdac
WO2007113644A2 (fr) * 2006-04-05 2007-10-11 Orchid Research Laboratories Limited Nouveaux inhibiteurs d'hdac
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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