WO2000063195A1 - Nouveaux derives d'amino carbonyle heterocyclique utiles comme inhibiteurs de la synthase de monoxyde d'azote - Google Patents

Nouveaux derives d'amino carbonyle heterocyclique utiles comme inhibiteurs de la synthase de monoxyde d'azote Download PDF

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WO2000063195A1
WO2000063195A1 PCT/US2000/008735 US0008735W WO0063195A1 WO 2000063195 A1 WO2000063195 A1 WO 2000063195A1 US 0008735 W US0008735 W US 0008735W WO 0063195 A1 WO0063195 A1 WO 0063195A1
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heterocyclyl
alkyl
aryl
haloalkyl
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WO2000063195A8 (fr
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R. Keith Webber
Melvin L. Rueppel
Donald W. Hansen, Jr.
E. Ann Hallinan
Timothy J. Hagen
Barnett S. Pitzele
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G.D. Searle & Co.
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Publication of WO2000063195A8 publication Critical patent/WO2000063195A8/fr

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    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
    • C07D291/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
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    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3
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    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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    • C07—ORGANIC CHEMISTRY
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    • C07D273/02—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and only one oxygen atom
    • C07D273/06—Seven-membered rings
    • 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
    • C07D285/15—Six-membered rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
    • C07D291/06—Six-membered rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
    • C07F9/65844—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a five-membered ring which may be condensed with another ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6587—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having two phosphorus atoms as ring hetero atoms in the same ring

Definitions

  • the present invention relates to halogenated 5,6 heptenoic acid derivatives and their use in therapy, in particular their use as nitric oxide synthase inhibitors.
  • endothelium-derived relaxing factor a labile humoral factor termed endothelium-derived relaxing factor (EDRF).
  • NO nitric oxide
  • EDRF endothelium-derived relaxing factor
  • Nitric oxide is the endogenous stimulator of the soluble guanylate cyclase. In addition to endothelium-dependent relaxation, NO is involved in a number of biological actions including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system.
  • a constitutive, Ca-H-/calmodulin dependent enzyme located in the endothelium, that releases NO in response to receptor or physical stimulation.
  • a constitutive, Ca++/calmodulin dependent enzyme located primarily in the brain, that releases NO response to receptor or physical stimulation.
  • the NO released by the two constitutive enzymes acts as a transduction mechanism underlying several physiological responses.
  • the NO produced by the inducible enzyme is a cytotoxic molecule for tumor cells and invading microorganisms. It also appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, may result largely from the effects of NO synthesized by the inducible NO synthase.
  • conditions in which there is an advantage in inhibiting NO production from L-arginine include arthritic conditions such as rheumatoid arthritis, osteoarthritis, gouty arthritis, juvenile arthritis, septic arthritis, spondyloarthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, and pyogenic arthritis.
  • NO inhibition may be useful include chronic or inflammatory bowel disease, cardivascular ischemia, diabetes, congestive heart failure, myocarditis, atherosclerosis, migraine, glaucoma, aortic aneurysm, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, asthma, bronchiectasis, hyperalgesia (allodynia), cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia (secondary to cardiac arrest), multiple sclerosis and other central nervous system disorders mediated by NO, for example Parkinson's disease and Alzheimer's disease.
  • neurodegenerative disorders in which NO inhibition may be useful include nerve degeneration and/or nerve necrosis in disorders such as hypoxia, hypoglycemia, epilepsy, and in external wounds (such as spinal cord and head injury), hyperbaric oxygen convulsions and toxicity, dementia e.g. pre-senile dementia, and AIDS-related dementia, Sydenham's chorea, Huntington's disease, Amyotrophic Lateral Sclerosis, Korsakoff s disease, imbecility relating to a cerebral vessel disorder, sleeping disorders, schizophrenia, depression, depression or other symptoms associated with Premenstrual Syndrome (PMS), anxiety and septic shock.
  • disorders such as hypoxia, hypoglycemia, epilepsy, and in external wounds (such as spinal cord and head injury), hyperbaric oxygen convulsions and toxicity
  • dementia e.g. pre-senile dementia, and AIDS-related dementia
  • Sydenham's chorea Huntington's disease
  • Amyotrophic Lateral Sclerosis Korsakoff s disease
  • Nitric oxide inhibition may also play a role in the treatment of pain including somatogenic (either nociceptive or neuropathic), both acute and chronic.
  • somatogenic either nociceptive or neuropathic
  • a nitric oxide inhibitor could be used in any situation that a common NS AID or opioid analgesic would traditionally be administered.
  • NO inhibiting agents may also be useful as antibacterial agents.
  • L-arginine include systemic hypotension associated with septic and/or toxic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short term immunosuppression in transplant therapy.
  • ocular conditions such as ocular hypertension retinitis uveitis, systemic lupus erythematosis (SLE), flomerulonephritis, restenosis, inflammatory sequelae of viral infections, acute respiratory distress syndrome (ARDS), oxidant-induced lung injury, IL2 therapy such as in a cancer patient, cachexia, immunosuppression such as in transplant therapy, disorders of gastrointestinal motility, sunburn, eczema, psoriasis, and bronchitis.
  • SLE systemic lupus erythematosis
  • ARDS acute respiratory distress syndrome
  • IL2 therapy such as in a cancer patient
  • cachexia such as in transplant therapy
  • immunosuppression such as in transplant therapy, disorders of gastrointestinal motility, sunburn, eczema, psoriasis, and bronchitis.
  • Some of the NO synthase inhibitors proposed for therapeutic use are non- selective; they inhibit both the constitutive and the inducible NO synthases. Use of such a non-selective NO synthase inhibitor requires that great care be taken in order to avoid the potentially serious consequences of over-inhibition of the constitutive NO-synthase including hypertension and possible thrombosis and tissue damage.
  • L-NMMA for the treatment of toxic shock it has been recommended that the patient must be subject to continuous blood pressure monitoring throughout the treatment.
  • NO synthase inhibitors which are selective in the sense that they inhibit the inducible NO synthase to a considerably greater extent than the constitutive isoforms of NO synthase would be of even greater therapeutic benefit and easier to use (S. Moncada and E. Higgs, FASEB J., 9, 1319-1330, 1995).
  • NO has been identified as being a neurotransmitter in pain pathways of the spinal cord.
  • Use of such a non-selective NO synthase inhibitor requires that great care be taken in order to avoid the potentially serious consequences of over- inhibition of the constitutive NO-synthase including hypertension and possible thrombosis and tissue damage.
  • L- NMMA for the treatment of toxic shock it has been recommended that the patient must be subject to continuous blood pressure monitoring throughout the treatment.
  • NO synthase inhibitors which are selective in the sense that they inhibit the inducible NO synthase to a considerably greater extent than the constitutive isoforms of NO synthase would be of even greater therapeutic benefit and easier to use (S. Moncada and E. Higgs, FASEB J., 9, 1319-1330, 1995).
  • the present invention is directed to novel compounds, pharmaceutical compositions and methods of using said compounds and compositions for inhibiting or modulating nitric oxide synthesis in a subject in need of such inhibition or modulation by administering a compound which preferentially inhibits or modulates the inducible isoform of nitric oxide synthase over the constitutive isoforms of nitric oxide synthase. It is also another object of the present invention to lower nitric oxide levels in a subject in need of such lowering.
  • the present compounds possess useful nitric oxide synthetase inhibiting activity, and are expected to be useful in the treatment or prophylaxis of a disease or condition in which the synthesis or oversynthesis of nitric oxide forms a contributory part.
  • the present compounds can be used to treat diseases involving cartilage degeneration which takes place in certain conditions such as arthritis and it is also known that NO synthesis is increased in rheumatoid arthritis and in osteoarthritis.
  • conditions in which there is an advantage in inhibiting NO production from L-arginine include arthritic conditions such as rheumatoid arthritis, osteoarthritis, gouty arthritis, juvenile arthritis, septic arthritis, spondyloarthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, and pyogenic arthritis.
  • Other conditions which the present compounds may be useful include chronic or inflammatory bowel disease, cardivascular ischemia, diabetes, congestive heart failure, myocarditis, atherosclerosis, migraine, glaucoma, aortic aneurysm, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, asthma, bronchiectasis, hyperalgesia (allodynia), cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia (secondary to cardiac arrest), multiple sclerosis and other central nervous system disorders mediated by NO, for example Parkinson's disease and Alzheimer's disease.
  • neurodegenerative disorders in which NO inhibition may be useful include nerve degeneration and/or nerve necrosis in disorders such as hypoxia, hypoglycemia, epilepsy, and in external wounds (such as spinal cord and head injury), hyperbaric oxygen convulsions and toxicity, dementia e.g. pre-senile dementia, and AIDS-related dementia, Sydenham's chorea, Huntington's disease, Amyotrophic Lateral Sclerosis, Korsakoff s disease, imbecility relating to a cerebral vessel disorder, sleeping disorders, schizophrenia, depression, depression or other symptoms associated with Premenstrual Syndrome (PMS), anxiety and septic shock.
  • disorders such as hypoxia, hypoglycemia, epilepsy, and in external wounds (such as spinal cord and head injury), hyperbaric oxygen convulsions and toxicity
  • dementia e.g. pre-senile dementia, and AIDS-related dementia
  • Sydenham's chorea Huntington's disease
  • Amyotrophic Lateral Sclerosis Korsakoff s disease
  • the present compounds may be useful in other conditions in which nitric oxide inhibition may also play a role in the treatment, such as pain including somatogenic (either nociceptive or neuropathic), both acute and chronic.
  • a nitric oxide inhibitor could be used in any situation that a common NSAID or opioid analgesic would traditionally be administered.
  • disorders which may be treated with the present compounds by inhibiting NO production include opiate tolerance in patients needing protracted opiate analgesics, and benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behavior, for example, nicotine and eating disorders. NO inhibiting agents may also be useful as antibacterial agents.
  • the present compounds may be advantagous systemic hypotension associated with septic and/or toxic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short term immunosuppression in transplant therapy.
  • the present compounds may also be useful in the treatment of ocular conditions such as ocular hypertension retinitis uveitis, systemic lupus erythematosis (SLE), flomerulonephritis, restenosis, inflammatory sequelae of viral infections, acute respiratory distress syndrome (ARDS), oxidant-induced lung injury, IL2 therapy such as in a cancer patient, cachexia, immunosuppression such as in transplant therapy, disorders of gastrointestinal motility, sunburn, eczema, psoriasis, and bronchitis.
  • ocular hypertension retinitis uveitis systemic lupus erythematosis (SLE), flomerulonephritis, restenosis, inflammatory sequelae of viral infections, acute respiratory distress syndrome (ARDS), oxidant-induced lung injury, IL2 therapy such as in a cancer patient, cachexia, immunosuppression such as in transplant therapy, disorders of gastrointestinal motility, sunburn, e
  • J and J are independently selected from the group consisting of OR , SR ,
  • NHR and N(R )R provided that A is R ;
  • J and J can be taken together to form a group selected from the group consisting of
  • OR S OR S, SR S, OR NR and SR NR provided that A is R ;
  • J and J can be taken together to form a covalent double bond attached to J
  • J is selected from the group consisting of O, NR and S provided that A is
  • G is selected from the group consisting of O, S, CH2, CHR , C(R )2, NH, and
  • 5 A is selected from the group consisting of O, N(R ), S and heterocyclyl with the proviso that J is selected from other than O and A is selected from other than O, S and heterocyclyl unless R is selected from other than the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl,
  • R is selected from other than the group consisting of hydrogen, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, formylalkyl, acylalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, CH OC(O)GR 15 , CH2
  • heterocyclic, aryl, and heteroaryl or R is present, or R is present, or a heterocyclyl comprised of L, U, and V selected from the group of rings consisting of rings containing one or more phosphorus atoms, rings containing one or more silicon atoms, rings larger than a 6-membered ring, or bicyclic or greater in ring number;
  • 5 A can be selected from the group consisting of O, N(R ) and S connected to the
  • R is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl,
  • R is selected from other than the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl,
  • R is present, or a heterocyclyl comprised of L, U, and V selected from the group of rings consisting of rings containing one or more phosphorus atoms, rings containing one or more silicon atoms, rings larger than a 6-membered ring, or bicyclic or greater in ring number;
  • A can be selected from the group consisting of O, N(R ) and S connected to the
  • A can be selected from the group consisting of O, N(R ) and S connected to X through a substituent selected from hydroxyl, sulfhydryl, amino, carboxyl, and carbonyl substituents of group X by a spacer selected from the group consisting of a covalent bond and a linear moiety having a chain length of 1 to 4 atoms to form C5 to CIO heterocyclyl;
  • A can be R , wherein R is selected from the group consisting of hydrogen, formyl, hydroxyalkyl, alkenyl, alkynyl, acyl, aroyl, aralkanoyl, heteroaroyl, alkylsulfinylalkyl, alkylsulfonylalkyl, heteroaralkylthioalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, cycloalkylalkenyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkenyloxyalkyl, cyanoalkyl, carboxy, carboxamido, carboalkoxy, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl
  • 27 27 5 7 A can be R , wherein R is selected from the group consisting of N(R )OR ,
  • N(R 5 )SR 7 N(R 5 )N(R ? )R 25 , N(R 5 )SO 2 R 13 , N(R 5 )C(O)R 15 , N(R 5 )C(S)R 15 ,
  • R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl,
  • R is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl,
  • 13 13 15 dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S(O)R , SO2R , C(O)R , and
  • Rl5 and R are independently selected from the group consisting of hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural amino acid, a synthetic amino acid, dialkylamino, aralkyl, and dihydropyridyl
  • J is selected from NR or S, or J and J are taken together to form a group
  • 28 28 28 28 28 24 selected from the group consisting of OR O, OR S, SR S, OR NR and
  • R is selected from other than the group selected from dialkylamino, aralkyl, dihydropyridyl hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, 15 ⁇ ⁇ cyanocycloalkyl, dicyanocycloalkyl and C(O)R wherein R 1D is selected from hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloal
  • U, and V selected from the group of rings consisting of those containing one or more phosphorus atoms, romgs containing one or more silicon atoms, rings larger than a 6- g membered ring, or being bicyclic or greater in ring number, or R is selected from other than the group selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl or
  • R is selected from the group selected from other than dialkylamino, aralkyl, dihydropyridyl hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, and cyanocycloalkyl where R 1 ⁇ can represent hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural amino acid, a
  • R is selected from other than the group selected from hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl,
  • Ri 5 and R 1 are selected from the group consisting of hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural amino acid, a synthetic amino acid, dialkylamino, aralkyl, and dihydropyridyl, or J
  • 22 1 2 is selected from NR or S, or J and J are taken together to form a group selected from
  • OR O OR S, SR S, OR NR and SR NR , or R is 27 present, or A is R , or a heterocyclyl comprised of L, U, and V selected from the group of rings consisting of those rings containing one or more phosphorus atoms, containing one or more silicon atoms, being larger than a 6-membered ring, or being bicyclic or
  • R is selected from other than the group selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl;
  • R and R can be taken together to form a substituent selected from the group
  • cycloalkenyl radicals may be optionally substituted with one or more R or R substituents, aryl radicals, heteroaryl radicals, saturated heterocyclic radicals and partially saturated heterocyclic radicals wherein said radicals are 1,2-disubstituted and said 1,2-
  • C(R )R , S(O), S(O)2, OP(OR )R , P(O)R , P(S)R , and Si(R )R and said 30 31 alkyl and alkenyl may be optionally substituted with one or more R or R substituents;
  • R is selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, heterocyclylalkyl, alkoxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, cyanocycloalkyl, dicyanocycloalkyl, OR , SR , amino, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanoalkyl, carboalkoxycyan
  • CH2OC(S)GR , CH2SC(S)GR heteroaryloxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, heteroaryloxyalkyl, alkenyloxy alkyl, alkylthioalkyl, arylthioalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkyl
  • R is selected from other than the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, heterocyclylalkyl, alkoxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, cyanocycloalkyl, and dicyanocycloalkyl, unless J is selected
  • R or a heterocyclyl comprised of L, U, and V selected from the group of rings consisting of those containing one or more phosphorus atoms, containing one or more silicon atoms, being larger than a 6-membered ring, or being bicyclic or greater in ring g number, or R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl;
  • R , R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 1 to 4 atoms to form C5 to C8 heterocyclyl;
  • R can be a heterocyclyl radical in which there is at least one carbon in one ring and in which 1 to about 4 members of said ring are heteroatoms independently selected from oxygen, nitrogen and sulfur wherein said heterocyclyl radical may be optionally substituted with alkyl, hydroxy, amino, nitro, halo, cyano, haloalkyl, alkoxy, heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, thio, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl
  • 28 28 28 28 28 28 24 group selected from the group consisting of OR O, OR S, SR S, OR NR and
  • SR NR or R is present, or A is R , or a heterocyclyl comprised of L, U, and V selected from the group of rings consisting of those containing one or more phosphorus atoms, containing one or more silicon atoms, being larger than a 6-membered ring, or
  • Q being bicyclic or greater in ring number, or R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl;
  • 6 R is selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaryloxyalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cyclo
  • 28 28 28 28 28 24 selected from the group consisting of OR O, OR S, SR S, OR NR and
  • SR NR or R is present, or A is R , or a heterocyclyl comprised of L, U, and V selected from the group of rings consisting of those containing one or more phosphorus atoms, containing one or more silicon atoms, being larger than a 6-membered ring, or
  • R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl;
  • R is selected from the group consisting of hydrogen, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, formylalkyl, acylalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, dicarboalkoxycycloalkyl,
  • R is selected from other than the group consisting of hydrogen, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, formylalkyl, acylalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, CH2OC(O)GR and CH2OC(O)R where G
  • R 5 can represent hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural
  • J 22 1 2 amino acid, a synthetic amino acid, a synthetic amino acid, unless J is selected from NR and S, or J and J are
  • SR S OR NR and SR NR , or R is present, or A is R , or a heterocyclyl comprised of L, U, and V is selected from the group of rings consisting of those containing one or more phosphorus atoms, containing one or more silicon atoms, being
  • R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl and cyanoalkyl;
  • R , R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 1 to 4 atoms to form C5 to C8 heterocyclyl; 7 R can be a heterocyclyl radical in which there is at least one carbon in one ring and in which 1 to about 4 members of said ring are heteroatoms independently selected from oxygen, nitrogen and sulfur and said heterocyclyl radical may be optionally substituted with alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, halo, haloalkyl, nitro, heteroarylamino, N-aryl-N-alkylamino, N- heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thi
  • 28 28 28 28 28 28 28 24 28 24 ⁇ 2 consisting of OR O, OR S, SR S, OR NR and SR NR , or J and J are
  • R is selected from the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl,
  • R 7 CH 2 OC(O)A-R 7 , CH 2 NR 19 C(O)A-R ? , CH NR 19 C(S)A-R 7 , CH 2 SC(O)A-R 7 ,
  • R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl unless J is selected from
  • R or a heterocyclyl comprised of L, U, and V is selected from the group of rings consisting of those containing one or more phosphorus atoms, containing one or more silicon atoms, being larger than a 6-membered ring, or being bicyclic or greater in ring number, or R is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl,
  • 13 13 15 dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S(O)R , SO2R , C(O)R , and
  • R!5 and R can represent hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural amino acid, a synthetic amino acid, dialkylamino, aralkyl, and dihydropyridyl;
  • R is independently selected from the group consisting of alkyl, alkylthio, alkoxy, cycloalkoxy, amino, aralkyl, heterocyclylalkyl, dihydropyridyl, alkylamino, alkylthioalkyl, aryloxydialkylamino, hydroxyalkyl, heteroaryloxyalkyl, arylthio, alkenyl, alkynyl, aryl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloal
  • R is independently selected from the group consisting of hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural amino acid, a synthetic amino acid, dialkylamino, aralkyl, aryloxy, heteroaryloxyalkyl, arylthio, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,
  • M is a pharmaceutically acceptable cation
  • X is selected from the group consisting of alkylene, alkenylene, and alkynylene groups
  • X can be -(CH2)pQ(CH2) r - wherein p is 1 to 3, r is 1 to 3 and Q is selected from
  • X can be -(CH2) S T(CH2) V - wherein s is O to 2, v is 0 to 2 and T is selected from the group consisting of a 3 to 6 membered carbocyclic radical, aryl radical and a heterocyclyl radical;
  • Y is selected from the group consisting of amino, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, alkylthio, haloalkyl, aryl heterocyclic, aralkyl, heterocyclylalkyl, alkylthioalkyl, alkoxyalkyl, alkenyloxyalkyl, cycloalkenyloxy, 9 10 9 10 cycloalkoxy, alkylaminoalkyl, and NR R where R and R are independently selected from the group consisting of hydroxyamino, alkoxyamino, hydrogen, alkyl, alkenyl, alkynyl, nitro, amino, alkoxy, alkylthio, alkylamino, hydroxy, thio, alkoxy, aryl,
  • R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl, or J
  • 22 l 2 is selected from NR and S, or J and J are taken together to form a group selected
  • 28 28 28 28 28 24 28 24 from the group consisting of OR O, OR S, SR S, OR NR and SR NR , or
  • R is present, or A is R , or a heterocyclyl comprised of L, U, and V selected from the group of rings consisting of those containing one or more phosphorus atoms, containing one or more silicon atoms, being larger than a 6-membered ring, or being bicyclic or greater in ring number, or R is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl,
  • R 5 and R can represent hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural amino acid, a synthetic amino acid, dialkylamino, aralkyl, and dihydropyridyl;
  • R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 2 to 7 atoms to form a C3 to C8 heterocyclyl; 19 20
  • R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl
  • R and R can be taken together to form a linear moiety spacer group having a chain length of 2 to 7 atoms to form a group consisting of C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl and C3 to C8 heterocyclyl;
  • R and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, halocycloalkyl, halocycloalkenyl, hal
  • R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyl
  • R and R can be taken together to form a spacer group independently selected from a linear moiety having a chain length of 4 to 7 atoms to form C5 to C8 heterocyclyl;
  • R is independently selected from a group consisting of CH(R )CH2,
  • R and R are independently selected from the group consisting of hydroxy, thiol, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, cycloalkoxy, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenyl, cycl
  • R and R can be taken together to form a linear moiety spacer group having a chain length of 2 to 7 atoms selected to form a group consisting of C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, and C3 to C8 heterocyclyl;
  • L, U, and V are independently selected from the group consisting of O, S, C(O),
  • R and R is independently selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, and dicyanocycloalkyl
  • 28 28 28 28 24 selected from the group consisting of OR O, OR S, SR S, OR NR and 28 24 26 27
  • A is R , or a heterocyclyl comprised of L, U, and V is selected from the group of rings consisting of those containing one or more phosphorus atoms, containing one or more silicon atoms, being larger than a 6-membered ring, or g being bicyclic or greater in ring number, or R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl, or R is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalky
  • Ri 5 and R can represent hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural amino acid, a synthetic amino acid, dialkylamino, aralkyl, and dihydropyridyl;
  • L, U, and V can be selected from the group consisting of cycloalkyl radicals, cycloalkenyl radicals wherein said cycloalkyl radicals and cycloalkenyl radicals may be
  • R or R substituents optionally substituted with one or more R or R substituents, aryl radicals, heteroaryl radicals, saturated heterocyclic radicals and partially saturated heterocyclic radicals wherein said radicals are 1,2-disubstituted and said 1,2-substitutents are independently
  • R is independently selected from the group consisting of aryloxy, aralkyloxy, alkoxy, alkylthio, acyloxy, aroyloxy, heteroaroyloxy, cycloalkoxy, cycloalkenyloxy, hydroxy, cycloalkylthio, cycloalkenylthio, heteroarylthio, heteroaralkylthio, heteroaryloxy, heteroaralkyloxy, arylthio, aralkylthio, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, alkoxysulfonylalkoxy, sulfonylalkoxy, a natural amino acid, a synthetic amino acid, and polyhydroxy compounds of carbon.
  • NIL which is disclosed in WO 93/13055 when the hydrochloride salt can be isolated as a colorless crystal, but has the property of deliquescence. The compound quickly becomes a very viscous sticky oil upon exposure to moisture in normal room air which makes it difficult to handle.
  • Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula 1 may be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid.
  • Suitable pharmaceutically-acceptable base addition salts of compounds of Formula 1 include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate acid or base with the compound of Formula I.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof (active ingredient) with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline, water-for-injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
  • Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the compounds of the invention may be administered orally or via injection at a dose of from 0.001 to 2500 mg/kg per day.
  • the dose range for adult humans is generally from 0.005 mg to 10 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the compounds of Formula I are preferably administered orally or by injection (intravenous or subcutaneous).
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.
  • alkyl either alone or within other terms such as “haloalkyl” and “alkylthio”, means an acyclic alkyl radical containing from 1 to about 10, preferably from 1 to about 8 carbon atoms and more preferably 1 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted with groups as defined below.
  • radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec -butyl, tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl and the like.
  • alkenyl refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond. Such radicals containing from about 2 to about 10 carbon atoms, preferably from about 2 to about 8 carbon atoms and more preferably 2 to about 6 carbon atoms. Said alkenyl radicals may be optionally substituted with groups as defined below.
  • alkenyl radicals examples include propylenyl, 2-chloropropylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2-methylbuten-l-yl, 3- methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-l-yl, hepten-1-yl, and octen-1-yl, and the like.
  • alkynyl refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 2 to about 8 carbon atoms and more preferably having 2 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below.
  • alkynyl radicals examples include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn- 1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-l-yl radicals and the like.
  • hydro denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a "hydroxyl” radical, one hydrido radical may be attached to a carbon atom to form a "methine” radical
  • carbon radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds.
  • cyano radical denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom.
  • hydroxyalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with a hydroxyl as defined above. Specifically embraced are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals.
  • alkanoyl embraces radicals wherein one or more of the terminal alkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylalkyl and dicarbonylalkyl radicals.
  • Examples of monocarbonylalkyl radicals include formyl, acetyl, and pentanoyl.
  • dicarbonylalkyl radicals examples include oxalyl, malonyl, and succinyl.
  • alkylene radical denotes linear or branched radicals having from 1 to about 10 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene, ethylene, methylethylene, and isopropylidene.
  • alkenylene radical denotes linear or branched radicals having from 2 to about 10 carbon atoms, at least one double bond, and having attachment points for two or more covalent bonds.
  • halo means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have either a bromo, chloro or a fluoro atom within the radical.
  • Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are "lower haloalkyl" radicals having one to about six carbon atoms.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • hydroxy haloalkyl embraces radicals wherein any one or more of the haloalkyl carbon atoms is substituted with hydroxy as defined above.
  • hydroxyhaloalkyl radicals include hexafluorohydoxypropyl.
  • haloalkylene radical denotes alkylene radicals wherein any one or more of the alkylene carbon atoms is substituted with halo as defined above.
  • Dihalo alkylene radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkylene radicals may have more than two of the same halo atoms or a combination of different halo radicals.
  • More preferred haloalkylene radicals are "lower haloalkylene" radicals having one to about six carbon atoms.
  • haloalkylene radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.
  • haloalkenyl denotes linear or branched radicals having from 1 to about 10 carbon atoms and having one or more double bonds wherein any one or more of the alkenyl carbon atoms is substituted with halo as defined above.
  • Dihaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkenyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
  • alkoxy and alkoxyalkyl embrace linear or branched oxy- containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical.
  • alkoxyalkyl also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.
  • More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy alkyls.
  • the "alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy” and "haloalkoxyalkyl” radicals.
  • haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.
  • haloalkoxyalkyl radicals include fluoromethoxy methyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxy ethyl, and trifluoroethoxymethyl.
  • alkenyloxy and “alkenyloxyalkyl” embrace linear or branched oxy-containing radicals each having alkenyl portions of two to about ten carbon atoms, such as ethenyloxy or propenyloxy radical.
  • alkenyloxyalkyl also embraces alkenyl radicals having one or more alkenyloxy radicals attached to the alkyl radical, that is, to form monoalkenyloxyalkyl and dialkenyloxyalkyl radicals. More preferred alkenyloxy radicals are "lower alkenyloxy" radicals having two to six carbon atoms.
  • radicals examples include ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxy alkyls.
  • the "alkenyloxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkenyloxy” radicals.
  • haloalkenyloxy examples include trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyloxy, and fluoropropenyloxy.
  • haloalkoxyalkyl also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals.
  • haloalkenyloxy also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals.
  • haloalkenyloxyalkyl also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxy alkyl and dihaloalkenyloxy alkyl radicals.
  • alkylenedioxy denotes alkylene radicals having at least two oxygens bonded to a single alkylene group.
  • alkylenedioxy examples include methylenedioxy, ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy.
  • haloalkylenedioxy denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group.
  • haloalkylenedioxy radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
  • perhaloaryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the aryl radical is substituted with 3 or more halo radicals as defined below.
  • heterocyclyl embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen.
  • saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms
  • heteroaryl radicals examples include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,
  • unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5- b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2- thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen
  • benzoxazolyl, benzoxadiazolyl, etc.] unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4- thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like.
  • the term also embraces radicals where heterocyclic radicals are fused with aryl radicals.
  • fused bicyclic radicals examples include benzofuran, benzothiophene, and the like.
  • Said "heterocyclyl" group may have 1 to 3 substituents as defined below.
  • Preferred heterocyclic radicals include five to ten membered fused or unfused radicals.
  • heterocyclic radicals include pyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3- oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1 ,4-dioxanyl, morpholinyl, 1,4
  • alkylsulfonyl embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above.
  • Alkylsulfonylalkyl embraces alkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • Haloalkylsulfonyl embraces haloalkyl radicals attached to a sulfonyl radical, where haloalkyl is defined as above.
  • Haloalkylsulfonylalkyl embraces haloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • the term “aminosulfonyl” denotes an amino radical attached to a sulfonyl radical.
  • alkylsulfinyl whether used alone or linked to other terms such as alkylsulfinyl, denotes respectively divalent radicals -S(O)-.
  • alkylsulfinyl embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above.
  • Alkylsulfinylalkyl embraces alkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • Haloalkylsulfinyl embraces haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above.
  • Haloalkylsulfinylalkyl embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • aralkyl embraces aryl-substituted alkyl radicals.
  • Preferable aralkyl radicals are "lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable.
  • heteroarylkyl embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or more substituents as defined above for aralkyl radicals.
  • perhaloaralkyl embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above.
  • aralkylsulfinyl embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above.
  • Aralkylsulfinylalkyl embraces aralkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • aralkylsulfonyl embraces aralkyl radicals attached to a sulfonyl radical, where aralkyl is defined as above.
  • Aralkylsulfonylalkyl embraces aralkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • the term “cycloalkyl” embraces radicals having three to ten carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl” radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • cycloalkylalkyl embraces cycloalkyl-substituted alkyl radicals.
  • Preferable cycloalkylalkyl radicals are "lower cycloalkylalkyl” radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include cyclohexylhexyl.
  • cycloalkenyl embraces radicals having three to ten carbon atoms and one or more carbon-carbon double bonds.
  • Preferred cycloalkenyl radicals are "lower cycloalkenyl” radicals having three to seven carbon atoms.
  • halocycloalkyl embraces radicals wherein any one or more of the cycloalkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl radicals.
  • a monohalocycloalkyl radical for one example, may have either a bromo, chloro or a fluoro atom within the radical.
  • Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred halocycloalkyl radicals are "lower halocycloalkyl" radicals having three to about eight carbon atoms. Examples of such halocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl.
  • halocycloalkenyl embraces radicals wherein any one or more of the cycloalkenyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and poly halocycloalkenyl radicals.
  • cycloalkoxy embraces cycloalkyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexoxy and cyclopentoxy.
  • cycloalkoxyalkyl also embraces alkyl radicals having one or more cycloalkoxy radicals attached to the alkyl radical, that is, to form monocycloalkoxyalkyl and dicycloalkoxyalkyl radicals. Examples of such radicals include cyclohexoxy ethyl.
  • cycloalkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkoxy” and "halocycloalkoxyalkyl” radicals.
  • cycloalkylalkoxy embraces cycloalkyl radicals attached to an alkoxy radical. Examples of such radicals includes cyclohexylmethoxy and cyclopentylmethoxy.
  • cycloalkenyloxy embraces cycloalkenyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexenyloxy and cyclopentenyloxy.
  • cycloalkenyloxyalkyl also embraces alkyl radicals having one or more cycloalkenyloxy radicals attached to the alkyl radical, that is, to form monocycloalkenyloxyalkyl and dicycloalkenyloxyalkyl radicals. Examples of such radicals include cyclohexenyloxy ethyl.
  • cycloalkenyloxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkenyloxy” and "halocycloalkenyloxyalkyl” radicals.
  • cycloalkylenedioxy radicals denotes cycloalkylene radicals having at least two oxygens bonded to a single cycloalkylene group.
  • alkylenedioxy radicals include 1,2-dioxycyclohexylene.
  • cycloalkylsulfinyl embraces cycloalkyl radicals attached to a sulfinyl radical, where cycloalkyl is defined as above.
  • Cycloalkylsulfinylalkyl embraces cycloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • Cycloalkylsulfonyl embraces cycloalkyl radicals attached to a sulfonyl radical, where cycloalkyl is defined as above.
  • Cycloalkylsulfonylalkyl embraces cycloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • alkylthio embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. More preferred alkylthio radicals are "lower alkylthio" radicals having one to six carbon atoms. An example of “lower alkylthio” is methylthio (CH 3 -S-).
  • the "alkylthio" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkylthio" radicals.
  • radicals include fluoromethylthio, chloromethylthio, trifluoromethylthio, difluoromethylthio, trifluoroethylthio, fluoroethylthio, tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio .
  • alkylamino denotes "monoalkylamino” and “dialkylamino” containing one or two alkyl radicals, respectively, attached to an amino radical.
  • arylamino denotes "monoarylamino” and “diarylamino” containing one or two aryl radicals, respectively, attached to an amino radical.
  • examples of such radicals include N-phenylamino and N-naphthalylamino.
  • Aralkylamino embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above.
  • aralkylamino denotes "monoaralkylamino” and “diaralkylamino” containing one or two aralkyl radicals, respectively, attached to an amino radical.
  • aralkylamino further denotes "monoaralkyl monoalkylamino" containing one aralkyl radical and one alkyl radical attached to an amino radical.
  • arylsulfinylalkyl denotes arylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
  • Arylsulfonyl embraces aryl radicals attached to a sulfonyl radical, where aryl is defined as above.
  • Arylsulfonylalkyl embraces arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • heteroarylsulfinylalkyl denotes heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
  • Heteroarylsulfonyl embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above.
  • Heteroarylsulfonylalkyl embraces heteroarylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • aryloxy embraces aryl radicals, as defined above, attached to an oxygen atom.
  • radicals include phenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 3-chloro-4-ethylphenoxy, 3,4-dichlorophenoxy, 4- methylphenoxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylphenoxy, 4- fluorophenoxy, 3,4-dimethylphenoxy, 5-bromo-2-fluorophenoxy, 4-bromo-3- fluorophenoxy, 4-fluoro-3-methylphenoxy, 5,6,7, 8-tetrahydronaphthalyloxy, and 4- tert -butylphenoxy.
  • aroyl embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl.
  • aralkanoyl embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, phenylacetyl.
  • aralkoxy embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy” radicals having phenyl radicals attached to lower alkoxy radical as described above. Examples of such radicals include benzyloxy, 1-phenylethoxy, 3- trifluoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy, 3,5-difluorobenyloxy, 3- bromobenzyloxy, 4-propylbenzyloxy, 2-fluoro-3-trifluoromethylbenzyloxy, and 2- phenylethoxy.
  • aryloxyalkyl embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxy methyl.
  • haloaryloxy alkyl embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group.
  • heteroaryloxy embraces heteroaryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include pyridyloxy and furyloxy.
  • heteroaroyl embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include furoyl and nicotinyl.
  • heteroaralkanoyl embraces heteroaralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, pyridylacetyl and furylbutyryl.
  • heteroaralkoxy embraces oxy-containing heteroaralkyl radicals attached through an oxygen atom to other radicals. More preferred heteroaralkoxy radicals are “lower heteroaralkoxy” radicals having heteroaryl radicals attached to lower alkoxy radical as described above.
  • heteroaryloxyalkyl embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridyloxy methyl .
  • haloheteroaryloxyalkyl embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group.
  • heteroarylamino embraces heterocyclyl radicals, as defined above, attached to an amino group. Examples of such radicals include pyridylamino.
  • heteroarylaminoalkyl embraces heteroarylamino radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridylmethylamino.
  • heteroaryloxy embraces heterocyclyl radicals, as defined above, attached to an oxy group.
  • examples of such radicals include 2-thiophenyloxy, 2- pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy, and 4-pyridyloxy.
  • heteroaryloxyalkyl embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include 2- pyridyloxymethyl, 3-pyridyloxyethyl, and 4-pyridyloxymethyl.
  • arylthio embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio.
  • arylthioalkyl embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl.
  • alkylthioalkyl embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl.
  • alkoxyalkyl embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl.
  • carbonyl denotes a carbon radical having two of the four covalent bonds shared with an oxygen atom.
  • carboxy embraces a hydroxyl radical, as defined above, attached to one of two unshared bonds in a carbonyl group.
  • carboxamide embraces amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshared bonds in a carbonyl group.
  • carboxyalkyl embraces carboxamide radicals, as defined above, attached to an alkyl group.
  • carboxy radical as defined above, attached to an alkyl group.
  • carbboalkoxy embraces alkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group.
  • the term "carboaralkoxy” embraces aralkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group.
  • the term “monocarboalkoxyalkyl” embraces one carboalkoxy radical, as defined above, attached to an alkyl group.
  • the term “dicarboalkoxyalkyl” embraces two carboalkoxy radicals, as defined above, attached to an alkylene group.
  • the term “monocyanoalkyl” embraces one cyano radical, as defined above, attached to an alkyl group.
  • dicyanoalkylene embraces two cyano radicals, as defined above, attached to an alkyl group.
  • the term “carboalkoxycyanoalkyl” embraces one cyano radical, as defined above, attached to an alkylene group.
  • acyl alone or in combination, means a carbonyl or thionocarbonyl group bonded to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy, arylthio, and alkylthioalkyl.
  • acyl are formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.
  • haloalkanoyl embraces one or more halo radicals, as defined herein, attached to an alkanoyl radical as defined above. Examples of such radicals include, for example, chloroacetyl, trifluoroacetyl, bromopropanoyl, and heptafluorobutyry 1.
  • phosphono embraces a pentavalent phosphorus attached with two covalent bonds to an oxygen radical.
  • dialkoxyphosphono denotes two alkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds.
  • diaralkoxyphosphono denotes two aralkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds.
  • dialkoxyphosphonoalkyl denotes dialkoxyphosphono radicals, as defined above, attached to an alkyl radical.
  • diaralkoxyphosphonoalkyl denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical.
  • heterooaralkoxy alkyl may optionally have 1 to 3 substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy,
  • spacer can include a covalent bond and a linear moiety having a backbone of 1 to 7 continuous atoms.
  • the spacer may have 1 to 7 atoms of a univalent or multi-valent chain.
  • Univalent chains may be constituted by a radical selected from
  • Multi-valent chains may consist of a straight chain of
  • the chain may be constituted of one or more radicals selected from: lower alkylene, lower alkenyl, -O-, -O-CH2-, -S-CH2-, -CH2CH2-, ethenyl, -
  • CH CH(OH)-, -OCH 2 O-, -O(CH 2 )2O-, -NHCH 2 -, -OCH(R 6 )O-, -O(CH 2 CHR 6 )O-, -
  • Side chains may include substituents such as 1 to 3 substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy,
  • prodrug refers to a compound that is made more active in vivo.
  • treatment of a patient is intended to include prophylaxis.
  • Compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention.
  • Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric are also included within the invention.
  • cis and trans denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have two highest ranking groups on the same side of the double bond ("cis") or on opposite sides of the double bond (“trans”).
  • Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or "E” and "Z” geometric forms.
  • Some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present.
  • Some of the compounds described herein may contain one or more ketonic or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system.
  • Such carbonyl groups may exist in part or principally in the "keto” form and in part or principally as one or more "enol” forms of each aldehyde and ketone group present.
  • Compounds of the present invention having aldehydic or ketonic carbonyl groups are meant to include both “keto” and “enol” tautomeric forms.
  • Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist in part or principally in the “imine” form and in part or principally as one or more "enamine” forms of each group present. Compounds of the present invention having said imine or enamine groups are meant to include both “imine” and “enamine” tautomeric forms.
  • R -reagent such as R -Br, R -OTs, R -oxirane, thiirane, or aziridine, or CMR-Cl
  • R -reagent such as R ,8 -Br, R ,8 -OTs, R -oxirane
  • EX-la Ethyl 6-(N-(l-oximinoethyl)amino)-2-methyl-2-(N-Boc-amino)hexanoate (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling in an ice bath, 2,2-dimethylmalonyl chloride (10.5 mmol) is added to the mixture over 20 minutes. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water.
  • Ethyl 6-(4-( 1 ,5,6,7-tetrahydro-3,6,6-trimethyl-5,7-dioxo- 1 ,2,4-oxadiazepinyl))-2-methyl- 2-(N-Boc-amino)hexanoate is deprotected by allowing it to stand in 2N HCl in dioxane at 25°C for two hours. Concentrating in vacuo affords ethyl 6-(4-(l,5,6,7-tetrahydro-3,6,6- trimethyl-5,7-dioxo- 1 ,2,4-oxadiazepinyl))-2-methyl-2-aminohexanoate hydrochloride.
  • EX-2a Ethyl 6-(N-(l-oximinoethyl)amino)-2-(N-Boc-amino)hexanoate (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling to 10 °C, dichloroethylphosphine (10.5 mmol) is added to the mixture over 20 minutes. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water.
  • Ethyl 6-(3-(2-ethyl-l,2-dihydro-5-methyl-l,2,3,5-oxaphosphadiazolyl))-2-(N-Boc- amino)hexanoate is deprotected by allowing it to stand in 2N HCl in dioxane at 25 °C for two hours. Concentrating in vacuo affords ethyl 6-(3-(2-ethyl-l,2-dihydro-5-methyl- l,2,3,5-oxaphosphadiazolyl))-2-aminohexanoate hydrochloride.
  • EX-3a Ethyl S-(2-(N-(l-oximinoethyl)amino)ethyl)-4-thia-2-(N-Z-amino)butanoate (10 mmol) is mixed with 45 mL of anhydrous methylcyclohexane containing 22 mmol of pyridine. After cooling in an ice bath, dichlorodimethylsilane (10.5 mmol) is added to the mixture over 20 minutes. After warming to room temperature and standing for 2 hours, the reaction mixture is cooled and filtered under an inert atmosphere to remove the pyridine hydrochloride.
  • Ethyl S-(2-(3-( 1 ,2-dihydro-2,2,4-trimethyl- 1 ,2,3,5-oxasiladiazolyl))ethyl)-4-thia-2-(N-Z- amino)butanoate in methylcyclohexane is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen.
  • a hydrogenation catalyst such as palladium on carbon and hydrogen.
  • This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z- function generating the product ethyl S-(2-(3-(l,2-dihydro-2,2,4-trimethyl- 1,2,3,5- oxasiladiazolyl))ethyl)-4-thia-2-aminobutanoate.
  • EX-4a Ethyl 6-(N-(l-oxirninoethyl)amino)-2-(N-Boc-amino)hexanoate (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling to - 10 °C, propane-2,2-disulfonyl dichloride (10.5 mmol) is added to the mixture over 20 minutes. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, back washed with water, dried over MgSO4, and concentrated to afford ethyl 6-(5-(l,2,3,4-tetrahydro-3,3,6-trimethyl-
  • Ethyl 6-(5-(l,2,3,4-tetrahydro-3,3,6-trimethyl-2,2,4,4-tetraoxo-l,2,4,5,7- oxadithiadiazepinyl))-2-(N-Boc-amino)hexanoate is deprotected by allowing it to stand in 2N HCl in dioxane at 25°C for two hours. Concentrating in vacuo affords ethyl 6-(5- (l,2,3,4-tetrahydro-3,3,6-trimethyl-2,2,4,4-tetraoxo-l,2,4,5,7-oxadithiadiazepinyl))-2- aminohexanoate hydrochloride.
  • N-(Methylthiomethyl)-N-(methylsulfonyl)-6-(N-( 1 -oximinoethyl)amino)-2-(N- Boc-amino)hexanamide (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling to -10 °C, thionyl chloride (10.5 mmol) is added to the mixture over 20 minutes. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, back washed with water, dried over MgSO4, and concentrated to afford N-(methylthiomethyl)-
  • N-(Methylthiomethyl)-N-(methylsulfonyl)-6-(3-(4-methyl-2-oxo-l,2-dihydro-l,2,3,5- oxathiadiazolyl))-2-(N-Boc-amino)hexanamide is deprotected by allowing it to stand in 2N HCl in dioxane at 25 °C for two hours.
  • EX-6a Ethyl S-(2-(N-( 1 -oximinoethyl)amino)ethyl)-4-thia-2-(N-Boc-amino)butanoate (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling in an ice bath, ethyl dichlorophosphine (10.5 mmol) is added to the mixture over 20 minutes. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water.
  • Ethyl S-(2-(3-(2-ethyl-l,2-dihydro-4-methyl-2-oxo-l,2,3,5-oxaphosphadiazolyl))ethyl)-4- thia-2-(N-Boc-amino)butanoate is deprotected by allowing it to stand in 2N HCl in dioxane at 25°C for two hours.
  • reaction mixture is cooled, filtered to remove crystallized pyridine hydrochloride, and then is concentrated in vacuum giving ethyl 6-(4- (5,7-dichloro-l,5,6,7-tetrahydro-5,7-dioxo-3,6,6-trimethyl-l,5,7,2,4- oxadiphosphadiazepinyl))-2-(N-Boc-amino)hexanoate.
  • EX-7b) Ethyl 6-(4-(5,7-dichloro-l,5,6,7-tetrahydro-5,7-dioxo-3,6,6-trimethyl-l,5,7,2,4- oxadiphosphadiazepinyl))-2-(N-Boc-amino)hexanoate is cooled to -10 °C and treated with ethanol (21 mmol) and pyridine (21 mmol). The mixture is allowed to warm to room temperature. Upon completion, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water.
  • Ethyl 6-(4-(5,7-diethoxy- 1 ,5,6,7-tetrahydro-5,7-dioxo-3,6,6-trimethyl- 1 ,5,7,2,4- oxadiphosphadiazepinyl))-2-(N-Boc-amino)hexanoate is deprotected by allowing it to stand in 2N HCl in dioxane at 25 °C for two hours.
  • EX-8a Ethyl 6-(N-(l-oximinoethyl)amino)-2-(N-Boc-amino)hexanoate (10 mmol) is dissolved in 45 mL of anhydrous methylcyclohexane containing 21 mmol of pyridine. After cooling to -10 °C, pyrophosphoryl tetrachloride (10.5 mmol) is added to the mixture over 20 minutes.
  • reaction mixture After warming to room temperature and standing for 2 hours, the reaction mixture is cooled, filtered to remove crystallized pyridine hydrochloride, and then is concentrated in vacuum giving ethyl 6-(5-(2,4-dichloro-l,2,3,4-tetrahydro-6- methyl-2,4-dioxo-l, 3,2,4,5 ,7-dioxadiphosphadiazepinyl))-2-(N-Boc-amino)hexanoate.
  • EX-8b) Ethyl 6-(5-(2,4-dichloro- 1 ,2,3,4-tetrahydro-6-methyl-2,4-dioxo- 1 ,3,2,4,5,7- dioxadiphosphadiazepinyl))-2-(N-Boc-amino)hexanoate is cooled to -10 °C and treated with ethanol (21 mmol) and pyridine (21 mmol). The mixture is allowed to warm to room temperature. Upon completion, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water.
  • Ethyl 6-(5-(2,4-diethoxy-l,2,3,4-tetrahydro-6-methyl-2,4-dioxo-l,3,2,4,5,7- dioxadiphosphadiazepinyl))-2-(N-Boc-amino)hexanoate is deprotected by allowing it to stand in 2N HCl in dioxane at 25°C for two hours.
  • N-Methylthio-N-(2-oxazolyl)-S-(2-(4-(3-fluoromethyl-l,5-dihydro-5-oxo- 1,2,4- oxadiazolyl))ethyl)-2-(N-Boc-amino)-4-thiabutanamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed.
  • N-methyl-N-(2-pyrrolyl)-3-(5-(2-(5-(l,2,3,4-tetrahydro-2,2,4,4,6-pentamethyl- 1,3,5,7,2,4- dioxadiazadisilapinyl)methyl)thiophenyl)-2-(N-pnZ-amino)propanamide is dissolved in anhydrous methylcyclohexane and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen.
  • N-(5-tetrazolyl)-6-(4-( 1 ,5-dihydro-3-fluoromethyl-6,7-dimethyl-5-oxo- 1 ,2,4- oxadiazepinyl))-2-(N-TCC-amino)hex-4-enamide is dissolved in acetic acid (50 mL). Zinc dust is added until completion of removal of the TCC-function. The reaction mixture is concentrated in vacuo and the residue neutralized with excess saturated aqueous sodium carbonate. The precipitant is removed by filtration.
  • aqueous solution is exhaustively extracted with methylene chloride, the extract dried over MgSO4, concentrated, and purified by chromatography to afford the amino product N-(5- tetrazolyl)-6-(4-( 1 ,5-dihydro-3-fluoromethyl-6,7-dimethyl-5-oxo- 1 ,2,4-oxadiazepinyl))-2- aminohex-4-enamide .
  • N-Ethoxy-N-ethyl-2-(N-Boc-amino)-2-methyl-O-(2-(l-(2-fluoromethyl-4,5,6-trihydro- 5,5-dimethyl-4,6-dioxopyrimidinyl))ethyl)-4-oxybutanamide is deprotected by allowing it to stand in 2N HCl in dioxane at 25°C for two hours.
  • reaction mixture is cooled, filtered to remove crystallized pyridine hydrochloride, and then concentrated in vacuum giving tert-butyl 6-(l-(4,6-Dichloro-2-fluoromethyl- 4,5,6-trihydro-5,5-dimethyl-4,6-dioxo-4,6-diphosphapyrimidinyl))-2-(N-Boc-amino)-5,5- dimethylhexanoate .
  • the methylene chloride layer is separated, back washed with water, dried over MgSO4, and concentrated in vacuum.
  • the material is purified by passing it through a reverse phase chromatographic column to give tert-Butyl 6-(l-(4,6-diethoxy-2-fluoromethyl-4,5,6-trihydro-5,5-dimethyl-4,6-dioxo-4,6- diphosphapyrimidinyl))-2-(N-Boc-amino)-5,5-dimethylhexanoate.
  • tert-Butyl 6-(l-(4,6-diethoxy-2-fluoromethyl-4,5,6-trihydro-5,5-dimethyl-4,6-dioxo-4,6- diphosphapyrimidinyl))-2-(N-Boc-amino)-5,5-dimethylhexanoate is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours.
  • reaction mixture is cooled, filtered to remove crystallized pyridine hydrochloride, and then concentrated in vacuum giving tert-butyl 6- (3-(2,6-dichloro- 1 ,2,6-trihydro-4-methyl-2,6-dioxo- 1 ,2,6-oxadiphosphapyrimidinyl))-2- (N-Boc-amino)hex-4-enoate.
  • the material is purified by passing it through a reverse phase chromatographic column to give tert-butyl 6-(3-(2,6-diethoxy- 1 ,2,6-trihydro-4-methyl-2,6-dioxo- 1 ,2,6- oxadiphosphapyrimidinyl))-2-(N-Boc-amino)hex-4-enoate.
  • tert-Butyl 6-(3-(2,6-diethoxy-l,2,6-trihydro-4-methyl-2,6-dioxo- 1,2,6- oxadiphosphapyrimidinyl))-2-(N-Boc-amino)hex-4-enoate is deprotected by allowing it to stand in anhydrous trifluoroacetic acid until the tert-butyl groups are removed.
  • Example 16 l,3-Dichloro-l,l,3,3,-tetraethyldisiloxane (10.5 mmol), 45 mL anhydrous methylcyclohexane and pyridine (22 mmol) is cooled to -10 °C and treated with ethyl 6- N-(l-iminoethyl)amino-2-(N-acetamido)-2-methyl-hex-4-ynoate (10 mmol). The mixture is allowed to warm to room temperature.
  • reaction mixture is cooled, filtered to remove crystallized pyridine hydrochloride, and then concentrated in vacuum giving tert-butyl giving ethyl 6-(3-(2,2,6,6-tetraethyl-l,2,6-trihydro-4-methyl- 1,2,6- oxadisilapyrimidinyl))-2-acetamido-2-methyl-hex-4-ynoate.
  • the methylene chloride layer is separated, back washed with water, dried over MgSO4, and concentrated in vacuum.
  • the material is purified by passing it through a reverse phase chromatographic column to give N-(5-tetrazolyl)-S-(2-(l-(4,5,6,7-tetrahydro-2- methyl-4,7-dioxo-5 ,6-trimethylene- 1 ,3-diazepinyl))ethyl)-a-(N-Boc)-2-methyl-L- cysteinamide.
  • N-(5-tetrazolyl)-S-(2-(l-(4,5,6,7-tetrahydro-2-methyl-4,7-dioxo-5,6-trimethylene-l,3- diazepinyl))ethyl)-a-(N-Boc)-2-methyl-L-cysteinamide is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours.
  • the material is purified by passing it through a reverse phase chromatographic column to give tert-Butyl 4-(2-(l-(5,6-benzo-4,7-dihydro-2- methyl-4,7-dioxo-l,3-diazepinyl)ethyl)sulfonyl-2-(N-Boc-amino)butanoate.
  • the material is purified by passing it through a reverse phase chromatographic column to give tert-Butyl 6-(l-(2-fluoromethyl-4,7-dihyd ⁇ o-5,6- imidazo-4,7-dioxo-l,3-diazepinyl))-2-(N-Boc-amino)-2-methyl-L-hexanoate.
  • 6-(4-(l, 5-dihydro-3-methyl-5-oxo-l,2,4-oxadiazolyl))-2-(N,N- dimethylcarbamido)-2-methylthiomethyl-L-hexanoate is deprotected by allowing it to stand in 2N HCl and dioxane at 25 °C for two hours. Concentrating in vacuo affords 6-(4- ( 1 ,5-dihydro-3-methyl-5-oxo- 1 ,2,4-oxadiazolyl))-2-(N,N-dimethylcarbamido)-2- methylthiomethyl-L-hexanoic acid.
  • tert-Butyl 3- (5-(2-(l-(4,5,6-trihydro-2-methyl-4,6-dioxo-5- (cyclopentanespiro)pyrimidinyl)methyl)thiophenyl)-2-(3-(N,N- dimethylaminomethyl)benzamido)propanoate.
  • Benzyl 6-(2-( 1 ,5,6-trihydro-3-methyl- 1 , 1 ,5,5-tetraoxo-6-cyclopentanespiro-l ,5- dithiapyrimidinyl))-2-(methoxycarbonylamido)-2-methylhexanoate is dissolved in ethanol containing 1 % acetic acid and combined with a hydrogenation catalyst such as palladium on carbon and hydrogen.
  • This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the benzyl- function generating the product 6-(2-( 1,5, 6-trihydro-3-methyl- 1,1,5, 5-tetraoxo-6- cyclopentanespiro-l,5-dithiapyrimidinyl))-2-(methoxycarbonylamido)-2-methylhexanoic acid.
  • Benzyl 6-(4-( 1 ,5-dihydro-3-fluoromethyl-5-oxo- 1 ,2,4-oxadiazolyl))-2- benzamidohexanoate is dissolved in ethanol containing 1% acetic acid and combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the benzyl-function generating the product 6-(4-(l,5-dihydro-3- fluoromethyl-5-oxo- 1 ,2,4-oxadiazolyl))-2-benzamidohexanoic acid.
  • a hydrogenation catalyst such as palladium on carbon and hydrogen
  • 6-(5-( 1 ,2,34-tetrahydro-6-methyl-2,3-dioxo- 1 ,4,5,7-dioxadiazepinyl))-2-(N- Boc-amino)hexanoate is deprotected by allowing it to stand in 2 M HCl in dioxane at 25°C for two hours. Concentrating in vacuo affords 6-(5-(l,2,34-tetrahydro-6-methyl- 2,3-dioxo- 1 ,4,5,7-dioxadiazepinyl))-2-aminohexanoic acid hydrochloride.
  • 6-(4-( 1 ,2,3-trihydro-2-methoxy-5-methyl- 1 ,3,2-dioxaphosphapyrimidinyl)-2- (N-B oc-amino)hexanoate is deprotected by allowing it to stand in 2M HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords 6-(4-(l,2,3-trihydro-2-methoxy-5-methyl- 1,3,2- dioxaphosphapyrimidinyl)-2-aminohexanoic acid hydrochloride.
  • Benzyl 6-(N-(l-oximinoethyl)-N-hydroxylamino)-2-(N-Z-amino)hexanoate (10 mmol) is placed in admixture with 45 mL of anhydrous methylcyclohexane containing 21 mmol of pyridine. After cooling in an ice bath, 1,1-dichlorocyclosilolane (10.5 mmol) is added to the mixture over 20 minutes.
  • 6-(4-( 1 ,2,3-trihydro-5-methyl-2-oxo- 1 ,3,2-dioxathiapyrimidinyl))-2-(N-Boc- amino)-2-methylthiomethylhexanoate is deprotected by allowing it to stand in dioxane and HCl at 25°C for two hours. Concentrating in vacuo affords 6-(4-(l,2,3-trihydro-5- methyl-2-oxo- 1 ,3,2-dioxathiapyrimidinyl))-2-amino-2-methylthiomethylhexanoic acid hydrochloride.
  • 6-(4-( 1 ,2,3-trihydro-5-methyl-2-thiono- 1 ,3-dioxapyrimidinyl))-2-(N-Boc- amino)-2-methylthiomethylhexanoate is deprotected by allowing it to stand in dioxane and HCl at 25°C for two hours. Concentrating in vacuo affords 6-(4-(l,2,3-trihydro-5- methyl-2-thiono- 1 ,3-dioxapyrimidinyl))-2-amino-2-methylthiomethylhexanoic acid hydrochloride.
  • Benzyl 6-(N-(l-oximinoethyl)-N-hydroxylamino)-2-(N-Z-amino)-2-hexanoate (10 mmol) is dissolved in 45 mL of anhydrous methylcyclohexane containing 21 mmol of pyridine. After cooling in an ice bath, l,3-dichloro-l,3-dicyclosilolanespirodisiloxane (10.5 mmol) is added to the mixture over 20 minutes.
  • N-(5-tetrazolyl)-N-(methoxy)-6-(4-(l,5,6-trihydro-3-methyl-5,6-dioxo-l- oxapyrimidinyl))-2-(N-tert-butoxymethyl-N-pnZ-amino)-hexanamide is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen.
  • N-(Methylthiomethyl)-N-(methylsulfonyl)-6-(N-( 1 -oximinoethyl)amino)-2-(N- pnZ-amino)-hexanamide (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling in an ice bath, phosgene (10.5 mmol) is added to the mixture over 20 minutes. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, back washed with water, dried over MgSO4, concentrated, and chromatographed to afford N-
  • N-(Methylthiomethyl)-N-(methylsulfonyl)-6-(4-( 1 ,5-dihydro-3-methyl-5-oxo- 1 ,2,4- oxadiazolyl))-2-(N-pnZ-amino)-hexanamide is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen.
  • EX-35a 5-(N-( 1 -oximinoethyl)amino)- 1 -(2-( 1 ,3-dioxolyl))pentanamine (10 mmol) is treated with benzyl chloroformate (10.5 mmol) and sodium carbonate in tetrahydrofuran and water to yield the Z protected product 5-(N-(l-oximinoethyl)amino)-l-(2-(l,3- dioxolyl))-l-(N-Z)-pentanamine after chromatography and concentration.
  • EX-35b 5-(N-( 1 -oximinoethyl)amino)- l-(2-(l ,3-dioxolyl))- 1 -(N-Z)-pentanamine ( 10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling in an ice bath, oxalyl chloride (10.5 mmol) is added to the mixture over 20 minutes. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water.
  • This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the pnZ- function generating the amino product 5-(4-(l,5,6-trihydro-3-methyl-5,6-dioxo-l- oxapyrimidinyl))-l-(2-(l,3-dioxolyl))pentanamine.
  • the subject compounds of formula (I) are expected to be found to inhibit nitric oxide synthase and posses useful pharmacological properties as demonstrated in one or more of the following assays:
  • NOS activity is measured by monitoring the conversion of L-[2,3- H]-arginine to
  • Mouse inducible NOS was prepared from an extract of LPS-treated mouse RAW 264.7 cells and rat brain constitutive NOS (rnNOS) was prepared from an extract of rat cerebellum. Both preparations are partially purified by DEAE-Sepharose chromatography.
  • Enzyme (10 m L) is added to 40 m L of 50 mM Tris (pH 7.6) and the reaction initiated by the addition of 50 m L of a solution containing 50 mM Tris (pH 7.6), 2.0 mg/mL bovine serum albumin, 2.0 mM DTT, 4.0 mM CaCl 2 , 20 mM FAD, 100 &M tetrahydrobiopterin, 2.0 mM NADPH and 60 mM L-arginine containing 0.9 m Ci of L-[2,3--1H]-arginine.
  • calmodulin is included at a final concentration of 40 nM. Following incubation at 37°C for 15 minutes, the reaction is terminated by addition of 300 m L cold buffer containing 10 mM EGTA,
  • RAW 264.7 cells are plated to confluency on a 96-well tissue culture plate grown overnight (17h) in the presence of LPS to induce NOS.
  • a row of 3-6 wells were left untreated and served as controls for subtraction of nonspecific background.
  • the media is removed from each well and the cells are washed twice with Kreb-Ringers-Hepes (25 mM, pH 7.4) with 2 mg/mL glucose.
  • the cells are then placed on ice and incubated with 50 mL of buffer containing L-arginine (30 mM) +/- inhibitors for lh.
  • the assay is initiated by warming the plate to 37%C in a water bath for lh. Production of nitrite by intracellular iNOS is linear with time.
  • the plate of cells is placed on ice and the nitrite-containing buffer removed and analyzed for nitrite using a previously published fluorescent determination for nitrite.
  • T. P. Misko et al Analytical Biochemistry, 214, 11-16 (1993). All values are the average of triplicate wells and are compared to a background-subtracted induced set of cells (100% value).
  • Rats are treated with an intraperitoneal injection of 10 mg kg of endotoxin (LPS) with or without oral administration of the nitric oxide synthase inhibitors.
  • Plasma nitrites were measured 5 hours post-treatment. The results show that the administration of the nitric oxide synthase inhibitor decreases the rise in plasma nitrites, a reliable indicator of the production of nitric oxide, induced be endotoxin.

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Abstract

L'invention concerne de nouveaux dérivés d'amino carbonyle hétérocyclique utiles comme inhibiteurs de la synthase de monoxyde d'azote.
PCT/US2000/008735 1999-04-19 2000-04-17 Nouveaux derives d'amino carbonyle heterocyclique utiles comme inhibiteurs de la synthase de monoxyde d'azote WO2000063195A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010537986A (ja) * 2007-08-31 2010-12-09 イデニク プハルマセウティカルス，インコーポレイテッド ホスファジアジンｈｃｖポリメラーゼ阻害剤ｉｖ

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995025717A1 (fr) * 1994-03-24 1995-09-28 G.D. Searle & Co. Derives amidino utiles comme inhibiteurs de la synthase d'oxyde nitrique
WO1996015120A1 (fr) * 1994-11-09 1996-05-23 G.D. Searle & Co. Derives d'aminotetrazole utiles en tant qu'inhibiteurs de la monoxyde d'azote synthetase
WO1999005131A1 (fr) * 1997-07-22 1999-02-04 G.D. Searle & Co. 1,3-diaza-heterocycles et leur utilisation en tant qu'inhibiteurs de la no synthetase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995025717A1 (fr) * 1994-03-24 1995-09-28 G.D. Searle & Co. Derives amidino utiles comme inhibiteurs de la synthase d'oxyde nitrique
WO1996015120A1 (fr) * 1994-11-09 1996-05-23 G.D. Searle & Co. Derives d'aminotetrazole utiles en tant qu'inhibiteurs de la monoxyde d'azote synthetase
WO1999005131A1 (fr) * 1997-07-22 1999-02-04 G.D. Searle & Co. 1,3-diaza-heterocycles et leur utilisation en tant qu'inhibiteurs de la no synthetase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ULHAQ S ET AL: "S-2-Amino-5-azolylpentanoic acids related to L-ornithine as inhibitors of the isoforms of nitric oxide synthase (NOS)", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 6, no. 11, November 1998 (1998-11-01), pages 2139 - 49, XP000930000 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010537986A (ja) * 2007-08-31 2010-12-09 イデニク プハルマセウティカルス，インコーポレイテッド ホスファジアジンｈｃｖポリメラーゼ阻害剤ｉｖ

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