WO1997016442A1 - Pyrroles de pyridyle substitues, compositions contenant de tels composes et mode d'utilisation - Google Patents

Pyrroles de pyridyle substitues, compositions contenant de tels composes et mode d'utilisation Download PDF

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Publication number
WO1997016442A1
WO1997016442A1 PCT/US1996/018539 US9618539W WO9716442A1 WO 1997016442 A1 WO1997016442 A1 WO 1997016442A1 US 9618539 W US9618539 W US 9618539W WO 9716442 A1 WO9716442 A1 WO 9716442A1
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Prior art keywords
aryl
alkyl
conr
cor
heteroaryl
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PCT/US1996/018539
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English (en)
Inventor
Stephen E. De Laszlo
Linda L. Chang
Dooseop Kim
Nathan B. Mantlo
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Merck & Co., Inc.
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Priority claimed from GBGB9605158.6A external-priority patent/GB9605158D0/en
Priority claimed from GBGB9612062.1A external-priority patent/GB9612062D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to EP96942022A priority Critical patent/EP0859771A4/fr
Priority to AU11208/97A priority patent/AU702887B2/en
Priority to JP9517642A priority patent/JPH11514651A/ja
Priority to CA 2234701 priority patent/CA2234701A1/fr
Publication of WO1997016442A1 publication Critical patent/WO1997016442A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to pyridyl substituted pyrroles. This invention also relates to compositions containing such compounds and methods of treatment.
  • Diabetes is a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose. Uncontrolled hyperglycemia is associated with an increased risk for microvascular and macrovascular diseases, including nephropathy, retinopathy, hypertension, stroke and heart disease. Control of glucose levels is, therefore, a major approach to the treatment of diabetes.
  • Glucagon is a major counter regulatory hormone that attenuates the inhibition of liver gluconeogenesis by insulin. Glucagon receptors are found primarily in the liver, although their presence has been documented in kidney and adipose tissue.
  • Type II diabetics have elevated levels of plasma glucagon and increased rates of hepatic glucose production.
  • the rate of hepatic glucose production positively correlates with fasting blood glucose levels in type II diabetics. Therefore, antagonists of glucagon are useful in improving insulin responsiveness in the liver, decreasing the rate of gluconeogenesis and lowering the rate of hepatic glucose output resulting in a decrease in the levels of plasma glucose.
  • Blood glucose homeostasis is also mediated by the hormone insulin, produced in the ⁇ cells of the pancreas. Deterioration of these cells is typically observed in Type I diabetics, and abnormalities in the function of these cells may occur in patients presenting the symptoms of Type II diabetes.
  • Cytokine mediated diseases refers to diseases or conditions in which excessive or unregulated production or activity of one or more cytokines occurs.
  • Interleukin-8 IL-8
  • Tumor Necrosis Factor TNF
  • IL-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions. [See, e.g., Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)].
  • the myriad of known biological activities of IL-1 include the activation of T-helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.
  • IL-1 interleukin-1
  • rheumatoid arthritis rheumatoid arthritis
  • osteoarthritis rheumatoid arthritis
  • endotoxemia rheumatoxemia
  • toxic shock syndrome other acute or chronic IL-1
  • inflammatory diseases such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis. Recent evidence also links IL-1 activity to diabetes and pancreatic ⁇ cells.
  • IL-6 is a cytokine effecting the immune system, hematopoiesis and acute phase reactions. It is produced by several mammalian cell types in response to agents such as IL- 1 and is
  • IL-8 is a chemotactic factor first identified and characterized in 1987. Many different names have been applied to IL-8, such as neutrophil attractant/activation protein-1 (NAP-1 ), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor. Like IL-1 , IL-8 is produced by several cell types, including
  • IL-8 stimulates a number of cellular functions in vitro. It is a chemoattractant for neutrophils, T-lymphocytes and basophils. It induces histamine release from basophils. It causes lysozomal enzyme release and respiratory burst from neutrophils, and it has been shown to increase the surface expression of Mac-1 (CD1 1b/CD 18) on neutrophils without de novo protein synthesis.
  • the compounds of formula I are also useful in treating diseases characterized by excessive IL-8 activity.
  • rheumatoid spondylitis rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions
  • sepsis septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcosis, bone resorption diseases, reperfusion injury, graft v. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS related complex (ARC), keloid formation, scar tissue formation,
  • AIDS cachexia secondary to acquired immune deficiency syndrome
  • ARC AIDS related complex
  • keloid formation scar tissue formation
  • Cytokines such as TNF have been shown to activate HIV replication in monocytes and/or macrophages [See Poli, et al., Proc. Natl. Acad. Sci., 87:782-784 (1990)]. Therefore, inhibition of TNF
  • TNF monokine production or activity aids in limiting HIV progression as stated above for T-cells.
  • TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV), influenza virus and the herpes virus.
  • CMV cytomegalovirus
  • influenza virus influenza virus
  • herpes virus the cytomegalovirus
  • the present invention is directed to a compound
  • each R a independently represents a member selected from the group consisting of: halo, aryl(R b )0-2, heteroaryl(R b )0-2, CF 3 , OCF 3 , CN, NO 2 , R 21 , OR 23 ; SR 23 , S(O)R 23 , SO 2 R 21 , NR 20 R 23 , NR 20 COR 21 , NR 20 CO 2 R 21 , NR 20 CONR 20 R 23 , NR 2 0 SO 2 R 21 ,
  • OCONR 20 R 23 OCONR 20 SO 2 R 21 , C(NR 20 )NR 20 R 23 ,
  • each R b independently represents a member selected from the group consisting of: halo, CF 3 , OCF 3 , CN, NO 2 , OR 23 ; SR 23 , S(O)R 23 , SO 2 R 21 , NR 20 R 23 , NR 20 COR 21 , NR 20 CO 2 R 21 , NR 20 CONR 20 R 23 , NR 20 SO 2 R 21 , NR 20 C(NR 20 )NHR 23 , COR 20 , CO 2 R 23 , CONR 20 R 23 , SO 2 NR 20 R 23 , SO 2 NR 20 COR 21 ,
  • R 1 is selected from the group consisting of: H, aryl, C 1 - 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl and heterocyclyl, said alkyl, aryl, alkenyl, alkynyl and heterocyclyl being optionally substituted with from one to three members selected from the group consisting of: aryl, heteroaryl, heterocyclyl, halo, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 21 , SO 2 R 21 , SO 2 NR 20 R 23 , SO 2 NR 20 COR 21 , SO 2 NR 20 CONR 20 R 23 , NR 20 COR 21 , NR 20 CO 2 R 21 , NR 20 CONR 20 R 23 , N(R 20 )C(NR 20 )NHR 23 , COR 20 , CO 2 R 23 , CONR 20 R 23 , CONR 20 SO 2 R 21 , NR 20 SO 2 R 21 , NR 20
  • R 2 is selected from the group consisting of: C 1 - 15 alkyl, aryl (with the proviso that aryl is not unsubstituted phenyl), heteroaryl (with the proviso that heteroaryl is not unsubstituted pyridyl), C 7- 15 alkenyl, C 2- 15 alkynyl, CONR 20 R 23 , SO 2 R 21 (wherein R 21 is not alkyl or C 1 -6 alkenyl), SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 21 ,
  • R 3 is selected from the group consisting of: H, aryl, C 1- 15 alkyl, C 2- 15 alkenyl, C 2- 15 alkynyl, halo, NO 2 , CN, CONR 20 R 23 , SO 2 R 21 , SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 21 , SO 2 NR 20 CON(R 20 ) 2 , COR 20 , CO 2 R 20 , CONR 20 SO 2 R 21 , SO 2 NR 20 CO 2 R 21 and heterocyclyl, said alkyl, alkenyl, alkynyl, aryl, and heterocyclyl being optionally substituted with from one to three members selected from the group consisting of: halo, C 1 - 15 alkyl, CF 3 , OCF 3 , CN, aryl, NO 2 , heteroaryl, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R
  • COOR 20 CONR 20 R 23 , aryl, heterocyclyl, C 1- 15 alkyl, C 3- 15 alkenyl, C 3-15 alkynyl, said alkyl, alkenyl and alkynyl group optionally
  • CONR 20 R 23 CONR 20 SO 2 R 21 , NR 20 SO 2 R 21 , SO 2 NR 20 CO 2 R 21 ,
  • R 20 represents a member selected from the group consisting of: H, C 1 - 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl and alkynyl being optionally substituted with 1-3 groups selected from halo, aryl and heteroaryl;
  • R 21 represents a member selected from the group consisting of: C 1 - 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl, aryl, heterocyclyl and heteroaryl; said alkyl, alkenyl or alkynyl being optionally interrupted by 1-2 heteroatoms selected from O, S, S(O), SO 2 or NR 24 and said alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl being optionally substituted with from 1 -3 of halo, heterocyclyl, heteroaryl, aryl(R a ) 0 -2, heteroaryl(R a ) 0-2 , CN, OR 20 ,
  • R 22 is selected from the group consisting of: C 1 - 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, and alkynyl being optionally substituted with 1 -3 halo, aryl or heteroaryl groups;
  • R 23 is R 21 or H
  • R 24 is selected from aryl, COR 22 , CO 2 R 22 , CON(R 20 ) 2 and SO 2 R 22 ;
  • R 20 groups when two R 20 groups are present, R 20 and R 21 are present, or R 20 and R 23 are present, said two R 20 groups, R 20 and R 21 or said R 20 and R 23 may be taken in combination with the atoms to which they are attached and any intervening atoms and represent heterocyclyl containing from 5-10 atoms, at least one atom of which is a heteroatom selected from O, S or N, said hetercyclyl optionally containing 1-3 additional N atoms and 0- 1 additional O or S atom.
  • a pharmaceutical composition which is comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier. Also included in the invention is a method of treating diabetic disease, comprising administering to a mammalian patient in need of such treatment an amount of a compound of formula I which is effective to treat said diabetic disease.
  • Also included in the invention is a method of treating cytokine mediated disease in a mammal, comprising administering to a mammalian patient in need of such treatment an amount of a compound of formula I which is effective to treat said cytokine mediated disease.
  • alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl.
  • Alkyl also includes a straight or branched alkyl group which contains or is interrupted by a cycloalkylene portion. Examples include the following: and
  • the alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.
  • alkyl groups When substituted, alkyl groups may be substituted with up to three substituent groups, as defined, at any available point of attachment.
  • One of the 15 carbon atoms can be carbonyl.
  • substitution may be in the straight or branched portion, or in the cycloalkyl portion.
  • alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 15 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic (non-resonating) carbon-carbon double bonds may be present.
  • Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
  • the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted when a substituted alkenyl group is provided.
  • alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 15 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present.
  • Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted when a substituted alkynyl group is provided.
  • Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like.
  • Aryl thus contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms.
  • the preferred aryl groups are phenyl and naphthyl.
  • Aryl groups may likewise be substituted with 1 -3 groups selected from R a .
  • Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
  • heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, and/or in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms.
  • the heteroaryl group is optionally substituted with up to three groups selected from R a .
  • Heteroaryl thus includes aromatic and partially aromatic groups which contain one or more heteroatoms. Examples of this type are pyrrole, furan, thiophene, pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole.
  • the preferred heteroaryls are those where only nitrogen heteroatoms are present when there is more than one. Typical of these are pyrazole, tetrazole, imidazole, pyridine, pyrimidine and pyrazine.
  • the group represents a heteroaryl group which contains from 5 to 10 atoms. One to four atoms are heteroatoms which are selected from O, S and N.
  • the heteroaryl group may be
  • heteroaryl groups represented by are as follows: pyridyl, quinolyl, purinyl, imidazolyl, imidazopyridinyl and pyrimidinyl.
  • heterocycloalkyl and “heterocyclyl” refer to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by heteroatoms.
  • the heterocyclyl is carbon or nitrogen linked, if said heterocyclyl is carbon linked and contains a nitrogen, then nitrogen may be substituted by R 24 .
  • One of the carbon atoms can be carbonyl.
  • heterocyclyls are piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydroimidazo[4,5-c]pyridine, imidazolinyl, piperazinyl, pyrolidine-2-one, piperidin-2-one and the like.
  • Oxo refers to carbonyl groups -C(O)-.
  • TNF mediated disease or disease state refer to disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another monokine to be released, such as but not limited to IL-1 or IL-6.
  • cytokine as used herein is meant any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response.
  • a cytokine includes, but is not limited to, monokines and lymphokines regardless of which cells produce them. Examples of cytokines include, but are not limited to, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF- ⁇ ) and Tumor Necrosis Factor-beta (TNF- ⁇ ).
  • IL-1 Interleukin-1
  • IL-6 Interleukin-6
  • TNF- ⁇ Tumor Necrosis Factor-alpha
  • TNF- ⁇ Tumor Necrosis Factor-beta
  • cytokine antagonizing, interfering or cytokine suppressive amount is meant an amount of a compound of formula I which will, cause a decrease in the in vivo presence or level of the cytokine to normal or sub-normal levels, when given to the patient for the prophylaxis or therapeutic treatment of a disease state which is exacerbated by, or caused by, excessive or unregulated cytokine production.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are contemplated to be within the scope of the present invention.
  • the present invention is directed to a compound
  • heteroaryl group 10 atoms, 1-4 of which are heteroatoms, 0-4 of which heteroatoms are N and 0-1 of which are O or S, said heteroaryl group being
  • each R a independently represents a member selected from the group consisting of: halo, aryl(R b )0-2, heteroaryl(R b )0-2, CF 3 , OCF 3 , CN, NO 2 , R 21 , OR 23 ; SR 23 , S(O)R 23 , SO 2 R 21 , NR 20 R 23 , NR 20 COR 21 , NR 20 CO 2 R 21 , NR 20 CONR 20 R 23 , NR 20 SO 2 R 21 ,
  • OCONR 20 R 23 OCONR 20 SO 2 R 21 , C(NR 20 )NR 20 R 23 ,
  • each R b independently represents a member selected from the group consisting of: halo, CF 3 , OCF 3 , CN, NO 2 , OR 23 ; SR 23 , S(O)R 23 , SO 2 R 21 , NR 20 R 23 , NR 20 COR 21 , NR 20 CO 2 R 21 , NR 20 CONR 20 R 23 , NR 20 SO 2 R 21 , NR 20 C(NR 20 )NHR 23 , COR 20 , CO 2 R 23 , CONR 20 R 23 , SO 2 NR 20 R 23 , SO 2 NR 20 COR 21 ,
  • R 1 is selected from the group consisting of: H, aryl, C 1 - 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl and heterocyclyl, said alkyl, aryl, alkenyl, alkynyl and heterocyclyl being optionally substituted with from one to three members selected from the group consisting of: aryl.
  • R 2 is selected from the group consisting of: C 1 - 15 alkyl, aryl (with the proviso that aryl is not unsubstituted phenyl), heteroaryl (with the proviso that heteroaryl is not unsubstituted pyridyl), C 7- 15 alkenyl, C 2- 15 alkynyl, CONR 20 R 23, SO 2 R 21 (wherein R 21 is not alkyl or C 1 -6 alkenyl), SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 21 ,
  • R 3 is selected from the group consisting of: H, aryl, C 1- 15 alkyl, C 2- 15 alkenyl, C 2- 15 alkynyl, halo, NO 2 , CN, CONR 20 R 23 , SO 2 R 21 , SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 21 , SO 2 NR 20 CON(R 20 ) 2 , COR 20 , CO 2 R 20 , CONR 20 SO 2 R 21 , SO 2 NR 20 CO 2 R 21 and heterocyclyl, said alkyl, alkenyl, alkynyl, aryl, and heterocyclyl being optionally substituted with from one to three members selected from the group consisting of: halo, C 1 - 15 alkyl, CF 3 , OCF 3 , CN, aryl, NO 2 , heteroaryl, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R
  • R 4 is selected from the group consisting of COR 20 ,
  • COOR 20 CONR 20 R 23 , aryl, heterocyclyl, C 1- 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl, said alkyl, alkenyl and alkynyl group optionally interrupted by 1-2 oxo or heteroatoms selected from O, S, S(O), SO 2 or NR 24 and said C 1 - 15 alkyl, aryl, heterocyclyl, C 3- 15 alkenyl, C 3- 15 alkynyl being optionally substituted with from 1 -3 of R 21 , halo, aryl(R a )0-3, heteroaryl(R a )0-3, heterocyclyl, CN, CF 3 , NO 2 , OR 23 , SR 23 , NR 20 R 23 , S(O)R 21 , SO 2 R 21 , SO 2 NR 20 R 23 , SO 2 NR 20 COR 21 , OR 20 CO 2 R 23 , SO 2 NR 20 CONR 20 R 23 , SO 2
  • CONR 20 R 23 CONR 20 SO 2 R 21 , NR 20 SO 2 R 21 , SO 2 NR 20 CO 2 R 21 ,
  • R 20 represents a member selected from the group consisting of: H, C 1- 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl and alkynyl being optionally substituted with 1-3 groups selected from halo, aryl and heteroaryl;
  • R 21 represents a member selected from the group consisting of: C 1- 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl, aryl, heterocyclyl and heteroaryl; said alkyl, alkenyl or alkynyl being optionally interrupted by 1 -2 heteroatoms selected from O, S, S(O), SO 2 or NR 24 and said alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl being optionally substituted with from 1-3 of halo,
  • heterocyclyl heteroaryl, aryl(R a ) 0-2 , heteroaryl(R a ) 0-2 , CN, OR 20 ,
  • R 22 is selected from the group consisting of: C 1- 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, and alkynyl being optionally substituted with 1 -3 halo, aryl or heteroaryl groups;
  • R 23 is R 21 or H
  • R 24 is selected from aryl, COR 22 , CO 2 R 22 , CON(R 20 ) 2 and SO 2 R 22 ;
  • R 20 groups when two R 20 groups are present, R 20 and R 21 are present, or R 20 and R 23 are present, said two R 20 groups, R 20 and R 21 or said R 20 and R 23 may be taken in combination with the atoms to which they are attached and any intervening atoms and represent heterocyclyl containing from 5-10 atoms, at least one atom of which is a heteroatom selected from O, S or N, said hetercyclyl optionally containing 1-3 additional N atoms and 0-1 additional O or S atom. More particularly, a preferred aspect of the present invention is directed to a compound represented by formula I:
  • heteroaryl group containing from 5 to 10 atoms, 1-4 of which are heteroatoms, 0-4 of which heteroatoms are N and 0-1 of which are O or S, said heteroaryl group being
  • each R a independently represents a member selected from the group consisting of: halo, aryl(R b )0-2, heteroaryl(R b )0-2, CF 3 , OCF 3 , CN, NO 2 , R 21 , OR 23 ; SR 23 , S(O)R 23 , SO 2 R 21 , NR 20 R 23 , NR 20 COR 21 , NR 20 CO 2 R 21 , NR 20 CONR 20 R 23 , NR 20 SO 2 R 21 ,
  • OCONR 20 R 23 OCONR 20 SO 2 R 21 , C(NR 20 )NR 20 R 23 ,
  • R b is R a minus aryl, heteroaryl and R 21 ;
  • R 1 is selected from the group consisting of: H, aryl, C 1 - 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl and heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, and heterocyclyl being optionally substituted with from one to three members selected from the group consisting of: aryl, heteroaryl, heterocyclyl, halo, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 21 ,
  • R 2 is selected from the group consisting of: aryl (wherein aryl is not unsubstituted phenyl), heteroaryl (wherein heteroaryl is not unsubstituted pyridyl), C 7- 15 alkenyl, C 2- 15 alkynyl, CONR 20 R 23 , SO 2 R 21 (wherein R 21 is not alkyl or C 1 -6 alkenyl), SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 21 , SO 2 NR 20 CON(R 20 ) 2 , COR 20 , CO 2 R 20 (wherein R 20 is not C 1 -6 alkyl or hydrogen), CONR 20 SO 2 R 21 ,
  • R 3 is selected from the group consisting of: H, aryl, C 1- 15 alkyl, C 2- 15 alkenyl, C 2- 15 alkynyl, halo, NO 2 , CN, CONR 20 R 23 , SO 2 R 21 , SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 21 , SO 2 NR 20 CON(R 20 ) 2 , COR 20 , CO 2 R 20 , CONR 20 SO 2 R 21 , SO 2 NR 20 CO 2 R 21 and
  • heterocyclyl said alkyl, alkenyl, alkynyl, aryl, and heterocyclyl being optionally substituted with from one to three members selected from the group consisting of: halo, C 1 - 15 alkyl, CF 3 , OCF 3 , CN, aryl, NO 2 , heteroaryl, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 22 , SO 2 NR 20 CON(R 20 ) 2 , NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , NR 22 C(NR 22 )NHR 22 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , CONR 20 SO 2 R 22 , NR 20 SO 2 R 22 , SO 2 NR 20 CO 2 R 22 , OCONR 20 SO 2 R 22
  • COOR 20 CONR 20 R 23 , aryl, heterocyclyl, C 1-15 alkyl, C 3-15 alkenyl, C 3-15 alkynyl, said alkyl, alkenyl and alkynyl group optionally interrupted by 1-2 oxo or heteroatoms selected from O, S, S(O), SO 2 or NR 24 and said C 1 - 15 alkyl, aryl, heterocyclyl, C 3- 15 alkenyl, C 3- 15 alkynyl being optionally substituted with from 1-3 of R 21 , halo, aryl(R a )0-3, heteroaryl(R a )0-3, heterocyclyl, CN, CF 3 , NO 2 , OR 23 , SR 23 , NR 20 R 23 , S(O)R 21 , SO 2 R 21 , SO 2 NR 20 R 23 , SO 2 NR 20 COR 21 , OR 20 CO 2 R 23 , SO 2 NR 20 CONR 20 R 23 , NR 20
  • CONR 20 R 23 CONR 20 SO 2 R 21 , NR 20 SO 2 R 21 , SO 2 NR 20 CO 2 R 21 ,
  • R 20 represents a member selected from the group consisting of: H, C 1- 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl and alkynyl being optionally substituted with 1-3 groups selected from halo, aryl and heteroaryl;
  • R 21 represents a member selected from the group consisting of: C 1- 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl, aryl,
  • heterocyclyl and heteroaryl said alkyl, alkenyl or alkynyl being optionally interrupted by 1-2 heteroatoms selected from O, S, S(O), SO 2 or NR 24 and said alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl being optionally substituted with from 1-3 of halo,
  • heterocyclyl heteroaryl, aryl(R a ) 0-2 , heteroaryl(R a ) 0-2 , CN, OR 20 , O((CH 2 ) n O) m R 20 , NR 20 ((CH 2 ) n O) m R 20 wherein n represents an integer of from 1 to 4, and m represents an integer of from 1 to 4; SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 22 ,
  • R 22 is selected from the group consisting of: C 1 - 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, and alkynyl being optionally substituted with 1-3 halo, aryl or heteroaryl groups;
  • R 23 is R 21 or H
  • R 24 is selected from aryl, COR 22 , CO 2 R 22 , CON(R 20 ) 2 and SO 2 R 22 ;
  • said two R 20 groups, R 20 and R 21 or said R 20 and R 23 may be taken in combination with the atoms to which they are attached and any intervening atoms and represent heterocyclyl containing from 5-10 atoms, at least one atom of which is a heteroatom selected from O, S or N, said hetercyclyl optionally containing 1-3 additional N atoms and 0-1 additional O or S atom.
  • a subset of compounds of the invention includes compounds of formula I wherein R 1 represents H, alkyl, substituted alkyl, aryl and substituted aryl, said substituted groups being substituted with from 1 to 3 groups selected from R a . All other variables of formula I are as originally defined.
  • R 2 represents aryl (wherein aryl is not unsubstituted phenyl), heteroaryl (wherein heteroaryl is not unsubstituted pyridyl), C 1- 15 alkyl, C 7- 15 alkenyl, C 2- 15 alkynyl, and heterocyclyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and
  • Another subset of compounds of the invention includes compounds of formula I wherein R 3 represents H, alkyl, halo, NO 2 , CN, CONR 20 R 23 , SO 2 R 21 and CO 2 R 20 , said alkyl group being unsubstituted or substituted with 1 to 3 groups of R a . All other variables of formula I are as originally defined.
  • Another subset of compounds of the invention includes compounds of formula I wherein R 4 is aryl, alkyl, alkenyl, alkynyl, heterocyclyl, CO 2 R 20 or CONR 20 R 23 , said aryl, alkyl, alkenyl, alkynyl, and heterocyclyl being unsubstituted or substituted with 1 to 3 groups of R a. All other variables of formula I are as originally defined.
  • Another subset of compounds of the invention includes compounds of formula I wherein Har represents a member selected from the group consisting of: pyridinyl, quinolyl, purinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrrolyl, triazolyl and the like.
  • a subset of compounds of the present invention includes compounds of formula I wherein Har represents a member selected from the following:
  • Har represents 3- or 4- pyridinyl. All other variables of formula I are as originally defined.
  • R a is independently selected from the group consisting of: halo, aryl(R b )0-2, heteroaryl(R b )0-2, CF 3 , OCF 3 , NO 2 , R 21 , OR 23 ; SR 23 , S(O)R 23 , SO 2 R 21 , NR 20 R 23 , NR 20 COR 21 ,
  • each R b , R 20 , R 21 R 22 , R 23 and R 24 is as originally defined.
  • R 1 is H, aryl, or C 1 - 1 5 alkyl
  • R 2 is aryl (wherein aryl is not unsubstituted phenyl), heteroaryl
  • heteroaryl is not unsubstituted pyridyl
  • C 7- 15 alkenyl C 2- 15 alkynyl, heterocyclyl
  • R 3 is H, halo, NO 2 , CO2R 20 , CONHiPr or CN
  • R 4 is aryl, C 1 - 15 alkyl, C 2-15 alkenyl, C 2- 1 5 alkynyl, CO 2 R 20 ,
  • R 1 is H or aryl
  • R 2 is aryl (wherein aryl is not unsubstituted phenyl), heteroaryl
  • heteroaryl is not unsubstituted pyridyl), or heterocyclyl
  • R 3 is H or halo;
  • R 4 is aryl, C 1 -C 6 alkyl, C 2- 15 alkenyl, C 2-15 alkynyl,
  • a preferred set of compounds of formula I is that wherein:
  • (R a )0-3-HAr is: a) 4-pyridinyl, b) 2-(methyl)-4-pyridinyl, c) 3-(methyl)-4-pyridinyl, d) 2-(amino)-4-pyridinyl, e) 2-(benzylamino)-4-pyridinyl, f) 2-(acetylamino)-4-pyridinyI, g) 4-quinolinyl-,
  • R 1 is H or 2-(OH)-Phenyl
  • R 2 is 1) Cl-Ph
  • spiroindene-1 is:
  • heterocycle-1 is:
  • spiroindane-1 is:
  • a further set of compounds includes compounds represented by formula:
  • each R a independently represents a member selected from the group consisting of: halo; CN, NO 2 , R 21 ; OR 23 ; SR 23 ; S(O)R 21 ; SO 2 R 21 ; NR 20 R 23 ; NR 20 COR 21 ; NR 20 CO 2 R 21 ; NR 20 CONR 20 R 23 ;
  • R 1 is selected from the group consisting of: H, aryl, C 1- 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl; and heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, and heterocyclyl being optionally substituted with from one to three members selected from the group consisting of: aryl, heteroaryl, heterocyclyl, halo, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 21 , SO 2 R 21 , SO 2 NR 20 R 23 , SO 2 NR 20 COR 21 , SO 2 NR 20 CONR 20
  • R 2 is selected from the group consisting of: aryl, heteroaryl, heterocyclyl, C 1 - 15 alkyl, C 2- 15 alkenyl, C 2- 15 alkynyl, said alkyl, alkenyl and alkynyl group optionally interupted by 1-2 heteroatoms selected from O, S, S(O), SO 2 or NR 24 and said aryl, heteroaryl, heterocyclyl, alkyl, alkenyl, alkynyl being optionally substituted with from 1-3 of halo, aryl, heteroaryl, aryl(R a ) 1-2 , C 1 - 15 alkyl, heteroaryl(R a ) 1-2 , CN, CF 3 , NO 2 , heterocyclyl, OR 23 , SR 23 , NR 20 R 23 , S(O)R 21 , SO 2 R 21 , SO 2 NR 20 R 23 , SO 2 NR 20 COR 21 , SO 2 NR 20 CONR 20 R
  • R 3 is selected from the group consisting of: H, C 1- 15 alkyl, aryl, C 2- 15 alkenyl, C 2- 15 alkynyl, halo, NO 2 , CO 2 R 22 , CN,
  • SO 2 NR 20 CO 2 R 21 and heterocyclyl, said alkyl, alkenyl, alkynyl, aryl, and heterocyclyl being optionally substituted with from one to three members selected from the group consisting of: halo, C 1 - 15 alkyl, CF 3 , CN, aryl, NO 2 , heteroaryl, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 22 , SO 2 NR 20 CON(R 20 ) 2 , NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , NR 22 C(NR 22 )NHR 22 , CO 2 R 20 ,
  • R 4 is selected from the group consisting of COR 21 ,
  • CONR 20 R 23 aryl, heteroaryl, heterocyclyl, C 1 - 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl, said alkyl, alkenyl and alkynyl group optionally
  • heteroatoms selected from O, S, S(O), SO 2 or NR 24 and said aryl, heteroaryl, heterocyclyl, C 3- 15 alkenyl, C 3- 15 alkynyl being optionally substituted with from 1-3 of R 21 , halo, CN, CF 3 , NO 2 , OR 23 , SR 23 , NR 20 R 23 , S(O)R 21 , SO 2 R 21 , SO 2 NR 20 R 23 ,
  • CONR 20 R 23 CONR 20 SO 2 R 21 , NR 20 SO 2 R 21 , SO 2 NR 20 CO 2 R 21 ,
  • R 20 represents a member selected from the group consisting of: H, C 1 - 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl and alkynyl being optionally substituted with 1 -3 groups selected from halo, aryl and heteroaryl;
  • R 21 represents a member selected from the group consisting of: C 1- 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl, aryl,
  • heterocyclyl and heteroaryl said alkyl, alkenyl or alkynyl being optionally interrupted by 1-2 heteroatoms selected from O, S, S(O), SO 2 or NR 24 and said alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl being optionally substituted with from 1-3 of halo,
  • heterocyclyl aryl, heteroaryl, aryl(R a ) 1-2 , heteroaryl(R a ) 1-2 , CN, OR 20 , O((CH 2 ) n O) m R 20 , NR 20 ((CH 2 ) n O) m R 20 wherein n represents an integer of from 2 to 4, and m represents an integer of from 1 to 3; SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 22 ,
  • R 22 is selected from the group consisting of: C 1 - 15 alkyl, C 3- 15 alkenyl, C 3- 15 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, and alkynyl being optionally substituted with 1-3 halo, aryl or heteroaryl groups;
  • R 23 is R 21 or H;
  • R 24 is selected from aryl, COR 22 , CO 2 R 22 , CON(R 20 ) 2 and SO 2 R 22 ;
  • R 1 is H, aryl or C 1 - 15 alkyl, wherein H, aryl and C 1 - 15 alkyl are defined above;
  • R2 is aryl, C 1 - 15 alkyl, heteroaryl or heterocyclyl,
  • heterocyclyl are defined above;
  • R 3 is H, halo, NO 2 or CN
  • R 4 is aryl, C 1 - 15 alkyl, heteroaryl, COR 21 , CONR 20 R 23
  • heteroaryl COR 21 , CONR 20 R 23 or heterocyclyl are defined above.
  • Still another subset of compounds in accordance with claim 1 is realized when:
  • R 1 is H, or substituted alkyl
  • R 2 is aryl, C 1 -C 6 - alkyl, heteroaryl, or heterocyclyl
  • R 4 is aryl, C 1 -C 6 alkyl, heteroaryl, heterocyclyl, or
  • R3 is H or halo
  • HAr is a) pyridyl
  • HAr is a) 4-pyridyl-
  • R 1 is H
  • R 2 is phenyl substituted with
  • R 3 is H
  • R 4 is a) phenyl optionally substituted with:
  • the pharmaceutically acceptable salts of the compounds of formula I include the conventional non-toxic salts or the
  • non-toxic inorganic or organic acids such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
  • the compounds of the present invention also may have different tautomeric forms.
  • Har-(R a ) 0-3 represents a 4-hydroxy-3-pyridyl group
  • the following tautomers are equivalent and within the present invention:
  • This invention relates to method of antagonizing or inhibiting the production or activity of glucagon, thereby reducing the rate of gluconeogenesis and the concentration of glucose in plasma.
  • the compounds of formula I can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of disease states in mammals caused by elevated levels of glucose.
  • This invention also relates to a method of inhibiting or antagonizing the production or activity of cytokines in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of formula I to antagonize or inhibit cytokine production or activity, such that it is regulated down to normal levels, or in some cases to subnormal levels, so as to ameliorate or prevent the disease state.
  • the compounds of formula I can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of disease states in mammals, which are exacerbated or caused by excessive or unregulated cytokine production, more specifically IL-1 , IL-6, IL-8 or TNF production, by such mammal's cells, such as but not limited to monocytes and/or macrophages.
  • Compounds of formula I inhibit cytokines, such as IL-1 , IL-6, IL-8 and TNF and are therefore useful for treating inflammatory diseases such as rheumatoid arthritis, rheumatoid spondylitis,
  • the compounds of formula I may be used to treat other disease states mediated by excessive or unregulated cytokine production or activity.
  • diseases include, but are not limited to sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic
  • pulmonary inflammatory disease silicosis, pulmonary sarcoisosis, bone resorption diseases, such as osteoporosis, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia, secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDs related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, pyresis, AIDS and other viral infections, such as cytomegaliovirus (CMV), influenza virus, and the herpes family of viruses such as Herpes Zoster or Simplex I and II.
  • CMV cytomegaliovirus
  • influenza virus and the herpes family of viruses
  • herpes family of viruses such as Herpes Zoster or Simplex I and II.
  • the compounds of formula I may also be used topically in the treatment of inflammation such as for the treatment of rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; inflamed joints, eczema, psoriasis and other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.
  • Interleukin-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions. [See, e.g., Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)].
  • the myriad of known biological activities of IL-1 include the activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production,
  • neutrophil chemotaxis neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.
  • the compounds of formula I are also useful in treating diseases characterized by excessive IL-8 activity.
  • diseases characterized by excessive IL-8 activity.
  • diseases include psoriasis, inflammatory bowel disease, asthma, cardiac and renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis.
  • the invention includes a method of treating psoriasis, inflammatory bowel disease, asthma, cardiac and renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis, in a mammal in need of such treatment which comprises administering to said mammal a compound of formula I in an amount which is effective for treating said disease or condition.
  • the compounds of formula I are normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • This invention also relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier or diluent.
  • the compounds of formula I are administered in conventional dosage forms prepared by combining a compound of formula I with standard pharmaceutical carriers according to conventional procedures.
  • the compounds of formula I may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the pharmaceutical carrier employed may be, for example, solid or liquid.
  • Solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • Liquid carriers include syrup, peanut oil, olive oil, water and the like.
  • the carrier may include time delay material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the preparation can be in the form of a tablet, hard gelatin capsule, troche or lozenge.
  • the amount of solid will vary widely but preferably will be from about 0.025 mg to about 1 g.
  • the preparation is typically in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid or nonaqueous liquid suspension.
  • the compounds of formula I may also be administered topically in the form of a liquid, solid or semi-solid.
  • Liquids include solutions, suspensions and emulsions.
  • Solids include powders, poultices and the like.
  • Semi-solids include creams, ointments, gels and the like.
  • a representative, topical, anti inflammatory dose of a compound of formula I is from about 0.01 mg to about 1500 mg, administered one to four, preferably one to two times daily.
  • the active ingredient typically comprises about 0.001 % to about 90% w/w.
  • Drops according to the present invention may comprise sterile aqueous or oil solutions or suspensions, and may be prepared by dissolving the active ingredient in a suitable aqueous solution, optionally including a bactericidal and/or fungicidal agent and/or any other suitable preservative, and optionally including a surface active agent.
  • a suitable aqueous solution optionally including a bactericidal and/or fungicidal agent and/or any other suitable preservative, and optionally including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01 %) and chlorhexidine acetate (0.01 %).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous liquid, with the aid of suitable machinery, with a greasy or non-greasy base.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or macrogels.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicas, and other ingredients such as lanolin may also be included.
  • the methods of the instant invention may be carried out by delivering the monokine activity interfering agent parenterally.
  • the term 'parenteral' as used herein includes intravenous, intramuscular, intradermal and subcutaneous administration.
  • the intravenous and intramuscular forms of administration are preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • the instant invention can also be carried out by delivering the compound of formula I intranasally, rectally, transdermally or vaginally.
  • the compounds of formula I may also be administered by inhalation.
  • inhalation' is meant intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • Compounds of formula I may be prepared by the reaction of a benzoin 1, or protected version thereof with a methyl ketone 2 (commercially available or prepared by well established methods) in the presence of potassium cyanide followed by treatment with an alkyl or aryl amine or ammonia or equivalent thereof (ammonium acetate) at elevated temperature (Ceraulo, L. et al, J. Heterocyclic Chemistry 27, 255, 1990). See Scheme I
  • R 1 , R 2 , R 3 and R 4 are described above.
  • Compound 1 is prepared as described below. Aldehydes 3 may be converted to their trimethylsilyl cyanohydrins 4. Deprotonation and reaction with an aldehyde 5 will provide trimethyl silyl protected benzoins 1 (Hunig, S.; Wehner, G. Chem. Ber. 112, 2062 1979).
  • a protected heteroaryl methyl alcohol 5b may be deprotonated with a base such as n-butyl lithium in a polar aprotic solvent such as THF at a low temperature. Reaction of this anion with a Weinreb amide will provide alpha-hydroxy ketones 1.
  • a 1,4 diketone such as 6 may be reacted with ammonia (or a compound that gives rise to ammonia such as ammonium acetate) or a primary amine to provide compounds of formula I generally in the presence of an acid catalyst such as acetic acid or titanium tetrachloride at an elevated temperature. See Scheme II
  • 1 ,4 diketones 6 may be regioselectively constructed so that the appropriate groups are present on the pyrrole ring. Alkylation of 1,2-disubstitued heteroarylethanones 7 with bromoacetophenones or other leaving group substituted acetophenones provides 1 ,4 diketones 6 (Iyer, R. N.; Gopalachari, R. Ind. J. Chem. 11, 1260, 1973). Bromoacetophenones are readily prepared by bromination of acetophenones (for example by treatment with bromine in acetic acid or benzyltrimethylammonium bromide). Chloroketones may be prepared by treatment of activated (mixed anhydride) carboxylic acids with diazomethane followed by hydrogen chloride.
  • Ethanones 7 may be prepared by addition of anions 8 (derived by deprotonation of heteroaryl subtituted methyl groups, lithium halogen exchange of alkyl halides, or trialkyltin lithium exchange) to activated benzoic acids 9 (for example esters, acid chlorides, nitriles and N-methoxy-N-methyl amides) (see: Wolfe, J. F. et al J. Org. Chem. 39, 2006 1974 and Kaiser, E. M. et al. Synthesis 705 1975 and Ohsawa A. Chem. Pharm. Bull. 26, 3633, 1978).
  • anions 8 derived by deprotonation of heteroaryl subtituted methyl groups, lithium halogen exchange of alkyl halides, or trialkyltin lithium exchange
  • benzoic acids 9 for example esters, acid chlorides, nitriles and N-methoxy-N-methyl amides
  • 7 may also be prepared by alkylation of heteroaryl trimethyl silyl protected cyanohydrins 10.
  • Treatment of 10 with lithium diisopropyl amide in THF and addition of a heteroaryl methyl group functionalized with a leaving group L (for example:Br, I, Cl , tosylate, mesylate) followed by acid catalyzed hydrolysis of the silyl cyanohydrin group will provide ethanones such as 7 (Deuchert, K.; Hertenstein, U.; Hunig, S.; Wehner, G. Chem. Ber. 112, 2045, 1979).
  • 10a may be prepared from heteroaryl aldehydes by treatment with (MeO) 3 CH under acid catalysis.
  • 1,3 diketones 11 may be prepared by alkylation of 4 with bromoacetophenones. See Scheme III.
  • 1 ,4 diketones 13 may also be prepared as described below.
  • An aldehyde 14 may be condensed in the presence of a base (for example pyridine and diethylamine or sodium hydroxide) with a methyl ketone 15 to provide an a,b-unsaturated ketone 16.
  • a base for example pyridine and diethylamine or sodium hydroxide
  • a catalyst such as cyanide or a thiazolium salt a heteroaryl aldehyde 17 will react with 16 to give 13 (Stetter, H. J. Kuhlmann, H. Organic reactions 40, 407-496 Heterocyclic Chem. 14, 573, 1977).
  • Intermediate 16 may be prepared by the Horner-Emmons reaction of the anion of 18 with the aldehyde 14.
  • the reagent 18 may be prepared by reaction of the bromoketone 19 and triethyl phosphite or by reaction of the lithium salt of diethyl methylphosphonate with an ester 21.
  • the nitro group may be introduced into the pyrrole nucleus at the R 3 position (generic nomenclature) by electrophilic nitration of a compound such as 22 (or a less advanced intermediate) in the presence of fuming nitric acid and acetic anhydride (Pyrroles Part 1 , R. Alan Jones,ed., Heterocyclic Compounds , Vol 48 Part 1 , John Wiley, New York, 1990. Pages 330-345).
  • Hydroxymethyl substituted pyrroles 23 may be prepared by reduction of esters 25 by reducing agents such as lithium aluminum hydride.
  • the esters 25 may be prepared by classical techniques.
  • esters 25 Treatment of 1,2 disubstituted-2 halo ketones 26 with 3-keto esters 27 with ammonia or amines gives esters 25 (Hantzsch. Ber. Dtsch. Chem. Ges. 23, 1474, 1890). Alternatively, 2-amino ketones 28 react with 3-keto esters 27 to give 25.
  • a further method of synthesis of 23 is via reduction of the aldehyde 29 with a reducing agent such as sodium borohydride.
  • the aldehyde may be prepared by treatment of the R 3 -unsubstituted pyrrole with the Villsmeyer reagent (POCl 3 /DMF).
  • the pyrrole 22 may be silyated on nitrogen to give 30 by treatment with a silyl chloride and base in a solvent such as methylene chloride.
  • the pyrrole 30 may then be sulphinylated with a sulphinylchloride under basic conditions to provide 31 (J. Org. Chem. 6317, 1990).
  • Oxidation of 31 with a reagent such as m-chloroperoxybenzoic acid will give the sulphone 32.
  • Removal of the silyl group and derivatization of the pyrrole will give compounds of Formula 1. 22 may also be converted to the sulphide 33 by reaction of 22 with a symmetrical sulfoxide in the presence of trimethylsilychloride.
  • Oxidation of 33 with a reagent such as m-chloroperoxybenzoic acid will give 32.
  • the silyl pyrrole 30 may also be acylated with an acid chloride to give the ketone 34. Removal of the silyl group from 34 and derivatization of the pyrrole will give compounds of Formula 1.
  • Pyrroles such as 22 may also be sulphinylated directly without N-protection, by treatment with sulphinyl chlorides in a solvent such as dichloromethane at 0°C (J. Org. Chem. 5336, 1980). Oxidation as described above may provide pyrroles of Formula 1 where R 3 is SO 2 R 20 or 21. See Scheme VII
  • the amino acid ester 35 may be acylated with an acid 36 that is suitably activated (acid chloride or other activating group used in amide coupling reactions) to give 37. Hydrolysis of the ester protecting group will provide 38. Cyclization by treatment with an acid activating group such as DCC will give the oxazolium species 39. Addition of an alkyne 40 to 39 will give a pyrrole of Formula I via a 3+2 cycloaddition followed by loss of carbon dioxide. Various R 3 groups may be incorporated in this manner. See Scheme VIII.
  • Coupling chemistry may be utilized to introduce R 3 groups as shown below in Scheme IX.
  • 4-unsubstituted pyrroles optionally protected at nitrogen (P) 22 may be halogenated by treatment with electrophilic sources of bromine and iodine to provide 41.
  • the halogen may then be coupled with carbon monoxide in the presence of an alcohol to give, after removal of the protecting group, 4-alkoxycarbonyl substituted pyrroles of formula I.
  • Treatment of 41 with a hexalkylditin in the presence of a palladium catalyst see above for examples of catalysts) will give the stannyl pyrrole 42.
  • the stannyl pyrrole may then be coupled to acid chlorides to give ketones of formula I after deblocking, if required.
  • Reaction of 42 with chlorosulfonylisocyanate in the presence of a palladium catalyst will give the sulphonyl isocyanate 43.
  • Heteroaryl rings may be appended to a pyrrole ring system by utilization of organometallic coupling technology (Kalinin, V. Synthesis 413 1991). Two alternative approaches may be utilized for appending heteroaryl rings to the pyrrole ring.
  • the pyrrole ring may function as the electrophile or as the nucleophile as illustrated in Scheme X below:
  • Any appended aromatic or heteroaromatic rings may be attached to the pyrrole ring system (Alvarez, A. J. et al J. Org. Chem. 1653, 1992 (use of boronic acid and tributyl stannanes for coupling to aromatic and heteroaromatic rings)). Attachment of pyrrole pendant groups may be carried out with or without other HAr, R 2 , R 3 or R 4 groups attached.
  • Lithium anions are prepared by metalation of a regioselectively halogenated pyrrole, or the regioselective deprotonation of the pyrrole preferably by the use of a directing functional group.
  • the resulting anion may then be trapped by a trialkyl stannyl halide or a trialkyl borate or transmetalated to magnesium or zinc by treatment with appropriate halide salts.
  • a further method used to incorporate a trialkyl stannyl group is the coupling of a bromo, iodo or triflate substituted pyrrole with hexaalkylditin in the presence of a palladium catalyst.
  • pyrroles incorporating electrophilic groups may be carried out by the regioselective halogenation of a pyrrole (Pyrroles Part 1 , R. Alan Jones,ed., Heterocyclic Compounds,Vol 48 Part 1 , John Wiley, New York, 349-391 ,1990).
  • the synthesis of pyrroles incorporating electrophilic groups may be carried out by the regioselective halogenation of a pyrrole (Pyrroles Part 1 , R. Alan Jones,ed., Heterocyclic Compounds,Vol 48 Part 1 , John Wiley, New York, 349-391 ,1990).
  • Triflates may be prepared by acylation of hydroxy pyrroles with triflic anhydride.
  • reaction conditions used will depend on the nature of the coupling species.
  • the solvent used is normally toluene or DMF under anhydrous conditions.
  • boronic acid couplings a heterogenous system is used of water, toluene, dimethoxyethane or ethanol in the presence of a base such as sodium carbonate or bicarbonate. In general the reaction takes place at an elavated temperature (80-100 °C).
  • Catalysts used depend on the structure of the components to be coupled as well as the functional groups. Most commonly, tetrakistriphenylphosphinepalladium (0) or palladium bis triphenyl phosphine dichloride are utilized.
  • Substituents of the pendant groups of the pyrrole ring system are prepared utilizing methods well known to those skilled in the art.
  • functional groups such as halogens, sulfides, nitro groups, ethers and other groups stable to the reaction conditions used in the linear synthesis of the pyrroles are incorporated in the initial steps of the reaction sequence.
  • Sulfides may be oxidized to sulfoxides and sulfones with reagents such as m-chloroperbenzoic acid. Sulfides may also be converted to sulfonyl chlorides by oxidation and chlorination by chlorine in water.
  • Primary amines are prepared from nitro groups by catalytic (Pd/C, H 2 or Raney Nickle, H 2 ) or chemical means (CoCl 2 , NaBH 4 ).
  • Alkylation of amines to give secondary and tertiary amines is achieved by reductive alkylation (aldehyde, NaCNBH 4 ) or alkylation with an alkyl group substituted with a leaving group in the presence of a base such as K 2 CO 3 .
  • Tertiary amines may, alternatively, be carried through the reaction sequence to the pyrroles.
  • Acylation of primary or secondary amines with activated acids, achloroformates, isocyanates and chlorosulfonates will give rise to amides, carbamates, ureas and sulonamides respectively.
  • Carboxylic acids are best introduced as esters early in the synthesis. Saponification will provide carboxylic acids. Transesterification or esterification of the acids will give esters. Carboxylic acids may be converted to amides by activation and reaction with amines. Phenols are best introduced in a protected form early in the synthetic sequence to the pyrrole.
  • Phenols may be converted to aryl ethers by reaction with an aryl bismuthane in the presence of copper II acetate.
  • Aryl and heteroaryl groups may be attached to pyrrole pendant aryl and heteroaryl groups by application of coupling chemistry technology as outlined above.
  • the sequence and conditions of the reaction steps is dependant on the structure and functional groups present.
  • Protecting groups may be necessary and may be chosen with reference to "Protecting Groups in Organic Synthesis, Greene T. W., Wiley-Inerscience, New York, 1981 ".
  • the blocking groups are readily removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with fluoride ion, treatment with a transition metal catalyst and a nucleophile, and catalytic hydrogenation. Examples of suitable hydroxyl protecting groups are:
  • t-butylmethoxyphenylsilyl t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzy loxycarbonyl, t-butyloxy carbonyl, 2,2,2-trichloroethyloxycarbonyl, and allyloxycarbonyl.
  • carboxyl protecting groups examples include benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,
  • the reaction was warmed to 0°C and stirred for 1 hour and then was warmed to room temperature and was quenched by addition of 1 liter of 20% NH 4 Cl solution.
  • the aqueous phase was extracted with EtOAc (3 ⁇ 500 ml).
  • the combined organic phases were washed with water (1 ⁇ 500 ml) , 1 ⁇ 500 ml brine and were dried over MgSO 4 .
  • the mixture was filtered and the filtrate was concentrated in vacuo to give a dark oil.
  • the product was purified by flash
  • EtOAc ethyl acetate
  • the EtOAc phase was extracted with 1N HCl (2 ⁇ 10 ml).
  • the combined acidic aqueous phases were extracted with CH 2 Cl 2 (3 ⁇ 15 ml) and then made basic by addition of 3N NaOH solution.
  • the resulting emulsion was extracted with CH 2 Cl 2 (3 ⁇ 20 ml).
  • the combined organic extracts were washed with brine (1 20 ml) and dried over MgSO 4 to give the product sufficiently pure for conversion to pyrroles as described below.
  • Example 24 Using the procedure set forth in Example 24 (Method 2) and substituting the starting material identified in column two, the compounds of examples 26 - 40 were prepared. If the starting material is not specified, it was prepared as described in the foregoing examples using an appropriate change in the starting compounds.
  • pyridaldehyde is added to a suspension of 5 mole % NaCN in DMF under N 2 .
  • a red solution is formed.
  • the requisite chalcone in general prepared by condensation of an acetophenone and aldehyde in the presence of NaOH in MeOH.
  • EtOAc washed with water and brine, and dried over MgSO 4 .
  • the mixture is filtered and the filtrate is concentrated in vacuo to provide the crude 1 ,4-diketone.
  • the diketone is purified further by flash chromatography or committed directly to the condensation outlined below.
  • Example 41 The procedure set forth in Example 41 was utilized, substituting the product of Example 9 as the starting material.
  • the reaction mixture was extracted with ethyl acetate (3x 50 ml). The combined organic phases were washed with brine and dried over Na 2 SO 4 . The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluting with 50% EtOAc/hexanes to give the intermediate diazomethyl ketone.
  • the material was dissolved in 20 ml of ether and cooled to 0°C and then treated portionwise with 10 ml of 1 M HCl in ether. After 1 hour the reaction mixture was poured into 20 ml of saturated NaHCO 3 solution. The product was extracted with EtOAc (3 ⁇ 20 ml).
  • Step 2 The product of Step 2 (0.13 g (0.29 mmol) is heated in 2 ml of acetic acid in the presence of 0.5 g ammonium acetate at 1 10°C for 2 hours.
  • the reaction mixture is diluted with EtOAc (10 mL) and washed with water.
  • the combined organic phases are washed with brine and dried over MgSO 4 .
  • the mixture is filtered and the filtrate is concentrated in vacuo.
  • the residue is purified by rotary
  • a solution of the product of Example 47 in THF at room temperature is treated with 2 equivalents of lithium aluminium hydride.
  • the solution is refluxed for 2 hours, cooled to room temperature and treated with water, extracted with ethyl acetate and dried over sodium sulfate to give the desired product.
  • Example 49 Using the method disclosed in Example 49, the following compounds were prepared using the compounds disclosed in Examples 37 and 34 as starting materials.
  • the material was dissolved in 50 ml of acetic acid and heated with 5 grams of ammonium acetate until the starting material had been conxumed.
  • the reaction mixture was diluted with ethyl acetate, washed with water and dried by washing with brine and standing over MgSO 4 .
  • the mixture was filtered and the filtrate was concentrated in vacuo.
  • the crude product was purified by flash chromatography eluting with 5% MeOH/CH 2 Cl 2 .
  • Example 63 in 1 ml of DMF 0.025 g (0.16 mmol) of N-phenyl piperazine, 0.026 ml (0.25 mmol) of N-methyl morpholine, 0.032 g (0.24 mmol) of N-hydroxybenzotriazole and 0.045 g (0.24 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
  • the solution was stirred at room temperature over night and diluted with water.
  • the aqueous phase was extracted with ethyl acetate.
  • the organic phase was dried over MgSO 4 , filtered and concentrated in vacuo.
  • the residue was purified by rotory chromatography eluting with 4% MeOH/CH 2 Cl 2 to provide the desired product.
  • Example 3 in 48% aqueous HBr was added bromine (0.89 g, 5.58 mmol) at room temperature.
  • the reaction ixture was heated to 100°C for 1 hour and then cooled to room temperature and allowed to stand overnight.
  • the resulting yellow precipitate was filtered, washed with acetone and dried in vacou to provide the bromide.
  • Step 1 The product of Step 1 was combined with 3 equivalents of the requisite anhydride, and 5 mole % tetrakistriphenylphosphine in toluene at 100°C, and was heated until the starting material had been consumed.
  • the reaction mixture was concentrated in vacuo and purified by flash chromatography over silila gel eluting to provide the desired product.
  • the reagents are prepared as follows:
  • Protease Inhibitor Mix(1000X) 5mg leupeptin + 10mg benzamidine + 40mg bacitracin + 5mg soybean trypsin inhibitor per ml DMSO. Store aliquots at -20°C.
  • Assay Buffer 20mM Tris, pH 7.8; 1mM DTT; 3mM o-phenanthroline.
  • Assay Buffer w/ 0.1 % BSA (for dilution of label only, therefore 0.01 % final in assay): 10 ⁇ l 10% BSA (heat-inactivated) + 990 ⁇ l assay buffer
  • membrane preparations from CHO/hGLUR cells can be used in place of whole cells at the same assay volume. Final protein concentration of membrane preparation is determined on a per batch basis.
  • the determination of inhibition of glucagon binding is carried out by measuring the reduction of I 125 -glucagon binding in the presence of compounds of Formula I.
  • the assay is carried out in a 96-well box. The following reagents are combined:
  • the box is incubated for 60min. at 22°C on a shaker at 275rpm.
  • the wells are filtered over pre-soaked (0.5% polyethylimine(PEI)) GF/C filtermat using an Innotech Harvester or Tomtec Harvester with four washes of ice-cold 20mM Tris, pH 7.8 buffer. Count filters in Gamma- scintillation counter.
  • PBMC peripheral blood mononuclear cells
  • PBMC's are washed three times in Hanks Balanced Salt Solution and then resuspended to a final concentration of 2 ⁇ 10 6 cell/mL in RPMI containing 10% fresh autologous human serum, penicillin streptomycin (10 U/mL) and 0.05% DMSO.
  • Human peripheral blood mononuclear cells are isolated from fresh human blood according to the procedure of Chin and
  • erythrocytes are separated from the PBMC's by centrifugation on a Ficoll-Hypaque lymphocyte separation media. The PBMC's are washed three times in Hanks
  • cell culture supernatants are assayed for TNF- ⁇ , IL-6 and PGE2 synthesis using specific ELISA. Determination of IL-1 ⁇ , TNF- ⁇ , IL-6 and prostanoid production from LPS or IL-1 stimulated PBMC's
  • Human IL-1 ⁇ can be detected in cell-culture supernatants or whole blood with the following specific trapping ELISA.
  • Ninety-six well plastic plates (Immulon 4; Dynatech) are coated for 12 hours at 4°C with 1 mg/mL protein-A affinity chromatography purified mouse anti-human IL-1b monoclonal antibody (purchased as an ascites preparation from LAO Enterprise, Gaithersburg Maryland.) diluted in Dulbecco's phosphate-buffered saline (-MgCl 2 , -CaCl 2 ).
  • IL-1 ⁇ standards are prepared from purified recombinant IL-1 ⁇ produced from E. coli.. The highest concentration begins at 10 ng/mL followed by 1 1 two-fold serial dilution's. For detection of IL-1 ⁇ from cell culture supernatants or blood plasma, 10 - 25 mL of supernatant is added to each test well with 75 - 90 mL of PBS Tween.
  • Peroxidase activity was determined using TMB peroxidase substrate kit (Kirkegaard and Perry) with quantitation of color intensity on a 96-well plate Molecular Devices spectrophotometer set to deter mine absorbance at 450 nM. Samples are evaluated using a standard curve of absorbance versus concentration. Four-parameter logistics analysis generally is used to fit data and obtain concentrations of unknown compounds.
  • Immulon 4 (Dynatech) 96-well plastic plates are coated with a 0.5 mg/mL solution of mouse anti-human TNF- ⁇ monoclonal antibody.
  • the secondary antibody is a 1 :2500 dilution of a rabbit anti-human TNF- ⁇ polyclonal serum purchased from Genzyme. All other operations are identical to those described above for IL-1b.
  • the standards are prepared in PBS-Tween + 10% FBS or HS. Eleven 2 fold dilution's are made beginning at 20 ng/mL TNF- ⁇ .
  • IL-6 levels are also determined by specific trapping ELISA as described previously in Chin and Kostura, J. Immunol. 151, 5574-5585 (1993). (Dynatech) ELISA plates are coated with mouse anti-human IL-6 monoclonal antibody diluted to 0.5 mg/ml in PBS. The secondary antibody, a rabbit anti-human IL-6 polyclonal antiserum, is diluted 1 :5000 with PBS-Tween. All other operations are identical to those described above for EL-1 ⁇ . The standards are prepared in PBS-Tween + 10% FBS or HS. Eleven 2 fold dilution's are made beginning at 50 ng/mL IL-6.
  • Prostaglandin E2 is detected in cell culture supernatants from LPS or IL-1 stimulated PBMC's using a commercially available enzyme immunoassay .
  • the assay purchased from the Cayman
  • Interleukin8 The present compounds can also be assayed for IL-8 inhibitory activity as discussed below.
  • Primary human umbilical cord endothelial cells (HUVEC) (Cell Systems, Kirland, Wa) are maintained in culture medium supplemented with 15% fetal bovine serum and 1 % CS-HBGF consisting of ⁇ FGF and heparin. The cells are then diluted 20-fold before being plated (250 ⁇ l) into gelatin coated 96-well plates. Prior to use, culture medium is replaced with fresh medium (200 ⁇ l).
  • Buffer or test compound (25 ⁇ l, at appropriate concentrations) is then added to each well in quadruplicate wells and the plates incubated for 6h in a humidified incubator at 37°C in an atmosphere of 5% CO 2 . At the end of the incubation period, supernatant is removed and assayed for IL-8 concentration using an IL-8 ELISA kit obtained from R&D Systems (Minneapolis, MN). All data is presented as mean value
  • the following exemplary compounds were found to inhibit cytokine production at an IC 50 of less than about 100 ⁇ M and/or inhibit the binding of glucagon to its receptor at an IC 50 of less than 2 ⁇ M.
  • spiroindene-1 is:
  • heterocycle-1 is:
  • spiroindane-1 is:
  • heterocycle-2 is:

Abstract

La présente invention concerne des pyrroles de pyridyle substitués, des compositions contenant de tels composés et leur utilisation thérapeutique. Les composés de la présente invention sont des antagoniste du glucagon et des inhibiteurs de la biosynthèse et de l'action du facteur TNF-α et de l'IL1. Ces composés bloquent l'action du glucagon au niveau de ses récepteurs, ce qui diminue les niveaux de glucose du plasma. Les pyrroles de l'invention, qui sont également des inhibiteurs du facteur TNF-α et de l'IL1, peuvent servir d'antidiabétiques et contre d'autres affections à médiation des cytokines. L'interleukine-1 (IL-1) et le facteur de nécrose tumorale (TNF) sont des cytokines produites par diverses cellules qui interviennent au niveau de la régulation immunitaire et au niveau d'autres états physiologiques tels que les états inflammatoires.
PCT/US1996/018539 1995-10-31 1996-10-30 Pyrroles de pyridyle substitues, compositions contenant de tels composes et mode d'utilisation WO1997016442A1 (fr)

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AU11208/97A AU702887B2 (en) 1995-10-31 1996-10-30 Substituted pyridyl pyrroles, compositions containing such compounds and methods of use
JP9517642A JPH11514651A (ja) 1995-10-31 1996-10-30 置換ピリジルピロール、前記化合物を含む組成物及び使用方法
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US1556596P 1996-04-18 1996-04-18
US60/015,565 1996-04-18
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JPH11514651A (ja) 1999-12-14
EP0859771A1 (fr) 1998-08-26
AU702887B2 (en) 1999-03-11
EP0859771A4 (fr) 2000-03-15

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