WO1998021957A1 - Imidazoles a substitution triaryle, compositions renfermant de tels composes et modes d'utilisation - Google Patents

Imidazoles a substitution triaryle, compositions renfermant de tels composes et modes d'utilisation Download PDF

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Publication number
WO1998021957A1
WO1998021957A1 PCT/US1997/021019 US9721019W WO9821957A1 WO 1998021957 A1 WO1998021957 A1 WO 1998021957A1 US 9721019 W US9721019 W US 9721019W WO 9821957 A1 WO9821957 A1 WO 9821957A1
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alkyl
independently selected
substituted
groups independently
naphthyl
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PCT/US1997/021019
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English (en)
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Linda L. Chang
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Merck & Co., Inc.
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Priority claimed from GBGB9702823.7A external-priority patent/GB9702823D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU54427/98A priority Critical patent/AU728760B2/en
Priority to EP97948342A priority patent/EP0948257A4/fr
Priority to JP52379798A priority patent/JP2001504490A/ja
Priority to CA002271963A priority patent/CA2271963A1/fr
Publication of WO1998021957A1 publication Critical patent/WO1998021957A1/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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • 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
    • 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
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • C07D409/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to triaryl substituted imidazoles which antagonize the metabolic effect of glucagon and are inhibitors of the biosynthesis and/or action of cytokines including TNF- ⁇ and IL-1.
  • This invention also relates to compositions containing such compounds and methods of treatment using such compounds.
  • 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 micro vascular and macro vascular diseases, including nephropathy, retinopathy, hypertension, stroke and heart disease. Control of glucose homeostasis 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, pancreas, adipose tissues, heart, smooth muscles of vascular tissues, and some regions of the brain, stomach and adrenal glands.
  • 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.
  • Glu-mAb A monoclonal antibody to glucagon (Glu-mAb) has been utilized to test the acute effects of attenuation of glucagon action in streptozotocin-treated diabetic rats (Brand et al., Diabetologia 37:985, 1994).
  • injection of Glu-mAb attenuated the postprandial increase in blood glucose in moderately hyperglycemic rats (i.e.., rats with a moderate impairment in insulin secretion).
  • Glu-mAb injection did not lower blood glucose levels, but potentiated the hypoglycemic effect of a suboptimal dose of insulin.
  • glucagon homeostasis is also mediated by the hormone insulin, produced in the ⁇ cells of the pancreas.
  • glucagon antagonist might have utility in treating Type I diabetics.
  • the glucagon receptor is expressed in kidney tissues where glucagon has been demonstrated to have an effect on electrolyte homeostasis including the ions sodium, potassium, chloride, magnesium, calcium, and phosphate and the non-electrolytes urea and water (Ahloulay et al., Am. J. Physiol, 269: F225, 1995).
  • a glucagon antagonist may have use in treating disorders involving electrolyte imbalance.
  • the kidney is also gluconeogenic in response to glucagon (Amores et al., Molec. Cell. Biochem., 137: 117, 1994) and an antagonist would act to lower glucose production in kidney furthering the treatment of diabetes.
  • Glucagon receptors are present in the heart and in smooth muscles. Glucagon has a direct effect on cardiac output and heart rate (Glick et al., Circ. Res., 22: 789 (1968); Farah, Pharm. Rev., 35: 181, 1983).
  • a strong correlation has been observed in patients with hypertension and elevated plasma glucagon levels resulting from impaired hepatic catabolism (Silva et al., Heptatology, 11: 668, 1990).
  • Antagonism of the effects of elevelated glucagon levels may have an effect on certain types of hypertension, thus a glucagon antagonist may have utility in the treatment of certain types of hypertension associated with elevated glucagon production.
  • glucagon and glucagon receptors associated with adipose tissues The primary role for glucagon and glucagon receptors associated with adipose tissues is to induce lipolysis, thus providing free fatty acids as a substrate for fat burning tissues (Saggerson et al., Biochem. J., 238: 387, 1986).
  • An antagonist to this effect might be useful in treating conditions where there is excessive lipolysis of fat stores resulting from elevated glucagon levels, such as wasting disease (cachexia).
  • Glucagon and glucagon receptors have been localized to the hippocampus region of the brain (Hoosein and Gurd, Proc. Natl. Acad. Sci. USA, 81: 4368, 1984). This discovery suggests that glucagon may have a neuroendocrine role in initiating or elaborating basic behavior or somatic motor programs. Since glucagon secretion is increased in response to low blood glucose levels, increased glucagon levels in the brain may initiate behavior to respond to low glucose levels, such as eating. Thus, chronic hyperglucagonemia may also result in a constant craving for food resulting in obesity. A glucagon antagonist may have utility in treating obesity by altering feeding behavior associated with a response to glucagon.
  • Cytokine mediated diseases refers to diseases or conditions in which excessive or unregulated production of one or more cytokines occurs.
  • Interleukin- 1 IL-1
  • Interleukin-6 IL-6
  • Interleukin-8 IL-8
  • TNF Tumor Necrosis Factor
  • IL-1 Interleukin-1
  • IL-6 Interleukin-6
  • IL-8 Interleukin-8
  • TNF Tumor Necrosis Factor
  • IL-1 IL-1
  • rheumatoid arthritis rheumatoid arthritis
  • osteoarthritis endotoxemia
  • toxic shock syndrome other acute or chronic 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 affecting 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 correlated with disease states such as angiofollicular lymphoid hyperplasia.
  • Interleukin-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 mononuclear cells, fibroblasts, and endothelial cells. Its production is induced by IL-1, TNF and by lipopolysaccharide (LPS). IL-8 stimulates a number of cellular functions in vitro.
  • NAP-1 neutrophil attractant/activation protein- 1
  • MDNCF monocyte derived neutrophil chemotactic factor
  • NAF neutrophil activating factor
  • T-cell lymphocyte chemotactic factor T-cell lymphocyte chemotactic factor.
  • IL-8 is produced by several cell types, including mononuclear cells,
  • the compounds of formula I are also useful in treating diseases characterized by excessive IL-8 activity. There are many disease states in which excessive or unregulated IL-8 production is implicated in exacerbating and/or causing the disease. These diseases include psoriasis, inflammatory bowel disease, asthma, cardiac and renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis.
  • TNF production has been implicated in mediating or exacerbating rheumatoid arthritis, 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.
  • 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, Crohn's disease, ulcerative colitis and pyresis.
  • AIDS cachexia secondary to infection or malignancy
  • AIDS related complex ARC
  • keloid formation scar tissue formation, Crohn's disease, ulcerative colitis and pyresis.
  • Cytokines such as TNF
  • 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 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
  • cytokine suppressive or antagonistic i.e., compounds which are capable of interfering with, inhibiting or antagonizing cytokines such as IL-1, IL-6, IL-8 and TNF.
  • the compounds in the present invention are glucagon antagonists and inhibitors of the biosynthesis and action of IL-1, IL-6, IL- 8 and TNF.
  • the compounds block the action of glucagon at its receptors and thereby decrease the levels of plasma glucose.
  • the instant compounds thus are useful as antidiabetic agents.
  • Glucagon may have other direct effects on cardiac output, lipolysis, and feeding behavior and therefore may be useful as antihypertensive, anti-cachexia or antiobesity agents.
  • Compounds of the present invention are also useful for the treatment of cytokine mediated diseases. SUMMARY OF THE INVENTION
  • the present invention relates to 2,4-diaryl-5-pyridyl imidazoles which are glucagon receptor antagonists as well as cytokine inhibitors. These compounds are therefore useful for the treatment of diseases mediated by glucagon as well diseases mediated by cytokines. Diseases caused by excessive levels of glucagon, include diabetes and certain types of hypertension, cachexia and obesity.
  • Cytokine-mediated diseases are for example rheumatoid arthritis, osteoarthritis, endotoxemia, toxic shock syndrome, other acute or chronic inflammatory diseases, such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease (Crohn's disease, ulcerative colitis), tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis, angiofollicular lymphoid hyperplasia, psoriasis, inflammatory bowel disease, asthma, cardiac and renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis, rheumatoid spondylitis, gouty arthritis, and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome
  • compositions which comprise a compound of formula I in combination with a pharmaceutically acceptable carrier.
  • the present invention provides compounds of formula (I):
  • R 1 is 4-pyridyl, 4-pyrimidinyl, 4-quinolyl or pyridazinyl, each of which is unsubstituted or substituted with one or two substituents each of which is independently selected from the group consisting of
  • Ci-io alkyl wherein said alkyl is optionally substituted with from 1 to 5 halogen atoms, (4) -O-Ci-ioalkyl,
  • R2 is hydrogen, -C(Z)OC ⁇ _4alkyl, -C(Z)C ⁇ _4alkyl, or -S(0)2C alkyl;
  • R3 is phenyl, 1-naphthyl, 2-naphthyl or heteroaryl each of which is
  • Ci-io alkyl (2) R5, and
  • R4 is -X-Ar wherein X is a bond and Ar is substituted phenyl, substituted 1-naphthyl, or substituted 2-naphthyl, wherein said substituent is one or two groups each of which is independently selected from the group consisting of
  • phenyl optionally substituted with up to 5 groups independently selected from C i . i o alkyl, R5 , and C 1.10 alkyl substituted with up to 5 groups independently selected from R5,
  • X is -C ⁇ _4alkyl-, -C(Z)-, or -C(Z)C ⁇ _4alkyl- where -C(Z) is the point of attachment to the imidazole ring, and Ar is phenyl, 1-naphthyl, 2- naphthyl, or heteroaryl, and Ar is unsubstituted or substituted with one, two, or three substituents each of which is independently selected from the group consisting of
  • 2-naphthyl optionally substituted with up to 5 groups independently selected from Ci-io alkyl, R5, and Ci-io alkyl substituted with up to 5 groups independently selected from R5, (7) heteroaryl, optionally substituted with up to 5 groups independently selected from Ci-io alkyl, R5, and Ci-io alkyl substituted with up to 5 groups independently selected from R5,
  • Rl i or R8 and R9 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR12;
  • RlO and R20 is each independently selected from hydrogen and Ci-4 alkyl;
  • Rn is (1) Cl-10 alkyl,
  • Rl2 is (1) hydrogen
  • Ci-4 alkyl wherein the substituents may be halo, C1-3 alkoxy, amino, or carboxy
  • aryl C 1-4 alkyl wherein the substituents may be halo, C1-3 alkoxy, amino, or carboxy, or
  • R25; Rl4 and R24 is each independently selected from
  • Rl5 is (1) hydrogen
  • Rl8 and R19 are independently selected from
  • R 18 and R 19 together denote an oxo or thioxo ;
  • R21 is (1) Rl3,
  • Ci-io alkanoyl is (1) C 1-10 alkyl
  • Z is oxygen or sulfur; m is l or 2; n is 1 to 10; p is 1 to 10; a pharmaceutically acceptable salt thereof.
  • Rl is 4-pyridyl which is unsubstituted or substituted with one or two substituents each of which is independently selected from the group consisting of
  • Ci-io alkyl wherein said alkyl is optionally substituted with from 1 to 5 halogen atoms,
  • R2 is H or -C(Z)OCl_4alkyl
  • Z is oxygen or sulfur.
  • R3 is phenyl, 1-naphthyl or 2-naphthyl each of which is unsubstituted or substituted with one, two or three groups each of which is independently selected from the group consisting of (l) C l-l ⁇ alkyl,
  • R4 is -X-Ar
  • X is a bond and Ar is substituted phenyl, substituted 1-naphthyl, or substituted 2-naphthyl, wherein said substituent is one or two groups each of which is independently selected from the group consisting of (1) phenyl, optionally substituted with up to 5 groups independently selected from C ⁇ _ o alkyl, R5, and Ci- o alkyl substituted with up to 5 groups independently selected from R5,
  • phenyl optionally substituted with up to 5 groups independently selected from Ci-io alkyl, R5, and Ci-io alkyl substituted with up to 5 groups independently selected from R5, (5) 1-naphthyl, optionally substituted with up to 5 groups independently selected from Ci-io alkyl, R5, and Ci-io alkyl substituted with up to 5 groups independently selected from R5,
  • Rl is 4-pyridyl, 4-pyrimidinyl or 4-quinolyl
  • R2 is hydrogen or -C(Z)OC ⁇ _4alkyl
  • R3 is phenyl, 1-naphthyl, 2-naphthyl or heteroaryl each of which is unsubstituted or substituted with one, two or three substituents each of which is independently selected from the group consisting of (1) Cl-10 alkyl, (2) R5, and
  • R4 is -X-Ar herein
  • X is a bond and Ar is substituted phenyl, substituted 1-naphthyl, or substituted 2-naphthyl, wherein said substituent is one or two groups each of which is independently selected from the group consisting of (1) phenyl, optionally substituted with up to 5 groups independently selected from Cl-10 alkyl, R5, and Ci-io alkyl substituted with up to 5 groups independently selected from R5, (2) 1-naphthyl, optionally substituted with up to 5 groups independently selected from Ci-io alkyl, R5, and Ci-io alkyl substituted with up to 5 groups independently selected from R5,
  • heteroaryl optionally substituted with up to 5 groups independently selected from Ci-io alkyl, R5, and Ci-io alkyl substituted with up to 5 groups independently selected from R5, or X is -CH2- or -C(Z)-, and Ar is phenyl, 1-naphthyl, 2-naphthyl, or heteroaryl, and Ar is unsubstituted or substituted with one, two, or three substituents each of which is independently selected from the group consisting of (1) Cl-10 alkyl, (2) R5,
  • 1-naphthyl optionally substituted with up to 5 groups independently selected from Ci-io alkyl, R5, and Ci-io alkyl substituted with up to 5 groups independently selected from R5, (6) 2-naphthyl, optionally substituted with up to 5 groups independently selected from Ci-io alkyl, R5, and Ci-io alkyl substituted with up to 5 groups independently selected from R5, (7) heteroaryl, optionally substituted with up to 5 groups independently selected from Ci-io alkyl, R5, and Ci-io alkyl substituted with up to 5 groups independently selected from R5,
  • RlO and R20 is each independently selected from hydrogen and C1-.4 alkyl; Rl l is (1) Cl-10 alkyl, (2) halo-substituted Ci-io alkyl,
  • arylalkyl wherein the aryl portion is optionally substituted with OR 10; Z is oxygen or sulfur; a pharmaceutically acceptable salt thereof.
  • R3 is phenyl, 1-naphthyl or 2-naphthyl each of which is unsubstituted or substituted with one, two or three substituents each of which is independently selected from the group consisting of (1) halogen, and
  • R4 is -X-Ar wherein X is a bond and Ar is substituted phenyl, substituted 1-naphthyl, or substituted
  • phenyl optionally substituted with up to 5 groups independently selected from Ci-io alkyl, R5, and Ci-io alkyl substituted with up to 5 groups independently selected from R5,
  • phenyl optionally substituted with up to 5 groups independently selected from Cl-10 alkyl, R5, and Cl-10 alkyl substituted with up to 5 groups independently selected from R5, (5) 1-naphthyl, optionally substituted with up to 5 groups independently selected from Ci-io alkyl, R5, and Ci-io alkyl substituted with up to 5 groups independently selected from R5,
  • heteroaryl optionally substituted with up to 5 groups independently selected from Ci-io alkyl, R5, and Ci-io alkyl substituted with up to 5 groups independently selected from R5, R5 is
  • R8 is selected from (1) hydrogen
  • Rn; RlO and R20 . i each independently selected from hydrogen and C ⁇ _4 alkyl; Rl l is (1) Cl-10 alkyl,
  • Z is oxygen or sulfur; a pharmaceutically acceptable salt thereof.
  • Especially preferred compounds of formula I include:
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • alkyl refers to a monovalent alkane (hydrocarbon)-derived radical containing the designated number of carbon atoms. It may be straight or branched. Examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, sec-butyl, isopentyl and t- butyl.
  • alkenyl refers to a hydrocarbon radical, straight or branched, containing the designated number of 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. Examples of alkenyl groups include ethenyl, propenyl, butenyl and isobutenyl.
  • alkynyl refers to a hydrocarbon radical, straight or branched, containing the designated number of carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present. Examples of alkynyl groups include ethynyl, propynyl and butynyl.
  • Aryl refers to aromatic rings wherein all ring atoms are carbon, including phenyl and naphthyl.
  • heteroaryl (on its own or in any combination, such as “heteroaryloxy”) represents a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O and S, such as, but not limited to pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, thiadiazolyl, tetrazolyl, triazolyl, oxadiazolyl, oxazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl,
  • Heterocyclic (on its own or in any combination, such as “heterocyclylalkyl”) represents a saturated or wholly or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O and S.
  • heterocyclyls are piperidinyl, mo holinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydroimidazo[4,5-c]pyridine, imidazolinyl, piperazinyl, pyrazolindinyl and the like.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • 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.
  • 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- ⁇ ).
  • 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 occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included within the scope of the present invention.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids/bases and organic acids/bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as
  • Salts derived from inorganic acids include hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids include acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • 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.
  • This invention relates to a method of inhibiting the action of glucagon at its receptors thereby reducing the rate of gluconeogenesis and the concentration of glucose in plasma.
  • compounds of formula I can be used in the prophylaxis or treatment of disease states in mammals mediated by elevated levels of glucagon. Examples of such disease states include diabetes, obesity, hypertension, cachexia, and the like.
  • This invention also relates to a method of inhibiting 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 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, osteoarthritis, gouty arthritis and other arthritic conditions.
  • cytokines such as IL- 1 , IL- 6, IL-8 and TNF
  • inflammatory diseases such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions.
  • 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.
  • 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 cytomegalovirus (CMV), influenza virus, and the herpes family of viruses such as Herpes Zoster or Simplex I and II.
  • CMV cytomegalovirus
  • influenza virus and the 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, induction of acute phase proteins and the suppression of plasma iron levels.
  • IL- 1 production is implicated in exacerbating and/or causing the disease.
  • diseases states include rheumatoid arthritis, osteoarthritis, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states 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.
  • 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 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 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 active compounds of the present invention may be orally administered as a pharmaceutical composition, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • these active compounds may be incorporated with excipients and used in the form of tablets, pills, capsules, ampules, sachets, elixirs, suspensions, syrups, and the like.
  • Such compositions and preparations should contain at least 0.1 percent of active compound.
  • the percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • active compounds may also be administered parenterally, for example intravenously, intramuscularly, intradermally or subcutaneously.
  • Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy- propylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • 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. 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.
  • 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.
  • 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.
  • Compounds of the present invention may also be administered intranasally as, for example, liquid drops or spray; by intranasal or oral inhalation; rectally; trasdermally; or vaginally.
  • a representative dosing regimen for treating diabetes mellitus and/or hyperglycemia may involve administering a compound of formula I at a daily dosage of from about 0.001 milligram to about 100 milligram per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 0.07 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • Compounds of the present invention may be prepared by several general synthetic methods as described in, for example, M. R. Grimmett, Comprehensive Heterocyclic Chemistry, The Structure, ⁇ Reactions, Synthesis and Uses of Heterocyclic Compounds, A. R. Katritzky and C. W. Rees, eds., Vol. 5, Pergamon Press, Oxford, 1984, pp. 457-498.
  • the compounds of the present invention can be prepared by procedures illustrated in the accompanying schemes.
  • the three general methods for preparation of the imidazole nucleus are outlined in schemes 1, 2, and 3.
  • a suitably protected picolyl alcohol (1) is deprotonated with a strong base such as lithium diisopropyl amide or n-butyl lithium and the resulting anion is reacted with an appropriate N,0-dimethylhydroxamide (2) to give a protected alpha hydroxy ketone (3).
  • the protected alpha hydroxy ketone is then condensed with a suitably functionalized aldehyde (4) in the presence of copper(II) acetate and ammonium acetate in acetic acid to form the desired compound.
  • picoline (6) is deprotonated with a strong base such as lithium diisopropyl amide or n- butyl lithium and the resulting anion is reacted with N,0- dimethylhydroxamide (2) to give a pyridylarylmethyl ketone (7).
  • the dione (8) obtained by selenium dioxide oxidation of the pyridylarylmethyl ketone is then condensed with a suitably functionalized aldehyde (4) in the presence of ammonium acetate in acetic acid to form the desired imidazole (5).
  • bromomethylpyridyl ketone (9) is reacted with a suitably substituted benzamidine (10) to afford the disubstituted imidazole (11) which is then protected.
  • the protected imidazole (12) is deprotonated with a strong base such as n-butyl lithium, s-butyl lithium, or lithium diisopropyl amide followed by reaction with the appropriate alkylating or acylating agent (13, L may be for example halogen, alkylsulfonate, arylsulfonate, activated ester) yields the protected target compound. Removal of the N-protection on the imidazole affords the target compound (14).
  • Step A 4-t-Butydimethylsilyloxymethylpyridine
  • 4-pyridylcarbinol 50.3 g, 0.46 mol
  • methylene chloride 250 mL
  • triethylamine 9 mL
  • T 34 °C cooling
  • the reaction mixture was stirred overnight at room temperature.
  • the slurry was then filtered and the solvent removed by rotoevaporation.
  • the residue was suspended in toluene and filtered and the solvent removed by rotoevaporation.
  • the residue was suspended in diethyl ether and filtered and the solvent removed by rotoevaporation.
  • the same process was repeated with hexanes to yield 4-t-butydimethylsilyloxymethylpyridine as a brown oil.
  • Step B 4'-Ethyl-4-biphenyl 4-pyridyl-t-butyldimethylsilyloxymethyl ketone
  • Step C 2-f4-Chlorophenyl -4-f4'-ethyl-4-biphenylV5-(4- pyridyPimidazole
  • Step A 2-( " 4-chlorophenyl -4-(4-pyridyDimidazole To a cooled solution of 4-chlorobenzamidine (3.4 g, 22 mmol) in DMF (12 mL) at ' O °C was added batchwise bromomethyl 4-pyridyl ketone hydrobromide (1.47 g, 5.5 mmol) over a 15 min period. The reaction was stirred for 30 min at room temperature. The reaction was quenched by the addition of saturated ammonium chloride solution and the mixture was extracted with ethyl acetate (2 times). The combined extracts were successively washed with water (2 times) and saturated salt solution and dried over anhydrous sodium sulfate.
  • Step B 2-(4-chlorophenylV 1 -methoxymethyl-5-(4-pyridyl imidazole
  • Step C 4-Benzoyl-2-(4-chlorophenyD- 1 -methoxymethyl-5-(4- pyridyDimidazole To a cooled solution of 2-(4-chlorophenyl)-l-methoxymethyl-5-
  • Step D 4-Benzoyl-2-(4-chlorophenyl)-5-f4-pyridyl)imidazole
  • Step A l-(4-Bromophenyl)-2-(4-pyridyl -ethanone
  • THF 3 mL
  • n-butyl lithium 1.6 mL, 4.0 mmol, of a 2.5M solution in hexanes
  • the reaction was stirred between -45 and -10 °C for 0.75h.
  • 4-picoline 300 mg, 3.22 mmol
  • THF 1 mL
  • Step B 1 -C4-Bromophenyl)-2-f 4-pyridyl -ethan- 1.2-dione
  • Step C 4-(4-Bromophenyl)-2-(4-chlorophenyP-5-(4-pyridyl)imidazole
  • Step D 2-( -Chlorophenyl)-4-(4'-methoxybiphenyl-4-ylV5-f4- pyridyPimidazole
  • BIOLOGICAL ASSAYS The ability of compounds of the present invention to inhibit the binding of glucagon and the synthesis or the activity of cytokines can be determined by the following in vitro assays.
  • Protease Inhibitor Mix (1000X): 5 mg leupeptin + 10 mg benzamidine + 40 mg bacitracin + 5 mg soybean trypsin inhibitor per ml DMSO. Store aliquots at -20 °C.
  • Assay Buffer 20 mM Tris, pH 7.8; ImM 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
  • the determination of inhibition of glucagon binding is carried out by measuring the reduction of ll25_ i uca g 0n 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 60 min. at 22 °C on a shaker at 275 rpm.
  • 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 20 mM Tris, pH 7.8 buffer.
  • Count filters in Gamma- scintillation counter. Lipopolysaccharide mediated production of cytokines
  • PBMC Human peripheral blood mononuclear cells
  • the PBMC's are washed three times in Hanks Balanced Salt Solution and then resuspended to a final concentration of 2 x 10" cell/mL in RPMI containing 10% fresh autologous human serum, penicillin streptomycin (10 U/mL) and 0.05% DMSO.
  • Lipopolysaccharide (Salmonella type Re545; Sigma Chemicals) is added to the cells to a final concentration of 100 ng/mL.
  • An aliquot (0.1 mL) of the cells is quickly dispensed into each well of a 96 well plate containing 0.1 mL of the test compound, at the appropriate dilution, and are incubated for 24 h. at 37°C in 5% C ⁇ 2 .
  • cell culture supernatants are assayed for IL-l ⁇ , TNF- ⁇ , IL-6 and PGE2 production using specific ELISA.
  • Human peripheral blood mononuclear cells are isolated from fresh human blood according to the procedure of Chin and Kostura, J. Immunol. 151, 5574-5585 (1993).
  • Whole blood is collected by sterile venipuncture into 60 mL syringes coated with 1.0 mL of sodium- heparin (Upjohn, 1000 U/mL) and diluted 1 : 1 in Hanks Balanced Salt Solution (Gibco).
  • the 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 Balanced Salt Solution and then resuspended to a final concentration of 2 x 10 cell/mL in RPMI containing 10% fresh autologous human serum, penicillin streptomycin (10 U/mL) and 0.05% DMSO. Endotoxin free recombinant human IL-l ⁇ is then added to a final concentration of 50 pMolar. An aliquot (0.1 mL) of the cells is quickly dispensed into each well of a 96 well plate containing 0.1 mL of the compound at the appropriate dilution, and are incubated for 24 h at 37 °C in 5% C02 . At the end of the culture period, cell culture supernatants are assayed for TNF- , IL-6 and PGE2 synthesis using specific ELISA.
  • 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 h at 4°C with 1 mg/mL protein-A affinity chromatography purified mouse anti-human IL-l ⁇ monoclonal antibody (purchased as an ascites preparation from LAO Enterprise, Gaithersburg Maryland.) diluted in Dulbecco's phosphate-buffered saline (-MgCl2, -CaCl2). The plates are washed with
  • IL-l ⁇ standards are prepared from purified recombinant IL-l ⁇ produced from E. coli.. The highest concentration begins at 10 ng/mL followed by 11 two-fold serial dilution's. For detection of IL-l ⁇ 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 determine 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.
  • TNF- ⁇ ELISA 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-l ⁇ .
  • the standards are prepared in PBS-Tween + 10% FBS or H. 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 IL-l ⁇ . The standards are prepared in PBS-Tween + 10% FBS or H. 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 Chemical (Catalogue number 514010) and is run exactly according to the manufacturers instructions.
  • 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 6 h in a humidified incubator at 37 °C in an atmosphere of 5% C ⁇ 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 (ng/ml) of multiple samples based on the standard curve. IC50 values where appropriate are generated by non-linear regression analysis.

Abstract

Les 2,4-diaryl-5-pyridylimidazoles sont des antagonistes du glucagon et des inhibiteurs de la biosynthèse et/ou de l'action du TNF-α et d'IL-1. Ces composés bloquent l'action du glucagon au niveau de son récepteur et réduisent par conséquent le taux du glucose dans le plasma. Les présents imidazoles sont également des inhibiteurs du TNF-α et de IL-1. Les composés selon l'invention peuvent être utilisés pour le traitement des maladies liées au glucagon ou à la cytokine. Les maladies liées à la cytokine correspondent à des maladies ou états dans lesquels on observe une production excessive et non régulée d'une ou plusieurs cytokines. L'interleukine-1 (IL-1) et le facteur de nécrose des tumeurs ( TNF) sont des cytokines produites par diverses cellules qui interviennent dans l'immunorégulation et dans d'autres états physiologiques tels que l'inflammation.
PCT/US1997/021019 1996-11-20 1997-11-17 Imidazoles a substitution triaryle, compositions renfermant de tels composes et modes d'utilisation WO1998021957A1 (fr)

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AU54427/98A AU728760B2 (en) 1996-11-20 1997-11-17 Triaryl substituted imidazoles, compositions containing such compounds and methods of use
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JP52379798A JP2001504490A (ja) 1996-11-20 1997-11-17 トリアリール置換イミダゾール、そのような化合物を含む組成物及び使用方法
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EP0948257A4 (fr) 1999-12-29
AU728760B2 (en) 2001-01-18
CA2271963A1 (fr) 1998-05-28
JP2001504490A (ja) 2001-04-03
EP0948257A1 (fr) 1999-10-13
AU5442798A (en) 1998-06-10

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