EP0871444A1 - Pyrroles d'aryle substitues en position 2 et 5, compositions contenant de tels composes et leurs modes d'utilisation - Google Patents

Pyrroles d'aryle substitues en position 2 et 5, compositions contenant de tels composes et leurs modes d'utilisation

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Publication number
EP0871444A1
EP0871444A1 EP96928099A EP96928099A EP0871444A1 EP 0871444 A1 EP0871444 A1 EP 0871444A1 EP 96928099 A EP96928099 A EP 96928099A EP 96928099 A EP96928099 A EP 96928099A EP 0871444 A1 EP0871444 A1 EP 0871444A1
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EP
European Patent Office
Prior art keywords
phenyl
alkyl
group
pyridyl
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96928099A
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German (de)
English (en)
Other versions
EP0871444A4 (fr
Inventor
Stephen E. De Laszlo
Nathan B. Mantlo
Gerald S. Ponticello
Harold G. Selnick
Nigel J. Liverton
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Merck and Co Inc
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Merck and Co Inc
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Publication date
Priority claimed from GBGB9607253.3A external-priority patent/GB9607253D0/en
Priority claimed from GBGB9608472.8A external-priority patent/GB9608472D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0871444A1 publication Critical patent/EP0871444A1/fr
Publication of EP0871444A4 publication Critical patent/EP0871444A4/fr
Withdrawn legal-status Critical Current

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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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • 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
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Cytokine mediated diseases refers to diseases or conditions in which excessive or unregulated production of one or more cytokines occurs.
  • Interleukin- 1 (IL- 1 ) and Tumor Necrosis Factor (TNF) are cytokines produced by a variety of cells, which are involved in immunoregulation and other physiological conditions, such as inflammation.
  • 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 is implicated. Included among these diseases are 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.
  • 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 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 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.
  • Monokines 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 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
  • 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 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
  • the compounds of formula I are also useful in treating diseases characterized by excessive IL-8 activity.
  • 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.
  • the present invention is directed to a compound represented by formula I:
  • a and b represents integers, 0, 1 , 2 or 3, such that the sum of a plus b is 1 , 2, 3 or 4;
  • each R a independently represents a member selected from the group consisting of: halo; CN, NO2, R 21 ; OR23; SR23; S(0)R21; S0 2 R 21 ; NR2UR23; NR 0COR21; NR 0C0 2 R21; NR20CONR20R23; NR20S0 2 R 2 1; NR20C(NR20)NHR20 > C0 2 R 23 ; CONR20R23; SO 2 NR20R23 ; SO 2 NR 20 COR21; SO 2 NR20CONR20R23 ; SO 2 NR20CO 2 R21 ; OCONR20R23; OCONR20SQ2R20, C(O)OCH 2
  • R 1 is selected from the group consisting of: H, aryl, Ci- 1 5 alkyl, C3-15 alkenyl, C3.15 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, OR2 , SR20, N(R2 ) 2 , S(0)R 2 ', S0 2 R 2 1, SO 2 NR20R23 ?
  • R2 is selected from the group consisting of: H, Ci-15 alkyl, C2-15 alkenyl, C2- 15 alkynyl, halo, NO2, heterocyclyl, CN, S(0)R 21 , S0 2 R 2 1 , SO 2 N(R20) 2 , SO 2 NR2 COR21 , S0 2 NR20CON(R20) 2 , COR2 , CO 2 R2 , CONR20R23, CONR20s ⁇ 2 R 21 and SO 2 NR20c ⁇ 2 R21, said alkyl, alkenyl, alkynyl and heterocyclyl being optionally substituted with from one to three members selected from the group consisting of: halo, heterocyclyl, CN, aryl, heteroaryl, R20, OR 2 ", SR2«, NR20R23, S(0)R2i, S0 2 R 2 1, SO 2 NR20R23, SO2NR2 COR 1, SO 2 NR 2( >CONR20R23, NR
  • R 2 represents a member selected from the group consisting of:
  • R 1 represents a member selected from the group consisting of: Ci-i5 alkyl, C2-15 alkenyl, C2-15 alkynyl, heterocyclyl, aryl and heteroaryl, such alkyl, alkenyl and alkynyl being optionally interrupted with oxo and/or 1-2 heteroatoms selected from O, S, S(O), SO2 and NR20, sa id alkyl, alkenyl, alkynyl, aryl and heteroaryl being optionally substituted with from 1-3 of halo, heterocyclyl, aryl, heteroaryl, CN, OR20
  • R22 is selected from the group consisting of: Ci-15 alkyl, C 2 - 1 5 alkenyl, C2- 1 5 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, and alkynyl being optionally substituted with 1 -3 halo, aryl or heteroaryl groups;
  • R23 is R21 0 r H
  • R24 is selected from COR22, C ⁇ 2R 2 2, CON(R20) 2 , S ⁇ 2R 2 2 and R23; and when two R 2n groups are present, when R 2f) and R 1 are present, or when R 2f) and R23 are present, said two R 2() groups, R and R21 or said R 2f) and R23 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.
  • 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.
  • Also included in the invention is a method of treating a 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:
  • the alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.
  • substituted alkyl when substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups as defined with respect to each variable.
  • 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. As described above with respect to alkyl, 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 as defined below.
  • 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 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 R groups.
  • Heteroaryl thus includes aromatic and partially aromatic groups which contain one or more heteroatoms. Examples of this type are thiophene, purine, imidazopyridine, pyridine. oxazole, thiazole, pyrazole, tetrazole, imidazole, pyrimidine, pyrazine and triazine.
  • the groups represent 5-10 membered aryl or heteroaryl, each of which is substituted with 0 - 3 groups selected
  • R a such that a total of 1 to 4 groups is attached to Preferred are phenyl, naphthyl, pyridyl, pyrimidinyl, thiophenyl, furanyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, and isoxazolyl.
  • 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 unsubstituted or substituted with 0 -3 R a groups.
  • heteroaryl groups represented by — are as follows: pyridyl. quinolyl, purinyl, imidazolyl, imidazopyridine, 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, SO, S02 or N, and in which up to three additional carbon atoms may be optionally replaced by heteroatoms.
  • Heterocyclyl is carbon or nitrogen linked; if carbon linked and contains a nitrogen, then the nitrogen may be substituted by R24.
  • heterocyclyls are piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydroimidazo[4,5-c]pyridinyl, imidazolinyl, piperazinyl, pyrolidin-2-onyl, piperidin-2-onyl and the like.
  • TNF mediated disease or disease state refers to any and all 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 means 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), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF- ⁇ ) and Tumor Necrosis Factor-beta (TNF- ⁇ ).
  • IL-1 Interleukin-1
  • IL-6 Interleukin-6
  • IL-8 Interleukin-8
  • TNF- ⁇ Tumor Necrosis Factor-alpha
  • TNF- ⁇ Tumor Necrosis Factor-beta
  • cytokine interfering or cytokine suppressive amount is mean an effective amount of a compound of formula I which will, cause a decrease in the in vivo levels of the cytokine or its activity 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 or activity.
  • 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.
  • TMS Tetramethylsilane One subset of compounds of the invention includes compounds of formula I wherein Arl and Ar2 are independently selected from: a) phenyl, b) pyridyl, c) pyrimidinyl, d) thiophenyl, e) furanyl, f) imidazolyl, g) thiazolyl, h) isothiazolyl, i) oxazolyl, j) isoxazolyl, and k) napthyl.
  • Arl and Ar2 are independently selected from: a) phenyl, b) pyridyl, c) pyrimidinyl, d) thiophenyl, e) furanyl, f) imidazolyl, g) thiazolyl, h) isothiazolyl, i) oxazolyl, j) isoxazolyl, and k) napthyl.
  • Another subset of compounds of the invention includes compounds of formula I wherein HAr is selected from: a) pyridyl, b) quinolyl, c) purinyl, d) imidazolyl, e) imidazopyridine, and f) pyrimidinyl.
  • HAr is selected from: a) pyridyl, b) quinolyl, c) purinyl, d) imidazolyl, e) imidazopyridine, and f) pyrimidinyl.
  • Another subset of compounds of formula I includes compounds wherein Rl is hydrogen. Within this subset of compounds, all other variables are as originally defined with respect to formula I. Another subset of compounds of formula I includes compounds wherein R l represents Cl -15 alkyl, unsubstituted or substituted, as originally defined. Within this subset of compounds, all other variables are as originally defined with respect to formula I.
  • R represents a member selected from the group consisting of: a) H; b) alkyl; c) halo; d) CN; e) C(0)C ⁇ - 6 alkyl; f) C(0)C i-6 alky lphenyl; g) C0 2 H; h) C0 C i- 6 alkyl i) C ⁇ 2Ci- 6 alkylphenyl; j) CONH 2 ; k) CONHC1-6 alkyl; 1) C(0)N(C 1-6 alky I) 2 ; m) SO2NH2; n) SO2NHC 1 - 6 alkyl and o) S0 2 N(Ci-6 alkyl) 2 .
  • Arl and Ar2 are independently selected from: a) phenyl, b) pyridyl, c) pyrimidinyl, d) thiophenyl, e) furanyl, f) imidazolyl, g) thiazolyl, h) isothiazolyl, i) oxazolyl, j) isoxazolyl and k) napthyl; one, two or three R a groups are present and attached to Arl and Ar2, and each R a is independently selected from the group consisting of: halo, R21 , OR 3, NR20R23, C ⁇ 2R 2 , CONR20R23, S02R21 and S(0)R21 , R20, R21 and R23 are as originally defined;
  • HAr is selected from:
  • (R a )b-Ar2 is selected from the group consisting of: a) 4-(methylthio)-phenyl, b) 4-(ethylthio)-phenyl, c) 3-(methylthio)-phenyl, d) 2-(methylthio)-phenyl, e) 3-(ethylthio)-phenyl, f) 4-methylsulfonylphenyl, g) 4-ethylsulfonylphenyl, h) 3-methylsulfonylphenyl, i) 2-methylsulfonylphenyl, j) 4-methylsulfinylphenyl, k) 4-ethylsulfonylphenyl,
  • (R a ) ⁇ -3-HAr is selected from the group consisting of: a) 4-pyridyl, b) 4-(2-methylpyridyl), c) 4-(2-aminopyridyl), d) 4-(2-methoxypyridyl), e) 4-quinolinyl, f) 4-pyrimidinyl, g) 9-purinyl, h) 7-(imidazo[4,5-b]pyridinyl), i) 4-(3-methylpyridyl), j) 2-pyridyl, k) 3,5-dimethyl-4-pyridyl,
  • Rl is: H
  • R2 is selected from the group consisting of:
  • (R a )b-Ar2 i s selected from the group consisting of: a) 4-(methylthio)-phenyl, b) 4-(ethylthio)-phenyl, c) 3-(methylthio)-phenyl, d) 2-(methylthio)-phenyl, 5 e) 3-(ethylthio)-phenyl, f) 4-methylsulfonyIphenyl, g) 4-ethylsulfonylphenyl, h) 3-methylsulfonyIphenyl, i) 2-methylsulfonylphenyl,
  • (R a )o_3-HAr is selected from the group consisting of: a) 4-pyridyl, b) 4-(2-methylpyridyl), c) 4-(2-aminopyridyl), d) 4-(2-methoxypyridyl), e) 4-quinolinyl, f) 4-pyrimidinyl, g) 9-purinyl, h) 7-(imidazo[4,5-b]pyridinyl), i) 4-(3-methylpyridyl), j) 2-pyridyl, k) 3,5-dimethyl-4-pyridyl,
  • R 1 is: a) substituted or unsubstituted C ⁇ . [ 5 alkyl;
  • R2 is selected from the group consisting of:
  • a further subset of compounds of the invention includes compounds represented by formula I:
  • a and b represents integers, 0, 1 , 2 or 3, such that the sum of a plus b is 1 , 2,
  • ⁇ — represents a heteroaryl group containing from 5 to 10 atoms, 1 -3 of which are heteroatoms, 0-3 of which heteroatoms are N and 0-
  • each R a independently represents a member selected from the group consisting of: halo; CN, NO2, R 21 ; OR23; SR23; S(0)R 21 ; SO2R 21 ; NR 2 ⁇ ) R 3; NR20COR21 ; NR20C0 2 R 2 1 ; NR20CONR2 R23 ; NR20S0 2 R 2 1 ; NR20C(NR2 )NHR20, C0 2 R 23 ; CONR 2 ⁇ >R23 ; SO 2 NR 2 R23 ; SO NR 0COR21 ; SO 2 NR20CONR 2 «R23; SO NR20c ⁇ 2R 2 l ; OCONR2 R23; C(O)OCH 2 OC(O)R2 and C(NR20)NR20R23;
  • R 1 is selected from the group consisting of: H, aryl, Ci- 1 5 alkyl, C2-15 alkenyl, C 2 - 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, OR 2 ", SR 2() , N(R2") 2 , S(0)R 2 1 , S0 2 R21 , SO 2 N(R20) 2 , S0 2 NR2 COR21 , SO 2 NR2»CON(R2 ) 2 , NR2 () COR21 , NR20CO 2 R 2 1 , NR20CON(R20) 2 , N(R2 «)C(NR 2 «)NHR2 , C ⁇ 2 R 2( CON(R2 «) 2 , CONR2 0 SO 2 R 21 , NR2 0 SO
  • R2 is selected from the group consisting of: H, Ci- 15 alkyl, C2- 1 5 alkenyl, C 2 - 15 alkynyl, halo, NO2 and heterocyclyl, said alkyl, alkenyl, alkynyl and heterocyclyl being optionally substituted with from one to three members selected from the group consisting of: halo, heterocyclyl, CN, aryl, heteroaryl, R20, OR ⁇ SR 2() , N(R2 ⁇ >) 2 , S(0)R22, S0 2 R 2 2, SO 2 N(R20) 2 , S0 2 NR2 ⁇ >COR22.
  • R 2() represents a member selected from the group consisting of: H, Ci-15 alkyl, C 2 -15 alkenyl, C2- 1 5 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, C2-15 alkenyl, C2- 1 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, alkynyl, aryl and heteroaryl being optionally substituted with from 1 -3 of halo, heterocyclyl, aryl, heteroaryl, CN, OR 2() , O((CH 2 ) n O) m R20, NR20((CH 2 ) n O) m R2 0 wherein n represents an integer of from 2 to 4, and m represents an integer of from 1 to 3; heterocyclyl, SR 2() , N(R2 ) 2 , S(0)R 2, SO2R 22 , SO 2 N(R 2 0) 2 , SO 2 NR 2 0COR 22 , SO 2 NR20cON(R20) 2 , NR20COR22, NR20CO 2 R 2 2,
  • R22 i selected from the group consisting of: Ci- 1 5 alkyl, C 2 - 1 5 alkenyl, C2- 1 5 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, and alkynyl being optionally substituted with 1-3 halo, aryl or heteroaryl groups;
  • R23 is R21 0 r H
  • R24 is selected from COR22, C ⁇ 2R 2 2, CON(R20) 2 , S ⁇ 2R 2 2 and R23; and when two R 0 groups are present, when R20 and R 1 are present, or when R20 and R 3 are present, said two R20 groups, R20 nd
  • R21 or said R20 and R23 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.
  • Another subset of compounds of the invention includes compounds wherein Arl and Ar2 are independently selected from: a) phenyl,
  • R2 is selected from the group consisting of:: a) H, or b) alkyl and c) halo.
  • Still another subset of compounds of the invention includes compounds wherein Arl is selected from the group consisting of: a) phenyl, b) 4-fluorophenyl,
  • (R a )0-3-HAr is selected from the group consisting of:: a) 4-pyridyl, b) 4-(2-methylpyridyl), c) 4-(2-aminopyridyl), d) 4-(2-methoxypyridyl), e) 4-quinolinyl, f) 4-pyrimidinyl, g) 9-purinyl, h) 7-(imidazo[4,5-b]pyridinyl), and i) 4-(3-methyl ⁇ yridyl)
  • R 1 is: H and
  • R is selected from the group consisting of: a) H, b) F, c) Cl and d) Br.
  • the pharmaceutically acceptable salts of the compounds of formula I include the conventional non-toxic salts or the quarternary ammonium salts of the compounds of formula I formed e.g. from 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.
  • 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.
  • This invention also relates to a method of antagonizing or 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 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 1 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 cytokines production, more specifically IL-1 , IL-6, IL-8 or TNF, 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.
  • 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, e.g., gram negative sepsis, septic shock, endotoxic shock, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, such as osteoporosis, reperfusion injury, graft vs.
  • AIDS cachexia secondary to infection or malignancy
  • cachexi secondary to acquired immune deficiency syndrome
  • AIDS AIDS and other viral infections
  • ARC AIDs related complex
  • keloid formation scar tissue formation, Crohn's disease, ulcerative colitis
  • pyresis such as cytomegalo virus (CMV), influenza virus and the herpes family of viruses such, as Herpes Zoster or Simplex I and II.
  • CMV cytomegalo virus
  • 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 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 or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.
  • the compounds of formula I are normally formulated as pharmaceutical compositions, which are comprised of a compound of formula I and a pharmaceutically acceptable carrier.
  • the compounds of formula I may also be administered in combination with a 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 preparations typically be in the form of a tablet, hard gelatin capsule, a 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 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 inco ⁇ orate 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 also be carried out by delivering the agent parenterally.
  • parenteral' as used herein includes intravenous, intramuscular, or intradermal and subcutaneous administration.
  • the intravenous and intramuscular forms of administration are preferred. Appropriate dosage forms for such administration may be prepared as described above.
  • the instant invention can also be carried out by delivering the compounds of formula I intranasally, rectally, transdermally or vaginally.
  • the compounds of formula I may be administered by inhalation.
  • inhalation' is meant intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration include an aerosol formulations and metered dose inhalers.
  • Heteroaromatic aldehydes 3 may be converted to their trimethylsilyl cyanohydrins 4. Deprotonation and reaction with an aldehyde 5 will provide trimethyl silyl protected benzoins 1. (See, e.g., Hunig, S.et al., Chem. Ber. 112, 2062 (1979)).
  • L Leaving group such as Br, I, OTos, OMs
  • Ethanone 7 is prepared by the addition of a heteroaryl methyl anion 8 to an activated benzoic acid 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).
  • an activated benzoic acid 9 for example esters, acid chlorides, nitriles and N-methoxy-N-methyl amides
  • Compound 7 may also be prepared by alkylation of aryl 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 provides ethanone 7 (Deuchert, K.; Hertenstein, U.; Hunig, S.; Wehner, G. Chem. Ber. 112, 2045, 1979).
  • L for example: Br, I, Cl , tosylate, mesylate
  • the reductive cross coupling of a 1 ,3 diketone 11 with a nitrile 12 in the presence of zinc and titanium tetrachloride also gives rise to compounds of formula I, See Scheme III, (Gao, J. Hu, M.; Chen, J.; Yuan, S.; Chen, W. Tet Lett. 34, 1617, 1993).
  • the 1 ,3 diketone 11 may be prepared by alkylation of 4 with bromoacetophenones.
  • the 1 ,4 diketone 13 can also be prepared as described in Scheme IV.
  • a heteroaryl aldehyde 14 is condensed with a methyl ketone 15 to provide an ⁇ , ⁇ -unsaturated ketone 16.
  • a catalyst such as cyanide or a thiazolium salt the aryl aldehyde 17 reacts with 16 to give 13 (Stetter, H. J. et al Heterocyclic Chem. 14, 573, 1977 and Stetter, H. et. al. Organic Reactions, Vol. 40, 407-496).
  • Condensation of 13 with an amine provides compounds of formula I.
  • variations of Ar 2 may be introduced by addition of Ar 2 aldehydes to alkenes 17b that are readily available from the ketones 7 described above.
  • Intermediate 16 may be prepared by a Horner-Emmons reaction of the anion of 18 with the heteroaryl 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.
  • a nitro group may be introduced into the pyrrole nucleus at the 3 position (generic nomenclature - R2) by electrophilic nitration of a compound such as 22 (or a less advanced intermediate) in the presence of fuming nitric acid and acetic anhydride.
  • Other reagents are available to carry out this conversion, the choice of reagent being dependent on the presence of functional groups that may be sensitive to the reagent being utilized. See e.g., Pyrroles Part 1 , R. Alan Jones, ed., Heterocyclic Compounds ,Vol 48 Part 1 , John Wiley, New York, 1990. Pages 348-391. SCHEME VII
  • Hydroxy methyl substituted pyrroles 23 may be prepared by reduction of esters 25a through the reaction with a reducing agent such as lithium aluminum hydride.
  • the ester 25a may be prepared by treatment of 1 ,2-disubstituted-2 halo ketones 22 with 3-keto esters 27 and ammonia or an amine, producing ester 25a (Hantzsch. Ber. Dtsch. Chem. Ges. 23, 1474, 1890).
  • a 2-amino ketone 24 reacts with a 3-keto ester 27 to produce 25.
  • a further method of synthesis of 23 is via reduction of the aldehyde 26 with a reducing agent such as sodium borohydride.
  • the aldehyde may be prepared by treatment of the R 3 -unsubstituted pyrrole 25 with the Villsmeyer reagent (POCl 3 /DMF).
  • the ester and nitrile of formula I may be prepared as shown in
  • the pyrrole 22 prepared as described herein may be silylated on the nitrogen atom to give 27 by treatment with a silyl chloride and base in a solvent such as methylene chloride.
  • the pyrrole 27 may then be sulphenylated with a sulphenylchloride under basic conditions to provide 28 (J. Org. Chem. 6317 1990).
  • Oxidation of 28 with a reagent such as m- chloroperoxybenzoic acid will give the sulphone 29.
  • Removal of the silyl group and derivatization of the pyrrole will give compounds of Formula I.
  • Compound 22 may also be converted to the sulphide 30 by reaction of 22 with a symmetrical sulfoxide in the presence of trimethylsilylchloride (TMSC1) to give 30. Oxidation of 30 with a reagent such as m- chloroperoxybenzoic acid will give 29.
  • TMSC1 trimethylsilylchloride
  • Oxidation of 30 with a reagent such as m- chloroperoxybenzoic acid will give 29.
  • the silyl pyrrole 27 may also be acylated with an acid chloride to give the ketone 31.
  • Pyrroles such as 22 may also be sulfinylated directly without N-protection, by treatment with sulphinyl chloride in a solvent such as dichloromethane at 0°C (J. Org. Chem. 5336, 1980). Oxidation as described above thus provides pyrroles of formula I where R3 is SO2R 21 .
  • TBAF tetrabutyl
  • R 2 -C0 2 R 2() , -CN, -CONR 2 ⁇ R 23 ammonium fluoride S0 2 R 21 , COR 2()
  • the amino acid ester 32 may be acylated with an acid 33 that is suitably activated (acid chloride or other activating group used in amide coupling reactions) to give 34 (Scheme XI). Hydrolysis of the ester protecting group will provide 35. Cyclization by treatment with an acid activating group such as dicyclohexylcarbodiimide (DCC) will give the oxazolium species 36. Addition of an alkyne 37 to 36 may 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.
  • DCC dicyclohexylcarbodiimide
  • P R 1 or protecting group such as trialkyl silyl, benzyl, substituted benzyl, t-butyloxycarbonyl
  • Aryl and heteroaryl rings may also be appended to the pyrrole ring system by utilization of organometallic coupling technology (Kalinin, V. Synthesis 413 1991). See Scheme XIII.
  • the pyrrole ring may function as an electrophile or as a nucleophile.
  • any of the three appended aromatic or heteroaromatic rings may be attached to the pyrrole ring system (Alvarez, A. J. et al. J. Org.
  • pyrrole pendant groups may be carried out with or without other Ar, HAr, R 2 or R 3 groups attached.
  • the synthesis of pyrroles containing nucleophilic groups for coupling reactions depends on the pyrrole substitution pattern. 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 hexalkylditin 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., Heterocvclic Compounds Vol 48 Part 1 , John Wiley, New York, 349-391 ,1990).
  • the regioselectivity of halogenation will depend on the size, nature and substitution position on the pyrrole ring as well as the presence or absence of the N-alkyl protecting group.
  • 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 employed is toluene, or DMF under anhydrous conditions.
  • boronic acid couplings a heterogenous system is used of water, toluene, and dimethoxyethane, or ethanol in the presence of a base such as sodium carbonate, or bicarbonate. In general, the reaction takes place at an elevated temperature (80-100 °C,).
  • the catalysts used will most likely depend on the structure of the components to be coupled as well as the functional groups and belong to the group consisting of tetrakistriphenylphosphinepalladium (0), or palladium bis triphenyl phosphine dichloride.
  • 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 Nickel, H 2 ) or chemical means (CoCl 2 , NaBH ).
  • Alkylation of amines to give secondary and tertiary amines is achieved by reductive alkylation (aldehyde, NaCNBH or alkylation with an alkyl group substituted with a leaving group in the presence of a base such as K 2 C0 .
  • Tertiary amines may, alternatively, be carried through the reaction sequence to the pyrroles.
  • Acylation of primary or secondary amines with activated acids, chloroformates, isocyanates and chlorosulfonates will give rise to amides, carbamates, ureas and sulfonamides, respectively.
  • amides and ureas are useful; such as for example, treatment of the amine with phosgene, or an equivalent thereof, followed by acylation of an alcohol or amine with the intermediate activated chloroformamide.
  • Carboxylic acids are best introduced as esters early in the synthesis. Saponification will provide carboxylic acids. Transesterifi cation 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. Removal of the protecting group provides a phenol which may subsequently be alkylated in the presence of an alkylating agent and base to give an ether, or acylated with an isocyanate to give carbamates. Phenols may be converted to aryl ethers by reaction with an aryl bismethane 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 dependent on the structure and functional groups present.
  • Protecting groups may be necessary and may be chosen with reference to Greene, T.W., et al., Protective Groups in Organic Synthesis. John Wiley & Sons, Inc., 1991.
  • 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.
  • Suitable hydroxyl protecting groups are: t- butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, t- butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, and allyloxycarbonyl.
  • carboxyl protecting groups are benzhydryl, o- nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chIoroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethoylsilyl, t- butldiphenylsilyl, 2-(trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl and t-butyl.
  • PREPARATIVE EXAMPLE 40 4-pheny l-2-(4-pyridyP- 1 -(4-trifluoromethylphenyl)-butan- 1 ,4-dione A solution of 0.15 g (0.71 mMol) of l -phenyl-3-(4-pyridyl)- ethene-1 -one (Preparative Example 38), 0.14 g (7.8 mMol) of 4- trifluoromethylbenzaldehyde, 0.035 g (0.35 mMol) of triethylamine and 20 mg (0.07 mMol) of 3,4-dimethyl-5-(2-hydroxyethyl)-thiazolium iodide in 3 mL on ethanol was heated at 80°C for 3 hours.
  • reaction mixture was cooled to room temperature, diluted with 10 mL of water and was washed with water and brine and dried over MgSO The mixture was filtered and the filtrate was concentrated in vacuo and the residue was purified by MPLC over silica gel eluting with 2.5% MeOH/CH2Cl2 to give the desired product.
  • reaction mixture was stirred for 1 hour at -15°C and then treated with a solution of 108 g (0.59 mMol) of 4-fluoro-(N- methyl-N-methoxy)-benzamide dissolved in 100 mL of THF dropwise.
  • 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% NH4CI solution.
  • the aqueous phase was extracted with EtOAc (3 x 500 mL).
  • Method 1 To a solution of 0.35 g (0.99 mmol) of the compound of preparative example 1 1 in 15 mL of glacial acetic acid was added 0.35 g (4.7 mmol) ammonium acetate. The mixture was heated to 90- 1 10°C over 10 hours at which time a further 1 g of ammonium acetate was added. Heating was continued at 1 10°C for 6 hours. The reaction mixture was concentrated to 50% of the original volume, and 25 mL of water was gradually added. A solid formed, which was filtered and dried in vacuo to give the title compound.
  • Method 2 The condensation in method 1 is followed by an alternative work-up procedure.
  • the reaction mixture was diluted with 5 mL of water and extracted with ethyl acetate (3 x 4 mL).
  • the organic extracts are dried over MgS0 4 , filtered and the filtrate concentrated in vacuo.
  • the residue was purified by rotary chromatography to give the desired product.
  • EXAMPLES 45-49 The following compounds are prepared using the procedures described above. An alternative work up was utilized wherein the reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over MgS ⁇ 4, filtered and purified by flash chromatography eluting with 5% MeOH/CH2 ⁇ 2 to give the product.
  • EXAMPLES 55-63 This method is utilized to prepare the compounds listed below by coupling the appropriate amine to the acid derived from Example 51 , or coupling an acid to the aniline formed in Example 52 or 53. The compounds are shown below in Table VI.
  • Example 44 0.5 g (1.4 mmol) of the product of Example 44 was dissolved in a mixture of 4 mL of methanol and 16 mL of ethyl acetate. The solution was treated 0.045 g sodium tungstate dihydrate and 0.63 mL (5.6 mmol) of 30% hydrogen peroxide solution while heating at reflux over a period of 4 hours. A further 0.3 mL (2.8 mmol) hydrogen peroxide was added. The mixture was refluxed overnight and then cooled to room temperature. A white solid was recovered by filtration and was washed with water to provide the desired product.
  • Example 47 The product of Example 47 was converted to the desired sulfone as described in Example 65. A portion of the product may be isolated by filtration as described in Example 65. The balance of the product was recovered following washing of the reaction mixture with aqueous sodium sulfite, water and brine and drying over MgS ⁇ 4 . The crude product was purified by crystalization from CH 2 ⁇ 2/MeOH followed by recrystalization from isopropanol.
  • Example 5 The product of Example 5 is dissolved in methylene chloride and treated with 1.05 equivalents of n-propylsulfinyl chloride at 0°C under nitrogen. After 30 minutes triethylamine is added to neutralize the reaction mixture. The reaction mixture is diluted with ethyl acetate and washed with water and brine and dried over MgS04. The mixture is filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography over silica gel to give the desired product.
  • Example 129 The product of Example 129 is reacted with 1.05 equivalents of meta-chloroperoxybenzoic acid in CH2CI2 at 0°C. The reaction mixture is stirred ovemight at room temperature. The solution is diluted with EtOAc and washed with saturated sodium bicarbonate solution followed by brine. The solution is dried over MgS04, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography to produce the desired product.
  • Example 131 The product of Example 131 is dissolved in t-butyl alcohol and methyl -2-butene (6: 1 ratio). The solution is then treated with 1.5 eq of monobasic sodium phosphate and an aqueous solution of sodium chlorate. The reaction mixture is stirred at room temperature until the starting material is consumed. The pH is adjusted to 5.5 with dilute HCl. The product is extracted with ethyl acetate and the combined organic phase is washed with water and brine, and dried over MgS04. The mixture is filtered and the filtrate is concentrated in vacuo to give the desired product.
  • PBMC Human peripheral blood mononuclear cells
  • 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 (cell culture medium) 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 incubated for 24 hours, at 37°C in 5% C02 .
  • cell culture supernatants are assayed for IL-l ⁇ , TNF-oc, 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-1 ⁇ is then added to a final concentration of 50 pMolar.
  • Human IL-l ⁇ can be detected in cell-culture supematants 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- lb monoclonal antibody (purchased as an ascites preparation from LAO Enterprise, Gaithersburg Maryland) diluted in Dulbecco's phosphate- buffered saline (-MgCl2, -CaC ). The plates are washed with PBS
  • IL-l ⁇ standards are prepared from purified recombinant IL-l ⁇ produced from E. coli. The highest concentration begins at 10 ng/mL followed by 1 1 two-fold serial dilutions. For detection of IL-1 ⁇ from cell culture supematants or blood plasma, 10 - 25 mL of supernatant is added to each test well with 75 - 90 mL of PBS Tween. Samples are incubated at room temperature for 2 hours then washed 6 times with PBS Tween on an automated plate washer (Dennly).
  • Rabbit anti-human IL-1 ⁇ polyclonal antisera diluted 1 :500 in PBS-Tween is added to the plate and incubated for 1 hour at room temperature followed by six washes with PBS-Tween. Detection of bound rabbit anti-IL- 1 ⁇ IgG is accomplished with Fab' fragments of Goat anti-rabbit IgG-horseradish peroxidase conjugate (Accurate Scientific) diluted 1 :10,000 in 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
  • mice anti-human TNF- ⁇ monoclonal antibody 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-lb.
  • the standards are prepared in PBS-Tween + 10% FBS (fetal bovine serum) or HS (human serum). Eleven 2 fold dilutions 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- 1 ⁇ . The standards are prepared in PBS-Tween + 10% FBS or HS. Eleven 2 fold dilutions are made beginning at 50 ng/mL IL-6.
  • 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.
  • 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 (FBS) and 1 % CS- HBGF (cell culture additive) consisting of aFGF (acid fibroblast growth factor) and heparin.
  • FBS fetal bovine serum
  • CS- HBGF cell culture additive
  • 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% C02- 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.
  • the following compounds are found to inhibit cytokines at IC50 concentrations of less than 100 ⁇ M.

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Abstract

L'invention se rapporte à des pyrroles d'aryle substitués en position 2 et 5 correspondant à la formule (I) ou à un de leurs sels pharmaceutiquement acceptables, ainsi qu'à des compositions contenant de tels composés et à leurs modes d'utilisation. Les composés sont utiles dans le traitement des maladies induites par les cytokines, qui sont des maladies ou des pathologies dans lesquelles la production ou l'activité d'une ou de plusieurs cytokines est excessive ou non régulée. L'interleukine-1 (IL-1), l'interleukine-6 (IL-6), l'interleukine-8 (IL-8) et le facteur de nécrose tumorale (TNF) figurent parmi les cytokines qui interviennent dans l'immunomodulation et dans d'autres processus physiologiques, tels que l'inflammation. Lesdits composés ont également une activité antagoniste vis-à-vis du glucagon.
EP96928099A 1995-08-10 1996-08-06 Pyrroles d'aryle substitues en position 2 et 5, compositions contenant de tels composes et leurs modes d'utilisation Withdrawn EP0871444A4 (fr)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
US209495P 1995-08-10 1995-08-10
US2094 1995-08-10
US1418296P 1996-03-26 1996-03-26
US14182 1996-03-26
GB9607253 1996-04-04
GBGB9607253.3A GB9607253D0 (en) 1996-04-04 1996-04-04 2,5-Substituted aryl pyrroles, compositions containing such compounds of use
GB9608472 1996-04-25
GBGB9608472.8A GB9608472D0 (en) 1996-04-25 1996-04-25 2,5-Substituted aryl pyrroles,compositions containing such compounds and methods of use
PCT/US1996/012922 WO1997005878A1 (fr) 1995-08-10 1996-08-06 Pyrroles d'aryle substitues en position 2 et 5, compositions contenant de tels composes et leurs modes d'utilisation

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EP0871444A1 true EP0871444A1 (fr) 1998-10-21
EP0871444A4 EP0871444A4 (fr) 1999-01-13

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WO1997005878A1 (fr) 1997-02-20
AU6769196A (en) 1997-03-05
EP0871444A4 (fr) 1999-01-13
CA2228050A1 (fr) 1997-02-20
AU699148B2 (en) 1998-11-26

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