Classifications

• • 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
  • 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
  • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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

Definitions

• This invention relates to a novel group of pyrazole compounds, processes for the preparation thereof, the use thereof in treating cytokine mediated diseases and pharmaceutical compositions for use in such therapy.
• Interleukin-1 IL-1
• Tumor Necrosis Factor TNF
• IL-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions such as inflammation [See, e.g., Dinarello et al., Rev. Infect. Disease. , 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 coUagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.
• TNF production has been implicated in mediating or exacerbating a number of diseases including 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 sarcoisosis, 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), ADDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis.
• AIDS cachexia secondary to infection or malignancy
• cachexia secondary to acquired immune deficiency syndrome
• ADDS secondary to acquired immune deficiency syndrome
• ARC AIDS related complex
• keloid formation scar tissue formation
• Crohn's disease Crohn's disease
• ulcerative colitis ulcerative colitis
• HIV Human Immunodeficiency Virus
• HIV- 1 HIV- 1
• HIV-2 HIV-3
• HIV entry into the T lymphocyte requires T lymphocyte activation.
• Other viruses, such as HTV-1, HIV-2 infect T lymphocytes after T Cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation.
• T lymphocyte Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication.
• Monokines specifically TNF, are implicated in activated T-cell mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with monokine activity such as by inhibition of monokine production, notably TNF, in an HIV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HTV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection.
• Monocytes, macrophages, and related cells have also been implicated in maintenance of the HTV infection. These cells, like T-cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al.. The Immunopathogenesis of HIV Infection, Advances in Immunology, Vol. 57, (1989)]. 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 HTV progression as stated above for T-cells.
• TNF has also been implicated in various roles with other viral infections, such as the cytomegalia virus (CMV), influenza virus, and the herpes virus for similar reasons as those noted.
• CMV cytomegalia virus
• influenza virus influenza virus
• herpes virus herpes virus
• Interleukin -8 is a chemotactic factor first identified and characterized in 1987.
• IL-8 is produced by several cell types including mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. Its production from endothelial cells is induced by IL-1, TNF, or lipopolysachharide (LPS).
• Human IL-8 has been shown to act on Mouse, Guinea Pig, Rat, and Rabbit Neutrophils. 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.
• 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 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutrophils, T-lymphocytes, and basophils. In addition it induces histamine release from basophils from both normal and atopic individuals as well as lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CDl lb/CD18) on neutrophils without de novo protein synthesis, this may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration. Conditions associated with an increased in IL-8 production (which is responsible for chemotaxis of neutrophils into the inflammatory site) would benefit by compounds which are suppressive of IL-8 production.
• IL-1 and TNF affect a wide variety of cells and tissues and these cytokines as well as other leukocyte derived cytokines are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
• This invention relates to the novel compounds of Formula (I) and pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable diluent or carrier.
• This invention also relates to a method of inhibiting cytokines and the treatment of a cytokine mediated disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I).
• This invention more specifically relates to a method of inhibiting the production of IL-1 in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
• This invention more specifically relates to a method of inhibiting the production of IL-8 in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
• This invention more specifically relates to a method of inhibiting the production of TNF in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
• novel compounds of this invention are represented by the structure having the formula (I):
• Rl and R2 wherein one of Rl and R2 is selected from is 4-pyridyl, 4-pyrimidinyl, 4-quinolyl, 4- isoquinolinyl, 4-quinazolinyl, which is optionally substituted with one or two substituents each of which is independently selected from Ci-4 alkyl, halo, Ci-4 alkoxy, Ci-4 alkylthio, CH2OR8, NH2, mono- or di-Ci-6-alkylamino or N- heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR22; and the other of Rl and R2 is selected from an optionally substituted aryl or optionally substituted heteroaryl group, provided that both Ri and R2 are not the same heteroaryl group; wherein when one Rl and R2 is an optionally substituted aryl ring, the ring is substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl
• Ci-4 alkyl Ci-4 alkyl
• -ZC(Z)R36 Ci-4 alkyl
• -NRioC(Z)R23 Ci-4 alkyl
• -(CRl()R20)n NR10R2O halo
• the substituent groups include one or two substituents each of which is independently selected from Ci-4 alkyl, halo, Ci-4 alkoxy, Ci-4 alkylthio, NR10R2O.
• Q is an aryl or heteroaryl group; t is an integer having a value of 1 to 3;
• R4 is hydrogen, Ci-ioalkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylCi-io alkyl, C5.7 cycloalkenyl, C5.7 cycloalkenyl- Ci-io alkyl, aryl, arylCi-io alkyl, heteroaryl, heteroaryl-Ci-io-alkyl, heterocyclyl, heterocyclylCi-io alkyl, -(CR ⁇ oR2 ⁇ )n I OR12, (CRioR20)nORl3, (CRioR20)nS(O) m Rl8, (CR ⁇ oR2 ⁇ )nNHS(O)2Rl8.
• R6 is Ci-io alkyl, C3-7 cycloalkyl, aryl, arylCi-ioalkyl, heterocyclyl, heterocyclyl Ci-ioalkyl, heterocyclyl-Ci-ioalkyl, heteroaryl or heteroarylCi-ioalkyl;
• R5 is hydrogen, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties -SR5 being -SNR7R17 and -SOR5 being -SOH;
• Rl6 and R26 are independently hydrogen, or Ci-4 alkyl or Ri6 and R26 together with the nitrogen to which they are attached form a heterocyclic or heteroaryl ring of 5-7 members optionally conatining an additional heteroatom selected from oxygen, sulfur or NR22;
• Yl is independently selected from hydrogen, Ci-5 alkyl, halo-substituted C ⁇ _5 alkyl, halogen, or -(CRioR20)nY2;
• Y2 is hydrogen, halogen, -OR ⁇ , -NO2, -S(O)m'Rl l, -SR ⁇ , -S(O) m -OR8, -S(O) m NR8R9, -NR8R9
• R7 and R17 is each independently selected from hydrogen or C 1.4 alkyl or R7 and R17 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 NR22.
• R8 is hydrogen, Ci-io alkyl, C3.7 cycloalkyl, heterocyclyl, heterocyclylCi-ioalkyl, aryl, arylCi-loalkyl, heteroaryl or heteroarylCi-ioalkyl;
• R9 is hydrogen, Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5.7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or Rs and R9 may together with the nitrogen to which they are attached form a heterocyclic or heteroaryl ring of
• RlO and R20 is each independently selected from hydrogen or Ci-4 alkyl;
• Rll is Ci-io alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3.7 cycloalkyl, C5-7 cycloalkenyl, heterocyclic, heterocyclic Ci-ioalkyl, aryl, aryl
• Rl2 is hydrogen, -C(Z)Ri3, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl-Ci-4 alkyl, or S(O)2Rl8 .
• Rl3 is hydrogen, Ci-io alkyl, C3.7 cycloalkyl, heterocyclyl, heterocyclylCi-io alkyl aryl, arylCi-ioalkyl, heteroaryl or heteroarylCi-ioalkyl;
• Rl4 and R24 is each independently selected from hydrogen, alkyl, nitro or cyano;
• Rl5 is hydrogen, cyano, C1.4 alkyl, C3-7 cycloalkyl or aryl;
• Rl6 and R26 is each independently selected from hydrogen or optionally substituted C1-.4 alkyl, optionally substituted aryl or optionally substituted aryl-C ⁇ _4 alkyl, or together with the nitrogen 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;
• Rl8 is Ci-10 alkyl, C3-.7 cycloalkyl, aryl, arylCi-ioalkyl, heterocyclyl, heterocyclyl- Ci-ioalkyl, heteroaryl or heteroarylCi-ioalkyl;
• R19 is hydrogen, cyano, C ⁇ _ 4 alkyl, C3.7 cycloalkyl or ary
• R22 is RlO or C(Z)-Ci_4 alkyl
• R23 is Ci-4 alkyl, halo-substituted-Ci-4 alkyl, or C3-7 cycloalkyl
• R25 is Ci-lO alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5.7 cycloalkenyl, aryl, arylCi-io alkyl, heteroaryl, heteroarylCi-io alkyl, heterocyclyl, heterocyclylCi-io alkyl, (CR ⁇ oR2 ⁇ )nOR8. (CRioR20)nS(O) m Ri8, (CRioR20)nNHS(O)2Rl8. (CR ⁇ oR20)nNR7Rl7; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;
• R36 is hydrogen or R23; or a pharmaceutically acceptable salt thereof.
• Suitable heteroaryl moieties for Ri and R2 are 4-pyridyl, 4-pyrimidinyl, 4-quinolyl, or 6-isoquinolinyl, all of which may be optionally substituted.
• the heteroaryl group is a 4-pyridyl, 4-pyrimidinyl or 4-quinolyl. More preferred is an optionally substituted 4-pyrimidinyl or optionally substituted 4-pyridyl moeity, and most preferred is an optionally substituted 4-pyrimidinyl ring.
• Suitable substituent groups for the heteroaryl moieties, Ri and R2 include one or two substituents each of which are independently selected from Ci-4 alkyl, halo, hydroxy, Ci-4 alkoxy, C1.4 alkylthio, C1-4 alkylsulfinyl, CH2OR8, amino, mono- or di- Ci-6 alkyl substituted amino, or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur orNR22-
• Preferred substituents for the heteroaryl moieties Ri is Ci-4 alkyl, amino, and mono-Ci-6alkyl substituted amino.
• the C1-.4 alkyl is methyl
• the mono-Ci-6alkyl substituted amino is of 1-4 carbons in length or shorter, such as 1 to 2 carbons, preferably methyl.
• a preferred ring placement of the Ri substituent on the 4-pyridyl derivative is the 2-position, such as 2-methyl-4-pyridyl.
• a preferred ring placement on the 4-pyrimidinyl ring is also at the 2-position, such as in 2-methyl- pyrimidinyl, 2-amino pyrimidinyl or 2-methylaminopyrimidinyl.
• Suitable aryl groups for the other of Rl or R2 include optionally substituted phenyl, naphth-1-yl or naphth-2-yl.
• the aryl ring may be optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4- naphth-1-yl or 5-naphth-2-yl substituent, is halo, nitro, cyano, -C(Z)NR7Ri7, -C(Z)OR23, -(CRl0R20)nCOR36, -SR5, -S(O)R5, -OR36.
• the aryl ring is a phenyl which is optionally substituted.
• substitutions for the Rl or R2 group when it is a 4-phenyl, 4-naphth- 1-yl or 5-naphth-2-yl moiety are one or two substituents each independendy selected from halogen, -SR5, -SOR5, -OR36, or -(CRi ⁇ R20)nNRl ⁇ R20, and for other positions of substitution on these rings preferred substitution is halogen, -S(O)mR25 . -OR25, -(CRl0R20)nNR7Rl7, -(CRl ⁇ R2 ⁇ )nNRl ⁇ C(Z)R25 and -NR6S(O) m 'R6.
• substituents for the 4-position in phenyl and naphth-1-yl and on the 5-position in naphth-2-yl include halogen, especially fluoro and chloro, more especially fluoro, and -SR5 and -S(O)R5 wherein R5 is preferably a Ci-2 alkyl, more preferably methyl; of which fluoro is especially preferred.
• Preferred substituents for the 3-position in phenyl and naphth-1-yl include: halogen, especially chloro; -OR25, especially Ci-4 alkoxy; amino; -NR ⁇ oC(Z)R25, especially -NHCO(Cl-ioalkyl); and -NR ⁇ oS(O) ⁇ TR6, especially -NHSQ2(Ci-ioalkyl).
• the aryl group is an unsubstituted or substituted phenyl moiety.
• R3 is Q-(Yl)t wherein Q is an aryl or heteroaryl group; and t is an integer having a value of 1 to 3.
• Yi is independently selected from hydrogen, C1-5 alkyl, halo-substituted C1-.5 alkyl, halogen, or -(CRioR20)nY2-
• Y2 is hydrogen, halogen, -OR8, -NO2, -S(0) m * Rn, -SR ⁇ , -S(O)m-OR8. -S(O) m NR8R9, -NR8R9. -0(CR l ⁇ R2 ⁇ )nNR8R9, -C(O)Rs, -CO2R8,
• Q is phenyl which is optionally substitued.
• substituents include -(CRioR20)nY2 with Y2 as -S(O) m 'Rl 1, -SRs, halogen or -CO2R8; n is preferably 0 or 1.
• R4 is hydrogen, Ci-ioalkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-.7 cycloalkyl, C3-7cycloalkylC ⁇ _io alkyl, C5.7 cycloalkenyl, C5-7cycloalkenyl-Ci-i ⁇ alkyl, aryl, arylCi-io alkyl, heteroaryl, heteroaryl-Ci-io-alkyl, heterocyclyl, heterocyclylCi-io alkyl, -(CRioR20)n' OR12, (CRioR20)nORi3- (CRioR20)nS(O) m Ri8, (CR ⁇ oR2 ⁇ )nNHS(O)2Rl8.
• R4 is hydrogen, NRi6R26> NRi()C(Z)R ⁇ 1, NR ⁇ oC(Z)NRi6R26, or NRIQC(Z)ORIO.
• R4 is hydrogen or NR16 26*
• the Ri6 and R26 groups are independently hydrogen, or C alkyl or Ri6 and R26 together with the nitrogen to which they are attached form a heterocyclic or heteroaryl ring of 5-7 members optionally containing an additional heteroatom selected from oxygen, sulfur or NR22- The heterocyclic and heteroaryl ring may also be additionally substituted.
• the unsaturated linkage i.e., the vinylene or acetylene linkage is preferably not directly attached to the nitrogen, oxygen or sulfur moieties, for instance in C(Z)NR8OR9, NR ⁇ oC(Z)NR8R9, or OR25-
• halogen such as fluorine, chlorine, bromine or iodine
• hydroxy hydroxy substituted Ci-ioalkyl
• Ci-io alkoxy such as methoxy or ethoxy
• S(O)m Ci-io alkyl wherein m is 0, 1 or 2, such as methyl thio, methylsulfinyl or methyl sulfonyl
• amino, mono & di-substituted amino such as in the NR7R17 group; or where the R7R17 may together with the nitrogen to which they are attached cyclize to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from O N/S
• Ci-io alkyl, cycloalkyl, or cycloalkyl alkyl group such as methyl, ethyl, propyl, isopropyl, t-butyl, etc.
• Ci-io alkyl such as CF3
• an optionally substituted aryl such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, wherein these aryl moieties may also be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; Ci-io alkoxy; S(O) m alkyl; amino, mono and di-substituted amino, such as in the NR7R17 group; Ci-io alkyl, or halosubstituted alkyl, such as CF3.
• Rl is 4-pyridyl, 2-alkyl-4- pyridyl, 2-NRioR20"4-P>" r iclyl- 4-pyrimidinyl, 2-alkyl-4-pyrimidinyl, 2-NRi()R20-4- pyrimidinyl, wherein one of Rl ⁇ R20 is hydrogen, or 4-quinolyl; more preferably Ri is 2-amino-4-pyrimidinyl or 2 methylamino-4-pyrimidinyl; R2 is an optionally substituted phenyl group.
• R2 is phenyl or phenyl substituted by fluoro, chloro, Ci-4 alkoxy, S(O)mCl-4 alkyl, methanesulfonamido or acetamido;
• R3 is phenyl or optionally substituted phenyl and R4 is hydrogen or NR16R26-
• Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.
• pharmaceutically acceptable salts of compounds of formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent Yi in R3 comprises a carboxy group.
• Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
• halo ' - all halogens, that is chloro, fluoro, bromo and iodo;
• Cl-10 alkyl or “alkyl” both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, w ⁇ -propyl, n-butyl, sec-butyl, ito-butyl, t_rt-butyl, and the like;
• cycloalkyl is used herein to mean cyclic radicals, preferably of 3 to 7 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
• alkenyl is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like.
• aryl - phenyl and naphthyl;
• heteroaryl (on its own or in any combination, such as “heteroaryloxy”) - 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 or S, such as, but not limited to pyrrole, thiophene, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole;
• heterocyclic (on its own or in any combination, such as “heterocyclylalkyl”) - 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, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine or pyrazolidine;
• aralkyl or “heteroarylalkyl” or “heterocyclicalkyl” is used herein to mean CM alkyl as defined above unless otherwise indicated
• 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 included within the scope of the present invention.
• Pyrazole 3-Scheme 1 can be converted to the corresponding sulphonamide, amide, urea, guanidine or urethane by using techniques well known to those of skill in the art by the appropriate acylating agents, such as sulfonyl chlorides, acid chlorides, isocyanates, dicyanamides and chloroformates, respectively.
• 5-Aminopyrazole, 3 -Scheme 1 can also be converted to the 5-diazopyrazole, 4-Scheme 1 by treatment with NaNO2 and aqueous HCI. Following the procedure of Hodgson, H.H. et al., J. Chem. So. London, 1944, 8, treatment of 4-Scheme 1 with Cu2 ⁇ and HOAC/H2SO4) affords pyrazole 5-Scheme I.
• any acylsubstituted malonate ester can be reacted with a substituted hydrazine derivative to afford a 3-hydroxypyrazole such as 1-Scheme 2.
• a 3- hydroxypyrazole can be either deoxygenated as shown in scheme II, or can also be converted to afford a suitable derivative.
• the ester functionality can be transformed into a methyl ketone such as 2-Scheme 2 which can be reacted with a variety of reagents like Bredrick's reagent or DMF dimethylacetal, to yield an enamine such as 3-Scheme 2.
• Enamines Gike 3-Scheme 2 react efficiently with guanidine derivatives (or substituted guanidine derivatives ) to afford the corresponding 2-aminopyrimidine 4-Scheme 2.
• the triflate of compound 1-Scheme II can be reacted with both carbon and nitrogen nucleophiles to obtain compounds having R4 not equal to hydrogen.
• the triflate of 1- Scheme II can be displaced with either azide or cyanide to afford compounds which are themselves intermediates for the synthesis of compounds having respectively either a nitrogen (amines, amides, ureas) or carbon (ketones, esters, amides, alcohols) attachment to the pyrazole ring.
• the triflate or the halo (chloro, bromo, or iodo) derivative which may be prepared either from 1-Scheme II directly or from nucleophilic displacement of the triflate by the halo group, can be reacted under a variety of transition metal (Pd, Ni, etc.) catalyzed cross coupling conditions with a suitable organometallic based carbon nucleophiles (arylstannanes, boronic acids, organozincs) to afford R4 as an aryl, heteroaryl, olefin, acetylene, ester, or alkyl substituent.
• transition metal Pd, Ni, etc.
• organometallic based carbon nucleophiles arylstannanes, boronic acids, organozincs
• reaction of 3 -Scheme II with S-methyl thiourea produces a 2- thiomethyl substituted pyrimidine (4-Scheme II with S-methyl in place of NH2).
• This intermediate may be reacted under basic conditions with amine nucleophiles to produce analogs of 4-Scheme II (RHN in place of NH2 wherein R is a suitable substituent group, such as R13, S(O)2R, etc.) or preferably oxidized to the sulfoxide or sulfone which then undergo more facile displacement with amine nucleophiles to afford the analogs of 4- Scheme II.
• Suitable protecting groups for use in the present invention are well known in the art and described in many references, for instance, Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience, New York, 1981.
• compositions of formula (I) may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid in the presence of a suitable solvent.
• the compounds of Formula (I) or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or tiierapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by excessive or unregulated cytokine production by such mammal's cell, such as, but not limited to monocytes and/or macrophages.
• Compounds of formula (I) are capable of inhibiting proinflammatory cytokines, such as IL-1, IL-6, EL-8 and TNF and are therefore of use in therapy.
• IL-1, IL-8 and TNF affect a wide variety of cells and tissues and tiiese cytokines, as well as other leukocyte- derived cytokines, are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these pro-inflammatory cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
• the present invention provides a method of treating a cytokine- mediated disease which comprises administering an effective cytokine-interfering amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• compounds of formula (I) or a pharmaceutically acceptable salt thereof are of use in the prophylaxis or therapy of any disease state in a human, or other mammal, which is exacerbated by or caused by excessive or unregulated EL-1, IL-8 or TNF production by such mammal's cell, such as, but not limited to, monocytes and/or macrophages.
• this invention relates to a method of inhibiting the production of IL-1 in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• this invention relates to a metiiod of inhibiting the production of TNF in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• TNF production has been implicated in mediating or exacerbating a number of diseases including 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 sarcoisosis, bone resorption diseases, such as osteoporosis, reperfusion injury, graft vs.
• diseases including 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 sarcoisosis,
• 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 and pyresis.
• AIDS cachexia secondary to infection or malignancy
• AIDS cachexia secondary to acquired immune deficiency syndrome
• AIDS AIDS
• ARC AIDS related complex
• keloid formation scar tissue formation
• Crohn's disease Crohn's disease
• ulcerative colitis ulcerative colitis
• viruses of formula (I) are also useful in the treatment of viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo.
• the viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, direcdy or indirectiy, by the TNF inhibiting-compounds of formula (1).
• viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, Cytomegalovirus (CMV), Influenza, adenovirus and the Herpes group of viruses, such as but not limited to, Herpes Zoster and Herpes Simplex.
• this invention relates to a method of treating a mammal, preferably a human, afflicted with a human immunodeficiency virus (HTV) which comprises administering to such mammal an effective TNF inhibiting amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• HTV human immunodeficiency virus
• TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
• viruses include, but are not limited to, the lentivirus infections such as equine infectious anaemia virus, caprine arthritis virus, visna virus, or the maedi virus, or the retroviruses, such as feline immunodeficiency virus (FIV), bovine immunodeficiency virus, or canine immunodeficiency virus.
• the compounds of formula (I) may also be used topically in the treatment or prophylaxis of topical disease states mediated by or exacerbated by excessive cytokine production, such as by IL-1 or TNF respectively, such as 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.
• cytokine production such as by IL-1 or TNF respectively, such as 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.
• Another aspect of the present invention relates to a method of inhibiting the production of IL-8 (Interleukin-8, NAP) in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• IL-8 Interleukin-8, NAP
• the compounds of formula (I) are administered in an amount sufficient to inhibit cytokine, in particular IL-1, IL-8 or TNF, production such that it is regulated down to normal levels, or in some case to subnormal levels, so as to ameliorate or prevent the disease state.
• Abnormal levels of IL-1, IL-8 or TNF constitute: (i) levels of free (not cell bound) IL-1, IL-8 or TNF greater than or equal to 1 picogram per ml; (ii) any cell associated IL-1, IL-8 or TNF; or (iii) the presence of IL-1, IL-8 or TNF mRNA above basal levels in cells or tissues in which IL-1, IL-8 or TNF, respectively, is produced.
• the compounds of formula (I) are inhibitors of cytokines, specifically IL-1, IL-8 and TNF is based upon the effects of the compounds of formula (I) on the production of die IL-1, IL-8 and TNF in in vitro assays which are described herein.
• the term "inhibiting the production of IL-1 (IL-8 or TNF)” refers to: a) a decrease of excessive in vivo levels of the cytokine (IL-1, IL-8 or TNF) in a human to normal or sub-normal levels by inhibition of the in vivo release of the cytokine by all cells, including but not limited to monocytes or macrophages; b) a down regulation, at the genomic level, of excessive in vivo levels of the cytokine (IL-1, IL-8 or TNF) in a human to normal or sub-normal levels; c) a down regulation, by inhibition of the direct synthesis of the cytokine (IL-1, IL-8 or TNF) as a postranslational event; or d) a down regulation, at the translational level, of excessive in vivo levels of the cytokine (IL-1, IL-8 or TNF) in a human to normal or sub-normal levels.
• 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, JL-6 or IL- 8.
• cytokine refers to 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 Umited to, monokines and lymphokines, regardless of which cells produce them.
• a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte.
• Lymphokines are generally referred to as being produced by lymphocyte cells.
• cytokines include, but are not limited to, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF-a) and Tumor Necrosis Factor beta (TNF- ⁇ ) .
• cytokine interfering or “cytokine suppressive amount” refers to an effective amount of a compound of formula (I) which will cause a decrease in the in vivo levels of the cytokine to normal or sub-normal levels, when given to a patient for die prophylaxis or treatment of a disease state which is exacerbated by, or caused by, excessive or unregulated cytokine production.
• die cytokine referred to in the phrase "inhibition of a cytokine, for use in the treatment of a HIV-infected human" is a cytokine which is implicated in (a) the initiation and/or maintenance of T cell activation and/or activated T cell-mediated HIV gene expression and/or replication and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration.
• TNF-8 also known as lymphotoxin
• TNF - ⁇ also known as cachectin
• a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.
• This invention also relates to a pharmaceutical composition comprising an effective, non-toxic amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
• Compounds of formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniendy be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation.
• the compounds of formula (I) may be 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. It will be appreciated that the form and character of die pharmaceutically acceptable character or diluent is dictated by die amount of active ingredient with which it is to be combined, the route of administration and otiier well- known variables.
• the carriers must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• the pharmaceutical carrier employed may be, for example, either a solid or liquid.
• Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
• Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like.
• the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or witii a wax.
• the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
• the amount of solid carrier will vary widely but preferably will be from about 25mg. to about lg.
• die preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
• Compounds of formula (I) may be administered topically, that is by non-systemic administration. This includes die application of a compound of formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such tiiat the compound does not significantly enter the blood stream.
• systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
• Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
• the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1 % to 1 % w/w of the formulation.
• 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 die 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 fluid, 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, com, 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 a macrogel.
• the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
• Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
• Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably 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 die container by an 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 die preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
• Compounds of formula (I) may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration.
• the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
• Appropriate dosage forms for such administration may be prepared by conventional techniques.
• Compounds of formula (I) may also be administered by inhalation, that is by intranasal and oral inhalation administration.
• Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
• the daily oral dosage regimen will preferably be from about 0.1 to about 80 mg kg of total body weight, preferably from about 0.2 to 30 mg/kg, more preferably from about 0.5 mg to 15mg.
• the daily parenteral dosage regimen about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to about 30 mg/kg, and more preferably from about 0.5 mg to 15mg/kg.
• the daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, administered one to four, preferably two or three times daily.
• the daily inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day.
• the optimal quantity and spacing of individual dosages of a compound of formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and tiiat such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
• IL-1 Interleukin 1
• Human peripheral blood monocytes are isolated and purified from eitiier fresh blood preparations from volunteer donors, or from blood bank buffy coats, according to the procedure of Colotta et al, J Immunol, 132, 936 (1984). These monocytes (lxl ⁇ are plated in 24-well plates at a concentration of 1-2 million/ml per well. The cells are allowed to adhere for 2 hours, after which time non-adherent cells are removed by gentie washing.
• IL-1 Interleukin 1
• Test compounds are tiien added to the cells for lh before the addition of lipopolysaccharide (50 ng/ml), and the cultures are incubated at 37° C for an additional 24h. At the end of this period, culture supernatants are removed and clarified of cells and all debris. Culture supernatants are then immediately assayed for IL-1 biological activity, either by the method of Simon et al, J. Immunol. Methods, 84, 85, (1985) (based on ability of IL-1 to stimulate a Interleukin 2 producing cell line (EL-4) to secrete IL-2, in concert with A23187 ionophore) or the method of Lee et al, J. ImmunoTherapy, 6 (1), 1- 12 (1990) (ELISA assay).
• Tumor Necrosis Factor Human peripheral blood monocytes are isolated and purified from either blood bank buffy coats or plateletpheresis residues, according to die procedure of Colotta, R. et al, J Immunol, 132(2), 936 (1984). The monocytes are plated at a density of 1x106 cells/ml medium/well in 24-well multi-dishes. The cells are allowed to adhere for 1 hour after which time die supernatant is aspirated and fresh medium (1ml, RPMI-1640, Whitaker Biomedical Products, Whitaker, CA) containing 1% fetal calf serum plus penicillin and streptomycin (10 units/ml) added.
• fresh medium (1ml, RPMI-1640, Whitaker Biomedical Products, Whitaker, CA
• the cells are incubated for 45 minutes in the presence or absence of a test compound at InM-lOmM dose ranges (compounds were solubilized in dimetiiyl sulfoxide/ethanol, such that the final solvent concentration in the culture medium is 0.5% dimethyl sulfoxide/0.5% ethanol).
• Bacterial lipopoly- saccharide E. coli 055:B5 [LPS] from Sigma Chemicals Co.
• E. coli 055:B5 [LPS] from Sigma Chemicals Co.
• HUVEC Primary human umbilical cord endothelial cells
• CELL Systems, Kirland, Wa Primary human umbilical cord endothelial cells
• the cells are then diluted 20-fold before being plated (250 ⁇ l) into gelating coated 96-well plates.
• culture medium Prior to use, culture medium is replaced with fresh medium (200 ⁇ l).
• Buffer or test compound 25 ⁇ l, at concentrations between 1 and lO ⁇ M is then added to each well in quadruplicate wells and die plates incubated for 6h in a humidified incubator at 37° C in an atmosphere of 5% CC_ .
• Cytokine Specific Binding Protein Assay A radiocompetitive binding assay was developed to provide a highly reproducible primary screen for structure-activity studies. This assay provides many advantages over d e conventional bioassays which utilize freshly isolated human monocytes as a source of cytokines and ELISA assays to quantify them. Besides being a much more facile assay, the binding assay has been extensively validated to highly correlate with the results of the bioassay. A specific and reproducible CSAID binding assay was developed using soluble cystosolic fraction from THP.l cells and a radiolabeled compound.
• a suitable radiolabeled compound of the CSAID class is 4-(Fluorophenyl)-2-(4- hydroxyphenyl-3,5-t2)-5-(4-pyridyl)imidazole.
• the THP.l cytosol was routinely prepared from cell lysate obtained by nitrogen cavitation followed by a 10 K x g low speed and a 100 K x g high speed centrifugation, the supernatant of which was designated as the cytosolic fraction. THP.l cytosol was incubated with appropriately diluted radioligand at room temperature for a pre-determined time to allow the binding to achieve equilibrium.
• the binding protein may be in isolated form in solution, or in immobilized form, or may be genetically engineered to be expressed on the surface of recombinant host cells such as in phage display system or as fusion proteins. Alternatively, whole cells or cytosolic fractions comprising the CSBP may be employed in the screening protocol. Regardless of the form of the binding protein, a plurality of compounds are contacted with the binding protein under conditions sufficient to form a compound/ binding protein complex and compound capable of forming, enhancing or interfering with said complexes are detected.
• the CSAID Binding Assay is performed as follows: MATERIALS: Incubation buffer. 20 mM Tris, 1 mM MgCl2, 20 mM Hepes, 0.02% NaN3, store at 4°C. Elution buffer: 20 mM Tris, 50 mM 2-mercaptoethanol, NaN3, store at 4°C.
• G-10 Sephadex add 100 g Sephadex G-10 (Pharmacia, Uppsala, Sweden) to 400 mL dd H2O and allow to swell at room temperature for 2 hours. Decant fines and wash 3 times. Add NaN3 and qs with dd H2O to 500 mLs and store at 4°C.
• Assemble Columns Straw column, filter frit and tip (Kontes, SP 420160-000, 420162- 002). Lowsorb tubes (Nunc) used in binding reaction.
• THP.l cytosol spun at 15000 rpm for 5 min to clarify. THP.l cytosol prepared by hypnotic treatment of cells and lysis by decompression in nitrogen.
• Non-radioactive Compound I witii corresponding EtOH control (dilutions made in incubation buffer) and - ⁇ H-Compound I (dilutions in incubation buffer)
• Binding reaction mixture 100 ⁇ L cytosol, 10 uL cold Compound I or EtOH control, 10 ⁇ L -1H-Compound I (molar concentration depends on nature of study).
• the filtrate solution was evaporated to near dryness with a stream of nitrogen, and the residue was dissolved in about 1.2 mL of the HPLC mobile phase.
• the solution was separated by HPLC as shown below, and the peaks corresponding to Compounds I and la are collected separately.
• the pooled Compound I fractions totaled 32 mL in volume and the radioactive concentration was 1.52 mCi/mL (total 48.6 m Ci).
• the pooled SB Compound la [**-H] fractions (totaling 10.1 mCi) were evaporated to dryness and die residue was transferred quantitatively into a glass vial using 3.8 mL of absolute etiianol for further analysis.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Public Health (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Pulmonology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

Priority Applications (3)

Applications Claiming Priority (2)

Publications (1)

Family

ID=22916601

Family Applications (1)

Country Status (4)

Cited By (72)

Families Citing this family (38)

Citations (1)

Family Cites Families (3)

• 1994
  • 1994-05-16 US US08/242,906 patent/US5559137A/en not_active Expired - Lifetime
• 1995
  • 1995-05-16 EP EP95921292A patent/EP0871622A1/en not_active Withdrawn
  • 1995-05-16 US US08/454,170 patent/US5998425A/en not_active Expired - Fee Related
  • 1995-05-16 JP JP7529891A patent/JPH10500413A/ja not_active Ceased
  • 1995-05-16 WO PCT/US1995/006287 patent/WO1995031451A1/en not_active Ceased
• 1999
  • 1999-12-03 US US09/456,019 patent/US6306883B1/en not_active Expired - Fee Related

Patent Citations (1)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events