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WO1997009325A1 - Carboxylates de pyrimidine, composes connexes et methodes de traitement des etats inflammatoires - Google Patents

Carboxylates de pyrimidine, composes connexes et methodes de traitement des etats inflammatoires Download PDF

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Publication number
WO1997009325A1
WO1997009325A1 PCT/US1996/014089 US9614089W WO9709325A1 WO 1997009325 A1 WO1997009325 A1 WO 1997009325A1 US 9614089 W US9614089 W US 9614089W WO 9709325 A1 WO9709325 A1 WO 9709325A1
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WIPO (PCT)
Prior art keywords
carboxylate
ethyl
mmol
aminocitraconamido
compound
Prior art date
Application number
PCT/US1996/014089
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English (en)
Inventor
Mark J. Suto
Leah M. Gayo
Moorthy S. S. Palanki
Lynn J. Ransone-Fong
Original Assignee
Signal Pharmaceuticals, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US08/574,406 external-priority patent/US5852028A/en
Application filed by Signal Pharmaceuticals, Inc. filed Critical Signal Pharmaceuticals, Inc.
Priority to AU70130/96A priority Critical patent/AU726058B2/en
Priority to JP9511324A priority patent/JPH11512390A/ja
Priority to US08/807,677 priority patent/US5935966A/en
Publication of WO1997009325A1 publication Critical patent/WO1997009325A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates generally to compounds that block intracellular signal transduction and activation of transcription factors, and to methods for preventing or treating irnmunoinflammatory and autoimmune diseases.
  • T-cells In certain autoimmune diseases or chronic inflammatory states, continuous activation of T-cells eventually leads to a self-perpetuating destruction of normal tissues or organs. This is caused by the induction of adhesion molecules, chemotaxis of leukocytes, activation of leukocytes and the production of mediators of inflammation. All of these events are regulated at the level of transcription for the production of new proteins, including cytokines.
  • cytokines The production of cytokines, as well as a number of other cellular regulators, is controlled by a family of proteins known as transcription factors (TFs). These transcription factors, when activated, bind to specific regions on the DNA and act as molecular switches or messengers to induce or upregulate gene expression.
  • TFs transcription factors
  • RNA transcripts The activation of these TFs is caused by a variety of external signals including physiological stress, infectious agents and other bioregulatory molecules.
  • a cascade of protein kinases and second messengers are induced which, in turn, result in the production of RNA transcripts.
  • the end result is the production of proinflammatory proteins via translation and processing ofthe RNA transcripts.
  • This activation system can, at times, be very robust. For example, a specific set of external signals could result in a single transcription factor to induce many proteins responsible for a given disease. Therefore, regulating this process by disrupting the production of activated TF(s) has the potential to attenuate the production of the associated pathological proteins, thereby halting or reversing the course of the disease.
  • NFKB and AP-l Two transcription factors, NFKB and AP-l, have been shown to regulate the production of many proinflammatory cytokines and related proteins that are elevated in irnmunoinflammatory diseases. These TFs regulate interleukin- 1 (IL-1), interleukin-2 (IL-2), tumor necrosis factor- ⁇ (TNF ⁇ ), interleukin-6 (IL-6) and interleukin-8 (IL-8) levels in a variety of cell types.
  • IL-1 interleukin- 1
  • IL-2 interleukin-2
  • TNF ⁇ tumor necrosis factor- ⁇
  • IL-6 interleukin-6
  • IL-8 interleukin-8
  • NFKB and other related complexes are involved in the rapid induction of genes whose products function in protective and proliferative responses upon exposure of cells to external stimuli.
  • AP-l has a significant role in the regulation of interleukin-2 (IL-2) and tumor necrosis factor- ⁇ (TNF- ⁇ ) transcription during T-cell activation.
  • IL-2 interleukin-2
  • TNF- ⁇ and IL-1 are strong activators of collagenase, gelatinase and stromelysin gene expression, which require a single AP-l binding site in the promoter region of these genes. Therefore, an inhibitor of NFKB and/or AP-l activation would coordinately repress the activities of a series of proteinases.
  • cell adhesion molecules are also controlled by these TFs.
  • telomeres All of these proteins have been shown to play a role in diseases, including osteoarthritis, transplant rejection, ischemia, reperfusion injury, trauma, certain cancers and viral disorders, and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, glomerulonephritis, lupus and juvenile diabetes.
  • autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, glomerulonephritis, lupus and juvenile diabetes.
  • the role of these TFs is to act as a transducer for certain stimuli that lead to immune, inflammatory, and acute phase responses.
  • this invention is directed to compounds that block the activation of transcription factors (TFs), particularly NFKB and AP-l, and are believed to function through inhibition of a family of specific kinases.
  • TFs transcription factors
  • NFKB transcription factors
  • AP-l a transcription factor that influences the rate of a cell proliferation.
  • IL-1, IL-2, IL-8 and/or TNF ⁇ proinflammatory proteins
  • diseases such as rheumatoid arthritis, osteoarthritis, related autoimmune disorders and tissue rejection.
  • compounds of the present invention are useful in, for example, the prevention of organ and tissue rejection associated with transplantation.
  • the compounds of this invention also have utility in the prevention and/or treatment of immunoinflammatory and autoimmune diseases, as well as having general activity as anti-inflammatory agents.
  • R 2 , R 4 , R 5 and Rg are as defined in the following detailed description.
  • a pharmaceutical composition containing one or more compounds of this invention in combination with a pharmaceutically or prophylactically acceptable carrier or diluent.
  • methods are disclosed for preventing and/or treating inflammatory conditions by administering to a warm-blooded animal in need thereof an effective amount of a compound of this invention.
  • Such inflammatory conditions include both irnmunoinflammatory conditions and autoimmune diseases.
  • the compounds are preferably administered to the warm-blooded animal in the form or a pharmaceutical composition.
  • Figure 3 illustrates the ability of a representative compound of this invention to inhibit the activation of NFKB and AP-l .
  • Figure 4 illustrates the ability of a representative compound of this invention to inhibit IL-2 and IL-8.
  • the compounds of this invention block activation of transcription factors (TFs), and thus have utility as anti-inflammatory agents in general, and in the prevention and/or treatment of a variety of conditions, including (but not limited to) irnmunoinflammatory and autoimmune diseases.
  • the compounds are believed to function by inhibiting, at an early stage, transcription of deleterious proteins associated with such conditions or diseases. It is believed that this is achieved by inhibiting the kinase(s) that regulate the activation of TFs, such as NFKB and/or AP-l.
  • TFs transcription factors
  • R 2 , R 4 , R 5 and R ⁇ are as defined below.
  • R 5 is selected from the following chemical moieties (i), (ii) and (iii):
  • R 7 is selected from hydrogen and an unsubstituted or substituted C, .8 alkyl, C 6.12 aryl or C 7 . 12 aralkyl;
  • R g is an unsubstituted or substituted C ⁇ . g alkyl, C 6 . 12 aryl or C 7 . 12 aralkyl.
  • R 7 is a C,_ 8 alkyl, and in a more preferred embodiment is selected from methyl and ethyl.
  • R 8 is selected from methyl and phenyl.
  • the compounds of this invention further include pharmaceutically and prophylactically acceptable salts of compounds of structure (I).
  • Compounds of structure (I) may contain proton donating groups (e.g., a carboxylic acid group) and/or proton accepting groups (e.g., a group with a nitrogen atom having a free lone pair of electrons, such as an amine group), and the salts of compounds of structure (I) may be formed and utilized in the practice ofthe invention.
  • compounds ofthe invention may be in the form of a base addition salt (i.e., a salt of a proton donating group) or in the form of an acid addition salt (i.e., a salt of a proton accepting group), as well as the free acid or free base forms thereof.
  • the compounds of this invention also include those salts derived from inorganic bases such as the hydroxide or other salt of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, and organic bases such as substituted ammonium salts.
  • inorganic bases such as the hydroxide or other salt of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like
  • organic bases such as substituted ammonium salts.
  • a "C,. 8 alkyl” is a straight chain or branched, cyclic or non-cyclic, saturated or unsaturated carbon chain containing from 1 to 8 carbon atoms.
  • the C,. 8 alkyl is a fully saturated, straight chain alkyl selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl.
  • the C,. 8 alkyl is a straight chain or branched, cyclic or non-cyclic, saturated or unsaturated carbon chain containing from 1 to 8 carbon atoms.
  • the C,. 8 alkyl is a fully saturated, straight chain alkyl selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl.
  • the C,. 8 alkyl is a fully saturated cyclic alkyl selected from (but not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylenecyclopropyl and methy lenecyclohexyl.
  • the C,. 8 alkyl is a fully saturated, branched alkyl selected from (but not limited to) isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl and isohexyl.
  • the C,. 8 alkyl is an unsaturated straight chain alkyl selected from (but not limited to) ethylenyl, propylenyl, 1-butenyl, 1-pentenyl and 1-hexenyl.
  • a "C 6 . 12 aryl” is an aromatic moiety containing from 6 to 12 carbon atoms.
  • the C 6 . 12 aryl is selected from (but not limited to) phenyl, tetralinyl, and napthalenyl.
  • the C 6.I2 aryl is phenyl.
  • a "C 7 . I2 aralkyl” is an arene containing from 7 to 12 carbon atoms, and has both aliphatic and aromatic units.
  • the C 7.12 aralkyl is selected from (but not limited to) benzyl, ethylbenzyl, propylbenzyl and isobutylbenzyl.
  • a "substituted" C,. 8 alkyl, C 6 . 12 aryl or C 7 . 12 aralkyl is a C, .8 alkyl, C 6 . 12 aryl or C 7 . ]2 aralkyl having one or more hydrogens replaced with a substituent selected from halogen (including -F, -Cl, -Br and -I), -OH, -R, -OR, -COOH, -COOR, -COR, -CONH 2 , -NH 2 , -NHR, -NRR, -NO 2 , -SH, -SR, -SOOR, -SO 3 R and -SOR, where each occurrence of R is independently selected from an unsubstituted or substituted C,.
  • halogen including -F, -Cl, -Br and -I
  • the substituted C,. g alkyl is a C,. g haloalkyl including (but not limited to) -CF 3 and -C 2 F 5 .
  • R 2 is R 2a and R 4 is R 4a .
  • R 4a is selected from hydrogen, halogen and an unsubstituted or substituted C,. 8 alkyl, C 6 . 12 aryl, C 7 . 12 aralkyl, C 3 . 12 heterocycle or C 4 . 16 heterocyclealkyl; and R 2a is selected from the following chemical moieties (iv) through (vii):
  • D is a direct bond
  • Rg is selected from hydrogen, -CH 3 , -CH 2 CH 3 and -CH 2 C 6 H 5
  • R 10 and R ⁇ are the same or different and independently selected from hydrogen, -CH 3 , -CF 3 , -(CH 2 ) ] . 5 CH 3 , -C 6 H 5 , -CH 2 C 6 H 5 , and a substituted phenyl or benzyl moiety
  • n is 0.
  • R 2 is R 2b and R 4 is R 4b .
  • R 2b is selected from hydrogen, halogen and an unsubstituted or substituted C,. 8 alkyl, C 6 . 12 aryl, C 7 . I2 aralkyl, C 3 . 12 heterocycle or C 4 . 16 heterocyclealkyl
  • R 4b is selected from chemical moieties (iv) through (vii) identified above.
  • a "C 3 . 12 heterocycle” is a moiety that contains a ring made up of more than one kind of atom, and which contains 3 to 12 carbon atoms.
  • the C 3 . I2 heterocycle is selected from (but not limited to) pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, and thianaphthyl.
  • a "C 4 . 16 heterocyclealkyl” is a moiety that contains a C 3 . I2 heterocycle linked to a C,. 8 alkyl, and which contains 4 to 16 carbon atoms.
  • the C 4 . )6 heterocyclealkyl is a methylene furan having the following structure:
  • a "substituted" C 3 . 12 heterocycle or C 4 . 16 heterocyclealkyl is a C 3 . ]2 heterocycle or C 4 . 16 heterocyclealkyl having one or more hydrogens replaced with a substituent selected from halogen (including -F, -Cl, -Br and -I), -OH, -R, -OR, -COOH, -COOR, -COR, -CONH 2 , -NH 2 , -NHR, -NRR, -NO 2 , -SH, -SR, -SOOR, -SO 3 R and -SOR, where each occurrence of R is independently selected from an unsubstituted or substituted C,.
  • halogen including -F, -Cl, -Br and -I
  • -OH, -R, -OR, -COOH, -COOR, -COR -CONH 2 , -NH 2 ,
  • the compounds of this invention have structure (II) above, wherein R 2a , R 4a , R ⁇ and R 7 are selected from the moieties identified in Table 1 below.
  • the compounds of this invention have structure (III) above, wherein R 2b , R 4b , R 6 and R 7 are selected from the moieties identified in Table 2 below. Table 2
  • the compounds of this invention have structure
  • the compounds of this invention have structure (I) above wherein R 5 is the chemical moiety (iii).
  • the compounds disclosed herein have the following structures (VI) and (VII):
  • R 2a , R 2b , R 4a , R 4b , 1 ⁇ and R 7 are as defined above.
  • the compounds of this invention have structure (II) or (III) above and include (but are not limited to) the following: ethyl 2-(N-(l'- aminocitraconamido))-4-trifluoromethylpyrimidine-5-carboxylate; ethyl 2-(N-(l'- aminophthalimido))-4-trifluoromethylpyrimidine-5-carboxylate; 5-acetyl-2-(N-(l'- aminocitraconamido))-4-trifluoromethylpyrimidine; ethyl 2-(N-(l '-amino-3'- phenylmaleimido))-4-trifluoromethylpyrimidine-5 -carboxylate; ethyl 2-(N-(l '-amino- 3',4'-dimethylmaleimido))-4-trifluoromethylpyrimidine-5-carboxylate; ethyl 2-(N-(l '-amin
  • the compounds of this invention have structure (IV) or (V) above and include (but are not limited to) the following: 5-benzoyl-2- chloro-4-trifluoromethylpyrimidine; 5-acetyl-2-[N-( 1 '-aminocitraconamide)]-4- trifluoromethylpyrimidine ; 5 -benzoy 1-2- [N-( 1 '-aminocitraconamido)] -4- trifluoromethylpyrimidine; 5-benzoyl-2-[N-(l '-aminocitraconamido)]-4- ethylpyrimidine; 5-benzoyl-2-[N-(r-aminocitraconamido)-N-methyl]-4- ethylpyrimidine; and 5-butanoyl-2-[N-(r-aminocitraconamido)-N-methyl]-4- ethylpyrimidine.
  • the compounds of this invention have structures (VI) or (VII) above, and include (but are not limited to) the following: 5- methylol-2-pSf-(r-aminocitraconamido)]-4-ethylpyrimidine; 5-methylol-2-[N-(l'- aminocitraconamido)-N-methyl]-4-ethylpyrimidine; 5-methoxymethane-2-[N-(l'- aminocitraconamido)-N-methyl]-4-ethylpyrimidine; 5-methoxymethane-2-[N-( 1 '- aminocitraconamido)]-4-trifluoromethylpyrimidine; and 5-ethoxymethylcarbonate-2- [N-(r-aminocitraconamido)]-4-trifluoromethylpyrimidine.
  • Preferred compounds of the invention are ethyl 2-(N-(l'- aminocitraconamido))-4-trifluoromethylpyrimidine-5-carboxylate; ethyl 2-(N-(l '- aminophthalimido))-4-trifluoromethylpyrimidine-5-carboxylate; 5-acetyl-2-(N-( 1 '- aminocitraconamido))-4-trifluoromethylpyrimidine-5-carboxylate; ethyl 2-(N-(l '- amino-3'-phenylmaleimido))-4-trifluoromethylpyrimidine-5-carboxylate; ethyl 2-(N-(l'- amino-3',4'-dimethylmaleimido))-4-trifluoromethylpyrimidine-5-carboxylate; ethyl 2- (N-(l'- amino-3',4'-dimethylmaleimido))-4-trifluoromethylpyr
  • the compounds of this invention may be made by one skilled in organic synthesis by known techniques, as well as by the synthetic routes disclosed herein.
  • the compounds of this invention may be made from commercially available ⁇ -keto esters 1 by heating at elevated temperatures (75-110°C) with a mixture of urea and triethylorthoformate (or a substituted orthoformate) to provide ureido derivatives 2.
  • Compound 4 may be reacted with various nucleophiles in an aprotic solvent at ambient temperature to provide derivatives 7.
  • Compound 4 may also be converted to the carbonyl chloride 5 by treatment with base, such as hydroxide in water, followed by a chlorinating agent, such as oxalyl chloride in methylene chloride.
  • Base such as hydroxide in water
  • chlorinating agent such as oxalyl chloride in methylene chloride.
  • Compound 5 can be treated with an organometallic, such as methyl magnesium bromide in a solvent such as THF or ether at -35°C to -65°C, to give ketone 9.
  • This ketone may be treated with various nucleophiles in an aprotic solvent and at ambient temperature to provide compound 10.
  • compound 3 may be converted to the hydroxy carboxylic acid 6 by treatment with a strong base, such as sodium hydroxide, or strong acid, such as HCl, at elevated temperature (70-110°C).
  • a strong base such as sodium hydroxide
  • strong acid such as HCl
  • the hydroxy carboxylic acids may be converted to the chloro carbonyl chloride with thionyl chloride and/or phosphorous oxychloride.
  • Compound 4 can also be treated with hydrazine at ambient temperature in a solvent, such as THF, with pyridine as a catalyst to provide the intermediates of structure 8.
  • a solvent such as THF
  • pyridine as a catalyst
  • These hydrazino derivatives can be reacted with cyclic anhydrides, such as citraconic anhydride, in a solvent, such as chloroform, at elevated temperatures (35-65°C) to provide compounds of structure 11.
  • cyclic anhydrides such as citraconic anhydride
  • a solvent such as chloroform
  • Compounds of structures (VI) and (VII) may be prepared by reducing any of the compounds in Figure 1 so as to convert a carboxylate group to a methylol (-CH 2 OH) group.
  • Lithium aluminum hydride is a suitable reducing agent.
  • the methylol group may, if desired, be converted to -CH 2 OR 7 by standard alkylation chemistry (e.g., using a strong base and a nucleophile).
  • Derivative 15 may also be treated with hydrazine in a solvent such as THF in the presence of pyridine to give the hydrazino intermediates 17.
  • Treatment of 17 with various cyclic anhydrides, such as citraconic anhydride, in a solvent, such as chloroform, at elevated temperatures (34-65°C) provide compounds of structure 18.
  • compounds of structures (VI) and (VII) may be prepared from the corresponding carboxylate compounds as discussed above in connection with Figure 1.
  • a strong base e.g., NaH
  • the compounds of this invention may be formulated for administration to a warm-blooded animal by a variety of techniques known to those skilled in the art.
  • the compound is in the form of a pharmaceutical composition for prophylactic or therapeutic use, and which contains at least one compound of this invention in combination with a pharmaceutically acceptable carrier or diluent.
  • the compound is present in the composition in an amount which, upon administration to the animal, is effective in preventing or treating the condition of interest.
  • the composition includes a compound of this invention in an amount ranging from 0.01 mg to 250 mg per dosage, depending upon the route of administration, and more preferably from 1 mg to 60 mg. Appropriate concentrations, dosages and modes of administration may be readily determined by one skilled in the art.
  • Suitable carriers or diluents are familiar to those skilled in the formulation field.
  • acceptable carrier or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives.
  • the compositions of this invention may also be formulated as pills, capsules, granules or tablets which contain, in addition to the compound of this invention, diluents, dispersing and surface active agents, binders and lubricants.
  • the present invention provides methods for preventing or treating a variety of conditions. Such methods include administering a compound of this invention to a warm-blooded animal in need thereof in an amount sufficient to prevent or treat the condition.
  • Such methods include systemic administration of a compound of this invention, preferably in the form of a composition as disclosed above.
  • systemic administration includes oral and parental methods of administration.
  • suitable pharmaceutical compositions include powders, granules, pills, tablets and capsules, as well as liquids, syrups, suspensions and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives.
  • the compounds of the present invention may be prepared in aqueous injectable solutions which may contain, in addition to the compound of this invention, buffers, antioxidants, bacteriostats and other additives commonly employed in such solutions.
  • compounds of the present invention can be used to prevent or treat a wide variety of disorders, diseases and/or illnesses.
  • the compounds may be administered to a warm-blooded animal for prevention or treatment of rheumatoid arthritis, osteoarthritis, tissue and/or organ transplant rejection, sepsis, ARDS, asthma, trauma, oxidative stress, cell death, irradiation damage, ischemia, reperfusion, cancer, viral infection, and autoimmune diseases such as psoriasis, inflammatory bowel disease, glomerulonephritis, lupus, uveitis and chronic hepatitis.
  • Compounds of this invention may be screened by known and accepted techniques for their ability to function as prophylactically and/or therapeutically active agents.
  • the compounds may be evaluated in in vitro and/or in vivo assays indicative of the compound's anti-inflammatory and immunosuppressive properties.
  • such compounds may first be evaluated in a number of cell-based assays which determine the ability of a compound to prevent activation of NFKB and AP-l (see Example 126).
  • the compound's ability to attenuate cytokine levels (such as IL-2 and IL-8), which are known to be elevated in certain disease states, may be determined (see Example 127).
  • the compounds may then be evaluated in an appropriate animal model, including rodent models of inflammation and immunosuppression (see Example 128).
  • rodent models of inflammation and immunosuppression see Example 128, numerous studies have been performed directed to the activity of such drugs.
  • cyclosporin A has been used in clinical trials since the late 1970's as a second-line drug, and is recommended to be used only in patients with active RA.
  • Experiment 128 may be performed utilizing cyclosporin A as a positive control.
  • a recent review of such immunosuppressive drugs, including relevant assays for the same, is presented by R.P. Carlson in Exp. Opin. Invest. Drugs 4(9):853-
  • Examples 1-124 disclose the synthesis of representative compounds of this invention, as well as intermediates thereto;
  • Example 125 discloses the synthesis of representative compounds by combinational chemistry techniques;
  • Examples 126-127 disclose the ability of representative compounds of this invention to inhibit NFKB, AP-l and cytokines;
  • Example 128 discloses assays for evaluating activity of representative compounds of this invention in both graft versus host disease and contact sensitivity models.
  • Example 4 ETHYL UREIDOMETHYLENE BENZO YLACETATE
  • the title compound was prepared as described in Example 3, but employing ethyl benzoylacetate (30.0 g, 156 mmol), resulting in a yield of 21% (12g); m.p. 124-126°C.
  • PYRIMIDINE-5-CARBOXYLATE A solution of ethyl 2-chloro-4-trifluoromethyl-5-pyrimidine ester (0.25 g, 1.0 mmol), N-aminophthalimide (0.17 g, 1.0 mmol) and pyridine (0.09 ml, 1.0 mmol) in THF was heated at 60°C for 5 h and then concentrated. The residue was chromatographed (SiO 2 , hexanes/EtOAc, 1:1) to give the title compound (0.07 g, 17% yield); m.p. 46-48 °C.
  • Example 33 ETHYL 2-HYDRAZIN0-4-ETHYLPYRIMIDINE-5-CARB0XYLATE
  • the title compound was prepared as described in Example 18, but employing ethyl 2-chloro-4-ethylpyrimidine-5-carboxylate (1 g, 4.7 mmol), resulting in a yield of 41% (0.4 g); GC/MS calcd for C 9 H 14 N 4 O 2 (M + ) 210, found 210.
  • Example 37 ETHYL 2-[N-( 1 '-AMINOCITRACONAMIDO)]-4-PROPYLPYRIMIDINE-5-CARBOXYLATE
  • the title compound was prepared as described in Example 20, but employing ethyl 2-hydrazino-4-propylpyrimidine-5 -carboxylate (0.77 g, 3.4 mmol), resulting in a yield of 73% (0.7 g); m.p. 103-105°C.
  • PYRIMIDINE-5-CARBOXYLATE The title compound was prepared as described for ethyl 2-[N-(l'- aminocitraconamido)]-4-trifluoromethylpyrimidine-5-carboxylate but employing 3,4- dimethylmaleic anhydride (0.08 g, 0.63 mmol), resulting in a 47% yield (0.10 g); m.p.
  • PYRIMIDINE-5-CARBOXYLATE The title compound was prepared as described in Example 20, but employing a solution of ethyl 4-hydrazino-2-trifluoromethylpyrimidine-5-carboxylate (0.09 g, 0.36 mmol) and 3,4-dimethylmaleic anhydride (0.09 g, 0.72 mmol) resulting in a 89% yield (0.12 g); m.p. 116-117°C.
  • Example 52 ETHYL 2-[N-( 1 '-AMINOCITRACONAMIDO) ]-4-BENZYLPYRIMIDINE-5-CARBOXYLATE
  • the title compound was prepared as described in Example 20, but employing a solution of ethyl 2-hydrazino-4-benzylpyrimidine-5-carboxylate (0.34 g, 1.2 mmol) and citraconic anhydride (0.22 g, 2.0 mmol) resulting in a 37% yield (0.15 g) ofthe title compound; m.p. 34-36°C.
  • TRIFLUOROMETHYLPYRIMIDINE-5-CARBOXYLATE The title compound was prepared as described in Example 65, but employing methyl 2-[N-( 1 '-aminocitraconamido)]-4-trifluoromethylpyrimidine-5- carboxylate (0.02 g, 0.06 mmol), resulting in a yield of 94% (0.019 g); m.p. 66-68°C.
  • Example 20 From this, the title compound was prepared as described in Example 20, but employing the ethyl 2- hydrazino-4-[2'-(5'-chlorothiophene)]pyrimidine-5-carboxylate (3.0 g, 0.017 mol) ⁇ prepared according to the procedure of Example 19, but employing ethyl 2-mesyl-4- [2'-(5'-chlorothiophene)]pyrimidine-5-carboxylate described above ⁇ , resulting in a yield of 38% (1.3 g); m.p. 137-138°C.
  • Example 68 Example 68
  • the title compound was prepared as described in Example 20, employing ethyl 2-hydrazino-4-trifluoromethylpyrimidine-5-carboxylate (0.20 g, 0.8 mmol) and 4-methylphthalic anhydride (0.26 g, 1.6 mmol) where citraconic anhydride was used, resulting in a yield of 29% (0.09 g); m.p. 50-51°C.
  • Example 71 ETHYL 2-[N-(1'-CITRACONAMIDO)]-PYRIMIDINE-5-CARBOXYLATE
  • the title compound was prepared by (a) treating 2-chloropyrimidine-5- carbonylchloride (Example 13, 110 mg, 0.62 mmol) with ethanol (200 mg, 4.4 mmol in 1 mL of ethyl acetate) to provide 60% of ethyl 2-chloropyrimidine-5-carboxylate, (b) reaction of ethyl 2-chloropyrimidine-5-carboxylate (70 mg, 0.37 mmol) with hydrazine (100 mg, 3 mmol) to afford 44% of ethyl 4-hydrazinopyrimidine-5-carboxylate as in Example 19, (c) reaction of ethyl 4-hydrazinopyrimidine-5-carboxylate (0.36 g, 2.0 mmol) with citraconic anhydride (0.34 g, 3.0 mmol) in analogy to Example 21 to afford 10% (0.05 g) ofthe title compound; m.p. 95-98°C
  • Example 76 The title compound was prepared as described in Example 74, but employing ethyl 2-[N-(r-aminocitraconamido)]-4-trifluoromethylpyrimidine-5- carboxylate (0.14 g, 0.4 mmol), resulting in a yield of 67% (0.11 g); ⁇ NMR (CDC1 3 ) ⁇ 9.14 (s, IH), 6.55 (s, IH), 4.45 (q, 2H), 2.83 (s, 3H), 2.20 ( s, 3H), 1.39 (t, 3H).
  • Example 76 Example 76
  • Example 47 The title compound was prepared according to the procedure of Example 47 but employing a solution of methyl 2-chloro-4-pentafluoroethylpyrimidine-5- carboxylate (0.55 g, 1.9 mmol; itself prepared by a reaction of methanol with 2-chloro- 4-pentafluoroethylpyrimidine-5-carbonyl chloride (see Example 17)) and hydrazine (0.3 g, 9.4 mmol), resulting in a yield of 99% (0.54 g); 'HNMR (CDC1 3 ) ⁇ , 8.87 (s, IH), 7.09 (s, IH), 3.92 (s, 3H), 1.7 (s, 2H).
  • the title compound was prepared from t-butyl 2-hydrazino-4- trifluoromethylpyrimidine-5-carboxylate (0.88 g, 3.2 mmol) (prepared as described for Example 19, but employing t-butyl 2-chloro-4-trifluoromethylpyrimidine-5- carboxylate) as described in Example 20, resulting in a yield of 10% (0.12 g); ⁇ NMR (CDC1 3 ) ⁇ 8.84 (s, IH), 7. 50 (s, IH), 6.53 (s, IH), 2.20 (s, 3H), 1.55 (s, 9H).
  • TRIFLUOROMETHYLPYRIMIDINE-5-CARBOXYLATE The title compound was prepared from methyl 2-hydrazino-4- trifluoromethylpyrimidine-5-carboxylate (0.01 g, 0.42 mmol) (prepared as described for Example 19, but employing methyl 2-chloro-4-trifluoromethylpyrimidine-5- carboxylate) as described in Example 20, resulting in a yield of 69% (0.096 g); m.p. 118-120°C.
  • TRIFLUOROMETHYLPYRIMIDINE-5-CARBOXYLATE The title compound was prepared from methyl 2-[N-(l'- aminocitraconamido)]-4-trifluoromethylpyrimidine-5-carboxylate (0.20 g, 6.1 mmol) as described in Example 42, resulting in a yield of 10% (0.02 g); ⁇ NMR (CDC1 3 ) ⁇ 9.05 (s, IH), 6.49 (s, IH), 3.91 (s, 3H), 3.62 (s, 3H), 2.18 (s, 3H).
  • Example 82 METHYL 2-HYDRAZINO-4-(2'-THIENYL)PYRIMIDINE-5-CARBOXYLATE
  • Example 84 The title compound was prepared from methyl 2-hydrazino-4-(2'- thienyl)pyrimidine-5-carboxylate (0.16 g, 0.64 mmol) according to the procedure of Example 20, resulting in a yield of 90% (0.20 g); m.p. 112-113°C.
  • Example 84 The title compound was prepared from methyl 2-hydrazino-4-(2'- thienyl)pyrimidine-5-carboxylate (0.16 g, 0.64 mmol) according to the procedure of Example 20, resulting in a yield of 90% (0.20 g); m.p. 112-113°C.
  • Example 84 The title compound was prepared from methyl 2-hydrazino-4-(2'- thienyl)pyrimidine-5-carboxylate (0.16 g, 0.64 mmol) according to the procedure of Example 20, resulting in a yield of 90% (0.20 g); m.p. 112-113°C.
  • Example 84 The title
  • the title compound was prepared from 5-benzoyl-2-hydrazino-4- trifluoromethylpyrimidine (0.15 g, 0.53 mmol) (prepared as described for Example 19, but employing 5-benzoyl-2-mesyl-4-trifluoromethylpyrimidine) as described in
  • Example 20 resulting in a yield of 6% (0.015 g); 'H NMR (CDC1 3 ) ⁇ 8.5 (s,lH), 7.8 (m,2H), 7.65 (m,lH), 7.5 (m,2H), 6.5 (s,lH), 3.45 (s,lH), 2.2 (s,3H).
  • the title compound was prepared from ethyl 2-hydrazino-4-(3'- thienyl)pyrimidine-5-carboxylate (0.22 g, 0.88 mmol) (prepared in the same manner as Example 35) as described in Example 20, resulting in a yield of 40% (0.11 g); m.p. 47- 48°C.
  • the title compound was prepared from ethyl 2-hydrazino-4-[2'-(5'- methylthienyl)]pyrimidine-5-carboxylate (0.22 g, 0.88 mmol) (prepared in the same manner as Example 67) as described for Example 20, resulting in a yield of 40% (0.11 g); m.p. 138-139°C.
  • the title compound was prepared by (a) reaction of ethyl 2'- furanoylacetate (10 g, 0.055 mol) with N.N-dimethylformamide dimethyl acetal (7.3 g, 0.055 mol) as described for Example 67, (b) subsequent reaction with a solution NaOEt (0.058 mol) and S-methyl isothouronium sulfate (7.7 g, 0.028 mol) also described for Example 67, (c) oxidation with mCPBA (9.8 g, 0.057 mol) also described for Example 67, (d) reaction with hydrazine (1.5 mL, 0.05 mol) as described for Example 19, and (e) reaction with citraconic anhydride (4 mL, 0.05 mol) as described for Example 20, resulting in an overall yield of 1 % (0.18 g); m.p. 38-40°C.
  • the title compound was prepared by (a) reaction of ethyl 2'- benzothienoylacetate (24.8 g, 0.1 mol) with N-N-dimethylformamide dimethyl acetal (7.3 g, 0.055 mol) as described for Example 67, (b) subsequent reaction with a solution of NaOEt (0.12 mol) and S-methyl isothouronium sulfate (13.9 g, 0.05 mol) also described for Example 67, (c) oxidation with mCPBA (8.5 g, 0.05 mol) also described for Example 67, (d) reaction with hydrazine (1.5 mL, 0.05 mol) as described for Example 19, and (e) reaction with citraconic anhydride (4 mL, 0.05 mol) as described for Example 20, resulting in an overall yield of 0.1% (0.05 g); m.p. 165-166°C.
  • the title compound was prepared by (a) reaction of ethyl methoxyketoacetate (10.5 g, 0.07 mol) with triethyl orthoformate (9.7 g, 0.07 mol) and urea (3.9 g, 0.07 mol) as described for Example 3, (b) reaction with NaOEt (0.02 mol) as described for Example 5, (c) reaction with POCl 3 (6.5 mL, 0.07 mol) as described for Example 7, (d) reaction with hydrazine (2 mL, 0.07 mol) as described for Example 19, and (e) reaction with citraconic anhydride (6 mL, 0.07 mol) as described for Example 20, resulting in an overall yield of 8% (1.8 g); 'H NMR (CDC1 3 ) ⁇ 8.87 (s, IH), 8.2 (s, IH), 6.5 (s, IH), 4.87 (s, 2H), 4.35 (q, 2H), 3.47 (s, 3H), 2.18 (s, 3H), 1.35 (
  • the title compound was prepared by (a) reaction of 5-benzoyl-4-ethyl-2- methylthiopyrimidine (0.14 g, 0.54 mmol) and mCPBA (0.28 g, 1.6 mmol) as described for Example 67, (b) reaction with hydrazine (0.09 g, 2.7 mmol) as described for
  • Example 19 and (c) reaction with citraconic anhydride as described for Example 20, resulting in a overall yield of 25% (0.046 g); m.p. 49-50°C.
  • the title compound was prepared from ethyl 2-mesyl-4-(2'- thianaphthyl)pyrimidine-5 -carboxylate (2.0 g, 5.5 mmol) as described in Example 93, but employing methyl hydrazine (0.9 mL, 16.5 mmol) where hydrazine was used, this followed by reaction with citraconic anhydride (1.5 mL, 16.5 mmol) also in anology to Example 93; resulting in a yield of 69% (1.6 g); ⁇ NMR (CDC1,) ⁇ 8.8 (d, IH), 8.15 (d, IH), 7.8 (m, 2H), 7.3 (m, 2H), 6.6 (d, IH), 4.37 (q, 2H), 3.65 (d, 3H), 2.17 (s, 3H), 1.34 (t, 3H).
  • aqueous layer is acidified with concentrated HCl to pH ⁇ 3 then extracted into ether, dried (MgSO 4 ) and concentrated to provide the thiazole-2-carboxylic acid in 57% yield (3.2 g); ⁇ NMR (MeOD) ⁇ 8.00 (d, IH); 7.94 (d, IH).
  • the titie compound was then prepared by (a) oxidation of 4-ethyl-5- methoxymethyl-2-methylthiopyrimidine (0.66 g, 3.35 mmol) with mCPBA (1.18 g, 6.85 mmol) as described for Example 67, and (b) reaction with methyl hydrazine (0.36 mL, 6.85 mmol) followed by citraconic anhydride (0.77 g, 6.85 mmol) also described in Example 67; resulting in a yield of 41% (0.40 g) from 4-ethyl-5-methoxymethyl-2- methylthiopyrimidine; ⁇ NMR (CDC13) ⁇ 8.14 (s, IH), 6.43 (s, IH), 4.29 (s, 2H), 3.53 (s, 3H), 3.36 (s, 3H), 2.68 (m, 2H), 2.14 (s, 3H), 1.13 (m, 3H).
  • Example 112 The title compound was prepared as described for Example 112, but employing of 4-trifluoromethyl-5-hydroxymethyl-2-methylthiopyrimidine (0.50 g, 2.23 mmol) (prepared in analogy to Example 110) where 4-ethyl-5-hydroxymethyl-2- methylthiopyrimidine was used, and employing hydrazine (0.09 mL, 2.87 mmol) where methyl hydrazine was used, resulting in an overall yield of 35% (0.25 g); ⁇ NMR (CDC13) ⁇ 8.63 (s, IH), 8.20 (s, IH), 6.48 (s, IH), 4.46 (s, 2H), 3.75 (s, 3H), 2.12 (s, 3H).
  • Example 114 Example 114
  • the title compound was prepared by (a) reaction of diethylethoxy- methylenemalonate (31 g, 144 mmol) with benzamidine (22 g, 144 mmol) under basic conditions to afford ethyl 2-phenyl-4-hydroxypyrimidine-5 -carboxylate in 64% yield in analogy to Example 15, (b) reaction of ethyl 2-phenyl-4-hydroxypyrimidine-5- carboxylate (1.5 g, 6 mmol) and POCl 3 (9.4 g, 62 mmol) to afford 81% of ethyl 2- phenyl-4-chloropyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 2-phenyl-4-chloropyrimidine-5-carboxylate (12 g, 46 mmol) with hydrazine (4.4 g, 137 mmol) to afford 99% of ethyl 4-hydrazino-2-phenylpyrimidine-5
  • the title compound was prepared according to the procedure of Example 68 but employing ethyl 2-[N-( -aminocitraconamide)]-4-phenylpyrimidine-5- carboxylate (0.1 g, 0.3 mmol) and methyl iodide (0.09 g, 0.7 mmol) under basic conditions, resulting in a yield of 45% (0.05 g); m.p. 118-119°C.
  • METHYLPYRIMIDINE-5-CARBOXYLATE The title compound was prepared by (a) reaction of diethylethoxymethylenemalonate (6 g, 28 mmol) with acetamidine hydrochloride (3 g, 31 mmol) to afford 61% of ethyl 2-methyl-4-hydroxypyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 2-methyl-4-hydroxypyrimidine-5- carboxylate (2.8 g, 15 mmol) with POCl 3 (46 g, 300 mmol) to afford 28% of ethyl 4- chloro-2-methylpyrimidine-5-carboxylate, (c) reaction of ethyl 4-chloro-2- methylpyrimidine-5-carboxylate (0.25 g, 1.25 mmol) with hydrazine (0.2 g, 6.3 mmol) to afford 96% of 4-hydrazino-2-methylpyrimidine-5-carboxylate in analogy to Example
  • the title compound was prepared by (a) reaction of diethyl ethoxymethylenemalonate (11 g, 52 mmol) with phenylacetamidine (8 g, 60 mmol) to afford 40%) of ethyl 2-benzyl-4-hydroxypyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of 2-benzyl-4-hydroxypyrimidine-5-carboxylate (3 g, 12 mmol) with POCl 3 (18 g, 116 mmol) to afford 45% of 2-benzyl-4-chloropyrimidine-5- carboxylate in analogy to Example 7, (c) reaction of 2-benzyl-4-chloropyrimidine-5- carboxylate (1.5 g, 5.5 mmol) with hydrazine (0.5 g, 16 mmol) to afford 75% of 2- benzyl-4-hydrazinopyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 2-benzyl-4-hydra
  • the title compound was prepared by (a) reaction of diethyl ethoxymethylenemalonate ( 5 g, 24 mmol) with 3-nitrobenzamidine (5 g, 25 mmol) to afford 86% of ethyl 4-hydroxy-2-(3'-nitrophenyl)pyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 4-hydroxy-2-(3'-nitrophenyl)pyrimidine-5- carboxylate (6 g, 21 mmol) with (chloromethylene)dimethylammonium chloride (4 g, 31 mmol) concentration of reaction mixture, followed by hexane and ether wash afford 45% of ethyl 4-chloro-2-(3'-nitrophenyl)pyrimidine-5-carboxylate, (c) reaction of ethyl 4-chloro-2-(3'-nitrophenyl)pyrimidine-5 -carboxylate (1.9 g, 6 mmol) with hydrazine (
  • Example 122 ETHYL 4-[N-(1 '-AMINOCITRACONAMIDO)]-2- (2'-THIENYL)-PYRIMID ⁇ NE-5-CARBOXYLATE
  • the title compound was prepared by (a) reaction of diethyl ethoxymethylenemalonate (8 g, 35 mmol) with thienyl-2-formamidine hydrochloride
  • the title compound was prepared by (a) reaction of ethyl 4-chloro-2-(2'- thienylpyrimidine-5 -carboxylate (0.3 g, 1.1 mmol)) with methylhydrazine (0.25 g, 5.6 mmol)) to afford 99% of ethyl 4-(l'-methylhydrazino)-2-(2'-thienyl)pyrimidine-5- carboxylate in analogy to Example 18, (b) reaction of ethyl 4-(l'-methylhydrazino)-2- (2'-thienyl)pyrimidine-5-carboxylate (0.3 g, 1 mmol)) with citraconic anhydride (0.4 g, 3 mmol) in analogy to Example 21 to afford 52% (0.21 g) of the title compound; m.p. 126-127°C.
  • the title compound was prepared by (a) of diethyl ethoxymethylenemalonate (6 g, 27 mmol) with 3',4'- dichlorophenylacetamidine (5.5 g,
  • the resin was divided into 80 equal portions and placed into 80 separate reaction vessels (dispersion tubes).
  • the dispersion tubes were placed into separate test tubes each containing a different amine (2.5 mmol, Appendix I) and 2 mL of a O.IM solution of pyridine/DMF (5 molar equivalents of each amine in each test mbe).
  • the entire set of 80 reaction vessels was gently shaken for 5 hours to ensure complete reaction.
  • each ofthe dispersion tubes was removed from the test tube containing the amine and rinsed separately to remove any unreacted materials.
  • the dispersion tubes were then dried and submersed into 80 new test mbes (previously tared), each containing a solution of NaOMe (2.5 mL, 0.012 M solution, 0.03 mmol). The reaction was allowed to proceed overnight at room temperature under N 2 . Then the dispersion tubes were removed from the solution and individually rinsed with MeOH. The individual MeOH solutions were concentrated in the tared test tubes to provide known amounts of the desired 80 individual methyl esters substimted with different groups at the 2-position. Each compound was >85% pure by HPLC and had the conect molecular weight as determined by GC/MS.
  • Stable human Jurkat T-cells containing an NFKB binding site (from the MHC promoter) fused to a minimal SV-40 promoter driving luciferase expression were used in this experiment.
  • Cells were split to 3 x 10 5 cells/mL every 2-3 days (cell concentration should not exceed 1 x IO 6 cells/mL to keep the cells proliferating in log phase). These cells were counted, resuspended in fresh medium containing 10% Serum-Plus at a density of 1 x IO 6 cells/mL and plated in 96 well round bottom plates (200 ⁇ per well) 18 hours prior to starting the experiment.
  • Jurkat T-cells were used that contained a collagenase promoter driving luciferase expression.
  • concentration of PMA used was 5 ng/mL.
  • the murine popliteal lymph node (PLN) assay is a graft vs. host model that predicts activity of compounds in blocking human transplant rejection.
  • the delayed-type hypersensitivity response to oxazolone is a standard contact sensitivity model. Both of these models are used routinely to evaluate compounds that are used clinically. For example, cyclosporin and cyclophosphamide are active in these models and are used clinically (Morris et al., Transplantation Proceedings 22(Suppl. 1):110- 112, 1990).
  • Spleens are removed from donor BALB/c mice and splenocytes are isolated then inadiated (3,000 rads) to prevent donor cell proliferation. After washing and adjusting cell density, 2.5xl0 6 cells are injected subcutaneously into the left hind footpad of C3H mice. On day 4, the mice are sacrificed and left popliteal lymph nodes (PLNs) weighed.
  • PPNs left popliteal lymph nodes
  • a representative compound of this invention is administered once daily by intraperitoneal injection beginning one day before footpad injection (day 0) through day 4.
  • the compound is suspended, immediately prior to use, at a concentration of 5 mg/mL in 0.25% methyl cellulose (Sigma) using a glass-Teflon homogenizer.
  • a concentration of 5 mg/mL in 0.25% methyl cellulose (Sigma) using a glass-Teflon homogenizer.
  • appropriate dilutions of the stock solution are made so that 0.1 mL/10 g body weight is administered by intraperitoneal injection.
  • oxazolone 100 mL of a 3%) solution
  • a challenge application of oxazolone is applied (10 mL) around the right ear.
  • a representative compound of this invention is administered from days -2 to 7 by intraperitoneal injection.
  • the injectable solution is prepared immediately prior to use by suspending the compound in 0.25%> methyl cellulose (Sigma) using a glass-Teflon homogenizer.
  • 0.1 mL/10 g body weight of the suspension is administered.
  • the compound is prepared at the highest concentration for this study and appropriate dilutions ofthe stock solution are made so that 0.1 mL/10 g body weight is administered. Twenty four hours later, the difference in right vs. left ear thickness is measured.

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Abstract

Composés s'avérant utiles comme agents anti-inflammatoires d'une manière générale et, plus spécifiquement, pour la prévention et/ou le traitement des maladies immuno-inflammatoires et auto-immunes. Ces composés sont des composés contenant de la pyrimidine et, dans un mode de réalisation, sont des esters de celle-ci. L'invention porte également sur des méthodes de prévention et/ou de traitement des états inflammatoires par administration à un animal en ayant besoin d'une dose efficace d'un composé de cette invention, de préférence sous forme d'une composition pharmaceutique.
PCT/US1996/014089 1995-09-01 1996-08-30 Carboxylates de pyrimidine, composes connexes et methodes de traitement des etats inflammatoires WO1997009325A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8258129B2 (en) * 2006-07-06 2012-09-04 Boehringer Ingelheim International Gmbh 4-heterocycloalkylpyri(mi)dines, process for the preparation thereof and their use as medicaments

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4983608A (en) * 1989-09-05 1991-01-08 Hoechst-Roussell Pharmaceuticals, Inc. N-substituted-4-pyrimidinamines and pyrimidinediamines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4983608A (en) * 1989-09-05 1991-01-08 Hoechst-Roussell Pharmaceuticals, Inc. N-substituted-4-pyrimidinamines and pyrimidinediamines

Cited By (74)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6245774B1 (en) 1994-06-21 2001-06-12 Celltech Therapeutics Limited Tri-substituted phenyl or pyridine derivatives
US5935966A (en) * 1995-09-01 1999-08-10 Signal Pharmaceuticals, Inc. Pyrimidine carboxylates and related compounds and methods for treating inflammatory conditions
WO1998038171A1 (fr) * 1997-02-27 1998-09-03 Signal Pharmaceuticals, Inc. Carboxylates de pyrimidine et composes apparentes et procedes pour le traitement d'etats inflammatoires
WO1999001441A1 (fr) * 1997-07-01 1999-01-14 Signal Pharmaceuticals, Inc. Analogues de quinazoline et composes associes et methodes pour traiter les troubles inflammatoires
US5939421A (en) * 1997-07-01 1999-08-17 Signal Pharmaceuticals, Inc. Quinazoline analogs and related compounds and methods for treating inflammatory conditions
US6150372A (en) * 1997-07-01 2000-11-21 Signal Pharmaceuticals, Inc. Pyridopyrimidine analogs and related compounds and methods for treating inflammatory conditions
US6835726B2 (en) * 1998-02-17 2004-12-28 Amgen Inc. Pyrimidine derivatives
US6734180B1 (en) 1998-07-22 2004-05-11 Daiichi Suntory Pharma Co., Ltd. NF-κB inhibitor comprising an indan derivative as an active ingredient
EP1018514A4 (fr) * 1998-07-22 2001-05-30 Suntory Ltd INHIBITEURS DE NF-$g(k)B CONTENANT DES DERIVES D'INDANE EN TANT QU'INGREDIENT ACTIF
EP1110951A4 (fr) * 1998-08-27 2002-01-02 Sumitomo Pharma Derives de pyrimidine
US6458798B1 (en) 1998-08-27 2002-10-01 Sumitomo Pharmaceuticals Company, Limited Bicyclic pyrimidine compounds and therapeutic use thereof
US6951866B2 (en) 1998-08-27 2005-10-04 Sumitomo Pharmaceuticals Company, Limited Bicyclic pyrimidine compounds and therapeutic use thereof
GB2369360A (en) * 1999-06-18 2002-05-29 Celltech R&D Ltd 5-cyano-2-aminopyrimidine derivatives
WO2000078731A1 (fr) * 1999-06-18 2000-12-28 Celltech R&D Limited Derives de 5-cyano-2-aminopyrimidine
ES2188429A1 (es) * 1999-06-18 2003-06-16 Celltech Chiroscience Ltd Derivados de 5-ciano-2-aminopirimidina
AU778533B2 (en) * 1999-06-18 2004-12-09 Celltech R & D Limited 5-cyano-2-aminopyrimidine derivatives
WO2001021206A1 (fr) * 1999-09-17 2001-03-29 Suntory Limited MOYENS DE PREVENTION OU REMEDES CONTRE LA MYOCARDITE, LA CARDIOMYOPATHIE DILATEE ET L'INSUFFISANCE CARDIAQUE CONTENANT DES INHIBITEURS NF-λB EN TANT QU'INGREDIENT ACTIF
US6703421B1 (en) 1999-09-17 2004-03-09 Daiichi Suntory Pharma Co., Ltd. Methods of using phenylmethylbenzoquinone and hydroquinone compounds for treatment of myocarditis, dilated cardiomyopathy and heart failure
US7951820B2 (en) 2000-09-15 2011-05-31 Vertex Pharmaceuticals Incorporated Triazole compounds useful as protein kinase inhibitors
US7473691B2 (en) 2000-09-15 2009-01-06 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US7691853B2 (en) 2000-09-15 2010-04-06 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US7390815B2 (en) 2000-09-15 2008-06-24 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US7625913B2 (en) 2000-12-21 2009-12-01 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US8697698B2 (en) 2000-12-21 2014-04-15 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US7531536B2 (en) 2000-12-21 2009-05-12 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US8304414B2 (en) 2000-12-21 2012-11-06 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US7427681B2 (en) 2000-12-21 2008-09-23 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US6642227B2 (en) 2001-04-13 2003-11-04 Vertex Pharmaceuticals Incorporated Inhibitors of c-Jun N-terminal kinases (JNK) and other protein kinases
US7084159B2 (en) 2001-04-13 2006-08-01 Vertex Pharmaceuticals Incorporated Inhibitors of c-Jun N-terminal kinases (JNK) and other protein kinases
US7271181B2 (en) 2001-05-11 2007-09-18 Vertex Pharmaceuticals Incorporated Inhibitors of p38
WO2002092087A1 (fr) * 2001-05-11 2002-11-21 Vertex Pharmaceuticals Incorporated Derives de pyridine, pyrimidine, pyridazine 2,5-disubstitues et de 1, 2, 4-triazine utilises comme inhibiteurs de p38
US7291624B2 (en) 2001-05-29 2007-11-06 Bayer Schering Pharma Ag CDK-inhibitory pyrimidines, their production and use as pharmaceutical agents
US7235561B2 (en) 2001-05-29 2007-06-26 Schering Ag Compound and a composition including such a compound
US7521453B2 (en) 2001-12-07 2009-04-21 Astrazeneca Ab Pyrimidine derivatives as modulators of insulin-like growth factor-1 receptor (IGF-I)
US8268829B2 (en) 2002-06-20 2012-09-18 Vertex Pharmaceuticals Inc. Substituted pyrimidines useful as protein kinase inhibitors
US8779127B2 (en) 2002-06-20 2014-07-15 Vertex Pharmaceuticals Incorporated Processes for preparing substituted pyrimidines
US7557106B2 (en) 2002-06-20 2009-07-07 Vertex Pharmaceuticals Incorporated Substituted pyrimidines useful as protein kinase inhibitors
US7872129B2 (en) 2002-08-02 2011-01-18 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of GSK-3
US7491730B2 (en) 2002-08-02 2009-02-17 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of GSK-3
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
US8129403B2 (en) 2005-02-16 2012-03-06 Astrazeneca Ab Chemical compounds
US8114989B2 (en) 2005-05-16 2012-02-14 Astrazeneca Ab Pyrazolylaminopyrimidine derivatives useful as tyrosine kinase inhibitors
US8088784B2 (en) 2005-10-28 2012-01-03 Astrazeneca Ab 4-(3-aminopyrazole) pyrimidine derivatives for use as tyrosine kinase inhibitors in the treatment of cancer
US7767672B2 (en) 2005-11-03 2010-08-03 Vertex Pharmaceuticals Incorporated Aminopyrimidines useful as kinase inhibitors
US7820685B2 (en) 2005-11-03 2010-10-26 Vertex Pharmaceuticals Incorporated Aminopyrimidines useful as kinase inhibitors
US7528142B2 (en) 2005-11-03 2009-05-05 Vertex Pharmaceuticals Incorporated Aminopyrimidines useful as kinase inhibitors
WO2007062797A1 (fr) * 2005-11-30 2007-06-07 7Tm Pharma A/S Composes azo-heterocycliques amino-substitues destines au traitement de troubles inflammatoires
US8399478B2 (en) 2006-01-23 2013-03-19 Vertex Pharmaceuticals Incorporated Thiophene-carboxamides useful as inhibitors of protein kinases
US8759389B1 (en) 2006-01-23 2014-06-24 Vertex Pharmaceuticals Incorporated Thiophene-carboxamides useful as inhibitors of protein kinases
US7915305B2 (en) 2006-01-23 2011-03-29 Vertex Pharmaceuticals Incorporated Thiophene-carboxamides useful as inhibitors of protein kinases
US8188134B2 (en) 2006-04-13 2012-05-29 Vertex Pharmaceuticals Incorporated Thiophene-carboxamides useful as inhibitors of protein kinases
US7829590B2 (en) 2006-04-13 2010-11-09 Guy Brenchley Thiophene-carboxamides useful as inhibitors of protein kinases
US8039661B2 (en) 2006-05-23 2011-10-18 Vertex Pharmaceuticals Incorporated Thiophene-carboxamides useful as inhibitors of protein kinases
US8853244B2 (en) 2006-05-23 2014-10-07 Vertex Pharmaceuticals Incorporated Thiophene-carboxamides useful as inhibitors of protein kinases
US7851495B2 (en) 2006-05-23 2010-12-14 Vertex Pharmaceuticals Incorporated Thiophene-carboxamides useful as inhibitors of protein kinases
WO2009031040A3 (fr) * 2007-04-11 2009-05-14 Canbas Co Ltd Composés présentant une activité anti-cancéreuse
KR101475311B1 (ko) * 2007-04-11 2014-12-23 가부시키가이샤 캔버스 항암 활성을 갖는 화합물
US8084454B2 (en) 2007-04-11 2011-12-27 Canbas Co., Ltd. Compounds with anti-cancer activity
EP4074704A1 (fr) * 2007-04-11 2022-10-19 CanBas Co., Ltd. Composés de quinoline présentant une activité anticancéreuse
US8415357B2 (en) 2007-04-11 2013-04-09 Canbas Co., Ltd. Compounds with anti-cancer activity
AU2008294410B2 (en) * 2007-04-11 2012-09-06 Canbas Co., Ltd. Compounds with anti-cancer activity
CN105175394B (zh) * 2007-04-11 2018-06-08 三井有限公司 具有抗癌活性的化合物
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US8268811B2 (en) 2007-05-02 2012-09-18 Vertex Pharmaceuticals Inc. Thiazoles and pyrazoles useful as kinase inhibitors
US8486966B2 (en) 2007-05-04 2013-07-16 Astrazeneca Ab 9-(pyrazol-3-yl)-9H-purine-2-amine and 3-(pyrazol-3-yl) -3H-imidazo[4,5-B] pyridin-5-amine derivatives and their use for the treatment of cancer
US8598361B2 (en) 2007-07-31 2013-12-03 Vertex Pharmaceuticals Incorporated Process for preparing 5-fluoro-1H-pyrazolo [3,4-B] pyridin-3-amine and derivatives therof
US8541025B2 (en) 2008-09-03 2013-09-24 Vertex Pharmaceuticals Incorporated Co-crystals and pharmaceutical formulations comprising the same
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WO2010113834A1 (fr) 2009-03-30 2010-10-07 アステラス製薬株式会社 Composé pyrimidine
US8524727B2 (en) 2009-03-30 2013-09-03 Astellas Pharma Inc. Pyrimidine compound
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