EP0850228A1 - Carboxamides de pyrimidine et composes associes, et methodes de traitement d'etats inflammatoires - Google Patents

Carboxamides de pyrimidine et composes associes, et methodes de traitement d'etats inflammatoires

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Publication number
EP0850228A1
EP0850228A1 EP96933070A EP96933070A EP0850228A1 EP 0850228 A1 EP0850228 A1 EP 0850228A1 EP 96933070 A EP96933070 A EP 96933070A EP 96933070 A EP96933070 A EP 96933070A EP 0850228 A1 EP0850228 A1 EP 0850228A1
Authority
EP
European Patent Office
Prior art keywords
compound
trifluoromethyl
pyrimidine
carboxamide
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96933070A
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German (de)
English (en)
Inventor
Mark J. Suto
Mark E. Goldman
Leah M. Gayo
Lynn J. Ransone-Fong
Moorthy S. S. Palanki
Robert W. Sullivan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Signal Pharmaceuticals LLC
Original Assignee
Signal Pharmaceuticals LLC
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Filing date
Publication date
Priority claimed from US08/581,473 external-priority patent/US5811428A/en
Application filed by Signal Pharmaceuticals LLC filed Critical Signal Pharmaceuticals LLC
Publication of EP0850228A1 publication Critical patent/EP0850228A1/fr
Withdrawn legal-status Critical Current

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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
    • 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]
    • 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
    • C07D239/30—Halogen atoms or nitro radicals
    • 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
    • C07D239/34—One oxygen atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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 immunoinflammatory 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 ofthe disease.
  • NFKB and AP-1 Two transcription factors, NFKB and AP-1, have been shown to regulate the production of many proinflammatory cytokines and related proteins that are elevated in immunoinflammatory diseases. These TFs regulate interieukin- 1 (LL-1), interleukin-2 (IL-2), tumor necrosis factor- ⁇ (TNF ⁇ ), interleukin-6 (BL-6) and interleukin-8 (LL-8) levels in a variety of cell types.
  • IL-2 interleukin-2
  • TNF ⁇ tumor necrosis factor- ⁇
  • BL-6 interleukin-6
  • LL-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-1 has a significant role in the regulation of interleukin-2 (LL-2) and tumor necrosis factor- ⁇ (TNF- ⁇ ) transcription during T-cell activation.
  • TNF- ⁇ and IL-1 are strong activators of collagenase, gelatinase and stromelysin gene expression, which require a single AP-1 binding site in the promoter region of these genes. Therefore, an inhibitor of NFKB and/or AP-1 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-1, and are believed to function through inhibition of a family of specific kinases.
  • TFs transcription factors
  • NFKB transcription factors
  • AP-1 binds to a family of specific kinases.
  • proinflammatory proteins including LL-1, LL-2, LL-8 and/or TNF ⁇ , which are responsible for tissue and organ damage associated with 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.
  • a pharmaceutical composition containing one or more compounds of this invention in combination with a pharmaceutically or prophylactically acceptable carrier or diluent.
  • methods 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.
  • inflammatory conditions include both immunoinflammatory conditions and autoimmune diseases.
  • the compounds are preferably administered to the warm-blooded animal in the form of a pharmaceutical composition.
  • Figure 1 illustrates a reaction scheme for the synthesis of representative pyrimidine-containing compounds of this invention.
  • Figure 2 illustrates a reaction scheme for the synthesis of representative pyrazine-containing compounds of this invention.
  • Figure 3 illustrates the ability of a representative compound of this invention to inhibit the activation of NFKB and AP-1.
  • Figure 4 illustrates the ability of a representative compound of this invention to inhibit LL-2 and LL-8.
  • Figure 5 illustrates the ability of a representative compound of this invention to cause a dose-dependent suppression of alloantigen-induced PLN proliferation.
  • 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) immunoinflammatory and autoimmune diseases.
  • TFs transcription factors
  • 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-1.
  • TFs transcription factors
  • structure (I) wherein A is C-R ⁇ when B is N, and A is N when B is C-Ri, and wherein Ri, R 2 , R,, R 5 and R ⁇ are as defined below.
  • structure (I) is a pyrimidine-containing compound having structure (II)
  • structure (I) is a pyrazine-containing compound having structure (III):
  • R 5 is selected from the following chemical moieties (i) through (iv):
  • R 7 is selected from hydrogen, -CH 3 and -CH 2 C ⁇ Hs.
  • Rg is selected from hydrogen and an unsubstituted or substituted Ci-galkyl, C ⁇ -naryl, C . ⁇ 2 aralkyl, C 3- ⁇ 2 heterocycle and a C .i6heterocyclealkyl.
  • 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.
  • Ci-salkyl is a straight chain or branched, cyclic or non-cyclic, saturated or unsaturated carbon chain containing from 1 to 8 carbon atoms.
  • the Ci-galkyl is a fully saturated, straight chain alkyl selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl.
  • the Ci-galkyl is a fully saturated cyclic alkyl selected from (but not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylenecyclopropyl and methylenecyclohexyl.
  • the Ci-galkyl is a fully saturated, branched alkyl selected from (but not limited to) isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl and isohexyl.
  • the Ci-galkyl is an unsaturated straight chain alkyl selected from (but not limited to) ethylenyl, propylenyl, 1-butenyl, 1 -pentenyl and 1-hexenyl.
  • a "C ⁇ -i ⁇ aryl" is an aromatic moiety containing from 6 to 12 carbon atoms.
  • the C ⁇ - ⁇ aryl is selected from (but not limited to) phenyl, tetralinyl, and napthalenyl.
  • the C 6 - ⁇ 2 aryl is phenyl.
  • a "C .i 2 aralkyl” is an arene containing from 7 to 12 carbon atoms, and has both aliphatic and aromatic units.
  • the C 7- ⁇ 2 aralkyl is selected from (but not limited to) benzyl, ethylbenzyl, propylbenzyl and isobutylbenzyl.
  • a "C 3- ⁇ 2 heterocycle” is a compound that contains a ring made up of more than one kind of atom, and which contains 3 to 12 carbon atoms.
  • the C 3 - ⁇ 2 heterocycle is selected from (but not limited to) pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrrolidinyl, pyridinyl, pyrimidinyl and purinyl.
  • the C 3 . ⁇ 2 heterocycle includes the following structures:
  • A is a compound that contains a C3- ⁇ 2 heterocycle linked to a Ci-galkyl.
  • the C . ⁇ heterocyclealkyl is a methylene furan having the following structure:
  • Gn ⁇ heterocyclealkyl is a Ci-galkyl, C 7 .i 2 aralkyl, C 3 -i2heterocycle or
  • C-n ⁇ 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, -CONH2, -NH 2 , -NHR, -NRR, -SH, -SR, -SOOR, -SO 3 R and -SOR, where each occurrence of R is independently selected from an unsubstituted or substituted C ⁇ .galkyl,
  • the substituted C ⁇ -8 alkyl is a Ci-ghaloalkyl including (but not limited to)
  • R2a is selected from halogen, an unsubstituted or substituted Ci-galkyl, C ⁇ -naryl, C 7 . ⁇ 2 aralkyl, C 3 -i2heterocycle or Gn ⁇ heterocyclealkyl,
  • R is independently selected from an unsubstituted or substituted Ci-galkyl, C ⁇ -i ⁇ aryl, C . ⁇ 2 aralkyl,
  • R2 is selected from -Cl, -F, -CN and -CF 3 .
  • R2 b is halogen, such as -Cl or -F.
  • R ⁇ is selected from hydrogen, halogen, an unsubstituted or substituted C ⁇ .galkyl, C ⁇ - ⁇ 2 aryl, C 7 -i2aralkyl, Cs- ⁇ heterocycle or -CN, -OR, -NHR, -NRR and -NRNCOR, wherein each occurrence of R is independently selected from an unsubstituted or substituted Ci-galkyl, C ⁇ -i 2 aryl, C 7 .i 2 aralkyl, C 3 .i 2 heterocycle or O-i ⁇ heterocyclealkyl as defined above.
  • R a is selected from hydrogen, -CH 3 , -CF 3 , -C 2 F 5 , -C 2 H 5 , -C 6 H 5 and
  • structure (III) above is selected from hydrogen, halogen, -CN, and an unsubstituted or substituted C ⁇ .galkyl, C ⁇ -naryl, C 7 . ⁇ 2 aralkyl, C 3 -i2heterocycle or
  • R ⁇ is selected from hydrogen, halogen, and an unsubstituted or substituted Ci-galkyl, including (but not limited to) a Ci-ghaloalkyl (such as -CF 3 and -C 2 F 5 ). In one embodiment, R ⁇ is selected from hydrogen, -Cl, -F, -CH 3 and -CF 3 .
  • Ri is selected from hydrogen, -CH 3 , -CF 3 and -C 2 H 5 .
  • the compounds of this invention have structure (II) above, wherein Ri is the chemical moiety (i).
  • the compounds disclosed herein have the following structure (IV):
  • R2,, R4a, R ⁇ , R7 and Rg are as defined above.
  • representative compounds of structure (IV) contain za, R- , R ⁇ , 7 and Rg moieties as identified in Table 1 below.
  • X, Y and Z are the same or different, and independently selected from hydrogen, - OH, -R, -OR, - COOH, -COOR, -COR, -CONH 2 , -NH 2 , -NHR,
  • R is independently selected from an unsubstituted or substituted C ⁇ . 8 alkyl, C ⁇ - ⁇ 2 aryl,
  • X, Y and Z are the same or different, and independently selected from -H, -Cl, -F, -CF3, -OH, -CH3 and -OCH 3 .
  • Rg is a 3,5- bis(trifluoromethyl)phenyl moiety or a 3-trifluoromethyl-5-halo-phenyl moiety.
  • the compounds have structure (II).
  • u is -CF 3 and R- & is -Cl.
  • Such compounds include (but are not limited to): 2-chloro-4-trifluoromethyl-5-N-(3 l ,5'- bistrifluoromethylphenyl)pyrimidine carboxamide; 2-chloro-4-trifluoromethyl-5-N-(3',5 I - dichlorophenyl)pyrimidine carboxamide; 2-chloro-4-trifluoromethyl-5-N-(4'- trifluoromethylphenyl)pyrimidine carboxamide; 2-chloro-4-trifluoromethyl-5-N- (phenyl)pyrimidine carboxamide; 2-chloro-4-trifluoromethyl-5-N-(cyclohexyl)pyrimidine carboxamide; 2-chloro-4-trifluoromethyl-5-N-(3',4',5'-trichloropheny
  • R 2 a is a moiety other than -Cl.
  • Such compounds include (but are not limited to): 2-fluoro-4- trifluoromethyl-5-N-(3',5'-bistrifluoromethyl)pyrimidine carboxamide, 5-(3',5'- bis(trifluoromethyl)phenacyl)-2-methoxy-4-trifluoromethylpyrimidine; 4-trifluoromethyl- 5-N-(3',5'-dichlorophenyl)pyrimidine carboxamide; 2-dimethylamino-4-trifluoromethyl- 5-N-(3',5 l -dichlorophenyl)pyrimidine carboxamide; 2-triethylammonium chloride-4- trifluoromethyl-5-N-(3',5'-dichlorophenyl)pyrimidine carboxamide; 2-cyano-4- trifluoromethyl-5-N-[3 ⁇ 5 ⁇ bistrifluoromethyl
  • R-j is -Cl and t, is a moiety other than -CF .
  • Such compounds include (but are not limited to): 5-N-(3',5'- bis(trifluoromethyl)phenyl)-2,4-dichloro-6-methyl-pyrimidine carboxamide; 2-chloro-4- methyl-5-N-(3 l ,5 , -(bistrifluoromethyl)phenyl)pyrimidine carboxamide; 2,4-dichloro-5-N- (S'.S'-bis ⁇ rifluoromethy benzy pyrimidine-S-carboxamide; and 2-chloro-4-phenyl-5-N- (3 ⁇ 5'-(bistrifluoromethyl)phenyl)pyrimidine carboxamide.
  • the compounds of this invention have structure (III) above.
  • Ri is selected from hydrogen, -CH3 and -CF 3 .
  • Such compounds include (but are not limited to) pyrazine-containing compounds which correspond to the pyrimidine-containing compounds disclosed above.
  • b is -Cl
  • ib is -CF 3
  • R 5 is a moiety of structure (i) above.
  • novel compounds of this invention do not include compounds of structure (IV) above where R 7 and Rg are both hydrogen, and where R-* * is selected from an unsubstituted, straight chain or branched, non-cyclic, saturated C 1 .3 alkyl (i.e., -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 and -CH(CH 3 ) 2 ), -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 and -OR, where R is as defined above.
  • novel compounds of structure (IV) are subject to the following provisos: (a) when R-* is -Cl and R ⁇ is -H, R- a is not -CF 3 , -Cl, -CH 3 or -C(CH 3 ) 3 , (b) when R2a is -Cl and both R4, and R ⁇ are -H, Rg is not -CH(CN)C ⁇ H 5 or -(CH 2 ) 5 CH 3 , and (c) when R ⁇ is -Cl and R 4a is -Cl, R ⁇ is not -Cl or
  • novel compounds of this invention also do not include compounds of structure (II) when R 5 is moiety (iii) and (a) R ⁇ a is -CH 3 , -OCH 3 or -N(CH 3 ) 2 , or (b) Rg is -H or -CH 3 .
  • novel compounds of structure (III) when R 5 is moiety (i) are subject to the following proviso: when R2b is -Cl, H, and Ri are not both hydrogen.
  • 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. For purpose of convenience, the compounds have been separated into pyrimidine-containing (structure (II)) and pyrazine-containing (structure (III)) compounds as set forth below.
  • the pyrimidine-containing compounds of this invention may be prepared as illustrated by the reaction scheme of Figure 1.
  • ⁇ -keto esters 1 are heated at elevated temperatures (75-110°C) with a mixture of urea and triethylorthoformate (or a substituted orthoformate) to provide ureido derivatives 2.
  • the 2-hydroxypyrimidine esters 3 may also be treated with a mild base, such as lithium hydroxide, sodium hydroxide or potassium carbonate to provide the corresponding acid 3A, which may then be converted with a chlorinating agent, such as phosphorous oxychloride or thionyl chloride in an inert solvent or neat at 25-75°C, to the acid chloride 5.
  • a chlorinating agent such as phosphorous oxychloride or thionyl chloride in an inert solvent or neat at 25-75°C
  • Compounds of structure 6 may be prepared using standard conditions known in the art by reacting the acid chloride 5 with an amine in the presence of a base, such as potassium carbonate or dimethylaminopyridine (DMAP), in a non-protic solvent, such as methylene chloride or EtOAc at 25-40°C, followed by standard workup.
  • a base such as potassium carbonate or dimethylaminopyridine (DMAP)
  • pyrimidine-containing compounds of this invention may also be made by the following combinatorial procedure.
  • Commercially available and/or readily synthesized amines, anilines and related compounds may be reacted with the acid chloride 5 in EtOAc in the presence of basic Amberlyst 21 resin. The reactions are quenched with 50 ⁇ L of water and the final products are obtained in the organic layer and concentrated. This procedure may be done in a 96 well (1 mL deep well) plate and the final products isolated as dry powders. TLC analysis is performed on each compound and indicates the purity, and GC MS and HPLC analysis demonstrates that the desired products are synthesized (mass spectral analysis, molecular weight) and are greater than 80% pure. By this method, eighty distinct pyrimidine-containing compounds may be routinely synthesized at the same time in one 96 well plate.
  • compound 4 may be reacted with various nucleophiles in an aprotic solvent and at ambient temperature to provide derivatives 7. These compounds can be hydrolyzed with base to yield compounds having structure 8.
  • Compounds of structure 8 can be converted to the acid chloride as described above, and reacted with various amines to give compounds having structure 9 using known conditions, including the combinatorial approach described above.
  • compounds of structure 7 can also be prepared by reacting the ⁇ -keto ester 1 in a sequential fashion with triethylorthoformate and acetic anhydride or N,N-dimethylformamide dimethyl acetal in DMF to give intermediate 10. Reacting intermediate 10 with a variety of amidines in alcoholic solvents provides intermediate 11 which, upon addition of base, provides compounds of structure 7.
  • Pyrazine-containing compounds of structure (III) may be prepared as illustrated by the reaction scheme of Figure 2.
  • the synthesis of these compounds may begin with readily available pyruvic acid derivatives 12. These compounds are condensed with commercially available 2-cyano-l,2-diamino-2-substituted ethenes 13 in an alcoholic solvent (such as MeOH) in the presence of an acid (such as HCl) at ambient temperatures (25-60°C) to provide the cyano pyrazines of structure 14.
  • the pyrazines may then be converted to the corresponding carboxylic acids 15 using a strong base such as sodium hydroxide in water, or a strong acid such as HCl, at elevated temperatures (70-110°C).
  • carboxylic acids may then be converted to 5-chloro-2-carbonyl acid chloride derivatives 16 using a chlorinating agent such as POCI3 or SOCI2.
  • a chlorinating agent such as POCI3 or SOCI2.
  • Treatment of 16 with various amines or anilines at ambient temperatures in an inert solvent such as EtOAc or CH2CI2 provides compounds of structure 17.
  • the carboxylic acids of structure 15 can also be converted to the hydroxy ester 18 by treatment with SOCl 2 and MeOH at a temperature of 25-60°C .
  • Compound 19 can also be converted to the acid chloride 16 using a mild base such as potassium carbonate in an a protic solvent such as MeOH, followed by treatment with a chlorinating agent such as oxalyl chloride in an inert solvent such as methylene chloride at ambient temperatures.
  • the pyrazine-containing compounds of this invention may also be synthesized by appropriate combinatorial techniques as described.
  • commercially available and/or readily synthesized amines, anilines and related compounds may be reacted with the acid chloride 16 in EtOAc in the presence of basic Amberlyst 21 resin.
  • the reactions are quenched with 50 ⁇ L of water and the final products are obtained in the organic layer and concentrated. This procedure may be done in a 96 well (1 mL deep well) plate and the final products isolated as dry powders.
  • TLC analysis is performed on each compound and indicates the purity, and GC and HPLC analysis demonstrates that the desired products are synthesized (mass spectral analysis, molecular weight) and are greater than 80% pure.
  • 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.
  • 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 ofthe 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 antinflammatory 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(5ee Example 56).
  • the compound's ability to attenuate cytokine levels (such as LL-2 and LL-8), which are known to be elevated in certain disease states, may be determined (see Example 57).
  • the compounds may then be evaluated in an appropriate animal model, including rodent models of inflammation and immunosuppression (see Example 58).
  • Examples 1-54 disclose the synthesis of representative compounds of this invention, as well as intermediates thereof;
  • Example 55 discloses the synthesis of representative compounds by combinational chemistry techniques;
  • Examples 56-57 disclose the ability of representative compounds of this invention to inhibit NFKB, AP-1 and cytokines;
  • Example 58 discloses the activity of a representative compound of this invention in both graft versus host disease and contact sensitivity models.
  • Example 5 2-CHLORO-4-TRIFLUOROMETHYL- 5-N-(BENZYL)PYRIMIDINE CARBOXAMIDE
  • the title compound was prepared as described above in Example 1, but employing benzylamine (0.09 g, 0.92 mmol) and the acid chloride (0.25 g, 1.0 mmol), resulting in a 78% yield; m.p. 152-153°C.
  • N-acyl-2-fluoro-5-nitroaniline (0.99 g, 5.00 mmol) was dissolved in EtOH (25 mL), and then 10% Pd/C (0.12 g) was added and the solution stirred under H 2 for 5 h.
  • the suspension was filtered through celite and the filtrate evaporated to dryness.
  • the resulting oil was chromatographed (SiO 2 , 1:3 hexanes/EtOAc) to provide 3-N-acyl-4-fluoro-aniline as a yellow oil.
  • the aniline derivative was then coupled to 2- chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride as described in Example 1 to provide the title compound in a 47% yield; m.p. 126-127°C.
  • This compound was coupled to 2-chloro-4-trifluoromethylpyrimidine-5- carbonyl chloride as described and purified by chromatography (SiO ⁇ , 9:1 hexanes/EtOAc) to provide the title compound (15% yield) as a white foam; m.p. 102- 104°C.
  • the 2,4-dihydroxy-6-methyl pyrimidine-5-carboxylic acid was heated at reflux with POCI 3 .
  • the reaction mixture was concentrated and 2,4-dichloro-6- methylpyrimidine-5-carbonyl chloride was obtained by distillation (b.p. 70-80°C, 1.5 mm/Hg).
  • ETHYL UREIDOMETHYLE ⁇ E ACETOACETATE A mixture of ethyl acetoacetate (200 g, 1.54 mol), urea (105 g, 1.54 mole) and triethyl orthoformate (228 g, 1.54 mol) was heated at 140°C under ⁇ 2 for 22 h. The reaction mixture was cooled and filtered to provide the title compound in a 51% yield (156 g); m.p. 173-174°C.
  • Example 18 ETHYL UREIDOMETHYLENE BENZOYLACETATE
  • the title compound was prepared as described in Example 17, but employing ethyl benzoylacetate (30 g, 156 mmol), resulting in a yield of 21% (12 g); m.p. 124-126°C.
  • Example 26 2-CHLORO-4-PHENYLPYRIMIDINE-5-CARBONYL CHLORIDE The compound was prepared as described above in Example 25, but employing 2-chloro-4-phenylpyrimidine-5-carboxylic acid (3.8 g, 14 mmol), resulting in a yield of53 %; m.p. 42°C.
  • the desired acid chloride was obtained from 2,4-bis(trifluoromethyl)- pyrimidine-5-carboxylic acid in a manner similar to that described in Example 25 in a yield of 44%; b.p. 105°C (1.5 mm/Hg); 1HNMR (CDC1 3 ) ⁇ 9.12 (s, IH).
  • Example 45 2-[N-( 1 -AMINOCITRACONAMIDE)]-4-TRIFLUOROMETHYL- 5- ⁇ sf-(3 , ,5'-DICHLOROPHENYL)]-PYRIMIDINE-5-CARBOXAMIDE
  • a solution of 2-hydrazino-4-trifluoromethyl-5-[N-(3 l ,5'- dichlorophenyl)pyrimidine carboxamide (0.08 g, 0.21 mmol) and citraconic anhydride (0.024 g, 0.21 mmol) in CHC1 3 (2.1 mL) was heated at reflux under N 2 for 24 h. The solution was concentrated and chromatographed (Si ⁇ 2, 33% EtOAc/hexane) to afford the title compound (0.06 g, 62% yield); m.p. 182-183°C.
  • Example 49 2-CHLORO-5-N-(BISTRIFLUOROMETHYL ANILINE) PYRAZINE CARBOXAMIDE
  • the title compound was prepared in a yield of 51% (0.08 g) using the same procedure as outlined in Example 1, except substituting 2-chloro-5-pyrazine carbonyl chloride (0.1 g, 0.57 mmol.) in place of the pyrimidine carbonyl chloride; m.p. 101-102°C.
  • Example 52 2-FLUORO-4-TRIFLUOROMETHYL- 5-PYRIMIDINE CARBONYL CHLORIDE
  • the title compound was prepared as described in Example 25, but employing a solution of 2-fluoro-4-trifluoromethylpyrimidine-5-carboxylic acid (1.5 g, 7.1 mmol) and oxalyl chloride (1.0 g, 8 mmol), DMF (2 drops) in CH 2 C1 2 (30 mL) resulted in a 75% yield (1.2 g); 1H NMR (CDC1 3 ) ⁇ 9.42 (s, IH).
  • Example 53 2-FLUORC)-4-TRIF UOROMETHYL-5-N-[3 , ,5 , -BLS(TRIFLUOROMETHYL)PHENYL]
  • PYRIMIDINE CARBOXAMIDE The title compound was prepared as described in Example 1, but employing a solution of 2-fluoro-4-trifluoromethylpyrimidine-5-carbonyl chloride (0.05 g, 0.22 mmol) and 3,5-bis(trifluoromethyl)aniline (45 mg, 0.2 mmol) in EtOAc (2 mL) resulted in a 22% yield (0.02 g); m.p. 133-135°C.
  • 5-PYRIMIDINE CARBONYL CHLORIDE The title compound was prepared as described in Example 25, but employing a solution of 2-chloro-4-trifluoromethylpyrimidine-5-carboxylic acid (1.5 g, 7.1 mmol) and oxalyl chloride (1.0 g, 8 mmol) in CH 2 C1 2 (30 mL) resulted in a 70% yield (l.lg); 1H NMR (CDC1 3 ) ⁇ 9.31 (s, IH).
  • NFKB ASSAY 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 ⁇ L per well) 18 hours prior to starting the experiment.
  • the assay was run as described above for NFKB except stable 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 were removed from donor BALB/c mice and splenocytes were isolated then irradiated (3,000 rads) to prevent donor cell proliferation. After washing and adjusting cell density, 2.5x10 6 cells were injected subcutaneously into the left hind footpad of C3H mice. On day 4, the mice were sacrificed and left popliteal lymph nodes (PLNs) were weighed .
  • PPNs left popliteal lymph nodes
  • Example 1 The compound of Example 1, 2-chloro-4-trifluoromethyl-5-N-(3',5'- bistrifluoromethylphenyl)pyrimidine carboxamide, was administered once daily by intraperitoneal injection beginning one day before footpad injection (day 0) through day 4.
  • the compound was suspended, immediately prior to use, at a concentration of 5 mg/mL in 0.25% methyl cellulose (Sigma) using a glass-teflon homogenizer.
  • appropriate dilutions of the stock solution were made so that 0.1 mL/10 g body weight was administered by intraperitoneal injection.
  • Cyclophosphamide 50 (i.p.) 0.08 ⁇ 0.01 ⁇ 0.001
  • test compound (30 mg/kg i.p.) and cyclophosphamide (50 mg/kg i.p.) significantly attenuated the delayed-type response to oxazolone by 56% and 73%, respectively.

Abstract

Composés présentant une utilité comme agents anti-inflammatoires en général, 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 ou de la pyrazine, et dans un mode de réalisation, sont des carboxyamides de ces substances. Sont décrites également des méthodes de prévention et/ou de traitement d'états inflammatoires par l'administration à un animal ayant besoin d'un tel traitement d'une quantité efficace d'un composé de cette invention, de préférence sous la forme d'une préparation pharmaceutique.
EP96933070A 1995-09-01 1996-08-30 Carboxamides de pyrimidine et composes associes, et methodes de traitement d'etats inflammatoires Withdrawn EP0850228A1 (fr)

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US310995P 1995-09-01 1995-09-01
US3109P 1995-09-01
US08/581,473 US5811428A (en) 1995-12-18 1995-12-18 Pyrimidine carboxamides and related compounds and methods for treating inflammatory conditions
US581473 1995-12-18
PCT/US1996/015108 WO1997009315A1 (fr) 1995-09-01 1996-08-30 Carboxamides de pyrimidine et composes associes, et methodes de traitement d'etats inflammatoires

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