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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Definitions

• This invention relates to the use of a group of aryl ureas in treating cytokine mediated diseases and proteolytic enzyme mediated diseases, and pharmaceutical compositions for use in such therapy.
• MAP mitogen-activated protein
• the MAP kinases are responsible for the activation of a wide variety of transcription factors and proteins involved in transcriptional control of cytokine production.
• a pair of novel protein kinases involved in the regulation of cytokine synthesis was recently described by a group from SmithKline Beecham (Lee et al. Nature 1994, 372, 739). These enzymes were isolated based on their affinity to bond to a class of compounds, named CSAIDSs (cytokine suppressive anti-inflammatory drugs) by SKB.
• CSAIDSs cytokine suppressive anti-inflammatory drugs
• CSBP-1 and -2 The isolated enzymes, CSBP-1 and -2 (CSAID binding protein 1 and 2) have been cloned and expressed.
• a murine homologue for CSBP-2, p38 has also been reported (Han et al. Science 1994, 265, 808).
• CSAIDs function by interfering with m-RNA translational events during cytokine biosynthesis.
• Inhibition of p38 has been shown to inhibit both cytokine production (eg., TNF ⁇ , IL-1, IL-6, IL-8) and proteolytic enzyme production (eg., MMP-1, MMP-3) in vitro and/or in vivo.
• TNF ⁇ production and/or signaling have linked TNF ⁇ production and/or signaling to a number of diseases including rheumatoid arthritis (Maini. J. Royal Coll. Physicians London 1996, SO, 344).
• excessive levels of TNF ⁇ have been implicated in a wide variety of inflammatory and/or immunomodulatory diseases, including acute rheumatic fever (Yegin et al. Lancet 1997, 349, 170), bone resorption (Pacifici et al. J. Clin. Endocrinol. Metabol. 1997, 82, 29), postmenopausal osteoperosis (Pacifici et al. J. Bone Mineral Res. 1996, 11, 1043), sepsis (Blackwell et al. Br. J. Anaesth.
• TNF ⁇ levels have also been related to host-versus- graft reactions (Piguet et al. Immunol. Ser. 1992, 56, 409) including ischemia reperfusion injury (Colletti et al. J. Clin. Invest. 1989, 85, 1333) and allograft rejections including those of the kidney (Maury et al. J. Exp. Med. 1987, 166, 1132), liver (Imagawa et al. Transplantation 1990, 50, 219), heart (Boiling et al. Transplantation 1992, 53, 283), and skin (Stevens et al. Transplant. Proc. 1990, 22, 1924), lung allograft rejection (Grossman et al. Immunol.
• TNF ⁇ has also been linked to infectious diseases (review: Beutler et al. Crit. Care Med. 1993, 21, 5423; Degre. Biotherapy 1996, 8, 219) including tuberculosis (Rook et al. Med. Malad. Infect. 1996, 26, 904), Helicobacter pylori infection during peptic ulcer disease (Beales et al.
• HIV human immunodeficiency virus
• Poli. Proc. Nat 'I. Acad. Sci. USA 1990, 87, 782; Vyakaram et al. AIDS 1990, 4, 21; Badley et al. J. Exp. Med. 1997, 185, 55 human immunodeficiency virus
• MMP matrix-destroying metalloprotease
• Inhibitors of p38 are active in animal models of TNF ⁇ production, including a muirne lipopolysaccharide (LPS) model of TNF ⁇ production. Inhibitors of p38 are active in a number of standard animal models of inflammatory diseases, including carrageenan-induced edema in the rat paw, arachadonic acid-induced edema in the rat paw, arachadonic acid-induced peritonitis in the mouse, fetal rat long bone resorption, murine type II collagen-induced arthritis, and Fruend's adjuvant-induced arthritis in the rat.
• LPS muirne lipopolysaccharide
• inhibitors of p38 will be useful in treating diseases mediated by one or more of the above-mentioned cytokines and/or proteolytic enzymes.
• the need for new therapies is especially important in the case of arthritic diseases.
• the primary disabling effect of osteoarthritis, rheumatoid arthritis and septic arthritis is the progressive loss of articular cartilage and thereby normal joint function.
• No marketed pharmaceutical agent is able to prevent or slow this cartilage loss, although nonsteroidal antiinflammatory drugs (NSAIDs) have been given to control pain and swelling.
• NSAIDs nonsteroidal antiinflammatory drugs
• the end result of these diseases is total loss of joint function which is only treatable by joint replacement surgery.
• P38 inhibitors will halt or reverse the progression of cartilage loss and obviate or delay surgical intervention.
• This invention provides compounds, generally described as aryl ureas, including both aryl and heteroaryl analogues, which inhibit p38 mediated events and thus inhibit the production of cytokines (such as TNF ⁇ , IL-1 and IL-8) and proteolytic enzymes (such as MMP-1 and MMP-3).
• the invention also provides a method of treating a cytokine mediated disease state in humans or mammals, wherein the cytokine is one whose production is affected by p38. Examples of such cytokines include, but are not limited to TNF ⁇ , IL-1 and IL-8.
• the invention also provides a method of treating a protease mediated disease state in humans or mammals, wherein the protease is one whose production is affected by p38.
• proteases include, but are not limited to collagenase (MMP-1) and stromelysin (MMP-3). Accordingly, these compounds are useful therapeutic agents for such acute and chronic inflammatory and/or immunomodulatory diseases as rheumatoid arthritis, osteoarthritis, septic arthritis, rheumatic fever, bone resorption, postmenopausal osteoperosis, sepsis, gram negative sepsis, septic shock, endotoxic shock, toxic shock syndrome, systemic inflammatory response syndrome, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, Jarisch-Herxheimer reactions, asthma, adult respiratory distress syndrome, acute pulmonary fibrotic diseases, pulmonary sarcoidosis, allergic respiratory diseases, silicosis, coal worker's pneumoconiosis, alveolar injury, hepatic failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria including Plasmodium falciparum malaria and cerebral malaria, non-insulin-
• the present invention therefore, provides compounds generally described as aryl ureas, including both aryl and heteroaryl analogues, which inhibit the p38 pathway.
• the invention also provides a method for treatment of p38-mediated disease states in humans or mammals, e.g., disease states mediated by one or more cytokines or proteolytic enzymes produced and/or activated by a p38 mediated process.
• the invention is directed to compounds, compositions and methods for the treatment of diseases mediated by p38 kinase wherein a compound of Formula I is administered or a pharmaceutically acceptable salt thereof.
• D is -NH-C(O)-NH-
• A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M- L 1 ) q , where L is a 5 or 6 membered cyclic structure bound directly to D, L 1 comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L ! contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and
• B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur,
• L 1 is substituted by at least one substituent selected from the group consisting of -SO 2 R x , -C(O)R x and -C(NR y ) R z ,
• R y is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo,
• R z is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;
• R x is R z or NR a R b where R a and R are
• R a and R b together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or
• R a or R b is -C(O)-, a C 1 -C5 divalent alkylene group or a substituted -C 5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C ⁇ -C 5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;
• B is substituted, L is substituted or L 1 is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;
• each W is independently selected from the group consisting of - CN, -CO 2 R 7 , -C(O)NR 7 R 7 , -C(O)-R 7 , -NO 2 , -OR 7 , -SR 7 , -NR 7 R 7 , -NR 7 C(O)OR 7 , - NR 7 C(O)R 7 , -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of -CN, - CO 2 R 7 , -C(O)R 7 , -C(O)NR 7 R 7 , -OR 7 , -SR 7 , -NR 7 R 7 , -NO 2 , -NR 7 C(O)R 7 , - NR 7 C(O)OR 7 and halogen up to per-halo; with each R 7
• Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z nl , wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, - CO 2 R 7 , -C(O)R 7 , -C(O)NR 7 R 7 , -NO 2 , -OR 7 , -SR 7 -NR 7 R 7 , -NR 7 C(O)OR 7 , -
• NR C(O)R and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one
• R 7 7 or more substituents selected from the group consisting of -CN, -CO 2 R , -COR , - C(O)NR 7 R 7 , -OR 7 , -SR 7 , -NO 2 , -NR 7 R 7 , -NR 7 C(O)R 7 , and -NR 7 C(O)OR 7 , with R 7 as defined above.
• suitable hetaryl groups include, but are not limited to, 5-12 carbon-atom aromatic rings or ring systems containing 1-3 rings, at least one of which is aromatic, in which one or more, e.g., 1-4 carbon atoms in one or more of the rings can be replaced by oxygen, nitrogen or sulfur atoms.
• Each ring typically has 3-7 atoms.
• B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5- oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-l-, -4- or -5-yl, 1 ,2,4-triazol- 1-, -3- or -5-yl, 1- or 5-tetrazolyl, l,2,3-oxadiazol-4- or -5-yl, l,2,4-oxadiazol-3- or -5-yl, l,3,4-thiadiazol-2- or -5-yl, l,2,4-oxadiazol-3- or
• B can be 4-methyI-phenyl, 5-methyl-2-thienyl, 4-methyl-2- thienyl, l-methyl-3-pyrryl, l-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl- l,2,4-thiadiazol-2-yl.
• Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy, etc. throughout include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.
• Suitable aryl groups which do not contain heteroatoms include, for example, phenyl and 1- and 2-naphthyl.
• cycloalkyl refers to cyclic structures with or without alkyl substituents such that, for example, "C 4 cycloakyl” includes methyl substituted cyclopropyl groups as well as cyclobutyl groups.
• cycloalkyl as used herein also includes saturated heterocyclic groups. Suitable halogen groups include F, CI, Br, and/or I, from one to per- substitution (i.e. all H atoms on a group replaced by a halogen atom) being possible where an alkyl group is substituted by halogen, mixed substitution of halogen atom types also being possible on a given moiety.
• the invention also relates to compounds per se, of formula I.
• the present invention is also directed to pharmaceutically acceptable salts of formula I.
• suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulphonic acid, p- toluenesulfonic acid, 1 -naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid.
• pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li + Na + or K + ), alkaline earth cations (e.g., Mg +2 , Ca +2 or Ba +2 ), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those arising from protonation or peralkylation of triethylamine, NN-diethylamine, NN- dicyclohexylamine, lysine, pyridine, NN-dimethylaminopyridine (DMAP), 1,4- diazabiclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and l,8-diazabicyclo[5.4.0]undec-7-ene (
• a number of the compounds of Formula I possess asymmetric carbons and can therefore exist in racemic and optically active forms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art.
• the present invention encompasses any isolated racemic or optically active form of compounds described in Formula I which possess p38 kinase inhibitory activity.
• the compounds of Formula I may be prepared by use of known chemical reactions and procedures, some from starting materials which are commercially available. Nevertheless, the following general preparative methods are presented to aid one of skill in the art in synthesizing these compounds, with more detailed particular examples being presented in the experimental section describing the working examples.
• aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H 2 or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as LiAlH 4 (Seyden-Penne.
• aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H 2 or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)).
• Nitroaryls may also be directly reduced using a strong hydride source, such as LiAlH 4 (Seyden-Penne. Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic media.
• a metal catalyst such as Ni, Pd, or Pt
• H 2 such as a hydride transfer agent
• formate, cyclohexadiene such as formate, cyclohexadiene, or a borohydride
• Nitroaryls may also be directly
• H 2 / catalyst eg. Ni, Pd, Pt
• Nitroaryls are commonly formed by electrophilic aromatic nitration using HNO 3 , or an alternative NO 2 + source. Nitroaryls may be further elaborated prior to reduction. Thus, nitroaryls substituted with
• potential leaving groups may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme II) or phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme II).
• Nitroaryls may also undergo transition metal mediated cross coupling reactions.
• nitroaryl electrophiles such as nitroaryl bromides, iodides or triflates
• palladium mediated cross coupling reactions with aryl nucleophiles, such as arylboronic acids (Suzuki reactions, exemplified below), aryltins (Stille reactions) or arylzincs (Negishi reaction) to afford the biaryl (5).
• aryl nucleophiles such as arylboronic acids (Suzuki reactions, exemplified below), aryltins (Stille reactions) or arylzincs (Negishi reaction) to afford the biaryl (5).
• Either nitroaryls or anilines may be converted into the corresponding arenesulfonyl chloride (7) on treatment with chlorosulfonic acid.
• Reaction of the sulfonyl chloride with a fluoride source, such as KF then affords sulfonyl fluoride (8).
• Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source, such as tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to the corresponding trifluoromethylsulfone (9).
• TASF tris(dimethylamino)sulfonium difluorotrimethylsiliconate
• sulfonyl chloride 7 may be reduced to the arenethiol (10), for example with zinc amalgum.
• Reaction of thiol 10 with CHC1F 2 in the presence of base gives the difluoromethyl mercaptam (11), which may be oxidized to the sulfone (12) with any of a variety of oxidants, including CrO -acetic anhydride (Sedova et al. Zh. Org. Khim. 1970, 6, 568).
• non-symmetrical urea formation may involve reaction of an aryl isocyanate (14) with an aryl amine (13).
• the heteroaryl isocyanate may be synthesized from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or NN'-carbonyldiimidazole (CDI).
• the isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius-type rearrangement.
• reaction of acid derivative 16 with an azide source, followed by rearrangement affords the isocyanate.
• the corresponding carboxylic acid (17) may also be subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPP A) or a similar reagent.
• DPP A diphenylphosphoryl azide
• ureas may be further manipulated using methods familiar to those skilled in the art.
• the invention also includes pharmaceutical compositions including a compound of Formula I, and a physiologically acceptable carrier.
• the compounds may be administered orally, topically, parenterally, by inhalation or spray, vaginally, rectally or sublingually in dosage unit formulations.
• administration includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques.
• Dermal administration may include topical application or transdermal administration.
• One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients.
• compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions.
• Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations.
• Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc.
• the tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
• These compounds may also be prepared in solid, rapidly released form.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• water or an oil medium for example peanut oil, liquid paraffin or olive oil.
• Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used.
• excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbit
• the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, j-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
• the compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti- oxidant such as ascorbic acid.
• Compounds of the invention may also be administrated transdermally using methods known to those skilled in the art (see, for example: Chien; “Transdermal Controlled Systemic Medications”; Marcel Dekker, Inc.; 1987. Lipp et al. WO94/04157 3Mar94).
• a solution or suspension of a compound of Formula I in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms.
• a solution or suspension of a compound of Formula I may be formulated into a lotion or salve.
• Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane.
• Suitable solvents may also include mixtures of one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.
• Suitable penetration enhancing materials for transdermal delivery system include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated C -C 18 fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated C 8 -C ⁇ 8 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl isobutyl tertbutyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, diisopropy
• Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether.
• Suitable penetration enhancing formulations may also include mixtures of one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C 8 -C] 8 fatty alcohols, saturated or unsaturated C 8 -C ⁇ 8 fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated discarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.
• Suitable binding materials for transdermal delivery systems include polyacrylates, silicones, polyurethanes, block polymers, styrenebutadiene coploymers, and natural and synthetic rubbers.
• Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components. Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix.
• compositions of the invention may also be in the form of oil- in-water emulsions.
• the oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening and flavoring agents.
• Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
• sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
• Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
• the compounds may also be administered in the form of suppositories for rectal administration of the drug.
• These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug.
• suitable non-irritating excipient include cocoa butter and polyethylene glycols.
• the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.
• the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight.
• the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.
• the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.
• the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg.
• the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
• the daily inhalation dosage regimen will preferably be from 0.01 to 10 mg/Kg of total body weight.
• the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for a given patient depends on a variety of factors, including specific activity of the compound administered, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combination, and the severity of the condition undergoing therapy, etc.
• the optimal course of treatment i.e., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment tests.
• the compounds of Figure I are producible from known compounds (or from starting materials which, in turn, are producible from known compounds), e.g., through the general preparative methods shown above.
• the activity of a given compound to inhibit raf kinase can be routinely assayed, e.g., according to procedures disclosed below.
• the following examples are for illustrative purposes only and are not intended, nor should they be construed to limit the invention in any way.
• the entire disclosure of all applications, patents and publications cited above and below are hereby incorporated by reference, including non-provisional application Serial No. 09/257,265 filed February 25, 1999 and provisional application serial number 60/115,878, filed on January 13, 1999.
• N- cyclohexyl-N'-(methylpolystyrene)carbodiimide was purchased from Calbiochem- ⁇ ovabiochem Corp. 3-tert-Butylaniline, 5-tert-butyl-2-methoxyaniline, 4-bromo-3- (trifluoromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniline 2-methoxy-5-
• Thin-layer chromatography was performed using Whatman ® pre-coated glass-backed silica gel 60A F-254 250 ⁇ m plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ⁇ ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science ® silica gel.
• Carbon ( ,3 C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC1 3 ⁇ 77.0; MeOD-d 3 ; ⁇ 49.0; DMSO-d 6 ⁇ 39.5) as standard.
• Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (El) mass spectra or as fast atom bombardment (FAB) mass spectra.
• Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction. The ion source was maintained at 250 °C.
• Electron impact ionization was performed with electron energy of 70 eV and a trap current of 300 ⁇ A.
• Liquid-cesium secondary ion mass spectra FAB-MS
• FAB-MS Liquid-cesium secondary ion mass spectra
• CI-MS Chemical ionization mass spectra
• the direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared ( -1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan.
• HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120- 800 amu using a variable ion time according to the number of ions in the source.
• GC-MS Gas chromatography - ion selective mass spectra
• the resulting opaque brown solution was diluted with H 2 O (700 mL) followed by a 10% ⁇ aOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were washed separately with a saturated ⁇ aCl solution (3 x 150 mL), then they were combined, dried (MgSO 4 ) and filtered through a pad of silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane).
• Step 3a Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from methyl 4-chloropyridine-2-carboxylate
• Step 3b Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from 4- chloropyridine-2-carbonyI chloride
• Step 1 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene: To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-l -nitrobenzene (prepared from 2,5-dihydroxybenzoic acid in a manner analogous to that described in Method A13, Step 1, 12 mmol) in acetone (50 mL) was added K 2 CO 3 (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated at the reflux temp, overnight, then cooled to room temp, and filtered through a pad of Celite ® .
• Step 1 Synthesis of 5-(4-Nitrophenoxy)-2-methylisoindoline-l,3-dione: A slurry of 5-(4-nitrophenoxy)isoindoline-l,3-dione (A3 Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp, for 1 h, then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temp, overnight, then was cooled to °C and treated with water (10 mL).
• Step 2 Synthesis of 4-(2-(N-(2-Morpholin-4- ylethyl)carbamoyl)pyridyloxy)aniline.
• Step 1 Synthesis of 5-hydroxyisoindolin-l-one To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was slowly added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated at the reflux temp, for 40 min., filtered hot, and concentrated under reduced pressure.
• Step 1 Synthesis of 4-(3-ethoxycarbonylphenoxy)-l-nitrobenzene
• a mixture of 4-fluoro-l -nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 150 mmol) and K 2 CO 3 (41 g, 300 mmol) in DMF (125 mL) was heated at the reflux temp, overnight, cooled to room temp, and treated with water (250 mL).
• the resulting mixture was extracted with EtOAc (3 x 150 mL).
• the combined organic phases were sequentially washed with water (3 x 100 mL) and a saturated ⁇ aCl solution (2 x 100 mL), dried ( ⁇ a 2 SO ) and concentrated under reduced pressure.
• the residue was purified by column chromatography (10% EtO Ac/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-l -nitrobenzene as an oil (38 g).
• Step 2 Synthesis of 4-(3-carboxyphenoxy)-l-nitrobenzene
• 4-(3-ethoxycarbonylphenoxy)-l -nitrobenzene 5.14 g, 17.9 mmol
• a solution LiOH*H 2 O 1.50 g, 35.8 mmol
• water 36 mL
• Step 2 Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline
• a slurry of 4-(3 -(5 -methoxycarbonyl)pyridyloxy)-l -nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd/C in MeOH/EtOAc was stirred under an H 2 atmosphere (balloon) for 72 h.
• the resulting mixture was filtered and the filtrate was concentrated under reduced pressure.
• Step 3 Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)-l-nitrobenzene
• TFA 6 mL
• ⁇ a ⁇ O 2 0.097 g, 1.14 mmol
• Step 1 4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide
• 4-chloro-N-(2-hydroxyethyl)pyridine-2-carboxamide prepared in a manner analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol
• triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.
• imidazole (1.12 g, 16.4 mmol, 2.2 equiv.
• Step 1 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenzene.
• Step 1 4-(4-Methylsulfonylphenoxy)-l-nitrobenzene: To a solution of 4-(4- methylthiophenoxy)-l -nitrobenzene (2.0 g, 7.7 mmol) in CH 2 C1 2 (75 mL) at 0 °C was slowly added m-CPBA (57-86%, 4.0 g), and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was treated with a IN NaOH solution (25 mL).
• Step 2 4-(4-Methylsulfonylphenoxy)-l-aniIine: 4-(4-Methylsulfonylphenoxy)-l- nitrobenzene was reduced to the aniline in a manner analogous to that described in Method A18, step 3.
• One of the anilines to be coupled was dissolved in dichloroethane (0.10 M). This solution was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a bis(trichloromethyl) carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The vial was capped and heat at 80 °C for 5 h, then allowed to cool to room temp for approximately 10 h.
• the second aniline was added (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.).
• the resulting mixture was heated at 80 °C for 4 h, cooled to room temperature and treated with MeOH (0.5 mL).
• the resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.
• N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-( ⁇ -(3-( ⁇ -(3- pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70% EtO Ac/30% hexane) R/0.12.
• N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3- carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 1 mL, 1.7 mmol) and the resulting mixture was stirred at room temp, overnight, then concentrated under reduced pressure to give N-(4- chloro-3-((trifluoromethyl)phenyl)-N '-(4-(3 - methylcarbamoylphenyl)carboxyaminophenyl) urea as a white solid: mp 247; TLC (100% EtOAc) R 0.35.
• N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-methoxycarbonylpyridyl) oxyphenyl) urea was synthesized from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4-(3-(5-methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) in a manner analogous to Method Cla.
• Entry 5 According to Method C2d, 5 -tert-butyl-2-methoxy aniline was reacted with CDI followed by 4-(3-N-methylcarbamoyl)-4-methoxy ⁇ henoxy)aniline, which had been prepared according to Method A8, to afford the urea.
• Entry 6 5-(4-Aminophenoxy)isoindoline-l,3-dione was prepared according to Method A3.
• Method 2d According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI followed by 5-(4-aminophenoxy)isoindoline-l,3-dione to afford the urea.
• Method A2 Step 3b.
• the chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4-(4-(2-(N- methylcarbamoyl)phenylthio)aniline.
• 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl.
• 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4- (4-(2-(N-methylcarbamoyl)phenylthio)aniline according to Method Cla to afford the urea.
• N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5- methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 to afford the amide.
• N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5- methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with NN-dimethylethylenediamine according to Method D4, Step 2 to afford the amide.
• 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluorornethyl)-2- methoxyphenyl isocyanate according to Method Bl.
• the aniline was reacted with 4-chloro-3- (trifluoromethyl)phenyl isocyanate according to Method Cla to give N-(4-chloro-3- (trifluoromethyl)phenyl)-N'-(4-(2-(methoxycarbonyl)-5-pyridyloxy)phenyl) urea.
• the methyl ester was reacted with methylamine according to Method D2 to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-5- pyridyloxy)phenyl) urea.
• N-(4-Chloro-3-(trifluoromethyl)phenyl-N '-(4-aminophenyl) urea was prepared according to Method Cld.
• N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4- aminophenyl) urea was coupled with mono-methyl isophthalate according to Method Dla to afford the urea.
• N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was prepared according to Method Cld. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4- aminophenyl) urea was coupled with wo «o-methyl isophthalate according to Method Dla to afford N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3- methoxycarbonylphenyl)carboxyaminophenyl) urea.
• Method A2 Step 3b.
• the chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4-(4-(2-(N- methylcarbamoyl)phenylthio)aniline.
• Step 4 4-chloro-3- (trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(N- methylcarbamoyl)phenylthio)aniline to afford the urea.
• N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-carboxyphenyl) urea was coupled with 3 -methylcarbamoylaniline according to Method Dlb to give N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3- methylcarbamoylphenyl)carbamoylphenyl) urea.
• N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-(4-(3-(5- methoxycarbonylpyridyl) oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the amide.
• N-(5 -(Trifluoromethyl)-2-methoxyphenyl)-N '-(4-(3 -(5- methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with NN-dimethylethylenediamine according to Method D4, Step 2 to afford the amide.
• Entry 77 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3- carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 4-fluoroaniline according to Method Die.
• Entry 78 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3- carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 4-(dimethylamino)aniline according to Method Die.
• Entry 83 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3- carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with N-(2-pyridyl)piperazine according to Method Die. Entry 84: 4-Chloropyridine-2-carbonyl chloride HCI salt was reacted with 2- hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-N-(2- triisopropylsilyloxy)ethylpyridine-2-carboxamide.
• the in vitro inhibitory properties of compounds were determined using a p38 kinase inhibition assay.
• P38 activity was detected using an in vitro kinase assay run in 96-well microtiter plates.
• Recombinant human p38 0.5 ⁇ g/mL was mixed with substrate (myelin basic protein, 5 ⁇ g/mL) in kinase buffer (25 mM Hepes, 20 mM MgCl 2 and 150 mM NaCl) and compound.
• substrate myelin basic protein, 5 ⁇ g/mL
• kinase buffer 25 mM Hepes, 20 mM MgCl 2 and 150 mM NaCl
• One ⁇ Ci/well of 33 P-labeled ATP (10 ⁇ M) was added to a final volume of 100 ⁇ L.
• the reaction was run at 32 °C for 30 min. and stopped with a IM HCI solution.
• the in vivo inhibitory properties of selected compounds were determined using a murine LPS induced TNF ⁇ production in vivo model.
• BALB/c mice (Charles River Breeding Laboratories; Springfield, NY) in groups of ten were treated with either vehicle or compound by the route noted.
• endotoxin E. coli lipopolysaccharide (LPS) 100 ⁇ g was administered intraperitoneally (i.p.).
• TNF ⁇ levels in sera were measured using a commercial murine TNF ELISA kit

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