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Definitions

• the present disclosure provides aminopyridine- and aminopyrimidinecarboxamides useful as pharmaceutical agents, synthesis processes, and pharmaceutical compositions which include aminopyridine- and aminopyrimidinecarboxamides compounds. More specifically, the present disclosure provides a genus of CXCR2 inhibitor compounds that are useful for treating a variety of inflammatory and neoplastic disorders.
• Chemokines are chemo tactic proteins that have the potential to attract macrophages, T- cells, eosinophils, basophils, neutrophils and endothelial cells to sites of inflammation and tumor growth. Chemokines are typically low molecular mass (7-9 kD) proteins that can be divided into four subfamilies: CC (or ⁇ -chemokines), CXC, C (or ⁇ -chemokines) and CX3C (or ⁇ -chemokines). The chemokines are categorized through their primary amino acid structure. The CXC subfamily is characterized by two conserved Cys residues (C) near the N- terminus and separated by an amino acid (X).
• the CXC-chemokines include, for example, interleukin-8 (IL-8), neutrophil-activating protein- 1 (NAP-1), neutrophil-activating protein-2 (NAP-2), GROa, GROP, GROy, ENA-78, GCP-2, IP-10, MIG and PF4.
• the CXC subfamily of chemokines is further characterized by the presence or absence of a specific amino acid sequence, glutamic acid-leucine-arginine (or ELR for short) immediately before the first Cys residue of the CXC motif.
• Those chemokines with the ELR motif are important for the recruitment and activation of neutrophils to sites of inflammation.
• GROa and IL-8 are ELRCXC chemokines.
• CXC-chemokines mediate their chemotactic activity through interaction with the chemokine receptors CXCR1 and CXCR2.
• CXCR1 binds IL-8 and GCP-2 with high affinity while CXCR2 binds all ELRCXC chemokines with high affinity.
• CXC-chemokines promote the accumulation and activation of neutrophils
• CXC-chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including COPD, psoriasis and rheumatoid arthritis. (Baggiolini et al., FEBS Lett.
• ELRCXC chemokines including IL-8, GROa, GRO , GROy, NAP-2, and ENA-78 (Strieter et al. /. Biol. Chem. 270:27348-57, 1995), have also been implicated in the induction of tumor angiogenesis (new blood vessel growth). Angiogenic activity is due to ELRCXC- chemokine binding to, and activation of CXCR2, and possibly CXCR1 for IL-8, expressed on the surface of vascular endothelial cells (ECs) in surrounding vessels.
• ECs vascular endothelial cells
• Chemokine production has been correlated with a more aggressive phenotype (Inoue et al. Clin. Cancer Res. 6:2104-2119, 2000) and poor prognosis (Yoneda et al. /. Nat. Cancer Inst. 90:447-454, 1998).
• Chemokines are potent chemotactic factors and the ELRCXC chemokines, in particular, have been shown to induce EC chemotaxis.
• these chemokines are thought to induce chemotaxis of endothelial cells toward their site of production in the tumor. This may be a critical step in the induction of angiogenesis by the tumor.
• Inhibitors of CXCR2 or dual inhibitors of CXCR2 and CXCR1 will inhibit the angiogenic activity of the ELRCXC chemokines and therefore block the growth of the tumor.
• This anti-tumor activity has been demonstrated for antibodies to IL-8 (Arenberg et al. /. Clin. Invest. 97:2792-2802, 1996), ENA-78 (Arenberg et al., /. Clin. Invest. 102:465-72, 1998), and GROa (Haghnegahdar et al., /. Leukoc. Biology 67:53-62, 2000).
• the disclosure provides a pharmaceutical composition comprising at least one compound of the formula (1) or a pharmaceutically acceptable salt, or solvate thereof and a pharmaceutically acceptable carrier.
• this disclosure provides a novel class of compounds that are CXC chemokine-modulators, pharmaceutical compositions comprising one or more of such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with CXC chemokine mediation using the compounds and compositions disclosed herein.
• the present disclosure further provides a compound comprising formula (1) or formula
• R'and R 2 are independently selected from the group consisting of hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
• R 3 and R 4 are independently selected from the group consisting of hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, or R 3 and R 4 are
• an ionizing group selected from the group consisting of carboxylates, amines, phosphonates, and phosphates;
• R 7 is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl , heterocyclyl and heterocyclylalkyl;
• M + is a Group I or a Group II metal
• R 5 and R 6 are independently selected from the group consisting of hydrogen, hydroxyl, aryloxy, or alkoxy, or wherein R 5 and R 6 together form a cyclic ester, or an acid anhydride (either mixed or symmetrical);
• R 8 and R 9 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, hetercyclyl and heterocyclylalkyl; R 8 and R 9 are both oxygen to form a nitro group; or R 8 and R 9 together with the nitrogen to which they are attached , form a heterocyclyl; and
• X 1 is carbon or nitrogen; and pharmaceutical compositions thereof.
• X 1 is carbon.
• R 1 is hydrogen and R 2 is 4-fluoro-phenyl.
• R 3 is either hydrogen or methyl.
• R 4 is 4-phenylboronic acid.
• the present disclosure further provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (1) or formula (2):
• the present disclosure further provides a compound comprising formula (1) or formula (2):
• R J and R 2 are independently selected from the group consisting of hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
• R 3 and R 4 are independently selected from the group consisting of hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, or R 3 and R4 are
• R 3 may be also equivalent to R 4 ;
• M + is a Group I or a Group II metal
• R 5 and R 6 are independently selected from the group consisting of hydrogen, hydroxyl, aryloxy, or alkoxy, or wherein R 5 and R 6 together form a cyclic ester, or an acid anhydride (either mixed or symmetrical);
• R 8 and R 9 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, hetercyclyl and heterocyclylalkyl; R 8 and R 9 are both oxygen to form a nitro group; or R 8 and R 9 together with the nitrogen to which they are attached , form a heterocyclyl; and
• X 1 is carbon or nitrogen; and pharmaceutical compositions thereof.
• X 1 is carbon.
• R 1 is hydrogen and R 2 is 4-fluoro-phenyl.
• R 3 is either hydrogen or methyl.
• R 4 is 4-phenylboronic acid.
• the present disclosure provides a method for treating a disease or disorder selected from the group consisting of pain (e.g., acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain), acute inflammation, chronic inflammation, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, bronchopulmonary dysplasia, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, ischemia reperfusion injury, renal reperfusion injury, glomerulonephritis, thrombosis,
• pain e.g., acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain
• acute inflammation chronic inflammation
• rheumatoid arthritis psoriasis
• atopic dermatitis asthma, bronchopulmonary dysplasia
• COPD chronic respiratory disease
• adult respiratory disease arthritis
• an effective amount or a “therapeutically effective amount” means to describe an amount of compound of the present disclosure or another agent effective to treat a mammal (e.g., a human) having a disease or CXC chemokine-mediated condition, and thus producing the desired therapeutic effect.
• Composition includes a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• Prodrug denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of either formula (1) or formula (2) or a salt and/or solvate thereof.
• a discussion of pro-drugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Volume 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
• the alkyl group has zero branches ⁇ i.e. , is a straight chain), one branch, two branches, or more than two branches.
• the alkyl group is saturated.
• the alkyl group is unsaturated.
• the unsaturated alkyl may have one double bond, two double bonds, more than two double bonds, and/or one triple bond, two triple bonds, or more than two triple bonds.
• Alkyl chains may be optionally substituted with 1 substituent ⁇ i.e., the alkyl group is mono-substituted), or 1-2 substituents, or 1-3 substituents, or 1-4 substituents, etc.
• “Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which chain may be straight or branched.
• suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, and decyl.
• Alkoxy means an alkyl-O-group wherein alkyl is as defined above.
• Non-limiting examples of alkoxy groups include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy. The bond to the parent moiety is through the ether oxygen.
• Alkylaryl means an alkyl-aryl-group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. The bond to the parent moiety is through the aryl.
• Aminoalkyl means an NH 2 -alkyl-group, wherein alkyl is as defined above, bound to the parent moiety through the alkyl group.
• Aryl (sometimes abbreviated “Ar”) is an aromatic carbocyclic hydrocarbon ring system.
• the ring system may be monocyclic or fused polycyclic (e.g., bicyclic, tricyclic, etc.).
• the aryl group is monocyclic, and is preferably a C 6 ring system, i.e. a phenyl ring is a preferred aryl ring, where preferred bicyclic aryl rings are C 8 -C 12 , or C9-C10.
• a naphthyl ring which has 10 carbon atoms, is a preferred polycyclic aryl ring.
• aryl as used herein is meant to include aryl rings optionally substituted by one or more substituents selected from acyl (-C(O)-R), alkoxy (-0-R), alkyl, aryl, alkylamino (-N(H)-R and -N(R)R), alkylthio (-S-R), amino (-NH 2 ), azido (-N 3 ), boronyl (-B(R)R or -B(OH) 2 or -B(OR) 2 ), carboxy (-C(O)-OH), alkoxycarbonyl (-C(O)-OR), aminocarbonyl (-C(0)-NH 2 ), aminosulfonyl (-S(0) 2 -NH 2 ), alkylaminocarbonyl (-C(0)-N(H)R and -C(0)-N(R)R), cyano, halo (fluoro, bromo, chloro, iod
• Arylalkyl refers to an alkyl group as defined substituted by one or more aryl groups as defined below. Phenyl and naphthyl are preferred aryl groups in an arylalkyl group. A preferred alkyl group is methyl, so that a preferred arylalkyl group is benzyl or benzyl having one or more substituents on the phenyl ring.
• arylalkyl as used herein is meant to include arylalkyl groups wherein the aryl ring therein is optionally substituted by one or more substituents selected from acyl (-C(O)-R), alkoxy (-0-R), alkyl, aryl, alkylamino (-N(H)-R and -N(R)R), alkylthio (-S-R), amino (-NH 2 ), azido (-N 3 ), boronyl (-B(R)R or -B(OH) 2 or -B(OR) 2 ), carboxy (-C(O)-OH), alkoxycarbonyl (-C(O)-OR), aminocarbonyl (-C(0)-NH 2 ), aminosulfonyl (-S(0) 2 -NH 2 ), alkylaminocarbonyl (-C(0)-N(H)R and -C(0)-N(R)R), cyano, halo (
• Arylalkyl means an aryl-alkyl-group in which the aryl and alkyl are as previously described. Preferred arylalkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and napthalenylmethyl. The bond to the parent moiety is through the alkyl.
• Aryloxy means an aryl-O-group in which the aryl group is as previously described.
• suitable aryloxy groups include phenoxy and naphthoxy.
• the bond to the parent moiety is through the ether oxygen.
• Carboxyalkyl means an HOOC-alkyl-group, wherein alkyl is as defined above, bound to the parent moiety through the alkyl group.
• Cyclookine means a protein molecule involved in chemotaxis.
• a "chemokine- mediated disease” means a disease in which at least one element or cause is related to regulation of a CXC chemokine.
• “Commercially available chemicals” and the chemicals used in the Examples set forth herein may be obtained from standard commercial sources, where such sources include, for example, Acros Organics (Pittsburgh, PA), Sigma-Adrich Chemical (Milwaukee, WI), Avocado Research (Lancashire, U.K.), Bionet (Cornwall, U.K.), Boron Molecular (Research Triangle Park, NC), Combi-Blocks (San Diego, CA), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co.
• Cycloalkyl means a non-aromatic mono-or multicyclic ring system comprising about
• a multicyclic cycloalkyl substituent may include fused, spiro, or bridged ring structures.
• suitable monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
• suitable multicyclic cycloalkyls include 1-decalin, norbornyl, adamantly and the like. Cycloalkyl substituents may be substituted or unsubstituted.
• the cycloalkyl is unsubstituted. In another embodiment, the cycloalkyl is substituted with, e.g., 1 substituent (i.e., the cycloalkyl group is mono-substituted), or 1-2 substituents, or 1-3 substituents, or 1-4 substituents, etc.
• the substituents that may be present on the cycloalkyl aliphatic ring are selected from acyl (-C(O)-R), alkoxy (- O-R), alkyl, aryl, alkylamino (-N(H)-R and -N(R)R), alkylthio (-S-R), amino (-NH 2 ), azido (- N 3 ), boronyl (-B(R)R or -B(OH) 2 or -B(OR) 2 ), carboxy (-C(O)-OH), alkoxycarbonyl (-C(O)- OR), aminocarbonyl (-C(0)-NH 2 ), aminosulfonyl (-S(0) 2 -NH 2 ), alkylaminocarbonyl (-C(O)- N(H)R and -C(0)-N(R)R), cyano, halo (fluoro, bromo, chloro, iodo), haloal
• Cycloalkylaryl means a cycloalkyl group bound to the parent moiety through an aryl group. Non-limiting examples include: cyclopropylphenyl and cyclohexylphenyl.
• Fluoroalkoxy means an alkoxy group as defined above wherein one or more hydrogen atoms on the alkoxy is or are replaced by a fluoro group.
• Fluoroalkyl means an alkyl group as defined above wherein one or more hydrogen atoms on the alkyl are replaced by a fluoro group.
• Heteroalkyl is a saturated or unsaturated, straight or branched, chain containing carbon and at least one heteroatom.
• the heteroalkyl group may, in various embodiments, have on heteroatom, or 1-2 heteroatoms, or 1-3 heteroatoms, or 1-4 heteroatoms.
• the hteroalkyl chain contains from 1 to 18 (i.e., 1-18) member atoms (carbon and heteroatoms), and in various embodiments contain 1-12, or 1-6, or 1-4 member atoms.
• the heteroalkyl group has zero branches (i.e., is a straight chain), one branch, two branches, or more than two branches.
• the htereoalkyl group is saturated.
• Heterocyclic refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to 10 ring atoms (e.g., 3 to 7 ring atoms), or 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
• Examples of heterocyclics or heterocycloalkyls include rings having 5 to 6 ring atoms.
• the prefix aza, oxa or thia before the heterocyclic or heterocycloalkyl root name means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom.
• the nitrogen or sulfur atom of the heterocyclic or heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Any nitrogen atoms may be optionally quaternized.
• Non-limiting examples of monocyclic heterocyclic or heterocycloalkyl rings include: piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophen-yl, and tetrahydrothiopyranyl
• the heterocyclyl may be unsubstituted or substituted. In one embodiment, the heterocyclyl is unsubstituted. In another embodiment, the heterocyclyl is substituted.
• the substituted heterocyclyl ring may contain 1 substituent, or 1-2 substituents, or 1-3 substituents, or 1-4 substituents, etc. In one
• Heterocycloalkylalkyl means a heterocycloalkyl-alkyl group, wherein said heterocycloalkyl and said alkyl are as defined above, bound to a parent moiety through the alkyl group.
• the heteroaryl may be unsubstituted or substituted. In one embodiment, the heteroaryl is unsubstituted. In another embodiment, the heteroaryl is substituted.
• the substituted heteroaryl ring may contain 1 substituent, or 1-2 substituents, or 1- 3 substituents, or 1-4 substituents, etc.
• Hydroalkyl means an HO-alkyl-group, in which alkyl is previously defined.
• Preferred hydroxyalkyls contain lower alkyl.
• suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxy ethyl.
• DMARDs Disease modifying antirheumatic drugs
• TNFa directed agents e.g., infliximab, etanercept, and adalimumab
• IL-1 directed agents e.g., anakinra
• B cell directed agents e.g., rituximab
• T cell directed agents e.g., alefacept, efalizumab, and CTLA4-lg
• TNFfl-converting enzyme inhibitors interleukin- 1 converting enzyme is inhibitors, and p38 kinase inhibitors.
• the salts can be pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts, although other salts are also useful.
• Salts of the compounds of the formula (1) or formula (2) may be formed, for example, by reacting a compound of formula (1) or formula (2) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
• Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-napthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,
• dicyclohexylamines dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N- methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
• Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides ⁇ e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates ⁇ e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides ⁇ e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides), arylalkyl halides ⁇ e.g., benzyl and phenethyl bromides), and others.
• agents such as lower alkyl halides ⁇ e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates ⁇ e.g., dimethyl, diethyl, dibutyl, and
• Prodrugs of the compounds of formula (1) or formula (2) or pharmaceutically acceptable salts or solvates thereof are within the scope of this disclosure.
• All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this disclosure.
• Individual stereoisomers of the compounds of this disclosure may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
• the chiral centers of the compounds herein can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
• the use of the terms “salt”, “solvate”, “prodrug” and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the disclosed compounds.
• chemotherapeutic agent examples include: alkylating agents, antimetabolites, natural products and their derivatives, hormones and steroids (including synthetic analogs), and synthetics. Examples of compounds within these classes are given below.
• Alkylating agents including nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes: Uracil mustard, Chlormethine, Cyclophosphamide, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylene-melamine,
• Triethylenethiophos-phoramine Busulfan, Carmustine, Lomustine, Streptozocin, dacarbazine, and Temozolomide.
• Antimetabolites including folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors: Methotrexate, Aminopterin, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine.
• Natural products and their derivatives including vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins: Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, paclitaxel (Taxol®), Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Interferons (especially IFN- ), etoposide, and Teniposide.
• Hormones and steroids (including synthetic analogs): 17 -Ethinylestradiol,
• Diethylstilbestrol Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, Zoladex.
• Synthetics including inorganic complexes such as platinum coordination complexes: Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, and Hexamethylmelamine.
• a microtubule affecting agent is a compound that interferes with cellular mitosis, i.e., having an anti-mitotic effect, by affecting microtubule formation and/or action.
• agents can be, for instance, microtubule stabilizing agents or agents that disrupt microtubule formation.
• Microtubule affecting agents useful in this disclosure are well known to those of skilled in the art and include, but are not limited to allocolchicine (NSC 406042), Halichondrin B
• NSC 609395 colchicine
• NSC 757 colchicine derivatives
• colchicine derivatives e.g., NSC 33410
• dolastatin 10 NSC 376128
• maytansine NSC 153858
• rhizoxin NSC 332598
• paclitaxel Taxol, NSC 125973
• Taxol derivatives e.g., derivatives (e.g., NSC 608832), thiocolchicine (NSC
• Suitable hydroxyl protecting groups include trialkylsilyl or diarylsilyl ethers ⁇ e.g., trimethylsilyl, t-butyldimethylsilyl, or t- butyldiphenylsilyl), trityl ethers, benzyl ethers and the like.
• Suitable protecting groups for mercapto include thioethers ⁇ e.g. S-benzyl, S-p-nitrobenzyl, S-9-fluorenylmethyl, S-trityl), thioesters -C(0)-R (where R is alkyl, aryl or arylalkyl), and the like.
• Suitable protecting groups for carboxylic acid include alkyl, aryl, or arylalkyl esters.
• Another embodiment of the method of treating a CXCR2 chemokine mediated disease is administering (a) a therapeutically effective amount of at least one compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (b) at least one medicament selected from the group consisting of: disease modifying antirheumatic drugs; nonsteroidal anti-inflammatory drugs; COX-2 selective inhibitors; COX-1 inhibitors; immunosuppressives; steroids; biological response modifiers; and other anti-inflammatory agents or therapeutics useful for the treatment of CXCR1 and/or CXCR2 chemokine mediated diseases.
• Another embodiment of this disclosure is a method for treating cancer in a patient in need of such treatment, the method comprises administering to said patient a therapeutically effective amount of a compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
• Another embodiment of this disclosure is a method for treating cancer comprising administering to the patient a therapeutic amount of at least one compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (a) at least one antineoplastic agent selected from the group consisting of: (1) gemcitabine, (2) paclitaxel, (3) 5-Fluorouracil (5-FU), (4) cyclophosphamide, (5) temozolomide and (6) Vincristine or (b) at least one agent selected from the group consisting of (1) microtubule affecting agents, (2) antineoplastic agents, (3) anti- angiogenesis agents, (4) VEGF receptor kinase inhibitors, (5) antibodies against the VEGF receptor, (6) interferon,
• Another embodiment of this disclosure is a method for treating multiple sclerosis, comprising administering to the patient: (a) a therapeutically effective amount of at least one compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (b) a therapeutically effective amount of at least one compound selected from the group consisting of: glatiramer acetate, glucocorticoids, methotrexate, azothioprine, mitoxantrone, and CB2-selective inhibitors.
• Another embodiment of this disclosure is a method for treating stroke and ischemia reperfusion injury in a patient in need of such treatment the method comprising administering to the patient a therapeutically effective amount of: (a) at least one compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of:
• thrombolitics e.g., tenecteplase, TPA,reteplase
• antiplatelet agents e.g., gpllb/llla
• antagonists e.g., abciximab and eftiifbatide
• anticoagulants e.g., heparin
• other compounds indicated for the treatment of rheumatoid arthritis e.g., heparin
• Another embodiment of this disclosure is a method for treating stroke and ischemia reperfusion injury in a patient in need of such treatment the method comprising administering to the patient a therapeutically effective amount of: (a) at least one compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof concurrently or sequentially with (b) at least one compound selected from the group consisting of:
• Another embodiment of this disclosure is a method for treating psoriasis in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of: a) at least one compound of formula (1) or formula (2), or a
• immunosuppressives e.g., methotrexate, aminopterin, cyclosporin, efalizumab, alefacept, leflunimide and sulfasalazine
• steroids e.g., ⁇ -methasone
• anti-TNFot compounds e.g., etonercept and infliximab
• This disclosure also provides a method for treating CXCR2 mediated disease or condition selected from the group consisting of: pain (e.g., acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain), acute inflammation, chronic inflammation, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, bronchopulmonary dysplasia, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, ischemia reperfusion injury, renal reperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease, graft vs.
• pain e.g., acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain
• acute inflammation chronic inflammation
• rheumatoid arthritis psoriasis
• atopic dermatitis asthma, bronchopulmonary
• host reaction i.e., graft-versus-host disease
• allograft rejections e.g., acute allograft rejection, and chronic allograft rejection
• malaria acute respiratory distress syndrome, delayed type hypersensitivity reaction
• atherosclerosis cerebral ischemia, cardiac ischemia, osteoarthritis, multiple sclerosis, restinosis, angiogenesis, , angiogenesis associated with tumor growth, osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associated virus (i.e., Kaposi's sarcoma), meningitis, cystic fibrosis, pre-term labor, cough, pruritis, multi-organ dysfunction, trauma, strains, sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury, systemic tumors, CNS tumors, tumors dependent on angiogenesis for growth, leukopenia
• Another embodiment of this disclosure is a method for treating diseases such as allograft rejections, early transplantation rejections, autoimmune deafness, myocarditis, neuropathies, autoimmune diseases and vasculitis syndromes wherein said:
• allograft rejections are selected from the group consisting of acute allograft rejections and chronic allograft rejections;
• myocarditis is viral myocarditis
• neuropathies are selected from the group consisting of IgA neuropathy, membranous neuropathy and idiopathic neuropathy;
• autoimmune diseases are anemias
• vasculitis syndromes are selected from the group consisting of giant cell arteries, Behcet's disease and Wegener's granulomatosis.
• Another embodiment of this disclosure is a method for treating COPD in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of formula (1) or formula (2), or a
• Another embodiment of this disclosure is a method for treating arthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
• Another embodiment of this disclosure is a method for treating osteoarthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
• Another embodiment of this disclosure is a method for treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
• Another embodiment of this disclosure is a method for treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, and administering a therapeutically effective amount of at least one medicament selected from the group consisting of: NSAIDs, COXIB inhibitors (e.g., COX- 1 and COX-2 inhibitors), anti-depressants, and anti-convulsants.
• NSAIDs e.g., COX- 1 and COX-2 inhibitors
• Another embodiment of this disclosure is a method for treating acute pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of formula (1) or formula (2), or a
• Another embodiment of this disclosure is a method for treating acute inflammatory pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
• Another embodiment of this disclosure is a method for treating chronic inflammatory pain in a patient in need of such treatment comprising administering to said-patient a therapeutically effective amount of at least one compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
• Another embodiment of this disclosure is a method for treating neuropathic pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
• Another embodiment of this disclosure is a pharmaceutical composition
• a pharmaceutical composition comprising at least one compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, and at least one other agent, medicament, antibody and/or inhibitor disclosed above, and a pharmaceutically acceptable carrier.
• the compounds used to treat pain will have CXCR2 antagonistic activity.
• NSAIDs are well known to those skilled in the art and can be used in their known dosages and dosage regimens.
• NSAIDs include but are not limited to: piroxicam, ketoprofen, naproxen, indomethacin, and ibuprofen
• COXIB inhibitors are well known to those skilled in the art and can be used in their known dosages and dosage regimens.
• COXIB inhibitors include, but are not limited to: rofecoxib and celecoxib.
• Anti-depressants are well known to those skilled in the art and can be used in their known dosages and dosage regimens. Examples of anti-depressants include but are not limited to: amitriptyline and nortriptyline.
• Anti-convulsants are well known to those skilled in the art and can be used in their known dosages and dosage regimens. Examples of anti-convulsants include but are not limited to: gabapentin, carbamazepine, pregabalin, and lamotragine.
• compositions for preparing pharmaceutical compositions from the compounds described by this disclosure, inert, pharmaceutically acceptable carriers can be either solid or liquid.
• Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
• the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
• Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, Md. which is incorporated herein by reference.
• Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Liquid form preparations may also include dissolution in lipid-based, self-emulsifying drug delivery systems (SEDDS) such as Labrasol® or Gelucire® for oral administration.
• SEDDS self-emulsifying drug delivery systems
• Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
• a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. nitrogen.
• solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
• liquid forms include solutions, suspensions and emulsions.
• the compounds of this disclosure may also be deliverable transdermally.
• the tansdermal composition can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
• the compound can be administered orally.
• a suitable pharmaceutical preparation is in a unit dosage form.
• the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
• the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, or from about 0.01 mg to about 750 mg, or from about 0.01 mg to about 500 mg, or from about 0.01 mg to about 250 mg, according to the particular application.
• the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total dosage may be divided and administered in portions during the day as required.
• a typical recommended daily dosage regimen for oral administration can range from about 0.04 mg/day to about 4000 mg/day, in two to four divided doses.
• a dosage regimen of the compound of either formula (1) or formula (2) can be oral administration of from 10 mg to 2000 mg/day, or 10 to 1000 mg/day, or 50 to 600 mg/day, in two to four (or two) divided doses, to block tumor growth. Intermittent therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.
• the chemotherapeutic agent and/or radiation therapy can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent and/or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent and/or radiation therapy on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents (i.e.,
• antineoplastic agent or radiation on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.
• the initial order of administration of the compound of either formula (1) or formula (2), and the chemotherapeutic agent and/or radiation may not be important.
• the compound of either formula (1) or formula (2) may be administered first, followed by the administration of the chemotherapeutic agent and/or radiation; or the chemotherapeutic agent and/or radiation may be administered first, followed by the administration of the compound of either formula (1) or formula (2).
• This alternate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of
• the chemotherapeutic agent and/or radiation may be administered first, especially if it is a cytotoxic agent, and then the treatment continued with the administration of the compound of either formula (1) or formula (2) followed, where determined advantageous, by the administration of the chemotherapeutic agent and/or radiation, and so on until the treatment protocol is complete.
• the compound of either formula (1) or formula (2) and the chemotherapeutic agent do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes.
• the compound of either formula (1) or formula (2) may be administered orally to generate and maintain good blood levels thereof, while the chemotherapeutic agent may be administered intravenously.
• the initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
• the practicing physician can modify each protocol for the administration of a component (therapeutic agent; i.e., the compound from either formula (1) or formula (2), chemotherapeutic agent or radiation) of the treatment according to the individual patient's needs, as the treatment proceeds.
• a component therapeutic agent; i.e., the compound from either formula (1) or formula (2), chemotherapeutic agent or radiation
• the attending clinician in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.
• 6-Bromonicotinic acid (8.1 g, 40 mmol) was dissolved in anhydrous DMF (50 mL) under an N 2 atmosphere.
• 4-Fluoroaniline (3.9 mL, 41 mmol) and EEDQ (9.9 g, 40 mmol) were added and stirred at room temperature for 18 hours.
• the product was precipitated by dilution into deionized water (1.2 L), and the precipitate was filtered and washed with additional water. The product was dried under vacuum to yield 8.1 g (69%) of 2 as a white solid.
• 2-Bromobenzylamine hydrochloride (1.520g, 6.83 mmol) was dissolved in water and brought to pH 12 with 1 N NaOH (15 mL). The suspension was extracted twice with ethyl acetate, and the combined ethyl acetate extracts were dried over Na 2 S0 4 , filtered, and dried under vacuum. Compound 2 (1.915 g, 6.49 mmol) was placed in a pressure bottle, and 2-bromobenzylamine (1.244 g, 6.69 mmol) was added with stirring, dissolved in N-methylpyrrolidine (13 mL), under N 2 atmosphere.
• Triethylamine (1.92 mL, 13.8 mmol) was added under N 2 , and the bottle was heated to 130 °C for 3 days. The reaction was cooled to room temperature and added dropwise to a stirring solution of deionized water (300 mL), forming a fine precipitate. The suspension was refrigerated overnight and filtered. The crude solid was dried in a vacuum desiccator. The crude product was dissolved in tetrahydrofuran, combined with material from a previous synthesis (0.5 mmol scale), and adhered to silica gel (25 g).
• 6-Bromonicotinamide (590 mg, 2.0 mmol), 2-(N-methylaminomethyl)phenyl boronic pinacol ester (495 mg, 2.0 mmol), potassium tert-butoxide (450 mg, 4.0 mmol), and 18-crown-6 ether (28 mg, 0.1 mmol) were suspended in anhydrous toluene under N 2 atmosphere and brought to reflux for 22 hours.
• the reaction mixture was diluted with ethyl acetate extracted twice with aqueous saturated bicarbonate.
• 2-Chloropyrimidine-5-carboxylic acid (1.99 g, 12.5 mmol) was dissolved in anhydrous DMF (10 mL) under an N 2 atmosphere.
• 4-Fluoroaniline (1.2 mL, 12.5 mmol) and EEDQ (3.11 g, 12.6 mmol) were added and stirred at room temperature for 40 hours.
• the product was partitioned between deionized water and ethyl acetate. The aqueous layer was washed with ethyl acetate, and the combined ethyl acetate layers were dried over sodium sulfate, filtered, and dried in vacu.
• the reaction was filtered through Celite, rinsing with DMF, dried in vacu, and partitioned between water and ethyl acetate, and the aqueous layer was washed with ethyl acetate.
• the combined ethyl acetate layers were dried over Na 2 S0 4 , and filtered through a pad of silica gel (ethyl acetate).
• the filtrate was dried under vacuum, dissolved in ethyl acetate, and adhered to silica gel (20 g).
• silica adhered compound was purified by flash silica gel chromatography (200 g, 2: 1 hexanes:ethyl acetate) to yield 1.67 g (91%) of 16 as a white flaky solid.
• the reaction was filtered through Celite, rinsing with DMF, dried in vacu, and partitioned between water and ethyl acetate, and the aqueous layer was washed with ethyl acetate.
• the combined ethyl acetate layers were dried over Na 2 S0 4 , and filtered through a pad of silica gel (ethyl acetate).
• the filtrate was dried under vacuum, dissolved in ethyl acetate, and adhered to silica gel (7.5 g).
• the silica adhered compound was purified by flash silica gel chromatography (78 g, 5:2 hexanes:ethyl acetate) to yield 379 mg (86%) of 17 as a white solid.
• DMSO 1% final concentration
• the maximum change in fluorescence was used to determine the GROa response.
• the effect of each compound on the GROa response was normalized and expressed as a percent of the DMSO control, which was designated as "100% response.”
• Curve fitting and calculation of the compound inhibitory concentration that reduces the level of the GROa response by 50% (IC 50 ), or the compound agonist concentration that increases the level of the calcium release by 50% of the maximum agonist-induced change (EC 50 ) were determined by nonlinear regression analysis of the dose- response curves generated using Prism 4 (GraphPad Software, Inc., San Diego, CA).

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