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  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P11/00—Drugs for disorders of the respiratory system
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/08—Bronchodilators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems

Definitions

• Chemoattractant cytokines or chemokines are a family of proinflammatory mediators that promote recruitment and activation of multiple lineages of leukocytes, such as T lymphocytes. Chemokines can be released by many kinds of tissue cells after activation. Release of chemokines at sites of inflammation mediates the ongoing migration of effector cells during chronic inflammation.
• the chemokines are related in primary structure and contain four conserved cysteines, which form disulfide bonds.
• the chemokine family includes the C-X-C chemokines ( -chemokines), and the C-C chemokines ( ⁇ -chemokines), in which the first two conserved cysteines are separated by an intervening residue, or are adjacent, respectively (Baggiolini, M. and Dahinden, C. A., Immunology Today, 75:127-133 (1994)).
• the chemokine receptors are members of a superfamily of G protein-coupled receptors (GPCR) which share structural features that reflect a common mechanism of action of signal transduction (Gerard, C. and Gerard, N.P., Annu Rev. Immunol, 72:775-808 (1994); Gerard, C. and Gerard, N. P., Curr. Opin. Immunol, 6: 140-145 (1994)).
• GPCR G protein-coupled receptors
• conserveed features include seven hydrophobic domains spanning the plasma membrane, which are connected by hydrophilic extracellular and intracellular loops. The majority of the primary sequence homology occurs in the hydrophobic transmembrane regions with the hydrophilic regions being more diverse.
• C-C chemokine receptor 1 also referred to as CCR-1 or CKR-1; Neote, K., et al, Cell, 72:415-425 (1993); Horuk, R. et al, WO 94/11504, May 26, 1994; Gao, J.-L et al, J. Exp. Med., 77:1421-1427 (1993)).
• CCRl also binds the chemokines CCL2 (MCP-1) CCL4 (MlP-l ⁇ ), CCL7 (MCP-3), CCL8 (MCP-2), CCL13 (MCP-4), CCL14 (HCC-1), CCL15 (Lkn-1), CCL23 (MPIF-1).
• chemokines such as RANTES and MlP-l
• chemokines and chemokine receptors may play a critical role in chronic inflammatory diseases, since these diseases are characterized by destructive infiltrates of T cells and monocytes.
• C-C chemokine receptors e.g., CCRl
• their ligands including RANTES and MJ-P-lcc
• the invention relates to compounds having the formula:
• the invention further relates to a method for treating a disease characterized by pathogenic leukocyte recruitment, pathogenic leukocyte activation or pathogenic leukocyte recruitment and activation.
• the method comprises administering to a subject in need thereof an effective amount of a compound described herein.
• the invention further relates to compositions comprising a compound as described herein and a pharmaceutically or physiologically acceptable carrier or excipient.
• the invention further relates to the use of the compounds described herein in therapy (including palliative, curative and prophylactic therapy) or diagnosis, and to the use of such compounds for the manufacture of a medicament for the treatment of a particular disease or condition as described herein (e.g., inflammatory arthritis (e.g., rheumatoid arthritis), inflammatory demyelinating disease (e.g., multiple sclerosis)).
• the invention relates to compounds that are antagonists of C-C Chemokine Receptor 1 (CCRl), compositions comprising the compounds and methods of treating diseases or disorders that comprise administering one or more of the compounds.
• the antagonist compounds can inhibit binding of a ligand (e.g., a chemokine ligand such as CCL2 (MCP-1) CCL3 (MlP-l ⁇ ), CCL4 (MlP-l ⁇ ), CCL5 (RANTES), CCL7 (MCP-3), CCL8 (MCP-2), CCL13 (MCP-4), CCL14 (HCC-1), CCL15 (Lkn-1), CCL23 (MPEF-1)) to CCRl.
• a chemokine ligand such as CCL2 (MCP-1) CCL3 (MlP-l ⁇ ), CCL4 (MlP-l ⁇ ), CCL5 (RANTES), CCL7 (MCP-3), CCL8 (MCP-2), CCL13 (MCP-4), CCL14 (HCC
• processes or cellular responses mediated by the binding of a chemokine to CCRl can be inhibited (reduced or prevented, in whole or in part), including leukocyte migration, integrin activation, transient increases in the concentration of intracellular free calcium [Ca ⁇ J j , and/or granule release of proinflammatory mediators.
• the compounds have the formula:
• R 1 is a halogen.
• the halogen is selected from the group consisting of chloro, bromo and fluoro. More preferably, the halogen is chloro.
• compounds of Formula (I) and Formula (la) can be prepared as racemates or as substantially pure enantioniers (>99% enantiomeric excess).
• the optical configuration of the compounds of Formula (I) and Formula (la) are assigned using the (R),(S) method of Cahn-Ingold-Prelog. (See, J. March, "Advanced Organic Chemistry," 4 th Edition, Wiley Interscience, New York, pp.109- 111 (1992).)
• the compound of Formula (I) is the (S)- enantiomer, and has the structure:
• the compound of Formula (la) is the (S)- enantiomer, and has the structure:
• the compound is of Formula LTa wherein R 1 is chloro.
• the (S)- and (R)-enantiomers of the invention can be prepared using any suitable method.
• the enantioniers can be resolved from the racemate using chiral chromatography or recrystallization.
• the (S)- and/or (R)- enantiomers are prepared by stereospecific synthesis as described herein. h accordance with conventional methods for showing structural formulas of compounds, a terminal methyl group in a compound described herein can be shown as a straight line with or without "CH 3 " on its terminus:
• the compounds disclosed herein can be obtained as E- and Z-configurational isomers. It is expressly pointed out that the invention includes compounds of the E- configuration and the Z-configuration around the double bond connecting the tricyclic moiety to the remainder of the molecule, and a method of treating a subj ect with compounds of the E-configuration, the Z-configuration, and mixtures thereof. Accordingly, in the structural formulas presented herein, the symbol:
• the pyridyl ring and the piperidinyl ring are in the cis configuration as shown in Formula (II) and Formula (Ila).
• the invention includes all isomeric forms and racemic mixtures of the disclosed compounds, and a method of treating a subject with both pure isomers and mixtures thereof, including racemic mixtures.
• the compounds described herein can be prepared and administered as neutral compounds, salts, esters, amides and/or prodrugs.
• salts e.g., carboxylate salts, amino acid addition salts
• esters, amides, and prodrugs of the compounds of the present invention are those salts (e.g., carboxylate salts, amino acid addition salts), esters, amides, and prodrugs of the compounds of the present invention which are suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
• Pharmaceutically or physiologically acceptable acid addition salts of the compounds described herein include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, and salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
• nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like
• nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids
• Such acid additional salts include, for example, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate and methanesulfonate salts.
• Acid addition salts of compounds which contain a basic group can be prepared using suitable methods.
• acid addition salts can be prepared by contacting the free base form of a compound with a sufficient amount of a desired acid to produce the salt in the conventional manner.
• the free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
• the free base form of a compound can differ from a salt forms somewhat in certain physical properties such as solubility in polar solvents.
• Pharmaceutically or physiologically acceptable base addition salts can be formed with suitable metals or amines, such as alkali and alkaline earth metals or organic amines.
• Examples of metals which are suitable for use as cations in base addition salts include sodium, potassium, magnesium, calcium and the like.
• Amines suitable for use as cations in base addition salts include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine. (See, for example, Berge S.M. et al, "Pharmaceutical Salts," J Pharma. Set, 66:1 (1977).)
• Base addition salts of compounds which contain an acidic group e.g., carboxylic acid
• the free acid form of a compound can be contacted with a sufficient amount of the desired base to produce a salt in the conventional manner.
• the free acid form can be regenerated by contacting the salt form with a suitable acid and isolating the free acid in the conventional manner.
• the free acid form of a compound can differ from the base addition salt form somewhat in certain physical properties such as solubility in polar solvents.
• prodrug refers to compounds that can be transformed in vivo (e.g., following administration to an animal), by metabolic processes or other processes, to yield a compound of the above formulae, for example, by hydrolysis in blood.
• Suitable prodrugs include pharmaceutically or physiologically acceptable esters and amides of the compounds described herein.
• esters of the compounds of this invention include C,-C 6 alkyl esters.
• the alkyl group of the alkyl ester is a straight or branched chain C r C 6 alkyl group.
• Acceptable alkyl esters also include C 5 -C 7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. -C 4 esters are preferred.
• Esters of the compounds of the present invention can be prepared using any suitable method.
• amides of the compounds of this invention include amides derived from ammonia, primary C r C 6 alkyl amines and secondary C r C 6 dialkyl amines wherein the alkyl groups are straight or branched chain.
• the a ine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom.
• Amides derived from ammonia, C r C 3 alkyl primary amines, and C C 2 dialkyl secondary amines are preferred. Amides of the compounds of the invention maybe prepared using any suitable method.
• compositions which contain one or more of the compounds described herein.
• Such compositions can be formulated for administration by any desired route, such as orally, topically, by inhalation (e.g., intrabronchial, intranasal, oral inhalation or intranasal drops), rectally, transdermally, or parenterally.
• the compositions comprise a compound of the invention (i. e. , one or more compounds) as the active ingredient and a (one or more) suitable carrier, diluent, excipient, adjuvant and/or preservative.
• Formulation of a compound to be administered will vary according to the route of administration selected (e.g., solution, emulsion, capsule).
• microorganisms in the compositions can be controlled by various antibacterial and/or antifungal agents, for example, parabens, chlorobutanol, alcohols (e.g., phenol, benzyl alcohol), sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like.
• antibacterial and/or antifungal agents for example, parabens, chlorobutanol, alcohols (e.g., phenol, benzyl alcohol), sorbic acid, and the like.
• isotonic agents for example sugars, sodium chloride, and the like.
• compositions suitable for parenteral injection can comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
• suitable aqueous and nonaqueous carriers, diluents, solvents, excipients or vehicles include physiological saline, phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), vegetable oils (such as ohve oil) and injectable organic esters such as ethyl oleate, or any suitable mixture thereof.
• Fluidity can be adjusted, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
• agents that delay absorption for example, aluminum monostearate and gelatin can be included.
• Solid dosage forms for oral adierinistration include, for example, capsules, tablets, pills, powders, and granules.
• the active ingredient i.e., one or more compounds of the rnvention
• the active ingredient can be admixed with one or more carrier or excipient such as sodium citrate or dicalcium phosphate
• carrier or excipient such as sodium citrate or dicalcium phosphate
• fillers or extenders for example, starches, lactose, sucrose, glucose, mannitol, silicic acid, polyethyleneglycols, and the like
• binders for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia
• humectants for example, glycerol
• disintegrating agents for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate
• solution retarders for
• Solid compositions such as those for oral administration, can also comprise buffering agents. Such solid compositions or solid compositions that are similar to those described can be provided in soft- or hard-filled gelatin capsules if desired.
• Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings or other suitable coatings or shells.
• coatings and shells are well known in the art, and can contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner.
• embedding compositions which can be used are polymeric substances and waxes.
• the active compounds can also be used in microencapsulated form, if appropriate, with, for example, one or more of the above-mentioned carriers or excipients.
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
• the liquid dosage forms can contain a suitable carrier or excipient, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, ohve oil, castor oil and sesame oil, glycerol, tefrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
• a suitable carrier or excipient such as water or other solvents, solubilizing agents and emulsifiers
• the composition can also include wetting agents, emulsifying agents, suspending agents, sweetening, flavoring and/or perfuming agents.
• Suspensions can contain suspending agents, such as, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and the like.
• Suppositories can be prepared by mixing one or more compounds of the invention with suitable nonirritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax which is solid at room temperature but liquid at body temperature and melts in the rectum or vagina, thereby releasing the active ingredient.
• suitable nonirritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax which is solid at room temperature but liquid at body temperature and melts in the rectum or vagina, thereby releasing the active ingredient.
• Dosage forms for topical administration include ointments, powders, sprays and inhalants.
• the active ingredient can be admixed under suitable conditions (e.g., sterile conditions) with a physiologically acceptable carrier and any preservatives, buffers, or propellants as maybe required.
• Ophthalmic formulations, eye ointments, powders, and solutions can also be prepared, for example, using suitable carriers or excipients.
• the compound can be solubilized and loaded into a suitable dispenser for administration (e.g., an atomizer, nebulizer or pressurized aerosol dispenser).
• the quantity of active ingredient (one or more compounds of the invention) in the composition can range from about 0.1 % to about 99.9%) by weight. Preferably the quantity of active ingredient is about 10% to about 90%, or about 20% to about 80%) by weight.
• a unit dose preparation can contain from 1 mg to about 1000 mg active ingredient, preferably about 10 mg to about 100 mg active ingredient.
• composition can, if desired, also contain other compatible therapeutic agents, such as theophylline, ⁇ -adrenergic bronchodilators, corticosteroids, antihistamines, antiallergic agents, immunosuppressive agents (e.g., cyclosporin A, FK-506, prednisone, methylprednisolone), hormones (e.g., adrenocorticotropic hormone (ACTH)), cytokines (e.g., interferons (e.g., J-FN ⁇ -la, IFN ⁇ -lb)) and the like.
• other compatible therapeutic agents such as theophylline, ⁇ -adrenergic bronchodilators, corticosteroids, antihistamines, antiallergic agents, immunosuppressive agents (e.g., cyclosporin A, FK-506, prednisone, methylprednisolone), hormones (e.g., adrenocorticotropic hormone
• the composition comprises (S)-5- ⁇ 3-[4-(4-Chloro- phenyl)-4-hydroxy-3,3-dimethyl-piperidin-l-yl]-propylidene ⁇ -5,l l-dihydro-10-oxa- l-aza-dibenzo[ ⁇ , /]cycloheptene-7-carboxylic acid and a physiologically acceptable carrier or excipient.
• the composition is substantially free of (R)-5- ⁇ 3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-l-yl]-propylidene ⁇ - 5,ll-dihydro-10-oxa-l-aza-dibenzo[ ⁇ , ]cycloheptene-7-carboxylic acid (contains at least about 98%o or at least about 99% enantiomeric excess of (S)-5- ⁇ 3-[4-(4-Chloro- phenyl)-4-hydroxy-3,3-dimethyl-piperidin-l -yl]-propylidene ⁇ -5,11 -dihydro- 10-oxa- 1 -aza-dibenzo[ ⁇ , -f]cycloheptene-7-carboxylic acid).
• the composition comprises (S)-5- ⁇ 3-[4-(4-Chloro- phenyl)-4-hydroxy-3,3-dimethyl-piperidin- 1 -yl]-propylidene ⁇ -5, 11 -dihydro- 10-oxa- 1 -aza-dibenzo[ ⁇ , -f]cycloheptene-7-carboxylic acid, (R)-5- ⁇ 3-[4-(4-Chloro-phenyl)-4- hydroxy-3 ,3 -dimethyl-piperidin- 1 -yl] -propylidene ⁇ -5,11 -dihydro- 10-oxa- 1 -aza- dibenzo[ ⁇ ,-f]cycloheptene-7-carboxylic acid and a physiologically acceptable carrier or excipient.
• the composition comprises racemic-5- ⁇ 3-[4-(4- Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-l-yl]-propylidene ⁇ -5,ll-dihydro- 10-oxa-l-aza-dibenzo[ ⁇ ,c ]cycloheptene-7-carboxylic acid
• the ratio (S)-enantiomer:(R)-enantiomer (w/w) is at least about 2:1 or about 5:1 or about 10:1 or about 20:1 or about 50:1.
• the composition comprises (S)-5- ⁇ 3-[4-(4-Chloro- phenyl)-4-hydroxy-3 ,3-dimethyl-piperidin- 1 -yl] -propylidene ⁇ - 1 -oxy-5, 11 -dihydro- 10-oxa-l-aza-dibenzo[ , J]cycloheptene-7-carboxylic acid and a physiologically acceptable carrier or excipient.
• the composition is substantially free of (R)-5- ⁇ 3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl- piperidin- 1 -yl] -propylidene ⁇ - 1 -oxy-5, 11 -dihydro- 10-oxa- 1 -aza- dibenzo[ ⁇ , /]cycloheptene-7-carboxylic acid (contains at least about 98% or at least about 99% enantiomeric excess of (S)-5- ⁇ 3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3- dimethyl-piperidin- 1 -yl] -propylidene ⁇ - 1 -oxy-5, 11 -dihydro- 10-oxa- 1 -aza- dibenzo[ , -i]cycloheptene-7-carboxylic acid).
• the composition comprises (S)-5- ⁇ 3-[4-(4-Chloro- phenyl)-4-hydroxy-3 ,3 -dimethyl-piperidin- 1 -yl]-propylidene ⁇ - 1 -oxy-5, 11 -dihydro- 10-oxa- 1 -aza-dibenzo[ , i]cycloheptene-7-carboxylic acid, (R)-5- ⁇ 3-[4-(4-Chloro- phenyl)-4-hydroxy-3,3-dimethyl-piperidin- 1 -yl]-propylidene ⁇ -1 -oxy-5, 11 -dihydro- 10-oxa- 1 -aza-dibenzo[ ⁇ , d] cycloheptene-7-carboxylic acid and a physiologically acceptable carrier or excipient.
• the composition comprises r cemtc-5- ⁇ 3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-l-yl]- propylidene ⁇ - 1 -oxy-5, 11 -dihydro- 10-oxa- 1 -aza-dibenzo[ ⁇ , d] cycloheptene-7- carboxylic acid
• the ratio (S)-enantiomer:(R)-enantiomer (w/w) is at least about 2:1 or about 5:1 or about 10:1 or about 20:1 or about 50:1.
• the invention further relates to a method for treating (e.g., palliative, curative, prophylactic) a disease or disorder associated with pathogenic leukocyte recruitment, activation or recruitment and activation, mediated by chemokines or chemokine receptor function including chronic and acute inflammatory disorders.
• a method for treating e.g., palliative, curative, prophylactic
• a disease or disorder associated with pathogenic leukocyte recruitment, activation or recruitment and activation mediated by chemokines or chemokine receptor function including chronic and acute inflammatory disorders.
• pathogenic leukocyte recruitment, activation or recruitment and activation refers to leukocyte recruitment (e.g., accumulation of leukocytes at a sight of inflammation or injury) and/or activation (e.g., physiologic state in which leukocytes perform effector functions) that contributes to the conditions, processes or results of the disease or disorder to be treated.
• leukocyte recruitment e.g., accumulation of leukocytes at a sight of inflammation or injury
• activation e.g., physiologic state in which leukocytes perform effector functions
• T cells in joints e.g., synovial tissue or fluid
• pathogenic leukocyte recruitment, pathogenic leukocyte activation or pathogenic leukocyte recruitment and activation because recruited and activated T cells contribute to the tissue destruction characteristic of rheumatoid arthritis.
• Diseases and disorders characterized by pathogenic leukocyte recruitment, pathogenic leukocyte activation or pathogenic leukocyte recruitment and activation that can be treated according to the methods described herein include, for example, acute and chronic inflammatory disorders characterized by the presence of CCL2 (MCP-1) CCL3 (MJP-l ⁇ ), CCL4 (MlP-l ⁇ ), CCL5 (RANTES), CCL7 (MCP-3), CCL8 (MCP-2), CCL13 (MCP-4), CCL14 (HCC-1), CCL15 (Lkn-1) and/or CCL23 (MPIF-1) responsive cells, such as T cells, monocytes or eosinophils.
• Such diseases or disorders include, but are not limited to, inflammatory arthritis (e.g., rheumatoid arthritis), inflammatory demyelinating disease (e.g., multiple sclerosis), atherosclerosis, arteriosclerosis, restenosis, ischemia/reperfusion injury, diabetes mellitus (e.g., type 1 diabetes mellitus), psoriasis, inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, rejection (acute or chronic) of transplanted organs and tissues (e.g., acute allograft rejection, chronic allograft rejection), graft versus host disease, as well as allergies and asthma.
• inflammatory arthritis e.g., rheumatoid arthritis
• demyelinating disease e.g., multiple sclerosis
• arteriosclerosis e.g., arteriosclerosis, restenosis
• ischemia/reperfusion injury e.g., diabetes mellitus (e.g., type
• diseases associated with aberrant leukocyte recruitment and/or activation which can be treated (including prophylactic treatments) with the methods disclosed herein are inflammatory diseases associated with viral (e.g., Human Immunodeficiency Virus (HIV)), bacterial or fungal infection, such as, ADDS associated encephalitis, ADDS related maculopapular skin eruption, AIDS related interstitial pneumonia, AIDS related enteropathy, AIDS related periportal hepatic inflammation and AIDS related glomeralo nephritis.
• the method comprises administering to the subject in need of treatment an effective amount of a compound (i.e., one or more compounds) described herein.
• inflammatory demyelinating disease refers to acute and chronic inflammatory diseases characterized by demyelination of central nervous system tissue.
• the inflammatory demyelinating disease can be an acute inflammatory demyelinating disease, for example, acute disseminated encephalomyelitis, Guillain-Barre syndrome or acute hemorrhagic leukoencephalitis.
• the inflammatory demyelinating disease can be a chronic inflammatory demyelinating disease, for example, multiple sclerosis, chronic inflammatory demyelinating polyradiculoneuropathy.
• the invention provides a method of treating multiple sclerosis, comprising administering an effective amount of a compound of Formula (I), (la), (II) or (Ila) to a subject in need thereof.
• the manifestation of MS is variable and the clinical course of MS can be grouped into four categories: relapsing- remitting, primary progressive, secondary progressive and progressive-relapsing.
• the method of the invention can be used to treat MS which presents with each of the recognized clinical courses. Accordingly, a compound of the invention can be administered to a patient with a progressive course of MS to retard or prevent the progression of neurological impairment.
• a compound of the invention can also be administered to a subject with relapsing-remitting, secondary progressive or progressive-relapsing MS to inhibit relapse (e.g., an acute attack).
• a compound of the invention can be administered to a subject with relapsing-remitting MS during the remitting phase of the disease to prevent or delay relapse.
• inflammatory arthritis refers to those diseases of joints where the immune system is causing or exacerbating inflammation in the joint, and includes rheumatoid arthritis, juvenile rheumatoid arthritis and spondyloarthropathies, such as ankylosing spondylitis, reactive arthritis, Reiter's syndrome, psoriatic arthritis, psoriatic spondylitis, enteropathic arthritis, enteropathic spondylitis, juvenile-onset spondyloarthropathy and undifferentiated spondyloarthropathy.
• Inflammatory arthritis is generally characterized by infiltration of the synovial tissue and/or synovial fluid by leukocytes.
• the invention provides a method of treating rheumatoid arthritis, comprising administering an effective amount of a compound of Formula (I), (la), (II) or (Ha) to a subject in need thereof.
• a "subject” is preferably a bird or mammal, such as a human (Homo sapiens), but can also be an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, fowl, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
• an "effective amount" of a compound is an amount which inhibits binding of chemokine to receptor (e.g., CCRl) and thereby inhibits one or more processes mediated by the binding in a subject with a disease associated with pathogenic leukocyte recruitment, pathogenic leukocyte activation or pathogenic leukocyte recruitment and activation.
• chemokine to receptor e.g., CCRl
• processes include leukocyte migration, integrin activation, transient increases in the concentration of intracellular free calcium [Ca 2+ ] ; and granule release of proinflammatory mediators.
• an "effective amount" of a compound can achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in the prevention of or a decrease in the symptoms associated with a disease associated with pathogenic leukocyte recruitment, pathogenic leukocyte activation or pathogenic leukocyte recraitment and activation.
• the amount of compound administered to the individual will depend on the type and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of disease. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
• An antagonist of chemokine receptor function can also be administered in combination with one or more additional therapeutic agents, such as, theophylline, ⁇ -adrenergic bronchodilators, corticosteroids, antihistamines, antiallergic agents, immunosuppressive agents (e.g., cyclosporin A, FK-506, prednisone, methylprednisolone), hormones (e.g., adrenocorticotropic hormone (ACTH)), cytokines (e.g., interferons (e.g., IFN ⁇ -la, IFN ⁇ -lb)) and the like.
• additional therapeutic agents such as, theophylline, ⁇ -adrenergic bronchodilators, corticosteroids, antihistamines, antiallergic agents, immunosuppressive agents (e.g., cyclosporin A, FK-506, prednisone, methylprednisolone), hormones (e.g.,
• the compound can be administered by any suitable route, including, for example, orally in capsules, suspensions or tablets or by parenteral administration.
• Parenteral administration can include, for example, systemic administration, such as by intramuscular, intravenous, subcutaneous or intraperitoneal injection.
• the compound can also be administered orally (e.g., dietary), transdermally, topically, by inhalation (e.g., intrabronchial, intranasal, oral inhalation or intranasal drops), or rectally, depending on the disease or condition to be treated.
• Oral or parenteral administration are preferred modes of administration.
• the compound can be administered to the individual as part of a pharmaceutical or physiological composition.
• the activity of compounds of the present invention can be assessed using suitable assays, such as receptor binding assays or chemotaxis assays.
• suitable assays such as receptor binding assays or chemotaxis assays.
• small molecule antagonists of MIP- 1 binding have been identified utilizing THP-1 cells membranes.
• a high through-put receptor binding assay which monitors 125 I-MIP-l ⁇ binding to THP-1 cell membranes, was used to identify small molecule antagonists which block binding of MJ-P-l ⁇ .
• Compounds of the present invention can also be identified by virtue of their ability to inhibit the activation steps triggered by binding of a chemokine (e.g.
• CCR-1 receptor
• CCR-1 receptor
• RANTES RANTES
• CCL7 MCP-3
• CCL8 MCP-2
• CCL13 MCP-4
• CCL14 HCC-1
• CCL15 Lkn-1
• CCL23 MPIF-1
• Step 1 3,3-Dimethyl-4-oxo-piperidine-l-carboxylic acid tert-butyl ester
• 4-oxo-piperidine-l-carboxylic acid tert-butyl ester 125 g, 628 mmol
• anhydrous tetrahydrofuran 1 L
• methyl iodide 85 mL, 1365 mmol
• Sodium t- butoxide 150g, 1560 mmol
• Step 2 4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidine-l-carboxylic acid tert-butyl ester
• a 2-neck, 2-L round bottom flask was fitted with two 125 mL dropping funnels and a stir bar. The assembly was flame-dried under dry nitrogen. The flask was charged with THF (700 mL) and 4-bromo-chlorobenzene (33.7 g, 176 mmol, 2.5 eq.). The resulting solution was cooled to -78 °C in a dry ice/acetone bath. To one of the dropping funnels was added butyllithium (2.5 M in hexanes, 70 mL, 175 mmol, 2.5 eq) via canula. The butyllithium solution was slowly added to the cold THF solution over 1 hour. Stirring continued for an additional 0.5 hour affording a white suspension.
• Step 3 4-(4-Chloro-phenyl)-3 ,3-dimethyl-piperidin-4-ol
• 4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl- piperidine-1 -carboxylic acid tert-butyl ester 10.42 g, 30.7 mmol
• methylene chloride 300 mL
• trifluoroacetic acid 60 mL
• the resulting yellow solution was stirred at 0 °C for an additional 1.5 hours.
• Step 4 (S)-4-(4-chloro-phenyl)-3,3-dimethyl-piperidin-4-ol
• Racemic 4-(4-Chloro-phenyl)-3,3-dimethyl- piperidin-4-ol (202g, 843 mmol), E-(+)-tartaric acid (114 g, 759 mmol) and 4040 mL of a 9:1 butanone:water mixture were added to the flask. The mixture was heated to reflux.
• Step 5 5-Cyclopropyl-5,l l-dihydro[l]benzoxepino[2,3-b]pyridin-5-ol
• a dry 2L three-necked, round-bottomed flask was fitted with a magnetic stirring bar, a glass stopper, a rubber septum, and an argon inlet. Under an argon atmosphere, 50.0 g. of 5,l l-dihydro[l]benzoxepino[3,4-b]pyridine-5-one (prepared by the method of Inoue etal, Synthesis 1:113-116 (1997), (0.24 mole)) and 500 mL of dry tefrahydrofuran were added to the flask and the flask was cooled with an ice bath. A freshly prepared cyclopropylmagnesium bromide tetrahydrofuran solution (50.0 g.
• cyclopropylmagnesium bromide was prepared from cyclopropylbromide (0.41 mole) and 12.0 g. of magnesium turnings (0.49 mole) in 400 mL of dry tetrahydrofuran) was introduced by needle over a period of 5 minutes. The ice bath was removed, and the mixture was stirred for 30 minutes. The reaction mixture was slowly poured into 500 mL of saturated ammonium chloride solution, the mixture was extracted with two 300 mL portions of ethyl acetate, and the combined organic extracts are washed with 300 mL of saturated aqueous sodium chloride. The organic solution was dried with anhydrous magnesium sulfate, filtered, and evaporated (aspirator vacuum, ca.
• Step 6 5-(3-Bromopropylidene)-5,l l-dihydro[l]benzoxepino[2,3-b]pyridine
• the reaction mixture was poured to 1500 mL of saturated aqueous sodium bicarbonate, the mixture is extracted with two 800 mL portions of ethyl acetate, and the combined organic extracts are washed with 500 mL of saturated aqueous sodium chloride.
• the organic solution was dried with anhydrous magnesium sulfate, filtered, and evaporated (aspirator vacuum, ca. 30 °C).
• the oily residue was chromatographed on 500 g. of Silica gel 60 by eluting with 5:1 - 4:1 (v/v) hexane-ethyl acetate mixture. The elution was evaporated, giving the titled compound as a pale yellow oil.
• Step 7 7-Acetyl-5-(3-bromopropylidene)-5,l l-dihydro[l]benzoxepino[2,3- b]pyridine
• a dry 3L three-necked, round-bottomed flask was fitted with a magnetic stirring bar, a glass stopper, a rubber septum, and an argon inlet. Under an argon atmosphere, 94.0 g. of 5-(3-Bromopropylidene)-5,l l-dihydro[l]benzoxepino[2,3- b]pyridine (0.30 mole) and 900 mL of dry dichloromethane were added to the flask and the flask was cooled with an ice bath. To the solution was slowly added 78.5 g.
• Step 8 (S)-l-(5- ⁇ 3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-l- yl] -propylidene ⁇ -5, 11 -dihydro- 10-oxa- 1 -aza-dibenzo[a,d]cyclohepten- 7-yl)-ethanone
• the mixture was cooled to room temperature and acetonitrile was removed under reduced pressure.
• the aqueous layer was extracted with ethyl acetate (750 mL) and the extract was washed with brine, dried over sodium sulfate, filtered and concentrated.
• step 8 The product of step 8 (500 mg, 0.969 mmol), NaOH (2M in water, 4.84 mmol, 2.42 mL), sodium hypochlorite (4% available chlorine, 3.6 mmol) and DME (10 vols, 5mL) were charged to a 25 mL round bottom flask and stirred at room temperature overnight. After 12 hours, sodium bisulfite (5mL, saturated aq solution) was added and the reaction extracted with ethyl acetate (4 x 5mL); the organic layers were combined and dried over sodium sulfate, filtered and evaporated under reduced pressure to yield 500mg (96% yield) of a yellow solid.
• the solid was dissolved in water (20 vols, lOmL) and acidified with acetic acid to pH 6.15. Upon acidification, a cream-colored solid was precipitated; the solid was filtered and placed in a vacuum oven for about two days to afford the titled compound.
• the solids were removed by suction filtration and dried in vacuo.
• the dried salt was dissolved in hot isopropyl alcohol (ca. 50 mL), filtered through a cotton plug, and allowed to slowly cool to room temperature, undisturbed, overnight.
• the solids that formed on cooling were removed by suction filtration and shown by analytical HPLC to be enantiomerically pure.
• the salt was suspended in ethyl acetate and neutralized with sodium hydroxide (I N). The homogenous organic phase was washed with water and brine, dried over sodium sulfate, filtered and dried to afford R-4-(4-chloro-phenyl)-3,3-dimethyl-piperidin-4-ol.
• the racemic material was prepared essentially as described in Steps 5-9 of
• Example 1 but replacing (S)-4-(4-chloro-phenyl)-3,3-dimethyl-piperidin-4-ol with racemic 4-(4-chloro-phenyl)-3 ,3 -dimethyl-piperidin-4-ol.
• THP-1 Cell Membrane Preparation and Binding Assay Membranes were prepared from THP-1 cells (ATCC. #TIB202). Cells were harvested by centrifugation, washed twice with PBS (phosphate-buffered saline), and the cell pellets were frozen at -70 to -85°C.
• PBS phosphate-buffered saline
• the frozen pellet was thawed in ice-cold lysis buffer consisting of 5 mM HEPES (N-2-hydroxyethylpiperazine-N'-2-ethane- sulfonic acid) pH 7.5, 2 mM EDTA (ethylenediaminetetraacetic acid), 5 ⁇ g/ml each aprotinin, leupeptin, and chymostatin (protease inhibitors), and 100 ⁇ g/ml PMSF (phenyl methane sulfonyl fluoride - also a protease inhibitor), at a concentration of 1 to 5 x 10 7 cells/ml. This procedure results in cell lysis.
• HEPES N-2-hydroxyethylpiperazine-N'-2-ethane- sulfonic acid
• 2 mM EDTA ethylenediaminetetraacetic acid
• PMSF phenyl methane sulfonyl fluoride - also a protea
• the suspension was mixed well to resuspend all of the frozen cell pellet. Nuclei and cell debris were removed by centrifugation of 400 x g for 10 minutes at 4°C. The supernatant was transferred to a fresh tube and the membrane fragments were collected by centrifugation at 25,000 x g for 30 minutes at 4°C. The supernatant was aspirated and the pellet was resuspended in freezing buffer consisting of 10 mM HEPES pH 7.5, 300 mM sucrose, l ⁇ g/ml each aprotinin, leupeptin, and chymostatin, and 10 ⁇ g/ml PMSF (approximately 0.1 ml per each 10 8 cells).
• Binding Assays utilized the membranes described above. Membrane protein (2 to 20 ⁇ g total membrane protein) was incubated with 0.1 to 0.2 nM 125 ⁇ _ ⁇ a b e ⁇ e( ⁇ MlP-l with or without unlabeled competitor (MlP-l ) or various concentrations of compounds. The binding reactions were performed in 60 to 100 ⁇ l of a binding buffer consisting of 10 mM HEPES pH 7.2, 1 mM CaCl2, 5 mM MgCl2, and 0.5% BSA (bovine serum albumin), for 60 min at room temperature.
• BSA bovine serum albumin
• the binding reactions were terminated by harvesting the membranes by rapid filtration through glass fiber filters (GF/B or GF/C, Packard) which were presoaked in 0.3% polyethyleneimine.
• the filters were rinsed with approximately 600 ⁇ l of binding buffer containing 0.5 M NaCl, dried, and the amount of bound radioactivity was determined by scintillation counting. The activities of test compounds are reported in the Table.
• the Reference Example was prepared as described in WO 01/09138.
• Examples 1 and 3 have greater oral bioavailabihty and efficacy in comparison to the stracturally related compound of the Reference Example.
• Examples 1 and 3 also showed greater selectivity, compared to stracturally related compounds, when assayed on other G protein-coupled receptors and ion channels.

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