AU5239299A - Substituted anilide compounds and methods - Google Patents

Substituted anilide compounds and methods Download PDF

Info

Publication number
AU5239299A
AU5239299A AU52392/99A AU5239299A AU5239299A AU 5239299 A AU5239299 A AU 5239299A AU 52392/99 A AU52392/99 A AU 52392/99A AU 5239299 A AU5239299 A AU 5239299A AU 5239299 A AU5239299 A AU 5239299A
Authority
AU
Australia
Prior art keywords
ethoxy
methylethyl
bis
methoxyphenyl
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
AU52392/99A
Inventor
William E. Bondinell
Thomas W. Ku
Michael J. Neeb
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of AU5239299A publication Critical patent/AU5239299A/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/50—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to ring nitrogen atoms
    • C07D241/54—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D491/10—Spiro-condensed systems

Description

WO 00/06146 PCTIUS99/17121 SUBSTIrUTED ANILIDE COMPOUNDS AND METHODS FIELD OF THE INVENTION This invention relates to substituted anilide compounds which are 5 modulators, agonists or antagonists, of the CC chemokine receptor CC-CKR5 now designated as CCR5 (Nature Medicine 1996, 2, 1174-8). In addition, this invention relates to the treatment and prevention of disease states mediated by CCR5. BACKGROUND OF THE INVENTION 10 T cells are not only key regulators of the immune response to infectious agents but are believed critical for the initiation and maintenance of the inflammatory reaction in a variety of chronic diseases. Increased numbers or enhanced activation state of T cells, especially CD4+ T cells, have been demonstrated in the synovium of individuals with rheumatoid arthritis (M.J. Elliott 15 and R. N. Maini, Int. Arch. Allergy Immunol. 104: 112-1125, 1994), in the bronchial mucosa of asthmatics (C.J. Corrigan and A.B. Kay, Immunol. Today 13:501-506, 1992), in the lesions of multiple sclerosis (R. Martin and H. F. McFarland, Crit. Rev. Clin. Lab. Sci. 32: 121-182, 1995), in psoriatic lesions (J.L. Jones, J. Berth-Jone, A. Fletcher and P.E. Hutchinson, J. Pathol. 174: 77-82, 1994) and in the fatty streaks of 20 atherosclerosis (R. Ross, Annu. Rev. Physiol. 57: 791-804, 1995). T cells, as well as other inflammatory cells, will migrate into tissues in response to the production of a variety of chemotactic factors. Among these factors are a superfamily of 8-12 kDa proteins known as the chemokines. These proteins share structural features such as the presence of 3-4 conserved cysteine residues. 25 RANTES, which stands for Regulated upon Activation Normal T cell Expressed and Secreted, is an 8 kDa protein member of CC branch of the chemokine family. These proteins recruit and activate immune and inflammatory cells through an interaction with G-protein coupled receptors. The CC branch is defined by the absence of an intervening amino acid residue between the first two cysteine residues and members 30 of this family predominately elicit the migration of mononuclear cells, eosinophils and basophils (M. Baggiolini, B. Dewald, and B. Moser, Adv. Immunol. 55: 97-179, 1994; and J.J. Oppenheim, C.O.C. Zachariae, N. Mukaida, and K. Matsushima, Annu. Rev. Immunol. 9: 617-648, 1991). RANTES potently produces chemotaxis of T cells, basophils, eosinophils, 35 monocytes and mast cells. RANTES was originally identified as gene product induced late after antigen activation of T-cells (T.J. Schall, J. Jongstra, B.J. Dyer, J. Jorgensen, et al., J. Immunol. 141:1018-1025, 1988), however, RANTES has been shown to be synthesized and secreted by a diverse group of cells that include WO 00/06146 PCT/US99/17121 epithelial and endothelial cells (C. Stellato, L.A. Beck, G.A. Gorgone, D. Proud, et al., J. Immunol. 155: 410-418, 1995; and A. Marfaing-Koka, 0. Devergne, G. Gorgone, A. Portier, et al., J. Immunol. 154: 1870-1878, 1994), synovial fibroblasts (P. Rathanaswami, M. Hachicha, M. Sadick, T.J. Schall, et al., J. Biol. Chem. 268: 5 5834-5839, 1993) and dermal fibroblasts (M. Sticherling, M. Kupper, F. Koltrowitz, E. Bornscheuer, et al., J. Invest. Dermatol. 105: 585-591, 1995), mesangial cells (G. Wolf, S. Aberle, F. Thaiss, et al., Kidney Int. 44: 795-804, 1994) and platelets (Y. Koameyoshi, A. Dorschner, A.I. Mallet, E. Christophers, et al., J. Exp. Med. 176: 587-592, 1992). In these cells RANTES mRNA is rapidly upregulated in response 10 to IL-1 or TNF-. Although RANTES mRNA is not usually detected in normal tissues (J.M. Pattison, P.J. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-8, 1995), increased mRNA or protein has been found in diseases characterized by a mononuclear infiltrate. For example, RANTES mRNA was visualized using in situ hybridization in renal allografts undergoing rejection (J.M. Pattison, P.J. Nelson, and 15 A.M. Krensky, Clin. Immunother. 4: 1-8, 1995; and K.C. Nadeau, H. Azuma and N.I. Tilney, Proc. Natl. Acad. USA 92: 8729-8733, 1995) in the skin of atopic dermatitis patients after exposure to antigen (S. Ying, L. Taborda-Barata, Q. Meng, M. Humbert, et al., J. Exp. Med. 181: 2153-2159, 1995), and in endothelial cells of coronary arteries undergoing accelerated atherosclerosis after cardiac transplant 20 (J.M. Pattison, P.J. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-8, 1995). Further, increased immunoreactive protein for RANTES has been detected in bronchoalveolar lavage fluid (R. Alam, J. York, M. Boyers, et al., Am. J. Resp. Crit. Care Med. 149: A951, 1994) and sputum from asthmatic individuals (C.M. Gelder, P.S. Thomas, D.H. Yates, I.M. Adcock, et al., Thorax 50: 1033-1037, 1995). 25 Several receptors have been identified that bind RANTES. In particular, CCR5, when expressed in either HEK 293 cells or CHO cells, binds RANTES. This receptor is expressed in T-cells and in monocytes and macrophages, immune/inflammatory cells which are important in the maintenance of a chronic inflammatory reaction. Pharmacological characterization of CCR5 indicates 30 similarities to the RANTES binding site observed on isolated T cells. Therefore, antagonism of RANTES' action on CCR5, as well as antagonism of other natural modulators of CCR5, should inhibit the recruitment and activation of T cells and macrophages into inflammatory lesions and provide a novel therapeutic approach for the treatment of atopic and autoimmune disorders. 35 Since T cells and macrophages express CCR5, selective receptor modulators of CCR5, particularly antagonists, are likely to provide beneficial effects in diseases including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, 2 WO 00/06146 PCT/US99/17121 atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease, all in mammals, preferably humans. Furthermore, since CD8+ T cells and macrophages have been implicated in COPD, CCR5 may play a role in their recruitment and therefore antagonists to CCR5 could provide 5 potential therapeutic in the treatment of COPD. Also, since CCR5 is a co-receptor for the entry of HIV into cells, selective receptor modulators may be useful in the treatment of HIV infection. Surprisingly, it has now been discovered that this class of non-peptide compounds, in particular substituted anilide compounds of this invention, function 10 as CCR5 receptor modulators, and therefore, have utility in the treatment and prevention of disease states mediated by CCR5 receptor mechanisms. SUMMARY OF THE INVENTION In one aspect, the present invention is to novel compounds of formula (I), or 15 pharmaceutically active salts thereof, and their novel use in treating the above-mentioned CCR5-mediated disease states:
(R
2 )a' (RT )b. R 2 A P- L-E Formula I 20 wherein: the basic nitrogen in moiety E may be optionally quaternized with C 1 -6alkyl or is optionally present as the N-oxide; P l and P 2 are independently phenyl, fused bicyclic aryl, a monocyclic 25 heterocyclic ring of 5- to 7-members containing I to 3 heteroatoms selected from oxygen, nitrogen and sulfur, or a fused bicyclic heterocyclic ring of 8 to 11 -members containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur; A is C(R 4
')
2 , CR 4
'(OR
5 '), CO, C=NOR 6 ', NR 7 ', oxygen, or S(O)c'; L is a group of formula -C(=V)-DR 8 '-, -DR 9 '-C(=V)-, -CH 2 NH-, or 30
NHCH
2 -; V is oxygen or sulfur; D is nitrogen, carbon, or a CH group, R I' and R 2 ' are independently hydrogen,
C
1
-
6 alkyl, C 2
-
6 alkenyl, C 2 6alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, aryl, (CH2)d'NR10'R 1 1 ', 35 (CH2)d'NR 10
'COR
12 ' (CH 2 )d'NR 10
'CO
2
R
1 3', (CH2)d'NR 1'SO 2 R14', 3 WO 00/06146 PCT/US99/17121 (CH2)dCONR 15'R 1 6', hydroxyC 1- 6 alkyl, C 1 .4alkoxyalkyl (optionally substituted by a Ci-4alkoxy or hydroxy group), (CH2)d'CO 2 Cl- 6 alkyl, (CH2)eOC(O)R 17 '
CR
18
'=NOR
1 9', CNR 2 0
'=NOR
1 9', COR 2 1', CONR 15
'R
1 6', CONR 15 '(CN-2)fOC1: 4 alkyl, CONR 1 5 '(CH2)dCO2R 2 2', CONHNR 2 3
'R
2 4 ', CONR 15
'SO
2
R
2 5 ' 5 C0 2
R
2 6 ', cyano, trifluoromethyl, NR 10 'R 1 1 ', NR 10
'COR
12 '
NR
2 7 'CO(CH2)d'NR 2 7
'R
2 8 ', NR 2 7
'CONR
2 7
'R
2 8 ', NR 1 0
'CO
2
R
1 3 ',
NR
1 O's0 2
R
1 4', N=CNR 27
'NR
27
'R
2 8 ', nitro, hydroxy, C 1 -6alkoxy, hydroxyC1 6alkoxy, C1-6alkoxyC 1
-
6 alkoxy, OC(O)NR 2 9
'R
3 0', SR 3 1', SOR 3 2 ', S0 2
R
3 2 ' S0 2
NR
33
'R
34 ', halogen, CI-6alkanoyl, C02(CH 2 )dOR 35 ', or R l'is an optionally 10 substituted 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;
R
3 'is hydrogen, C 1 -6alkyl, C3-6cycloalkyl, C3-6cycloalkenyl, hydroxyC I 6 alkyl, Cl-6alkylOC 1
-
6 alkyl, CONR 3 6
'R
37 ', C0 2
R
3 8 ', cyano, aryl, trifluoromethyl, NR 3 9
'R
4 0 ', nitro, hydroxy, C 1-6alkoxy, C1-6alkanoyl, acyloxy, or 15 halogen;
R
4 ', R 5 ', R 6 ', R 7 ', R 18 ', R 19 ', R 20 ', R 2 1 ', R 2 2 ', R 2 3 ', R 2 4 ', R 27
',R
2 8
',R
3 1 ',
R
3 5 ', R 3 6 ', R 3 7 ', R 38 ', R 39 ', and R 4 0 ' are independently hydrogen or C 1
-
6 alkyl;
R
8 'is hydrogen or C 1
-
6 alkyl, providing that D is nitrogen or a CH group;
R
9 'is hydrogen or Cl- 6 alkyl, providing that D is nitrogen or a CH group; 20 R 10 ' and R 1 l' are independently hydrogen or C1- 6 alkyl, or R 10 ' and R 11 ' together with the nitrogen to which they are attached, forms a 5- to 6-membered heterocyclic ring, which may optionally be substituted by an oxo group, and, when there are six members, may optionally contain in the ring one oxygen or one sulfur atom; 25 R 12 ' is hydrogen, C1- 6 alkyl, or Cl-4alkoxyalkyl;
R
13 ', R 2 5 ', and R 32 ' are independently C1-6alkyl;
R
14 'is C 1
-
6 alkyl or phenyl;
R
15 ' and R 16 ' are independently hydrogen or C1-6alkyl, or R 1 5 ' and R 16 ' together with the nitrogen to which they are attached form a 5- to 6-membered 30 saturated heterocyclic ring which, when there are 6 ring members, may optionally contain in the ring one oxygen or one sulfur atom;
R
17 ' is C 1
-
4 alkyl, optionally substituted by C1-6alkoxy;
R
2 6 'is hydrogen or C 1
-
6 alkyl optionally substituted with one or two substituents selected from C 1
-
6 alkyl, CI-6alkoxy, hydroxy, or NR 10 'R 1 l'; 35 R 2 9 ' and R 3 0 ' are independently hydrogen or CI-6alkyl, or R 2 9 ' and R 3 0 ' together with the nitrogen to which they are attached form a 5- to 6-membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring one oxygen or sulfur atom; 4 WO 00/06146 PCT/US99/17121
R
3 3 ' and R 34 ' are independently hydrogen or C1- 6 alkyl, or R 3 3 ' and R 3 4 ' together with the nitrogen to which they are attached form 5- to 6-membered . heterocyclic ring which, when there are six ring members, may optionally contain iri the ring one oxygen or one sulfur atom; 5 a' and b' are independently 1, 2, or 3; c'is 0, 1, or 2; d'is 1, 2, 3, or 4; e'is 0, 1, 2, or 3; f is 1, 2, or 3; 10 E represents (a): B- (CR 1
R
2 )a -NR 3
R
4
(R
5 )b R6 (a); in which B is oxygen, S(O)c, CR 7
=CR
8 , or CR 7
R
8 , or B is NR 9 ; R 1 and R 2 are independently hydrogen or C 1
-
6 alkyl; alternatively 15 B(CR IR 2 )a is OCR 1
R
2
CR
1 (OH)CR IR 2 or OCR 1
R
2
CR
1
(OCOCH
3 )CR 1R 2 ;
R
3 and R 4 are independently hydrogen, C 1 -6alkyl, C3- 7 cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents 20 include C 1
-
6 alkyl, aryl, CONR 1 0 R 1 1 , NR 10 R 11 , hydroxy, OCOR 12 , NHCOCO 6alkyl where alkyl is optionally substituted by OH, NHCOCF 3 , NHSO 2
R
1 3 , and
NHCO
2
R
1 4 ;
R
5 is hydrogen, C 1
-
6 alkyl, aryl, CN, CONR 15
R
16 , C0 2
R
17 , trifluoromethyl,
NHCO
2
R
18 , hydroxy, C1-6alkoxy, benzyloxy,
OCH
2
CO
2
C
1 25 6alkyl, OCF 3 , S(O)dR1 9 , S0 2
NR
20
R
2 1 or halogen;
R
6 is hydrogen, C 1 -6alkyl, aryl, trifluoromethyl, hydroxy, Cl- 6 alkoxy or halogen, or R 6 taken together with R 8 ' forms a group D where D is (CR 2 2
R
23 )e or D is (CR 22
R
2 3 )f-G where G is oxygen, sulfur or CR 2 2
=CR
2 3 , CR 2 2 =N, =CR 22 0,
=CR
2 2 S, or =CR22-NR23; 30 R 7 , R8, R 10, R 11, R12, R15, R16, R17, R20, R21, R22, and R23 are independently hydrogen or C 1 -6alkyl;
R
9 is hydrogen, C 1
-
6 alkyl, or phenylC1- 6 alkyl;
R
13 , R1 4 , R1 8 , and R 19 are independently C1-6alkyl; a is 1, 2, 3, or 4; 35 b is 1 or 2; 5 WO 00/06146 PCTIUS99/17121 c and d are independently 0, 1 or 2; e is 2, 3 or 4; f is 0, 1, 2 or 3; alternatively, E represents (b): - R 28 R29C
R
2 6
R
27 C NR 30 (CR24R25)g
(CR
3
'R
32 )h 5 R3 (b);
R
24 , R 2 5 , R 2 6 , R 27 , R 2 8 , R 2 9 , R 3 1 , and R 32 are independently hydrogen or C - 6 alkyl;
R
3 0 is hydrogen, C 1
-
6 alkyl, or C3- 7 cycloalkyl;
R
3 3 is hydrogen, C 1
-
6 alkyl, trifluoromethyl, hydroxy, or halogen, or R 3 3 10 and R 8 ' together form a group -K- where K is (CR 34
R
3 5 )i or K is (CR 34
R
3 5)j -M and M is oxygen, sulfur, CR 34
=CR
35 , CR 34 =N, or N=N; J is oxygen, CR 3 6
R
37 , or NR 3 8 , or J is a group S(O)k;
R
34 , R 3 5 , R 3 6 , R 37 , and R 3 8 are independently hydrogen or C 1
-
6 alkyl; g is 1, 2 or 3; 15 h is 1, 2 or 3; i is 2, 3, or 4; j is 0, 1, 2, or 3; k is 0, 1 or 2; alternatively, E represents (c): - Q- (CR 39
R
40 ) -R41
(R
42 )m 20 R4 (c); in which: Q is oxygen, S(O)n, CR 4 4
=CR
4 5 , CR 4 4
R
4 5 , or Q is NR 4 6 ;
R
39 and R 4 0 are independently hydrogen or C1-6alkyl;
R
4 1 is a group of formula (d):
(CH
2 )o (CH 2 )p (CH 2 )q 25 N (d) or R 4 1 is a group of formula (e): 6 WO 00/06146 PCT/US99/17121
/CH
2 ), N
R
47 (e)
R
4 2 is hydrogen, CI -6alkyl, aryl, CN, CONR 4 8
R
4 9 , C0 2
R
5 0 , trifluoromethyl,
NHCO
2
R
5 1 , hydroxy, C1-6alkoxy, benzyloxy, OCH 2
CO
2 CI_ 6alkyl, OCF 3 , S(O)sR 5 2 , S0 2
NR
5 3
R
5 4 , or halogen; 5 R 4 3 is hydrogen or R 4 3 together with R 8 ' forms a group R where R is
CR
5 5
=CR
5 6 , CR 5 5
=CR
5 6
CR
5 5
R
5 6 , or (CR 55
R
56 )t;
R
4 4 , R 4 5 , R 4 6 , R 4 8 , R 4 9 , R 50 , R 5 3 , R 54 , R 55 , and R 5 6 are independently hydrogen or C1- 6 alkyl;
R
4 7 is hydrogen, C 1
-
6 alkyl, or C 3
-
7 cycloalkyl; 10 R 5 1 and R 52 are independently C 1
-
6 alkyl; I is 0, 1, 2, or 3; m is 1 or 2; n is 0, 1, or 2 o, p, and q are independently integers having the value 1, 2, or 3; 15 r is 0,1, 2, or 3; s is 0, 1, or 2; t is 2 or 3; alternatively, E represents (f):
W-(CR
57
R
58 )-- NR 59
R
6 0 T T (f); 20 R 5 7 and R 58 are independently hydrogen or Cl-6alkyl;
R
5 9 and R 60 are independently hydrogen, Cl- 6 alkyl, C 3
-
7 cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional 25 substituents include C 1
-
6 alkyl, aryl, CONR 6 1
R
6 2 , NR 6 1
R
6 2 , hydroxy, OCOR 6 3 ,
NHCOC
0
-
6 alkyl where alkyl is optionally substituted by OH, NHCOCF 3 ,
NHSO
2
R
6 4 , and NHCO 2
R
6 5 ; T is -(CR 66
R
67 )v- or -O(CR66R67)w W is oxygen, S(O)x, NR 6 8 , or W is CR 69
=CR
7 0 or CR69R70; 30 R 6 1 , R 62 , R 6 3 , R 6 6 , R 6 7
R
6 8 , R 6 9 , and R 7 0 are independently hydrogen or
C
1 -6alkyl;
R
64 and R 6 5 are independently C 1 -6alkyl; u is I to 4; 7 WO 00/06146 PCTIUS99/17121 v is 2or3; w is 1, 2, or 3; x is 0, 1 or 2; alternatively, E represents a group (g): 5 R 73
(R
72 )Y(g);
R
7 1 is an optionally substituted 5 to 7-membered saturated or partially saturated heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur or R 7 1 is an optionally substituted 6,6 or 6,5 bicyclic ring containing a nitrogen atom and optionally a further heteroatom selected from 10 oxygen, nitrogen or sulfur;
R
7 2 is hydrogen, C 1
-
6 alkyl, aryl, CN, CONR 74
R
7 5 , C0 2
R
7 6 , trifluoromethyl,
NHCO
2
R
77 , hydroxy, C1-6alkoxy, benzyloxy,
OCH
2
CO
2
C
1 6 alkyl, OCF 3 , S(O)zR 7 8 , S0 2
NR
79
R
80 , or halogen;
R
7 3 is hydrogen, C1- 6 alkyl, hydroxy, C1-6alkoxy or halogen, or R 7 3 and 15 R 8 ' taken together from a group -X- where X is (CR 8 1R 8 2 )aa or X is (CR 8 1
R
82 ) ab Y and Y is oxygen, sulfur or CR 8 1
=CR
8 2 ;
R
7 4 , R 7 5 , R 7 6 , R 79 , R 80 , R 8 1 , and R 82 are independently hydrogen or C 1 _ 6 alkyl;
R
7 7 and R 7 8 are independently C 1
-
6 alkyl; 20 y is 1 or 2; z is 0, 1, or 2; aa is 2, 3 or 4; ab is 0, 1, 2 or 3; alternatively, E represents group (h): Z (CR 83 R4) ac- NRSSR86 25
R
87 (h);
R
8 3 and R 8 4 are independently hydrogen or C 1
-
6 alkyl;
R
8 5 and R 8 6 are independently hydrogen, C 1
-
6 alkyl, C 3
-
7 cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an 30 additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C 1
-
6 alkyl, aryl, CONR 8 8
R
89 , NR 90
R
9 1 , hydroxy, OCOR 9 2 ,
NHCOC
0
-
6 alkyl where alkyl is optionally substituted by OH, NHCOCF 3 ,
NHSO
2
R
9 3 , and NHCO 2
R
9 4 ; 8 WO 00/06146 PCT/US99/17121
R
87 is hydrogen or C1- 6 alkyl, CI-6alkoxy, or halogen, or R 8 7 together with
R
8 ' forms a group -AA- where AA is (CR 9 5
R
9 6 )ad or AA is (CR 9 5
=CR
9 6 )aeAB and AB is oxygen, sulfur, CR 9 5
=CR
9 6 , CR 9 5 =N, CR 9 5
NR
9 6 or N=N; Z is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 5 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;
R
8 8 , R 89 , R 9 0 , R 9 1 , R 9 2 , R 9 5 , and R 9 6 are independently hydrogen or Cl 6 alkyl;
R
9 3 and R 9 4 are independently C1- 6 alkyl; ac is 0 to 4; 10 ad is 1, 2 or 3; ae is 0, 1 or 2; alternatively, E represents group (i):
(CH
2 )afNR 97
R
9 B
(CH
2 )ag 4 (CR(99R100)ah R101 A6 (i);
R
97 and R 9 8 are independently hydrogen, C1-6alkyl, C3-7cycloalkyl, 15 aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C 1
-
6 alkyl, aryl, CONR 10 2
R
10 3 , NR1 0 4
R
105 , hydroxy,
OCOR
10 6 , NHCOC 0
-
6 alkyl where alkyl is optionally substituted by OH, 20 NHCOCF 3 , NHSO 2
R
107 , and NHCO 2 R1 0 8 ;
R
99 and R 100 are independently hydrogen or Cl- 6 alkyl;
R
10 1 is hydrogen or C1- 6 alkyl or R 10 1 and R 8 ' together form a group -AD where AD is (CR 10 9
R
110 )ai or AD is (CR 10 9 R110)aj-AE and AE is oxygen, sulfur or CR 10 9
=CR
1 10; 25 AC is oxygen, CR 1 1
R
1 12 or NR113 or AC is a group S(O)ak;
R
10 2 , R 10 3 , R 10 4 , R 10 5 , R 10 6 , R 10 9 , R 1 10, R 1 11, R 1 12, and R 1 13 are independently hydrogen or C 1
-
6 alkyl;
R
10 7 and R 10 8 are independently C1- 6 alkyl; af is 0, 1, 2, 3, or 4; 30 ag is 1, 2, or 3; ah is 1, 2, 3 or 4; ai is 2, 3 or 4; aj is 0, 1, 2, or 3; and ak is 0, 1 or 2. 9 WO 00/06146 PCT/US99/17121 In another aspect, the present invention is to a method of treating CCR5 mediated disease states, including, but not limited to, COPD, asthma and atopic disorders (fQr example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic disease, psoriasis, autoimmune diseases such as multiple sclerosis, and 5 inflammatory bowel disease and HIV infection, all in mammals, preferably humans, comprising administering to such mammal in need thereof, a anilide of formula (I), or pharmaceutically active salts thereof. In yet another aspect, the present invention is to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier therefor. 10 In particular, the pharmaceutical compositions of the present invention are used for treating CCR5-mediated disease states, including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic disease, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, COPD and HIV all in mammals, preferably 15 humans. DETAILED DESCRIPTION OF THE INVENTION It has now been discovered that substituted anilides of formula (I) are CCR5 receptor modulators. It has also now been discovered that selective inhibition of CCR5 20 receptor mechanisms by treatment with the receptor modulators of formula (I), or a pharmaceutically acceptable salt thereof, represents a novel therapeutic and preventative approach to the treatment of a variety of disease states, including, but not limited to, COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic disease, psoriasis, 25 autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease, all in mammals, preferably humans ("CCR5-mediated diseases"). Also, since CCR5 is a co receptor for the entry of HIV into cells, selective receptor modulators may be useful in the treatment of HIV infection. The term "alkyl" is used herein at all occurrences to mean a straight or branched 30 chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like. The terms "cycloalkyl" and "cyclic alkyl" are used herein at all occurrences to mean cyclic radicals, preferably comprising 3 to 7 carbon atoms which may be mono- or bicyclo 35 fused ring systems which may additionally include unsaturation, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like. The terms "halo" or "halogen" are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine and bromine. 10 WO 00/06146 PCT/US99/17121 The term "heterocyclic ring" is used herein at all occurrences to mean a saturated or partially saturated 5-, 6-, or 7-membered ring system (unless the cyclic ring system is otherwise limited) in which the ring system contains one to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which ring system may be optionally substituted with C 1 5 6alkyl or C3-7cycloalkyl. Examples of such rings include, but are not limited to, piperidine, tetrahydropyridine, and piperazine. When the heterocyclic ring is fused to a phenyl group, the term "heterocyclic ring", together with the phenyl ring to which it is fused, forms a ring which includes, but is not limited to, dihydro- 1,4-benzoxazine and 1, 2 ,3, 4 -tetrahydroquinoline, which may be optionally substituted by C 1
-
6 alkyl or oxo. 10 The term "6,6 or 6,5 bicyclic ring" means a 6,6 or 6,5-bicyclic ring system containing a nitrogen atom and optionally a further heteroatom selected from nitrogen, oxygen, or sulfur, which ring system may be optionally substituted with C1-6alkyl. Examples of such ring systems include, but are not limited to, tropane, isoquinuclidine and granatane rings. 15 The term "CCR5 mediated disease state" is used herein at all occurrences to mean any disease state which is mediated (or modulated) by CCR5. The term "monocyclic heterocyclic ring" is used herein at all occurrences to mean a single aromatic ring of 5 to 7 members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur represented by PI and/or P 2 including thienyl, furyl, pyrrolyl, 20 and pyridyl. The term "fused bicyclic heterocyclic ring" is used herein at all occurrences to mean a fused bicyclic ring system of 8 to 11 members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur including indole, benzofuran, benzothiophene, quinoline, and isoquinoline rings. 25 Suitably, pharmaceutically acceptable salts of formula (I) include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate, or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p toluenesulfonate, palmitate, salicylate, and stearate. 30 The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like, are equivalent to the unsolvated forms for purposes of this invention. The compounds of the present invention may contain one or more asymmetric 35 carbon atoms and may exist in racemic and optically active forms. The stereocenters may be of any combination of R and S configuration, for example, (R,R), (R,S), (S,S) or (S,R). All of these compounds are within the scope of the present invention. 11l WO 00/06146 PCT/US99/17121 For the compounds of formula (I) various embodiments are as follows. It will be understood that the basic nitrogen in moiety E may be optionally quaternized with C 1 6 alkyl or is optionally present as the N-oxide. P I and P 2 are suitably independently phenyl, fused bicyclic aryl, a 5 monocyclic heterocyclic ring of 5- to 7-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, or a fused bicyclic heterocyclic ring of 8 to 11 -members containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur. Preferably, P 1 is phenyl and P 2 is pheni or quinoxalinyl. More preferably Pl and P 2 are phenyl. 10 When Rl' is a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, suitable heterocyclic rings include aromatic groups such as thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, and dioxanyl. Saturated and partially saturated rings 15 are also within the scope of the invention, in particular rings including an oxo or thioxo moiety such as lactams and thiolactams. Suitably, the heterocyclic ring can be linked to the remainder of the molecule via a carbon atom, or, when present, a nitrogen atom. Suitable substituents for these rings include one to two of R 3 ' A is C(R 4
')
2 , CR 4
'(OR
5 '), CO, C=NOR 6 ', NR 7 ', oxygen, or S(O)c' 20 Preferably A is C(R 4
')
2 , CO, C=NOR 6 ', NR 7 ', oxygen, or sulfur. More preferably, A is CH 2 , CO, C=NOH, oxygen or sulfur. Most preferably, A is CH 2 , CO, oxygen or sulfur. Preferably, A is attached to P I meta or para to L, more preferably, A is attached to Pl para to L. L is suitably a group of formula -C(=V)-DR 8 '-, -DR 9 '-C(=V)-, -CH 2 NH-, or 25 -NHCH 2 -. L is preferably -C(=V)-DR 8 '-. V is suitably oxygen or sulfur. V is preferably oxygen. D is suitably nitrogen, carbon or a CH group. D is preferably nitrogen. RI' and R 2 ' are suitably independently hydrogen, C 1
-
6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, aryl, (CH2)d'NR1 0 'R 1 l', 30 (CH2)d'NR 10
'COR
1 2', (CH2)d'NR1 0
'CO
2
R
1 3', (CH2)d'NR 10
'O
2 R14', (CH2)d'CONR 15'R 16 ', hydroxyC 1- 6 alkyl, C 1-4alkoxyalkyl (optionally substituted by a C1-4alkoxy or hydroxy group), (CH2)d'CO 2 Cl- 6 alkyl, (CH2)e'OC(O)R 17 ',
CR
1 8
'=NOR
1 9', CNR 20
'=NOR
1 9', COR 2 1 ', CONR 1 5
'R
1 6', CONR 1 5
'(CH
2 )f OC 1 4 alkyl, CONR 15 '(CH2)d'CO 2
R
2 2 ', CONHNR 2 3
'R
2 4 ', CONR 15 'gO 2
R
2 5 ', 35 C0 2
R
2 6 ', cyano, trifluoromethyl,
NR
10 'R 1l', NR 10
'COR
12 ',
NR
2 7
'CO(CH
2 )d'NR27'R28', NR 2 7
'CONR
2 7
'R
2 8 ', NR 10
'CO
2
R
1 3'
NR
10
'SO
2 R1 4 ', N=CNR 27
'NR
2 7
'R
2 8 ', nitro, hydroxy, C 1 -6alkoxy, hydroxyC 1 6alkoxy, C1-6alkoxyC -6alkoxy, OC(O)NR 2 9
'R
30 ', SR 3 1 ', SOR 32 ', 30 2
R
32 ', 12 WO 00/06146 PCTIUS99/17121 S0 2
NR
3 3
'R
34 ', halogen, Cl-6alkanoyl, CO2(CH2)dOR 3 5', or Rl' is an optionally_ substituted 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur. Rl' and R 2 ' are preferably hydrogen, Cl_ 6 alkyl, hydroxy, or halogen. 5 R 3 'is suitably hydrogen, Cl- 6 alkyl, C3-6cycloalkyl, C3-6cycloalkenyl, hydroxyCl-6alkyl, Cl-6alkylOCl-6alkyl,
CONR
3 6
'R
3 7 ', C0 2
R
3 8 ', cyano, aryl, trifluoromethyl,
NR
3 9
'R
4 0 ', nitro, hydroxy, Cl-6alkoxy, Cl-6alkanoyl, acyloxy, or halogen. R 3 ' is preferably hydrogen, nitro, sulfamoyl or Cl-6alkylamino.
R
4 ', R 5 ', R 6 ', R 7 ', R1 8 ', R 19 ', R 2 0 ', R 2 1 ', R 2 2 ', R 2 3 ', R 2 4 ', R 27 ', R 28 ', R 3 1 ', 10 R 3 5 ', R 3 6 ', R 37 ', R 3 8 ', R 39 ', and R 4 0 ' are suitably independently hydrogen or Cl_ 6alkyl;
R
8 'is suitably hydrogen or C 1
-
6 alkyl, providing that D is nitrogen or a CH group. R 8 'is preferably hydrogen.
R
9 'is suitably hydrogen or C 1
-
6 alkyl, providing that D is nitrogen or a CH 15 group.
R
10 ' and R 1 l' are suitably independently hydrogen or Cl- 6 alkyl, or R 10 ' and R 11 ' together with the nitrogen to which they are attached, forms a 5- to 6 membered heterocyclic ring, which may optionally be substituted by an oxo group, and, when there are six members, may optionally contain in the ring one oxygen or 20 one sulfur atom.
R
12 'is suitably hydrogen, C 1
-
6 alkyl, or C1-4alkoxyalkyl.
R
13 ', R 25 ', and R 3 2 'are suitably independently Cl- 6 alkyl. R1 4 'is suitably C 1
-
6 alkyl or phenyl.
R
15 ' and R 16 ' are suitably independently hydrogen or C 1
-
6 alkyl, or R 15 ' and 25 R 16 ' together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which, when there are 6 ring members, may optionally contain in the ring one oxygen or one sulfur atom.
R
17 'is suitably Cl- 4 alkyl, optionally substituted by Cl-6alkoxy.
R
2 6 'is suitably hydrogen or Cl- 6 alkyl optionally substituted with one or two 30 substituents selected from C 1
-
6 alkyl, C1-6alkoxy, hydroxy, or NR 10
'R
1 l'.
R
2 9 ' and R 30 ' are suitably independently hydrogen or Cl- 6 alkyl, or R 29 ' and
R
3 0 ' together with the nitrogen to which they are attached form a 5- to 6-membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring one oxygen or sulfur atom. 35 R 3 3 ' and R 34 ' are suitably independently hydrogen or C 1
-
6 alkyl, or R 3 3 ' and
R
3 4 ' together with the nitrogen to which they are attached form 5- to 6-membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring one oxygen or sulfur atom. 13 WO 00/06146 PCT/US99/17121 a' and b' are independently 1, 2, or 3. c'is suitably 0, 1, or 2. d'is suitably 1, 2, 3, or 4. e'is suitably 0, 1, 2, or 3. 5 fis suitably 1, 2, or 3. E suitably represents (a): - B- (CR 1
R
2 )a -- NR3R4
(R
5 ),
R
6 (a); in which B is suitably oxygen, S(O)c, CR 7
=CR
8 , or CR 7
R
8 , or B is NR 9 . B is 10 preferably CR 7
R
8 , or oxygen. More preferably, B is CH 2 or oxygen.
R
1 and R 2 are suitably independently hydrogen or CI-6alkyl; alternatively
B(CRIR
2 )a is OCR 1
R
2
CR
1 (OH)CR IR 2 or OCR 1
R
2
CR
1
(OCOCH
3 )CR 1
R
2 . Preferably, R I and R 2 are hydrogen.
R
3 and R 4 are suitably independently hydrogen, Cl- 6 alkyl, C 3
-
7 cycloalkyl, 15 aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C 1
-
6 alkyl, aryl, CONR 1
O
R 11, NR 1O R 11, hydroxy, OCOR 12 ,
NHCOC
0
-
6 alkyl where alkyl is optionally substituted by OH, NHCOCF 3 , NHSO 2 20 R 13 , and NHCO 2
R
14 . Preferably R 3 and R 4 are both C 1
-
6 alkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7 membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur. More preferably, R 3 and R 4 are C 3
-
6 alkyl, or together with the nitrogen to which they are attached form a 6-membered ring, 25 optionally substituted with one or more of C1 -6alkyl, N-acetamido, or hydroxy. Most preferably, R 3 and R 4 are isopropyl or R 3 is isopropyl and R 4 is tert-butyl, or together with the nitrogen to which they are attached are 1-(2,2,6,6 tetramethylpiperidinyl), 1-( 4 -acetamido- 2
,
2 ,6,6-tetramethylpiperidinyl), 1-(4 hydroxy- 2 ,2,6,6-tetramethylpiperidinyl), or 1-(4-hydroxy-2,2,4,6,6 30 pentamethylpiperidinyl). Preferably,
B-(CRIR
2 )a-NR 3
R
4 is ortho to R 5 , meta to L, and para to R6, and R 5 is para to L.
R
5 is suitably hydrogen, C 1
-
6 alkyl, aryl, CN, CONR 15
R
16 , C0 2
R
17 , trifluoromethyl,
NHCO
2 R 18, hydroxy,
C
1 -6alkoxy, benzyloxy,
OCH
2
CO
2
C
1 35 6alkyl, OCF 3 , S(O)dR1 9 , S0 2
NR
20
R
21 , or halogen. R 5 is preferably Cl-6alkoxy, 14 WO 00/06146 PCTIUS99/17121
SC
1
.
6 alkyl, or halogen; more preferably methoxy, methylthio, or iodo, most preferably methoxy. When R 5 is methoxy, it is preferably para to L.
R
6 is suitably hydrogen, C 1 -6alkyl, aryl, trifluoromethyl, hydroxy, C 1 . 6alkoxy, or halogen, or R 6 taken together with R 8 ' forms a group D where D is 5 (CR 22
R
2 3 )e or D is (CR 2 2
R
2 3 )f-G where G is oxygen, sulfur, or CR 2 2
=CR
2 3 ,
CR
22 =N, =CR 2 2 0, =CR 2 2 S, or =CR 22
-NR
2 3 . Preferably, R 6 is hydrogen.
R
7 , R 8 , R 10 , R 11, R 15 , R 16 , R 17 , R 20 , R 2 1 , R 22 , and R 2 3 are independently hydrogen or C 1 -6alkyl.
R
9 is hydrogen, C 1 -6alkyl, or phenylC 1-6alkyl. 10 R 12 , R 13 , R 14 , R1 8 , and R 19 are independently C1- 6 alkyl. a is suitably 1, 2, 3, or 4. Preferably, a is 2 or 3, more preferably, a is 2 or 3 when B is oxygen and a is 2 when B is CH 2 , most preferably, a is 2 when B is oxygen. b is suitably 1 or 2. Preferably, b is 1. 15 c and d are suitably independently 0, 1, or 2. e is suitably 2, 3, or 4. f is suitably 0, 1, 2, or 3. alternatively, E suitably represents (b):
R
28 R92CX
R
2 6
R
27 C NR 3 0 -- (CR 2 4
R
2 5 )g (CR31R32)h R33 (b); 20
R
2 4 , R 25 , R 26 , R 27 , R 2 8 , R 29 , R 3 1 , and R 32 are suitably independently hydrogen or C 1
-
6 alkyl. R 2 4 , R 25 , R 26 , R 2 7 , R 2 8 , R 29 , R 3 1 , and R 3 2 are preferably hydrogen.
R
30 is suitably hydrogen, Cl- 6 alkyl, or C3-7cycloalkyl. Preferably, R 3 0 is
C
1
-
6 alkyl, more preferably, R 3 0 is C 3
-
6 alkyl, most preferably, R 3 0 is isopropyl. 25 R 33 is suitably hydrogen, C 1
-
6 alkyl, trifluoromethyl, hydroxy, or halogen, or R 33 and R 8 ' together form a group -K- where K is (CR 34
R
3 5 ); or K is
(CR
34
R
3 5)j -M and M is oxygen, sulfur, CR 34
=CR
3 5 , CR 34 =N, or N=N. Preferably, R 3 3 is hydrogen. J is suitably oxygen, CR 36
R
37 , or NR 3 8 , or J is a group S(O)k, Preferably, 30 J is oxygen. Preferably, J is para to L.
R
34 , R 35 , R 3 6 , R 3 7 , R 38 are suitably independently hydrogen or C 1 -6alkyl. g is suitably 1, 2, or 3. Preferably, g is 2 or 3, more preferably 2. h is suitably 1, 2, or 3. Preferably, h is 1. i is suitably 2, 3, or 4. 35 j is suitably 0, 1, 2, or 3. 15 WO 00/06146 PCT/US99/17121 k is. suitably 0, 1 or 2. Known compounds overlapping with the scope of the instant invention are as follows. A subgenus of formula (I) wherein: the basic nitrogen in moiety E may be 5 optionally quaternized with C 1 -6alkyl or is optionally present as the N-oxide; E is (b); J is CH 2 ; g is 1, 2, or 3; h is 1, 2, or 3; R 2 4 , R 2 5 , R 2 6 , R 2 7 , R 2 8 , R 2 9 , R 3 1 , and R32 are hydrogen; R 30 is hydrogen or C1-6alkyl; R 33 is hydrogen, C 1 -6alkyl, trifluoromethyl, or halogen; L is CONR 8 ' or NR 9 'CO; R 8 ' and R 9 ' are independently hydrogen or C1- 6 alkyl; P 1 and P 2 are phenyl; A is CO, 0 or S(O) 0
-
2 ; R 'is 10 hydrogen; R 2 'is hydrogen or 1, 2, or 3 of hydroxy, C 1
-
3 alkyl, cyano, halogen, or trifluoromethyl; R 3 ' is hydrogen or 1 or 2 of hydroxy, cyano, halogen, trifluoromethyl, CONR 36
*R
37 *, COC 1
-
5 alkyl, C0 2
R
38 *, C 1
-
6 alkoxy, or phenyl; and R 3 6 *, R 37 *, and R 3 8 * are independently hydrogen or Cl- 6 alkyl, has been described in WO 98/25604, published 18 June 1998, as chemokine receptor 15 modulators. Further, a subgenus of formula (I) wherein: the basic nitrogen in moiety E may be optionally quaternized with C 1
-
6 alkyl or is optionally present as the N oxide; E is (b); J is CH 2 ; g is 1, 2, or 3; h is 1, 2, or 3; R 2 4 , R 2 5 , R 2 6 , R 2 7 , R 2 8 ,
R
2 9 , R 3 1 , and R 32 are hydrogen; R 30 is hydrogen or C1- 6 alkyl; R 3 3 is hydrogen, 20 C 1
-
6 alkyl, trifluoromethyl, or halogen; L is CH 2 NH; P 1 is heteroaryl, wherein heteroaryl is selected from the group consisting of benzimidazolyl, benzofuranyl, benzooxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl; A is CO, 0 or S(O) 0
-
2 ; p 2 is phenyl; R1* is hydrogen 25 or one of hydroxy, cyano, halogen, trifluoromethyl, NR1O*COR1 2 *, NRlO*CO 2 Rl 3 *, NR 2 7
*CONHR
2 8 *, NHS(O) 0
-
2 R14*, CONR15*R 1 6 *, COC 1 . 5 alkyl, C0 2
R
2 6 *, C1-6alkoxy, SR 3 1*, SOR 3 2 *, S0 2
R
32 *, or phenyl, or RI* is an optionally substituted heterocyclic ring selected from furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, 30 pyrimidyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl; R 2 * is hydrogen or 1, or 2 of hydroxy, cyano, halogen, trifluoromethyl, NR1O*COR1 2 *, NRlO*CO 2 Rl 3 *, NR 27
*CONHR
2 8 *, NHS(O)0- 2 Rl 4 *, CONR15*Rl 6 *, COCI 5alkyl, C0 2
R
2 6 *, Cl- 6 alkoxy, SR 3 1*, SOR 3 2 *, S0 2
R
32 *, or phenyl; R 3 is hydrogen or 1 or 2 of hydroxy, cyano, halogen, trifluoromethyl,
CONR
36
*R
37 *, 35 COCl- 5 alkyl, C0 2
R
3 8 *, Cl- 6 alkoxy, or phenyl; RIO*, R1 2 *, R15*, R1 6 *, R 27 *,
R
2 8 *, R 3 l*, R 3 6 *, R 3 7 *, and R 3 8 * are independently hydrogen or C1- 6 alkyl; R1 3 * and R 3 2 * are independently C1- 6 alkyl; R1 4 * is C 1 -6alkyl or phenyl; and R 26 * is hydrogen or C 1 -6alkyl optionally substituted with one or two of hydroxy, has been 16 WO 00/06146 PCT/US99/17121 described in WO 98/25604, published 18 June 1998, as chemokine receptor modulators. A preferred subgenus of the compounds of formula (I) are compounds of formula (Ia) in which R 1 ', R 2 ', R 3 ', pl, p 2 , A, a', b', L, R 2 4 , R 25 , R 2 6 , R 2 7 , R 2 8 , 5 R 2 9 , R 30 , R 3 1 , R 3 2 , R 3 3 , J, g, and h are defined as above:
(R
2 ')a, (R3')b, R 28 R2C 9
R
26
R
27 C NR 30
-(CR
24
R
2 5 )g R "' ~P2 -A Pi R P ACR 31
R
32 )h
R
33 Formula (Ia) 10 Among the preferred compounds of the invention are the following compounds: N-[4-[2-(Dimethylamino)ethyl]-3,4-dihydro-2H- 1,4-benzoxazin-6-yl)-4 phenoxybenzamide;
N-[
3
-[
2 -(Diethylamino)ethoxy]-4-methoxyphenyl]-4-phenoxybenzamide; 15 N-[4-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]]-4-phenoxybenzamide;
N-[
4
-[
2 -(Diethylamino)ethoxylphenyl]-4-phenoxybenzamide; N-[3-[2-[Bis(1 -methylethyl)amino]ethoxy]phenyl]-4-phenoxybenzamide; N-[3-[2-[Bis(1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 phenoxybenzamide; 20 N-[ 3
-[
2 -(Diethylamino)ethoxy]-4-methoxyphenyl]-3-phenoxybenzamide; N-[4-[2-[Bis(1 -methylethyl)amino]ethoxy]phenyl]-3-phenoxybenzaiide; N-[4-[2-[Bis(1 -methylethyl)amino]ethoxy]phenyl]-4 (phenylmethyl)benzamide;
N-[
2
-[
2 -(Diethylamino)ethoxy]phenyl]-4-(phenylmethyl)benzamide; 25 N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 phenoxybenzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (phenylmethyl)benzamide; N-[3-[2-[Bis(1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-2 30 (phenylmethyl)thiazole-4-carboxamide hydrochloride; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 phenoxybenzamide Methiodide; N-[ 1-[2-[Bis(1 -methylethyl)amino]ethyl]- 1,2,3,4-tetrahydroquinol-7-yl]-4 phenoxybenzamide; 17 WO 00/06146 PCT/US99/17121 .N- [3- [2- [Bis( 1 -methylethyl) amino] ethoxy] -4-methoxyphenyl] 4-(3 hydroxyphenoxyjbenzamide; N-[3-[2-[Bis(l1-methylethyl)amino]ethoxy]-4-methoxyphenyly-4 1(4 chloropheny1)sulfinyl]-3-nitrobenzaflijde; 5 N-[3-[2-[Bis(l1-methylethy)amino]ethoxy-4-methoxyphenyl]y4-[(2,4 dichlorophenyl)sulfiny-3nitrobenzamide; N-[3-[3-[Bis(l1-methylethyl)aminolpropyl-4-methoxyphenyl]y3 phenoxybenzamide; N- [3 -[2-(2,2,6,6-Tetramethy[- 1 -piperidinyl)ethoxy] 4-methoxyphenyl] 3 10 phenoxybenzamide; N- [3 -[3- B is (1 -methylethyl) amino Ipropylly4-methoxyphenyl 1 4 phenoxybenzamide; N- [ 3 -[2- (2,2,6,6-Tetramethyk. 1 -piperidinyl)ethoxy 4-methoxyphenyl 4 phenoxybenzainide; 15 N-[3-[2-[Bis(I1-methylethyl)amiinojethoxy-4-methoxyphenyl-4 benzoylbenzamide; N- [3- [3-[Bis( 1 -methylethyl) amino] propyl-4-methoxyphenyly 4 benzoylbenzamide; N- [ 3 -[2-(2,2,6,6-Tetramethyl. 1 -piperidinyl)ethoxyy 4-methoxyphenylly4 20 benzoylbenzamide; N-[3-[3-[Bis(I1-methylethyl)aminolpropyl-4-methoxyphenyl-4 (phenylmethyl)benzaflie; N- [3- [ 2 -(2,2,6,6-Tetramethyl - 1 -piperidinyl)ethoxy ]-4-methoxyphenyl 4 (phenylmethyl)benzanmjde; 25 N- [ 3-[2- [B is (1 -methylethy 1) amino] ethoxy [4-methoxypheny ] 4- [ (4 chlorophenyl)sulfonyl]benzamide; N- [3- [3 -[Bis (1 -methylethyl) amino] propyl-4-methoxyphenyl] 4- [(4 chlorophenyl)sulfonyl]benzamide; N-[3-[2-(2,2,6,6-Tetramethyl[ 1 -piperidinyl)ethoxy-4-methoxyphenyly4-[(4 30 chlorophenyl)sulfonyl]benzanmjde; N-[3-[2-[Bis( I -methylethy)amino]ethoxy-4methoxypheny]psbutylamino 4 -phenoxy-3-(sulfamoyl)benzamide; N-[3-[3-[Bis( 1 -methylethyl)aminolpropyl-4-methoxyphenyll-5butyl~amino 4 -phenoxy-3-(sulfamoyl)benzamide; 35 N-[ 3 -[2-(2,2,6,6-Tetramethyl- 1 -piperidinyl)ethoxy]-4-methoxyphenylys5 butylamino-4-phenoxy-3..(sulfamoyl)benzamide; N-[3- [2-[Bis( I -methylethyl)amino]etloxy-4methoxyphenyl]4(4 chlorophenoxy-3-nitrobenzamide; 18 WO 00/06146 PCT/US99/17121 N-[3-[3-[Bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-4-(4 chlorophenoxy)-3-nitrobenzamide; N-[3-[2-(2,2,6,6-Tetramethyl-1-piperidinyl)ethoxy]-4-methoxyphenyl]-4-(4chlorophenoxy)-3-nitrobenzamide; 5 N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(2 quinoxalinylamino)benzamide; N-[3-[3-[Bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-4-(2 quinoxalinylamino)benzamide; N-[3-[2-(2,2,6,6-Tetramethyl- 1 -piperidinyl)ethoxy]-4-methoxyphenyl]-4-(2 10 quinoxalinylamino)benzamide; N-[3-[2-[Bis(1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4 methylphenyl)sulfonyl]-3-nitrobenzamide; N-[3-[3-[Bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-4-[(4 methylphenyl)sulfonyl]-3-nitrobenzamide; 15 N-[3-[2-(2,2,6,6-Tetramethyl- 1-piperidinyl)ethoxy]-4-methoxyphenyl]-4-[(4 methylphenyl)sulfonyl]-3-nitrobenzamide; N-[3-[2-[Bis(1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 benzoylbenzamide; N-[3-[2-[Bis(1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 20 (methylphenylamino)benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (phenylamino)benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (phenylthio)benzamide; 25 N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (phenylsulfonyl)benzamide; N-[3-[2-[Bis(1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (phenylsulfinyl)benzamide; N-[3-[2-[Bis(1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 30 [(hydroxyimino)phenylmethyl]benzamide; N-[3-[2-[Bis(1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (hydroxyphenylmethyl)benzamide; N-[ 1 '-(1 -Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl] 4 -benzoylbenzamide trifluoroacetate; 35 N-[l'-(1-Methylethyl)spiro[benzofuran-3( 2 H),4'5-piperidin]-5-yl]-4 phenoxybenzamide; and N-[l'-(1-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4 (phenylthio)benzamide. 19 WO 00/06146 PCTIUS99/17121 Among the more preferred compounds of this invention are the following compounds: ,N-[3- [2-[Bis(l1-methylethyl)amiinolethoxy]-4-methoxyphenylp3 phenoxybenzamide; 5 .N-[3- [2-[Bis(I1-methylethyl)amino]ethoxy]-4-methoxyphenyly4 (phenylmethyl)benzanmjde; N-[3-[2-[Bis(I1-methylethyl)anlino]ethoxy]-4-methoxyphenyly4 phenoxybenzamide methiodide N- [3- [3- [Bis(l1-methylethyl)amino]propyl]-4-methoxyphenyly-3 10 phenoxybenzamide; N-[3-[2-(2,2,6,6-Tetramethyl-l1-piperidinyl)ethoxy]-4-methoxyphenyly3 phenoxybenzamide; N-[3- [3-[Bis(I1-methylethyl)aminolpropyll-4-methoxyphenyly4 phenoxybenzamide; 15 N- [3- [ 2 -(2,2,6,6-Tetramethyl- 1 -piperidinyl)ethoxy]-4-methoxyphenyl-4 phenoxybenzamide; N- [3-[2-[Bis(l1-methylethyl)amino]ethoxy-4-methoxyphenyl]-4 benzoylbenzamide; N-[3- [3-IIBis(I1-methylethyl)amino]propyly4-methoxyphenyly4 20 benzoylbenzamide;
N-[
3 -[2-(2,2,6,6-Tetramethyl-l1-piperidinyl)ethoxy]-4-methoxyphenyly4 benzoylbenzainide; N-[3-[3-[Bis(l1-methylethyl)amino]propyl]y4-methoxyphenyl-4 (phenylmethyl)benzamide; 25 N- [3- [ 2 -(2,2,6,6-Tetramethyl-l1-piperidinyl)ethoxy]-4-methoxyphenyl-4 (phenylmethyl)benzanmjde; N-1 3 -[2-(2,2,6,6-Tetramethyl. 1-piperidinyl)ethoxy]-4-methoxyphenyl].5 butylamino-4-phenoxy-3(sulfamoyl)benzamide; N-[3-[2-[Bis(l1-methylethyl)amino]ethoxy].4methoxyphenyly4-[(4 30 chlorophenyl)oxy]-3-nitrobenzayniide; N-13-[2-(2,2,6,6-Tetramethyp 1 -piperidinyl)ethoxy]-4-methoxyphenyly4-[(4 chlorophenyl)oxy]-3-nitrobenzanmjde; N-[3- [2-[Bis(I1-methylethyl)amino]ethoxy]-4.methoxyphenyly4 (phenylthio)benzamide; 35 N- [3-[2-[Bis(l1-methylethyl)amino]ethoxy-4-methoxyphenyl-4 [(hydroxyimino)phenylmethyl]benzamide; N-[ 1'-(1 -Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin] -5-yl] 4-benzoylbenzamide trifluoroacetate; 20 WO 00/06146 PCTIUS99/17121 N-[l '-(1-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4 phenoxybenzamide; and N-[1 '-(1-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4 (phenylthio)benzamide. 5 Among the most preferred compounds of this invention are the following compounds: N-[ 1 '-(1-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl] 4-benzoylbenzamide trifluoroacetate; N-[l 1'-(1-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4 10 phenoxybenzamide; and N-[1 '-(1-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4 (phenylthio)benzamide. Among compounds excluded from this invention are the following compounds: 15 N-[2-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-4-phenoxybenzamide;
N-[
2
-[
2 -(Diethylamino)ethoxy]phenyl]-4-phenoxybenzamide;
N-[
4
-[
2 -(Diethylamino)ethoxy]phenyl]-3-phenoxybenzamide; N-[2-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-3-phenoxybenzamide;
N-[
2
-[
2 -(Diethylamino)ethoxy]phenyl]-3-phenoxybenzamide; 20 N-[ 4
-[
2 -(Diethylamino)ethoxy]phenyl]-4-(phenylmethyl)benzamide; and N-[2-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-4 (phenylmethyl)benzamide. Formulation of Pharmaceutical Compositions The pharmaceutically effective compounds of this invention (and the 25 pharmaceutically acceptable salts thereof) are administered in conventional dosage forms prepared by combining a compound of this invention ("active ingredient") in an amount sufficient to treat COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, 30 inflammatory bowel disease, and HIV infection, ("CCR5-mediated disease states") with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. 35 The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or 21 WO 00/06146 PCT/US99/17121 diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax. A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in 5 powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1000 mg. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension. 10 The active ingredient may also be administered topically to a mammal in need of treatment or prophylaxis of CCR5 mediated disease states. The amount of active ingredient required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the disease state being treated and the mammal undergoing treatment, and is ultimately at the discretion of the 15 physician. A suitable dose of an active ingredient is 1.5 mg to 500 mg for topical administration, the most preferred dosage being 1 mg to 100 mg, for example 5 to 25 mg administered two or three times daily. By topical administration is meant non-systemic administration and includes the application of the active ingredient externally to the epidermis, to the buccal cavity 20 and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream. By systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration. While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. The active 25 ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the formulation. The topical formulations of the present invention, both for veterinary and for 30 human medical use, comprise an active ingredient together with one or more acceptable carrier(s) therefor and optionally any other therapeutic ingredient(s). The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Formulations suitable for topical administration include liquid or semi-liquid 35 preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. 22 WO 00/06146 PCT/US99/17121 Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous or alcoholic solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent. The 5 resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100 C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), 10 benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol. Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally 15 containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil. Creams, ointments or pastes according to the present invention are semi-solid 20 formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis. The basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural 25 origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic 30 materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included. The active ingredient may also be administered by inhalation. By "inhalation" is meant intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be 35 prepared by conventional techniques. The daily dosage amount of the active ingredient administered by inhalation is from about 0.1 mg to about 100 mg per day, preferably about I mg to about 10 mg per day. 23 WO 00/06146 PCT/US99/17121 In one aspect, this invention relates to a method of treating COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and 5 HIV infection, all in mammals, preferably humans, which comprises administering to such mammal an effective amount of a CCR5 receptor modulator, in particular, a compound of this invention. By the term "treating" is meant either prophylactic or therapeutic therapy. Such compound can be administered to such mammal in a conventional dosage form 10 prepared by combining the compound of this invention with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other 15 well-known variables. The compound is administered to a mammal in need of treatment for COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic diseases, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIV infection, in an amount sufficient to decrease symptoms 20 associated with these disease states. The route of administration may be oral or parenteral. The term parenteral as used herein includes intravenous, intramuscular, subcutaneous, intra-rectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally 25 preferred. The daily parenteral dosage regimen will preferably be from about 30 mg to about 300 mg per day of active ingredient. The daily oral dosage regimen will preferably be from about 100 mg to about 2000 mg per day of active ingredient. It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of this invention will be determined by 30 the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the compound given per day for a defined number of days, can be ascertained by those 35 skilled in the art using conventional course of treatment determination tests. Methods of Preparation 24 WO 00/06146 PCTIUS99/17121 Compounds of formula (I) are prepared by condensing suitably substituted aryl or heteroarylcarboxylic acids and suitably substituted anilines, which are commercially available or synthesized by methods known to the art from commercially available starting materials, using methods known to the art. For 5 example, suitably substituted aryl or heteroarylcarboxylic acids are treated with a suitable reagent, such as thionyl chloride, at a suitable temperature, such as at reflux, to afford aryl or heteroarylcarbonyl chlorides, and the aryl- or heteroarylcarbonyl chlorides are condensed with suitably substituted anilines in the presence of a suitable base, such as diisopropylethylamine, in a suitable solvent, such as 10 dichloromethane, to give compounds of formula (I). Many additional methods for converting a carboxylic acid to an amide are known, and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol. I-VI (published by Wiley-Interscience). Compounds of formula (I) are also prepared using solid-phase chemistry as 15 described in Scheme I and using the general method described in international patent application WO 99/01127, published 14 January 1999. For example, in Scheme 1, an appropriately substituted 3
-(
2 -aminoethoxy)-4-methoxyaniline 1-2, such as 3-[2 (diisopropylamino)ethoxy]-4-methoxyaniline, which is synthesized from the commercially available 2 -methoxy-5-nitrophenol, I-1, according to the procedures 20 described in WO 99/01127, is attached to a polymer support such as Merrifield resin-bound aldehyde 1-3, which is synthesized according to the general protocol of Boojamra et al., (J. Org. Chem., 1995, 60, 5742-3) by reductive amination employing a reducing agent such as sodium triacetoxyborohydride in dimethylformamide with 1% acetic acid to give 1-4. The resulting resin-bound 25 aniline 1-4 is acylated with a commercially available or synthetically accessible, suitably substituted aryl or heteroaryl carboxylic acid 1-5, for example 4 phenoxybenzoic acid, using, for example, N-bromo succinimide and triphenylphosphine in dichloromethane, or in dichloromethane in combination with dimethylformamide, in the presence of an organic base such as pyridine to afford I 30 6. For example, 1-4 is treated with a ten-fold excess of an equimolar mixture of a 3 aryl- or heteroaryl carboxylic acid, triphenylphosphine and N-bromosuccinimide, in a suitable solvent, such as dichloromethane, after which a ten-fold excess of a suitable base, such as pyridine, is added, and the mixture is gently agitated for a suitable time, for example, forty-eight hours, to afford the resin-bound amide 1-6. 35 Optionally, dimethylformamide may be added to the resulting mixture to increase the solubility of the 3-aryl- or heteroaryl carboxylic acid. Treatment of 1-6 with a mixture of a strong organic acid and organic solvent, such as trifluoroacetic 25 WO 00/06146 PCT/US99/17121 acid:dichloromethane:water (50:48:2), resulted in cleavage of the desired compound from the polymer support and afforded carboxanilide 1-7, a compound of formula L Scheme I:
OCH
3 3 OHC OH N__ OH NR4_ CH 3 0 0 O C H 3 a, b O CH 3 3 Merrifield
H
2 N c Ra 2 R3 R3 O N R4 (R 2 ')a (( 3 ) b O N R'-'- P2 A- P1 2 R*a,( 3 b Ja 5 HN OCH 3 R R p 2 A P N OCCH 3 d
CH
3 O 0
CH
3 0 0 Merrifield 6 Merrifield 4 R3 O N R4 e
(R
2 -)a, (Ra')b' O OCH 3 R p A pl N H 5 7 a) Cl(CH 2
)
2
NR
3
R
4 , K 2 C0 3 , CH 3
COCH
3 ; (b) H 2 , 5% Pd/C, MeOH; (c) Merrifield resin bound aldehyde (3); NaBH(OAc) 3 , 1% HOAc, DMF; (d) aryl/heteroaryl carboxylic acid, NBS, Ph 3 P, pyridine; (e) TFA, CH 2 Cl 2 , H 2 0. The invention will now be described by reference to the following examples 10 which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. In the Examples, mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated. EXAMPLES 15 Preparation 1 Preparation of 4 -(Methylphenylamino)benzoic acid 26 WO 00/06146 PCT/US99/17121 A solution of ethyl 4 -(methylphenylamino)benzoate (2.65 g, 10 mmol) (Tetrahedron Lett. 1997, 38, 6359-6362) in tetrahydrofuran (50 mL), ethanol (25 mL), and water (5 mL) was treated with 1 N sodium hydroxide (84 mL) and heated to 50'C for 20 h. The mixture was reduced in volume in vacuo, diluted with water, 5 and extracted three times with ethyl acetate. The aqueous phase was acidified with acetic acid to pH-6 and the white solid which precipitated was isolated by filtration, washed with water, and dried to give the title compound (1.95 g). MS (ES) m/e 227.8 (M+H)+. Preparation 2 10 Preparation of 1 '-(1-Methylethyl)spirofbenzofuran-3(2H),4'-piperidinl-5-amine a) 5- and 7 -nitrospiro[benzofuran-3(2H),4'-piperidine] A solution of 1 '-methyl-5- and 7 -nitrospiro [benzofuran-3(2H),4'-piperidine] (WO 96/11934) (3 g, 12 mmol) and diisopropylethylamine (2.5 g, 19 mmol) in 1,2 dichloroethane (80 mL) was treated with 1-chloroethyl chloroformate (2.3 g, 16 15 mmol) at RT, stirred for I h, and heated to reflux for 20 min. The mixture was cooled, concentrated in vacuo, and the residue was dissolved in methanol and heated to reflux for 2 h, concentrated in vacuo, and the residue was partitioned between dichloromethane (250 mL) and 5% sodium bicarbonate (50 mL). The organic phase was washed with 5% sodium bicarbonate (50 mL) and the combined aqueous phase 20 was extracted with dichloromethane (2 X 50 mL). The combined organic phase was dried (Na 2 SO4) and concentrated to afford the title compound (2. 65 g). b) l'-(tert-butoxycarbonyl)-5-nitrospiro[benzofuran-3(2H),4'-piperidine] A solution of the compound of Preparation 2(a)(2.65 g, 1.13 mmol) in tetrahydrofuran (300 mL) was treated with di-tert-butyl dicarbonate (2.6 g, 12 mmol) 25 and stirred at RT for 16 h. The mixture was concentrated in vacuo and the residue was crystallized from methanol to afford the title compound (2.1 g). c) 5-nitrospiro[benzofuran-3(2H),4'-piperidine] A solution of the compound of Preparation 2(b)(2.1 g, 6.3 mmol) in dichloromethane (50 mL) and trifluoroacetic acid (10 mL) was kept at RT for 5 h, 30 concentrated in vacuo, and the residue was partitioned between dichloromethane (300 mL) and 5% sodium bicarbonate. The organic phase was washed with 5% sodium bicarbonate and the combined aqueous washes were extracted with dichloromethane. The combined organic phase was dried (Na 2
SO
4 ) and concentrated in vacuo to give the title compound (1.45 g). MS(ES) m/e 235.1 35 [+H]+. d) 1'-(1-methylethyl)-5-nitrospiro[benzofuran-3(2H),4'-piperidine] A mixture of the compound of Preparation 2(c) (1.45 g, 6.2 mmol), powdered potassium carbonate (0.86 g, 6.2 mmol) and dimethylformamide (50 mL) 27 WO 00/06146 PCT/US99/17121 containing 2-iodopropane (1.1 g, 6.4 mmol) was stirred and heated to 50'C for 4 h, treated with 2-iodopropane (0.17 g, 1 mmol) at 50'C for 90 min, and treated with 2 iodopropane (0.1 g, 1 mmol) at 50 0 C for 2 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and water (20 5 mL). The organic phase was washed, dried (MgS04), concentrated in vacuo, and the residue was chromatographed (silica gel, 5% methanol:dichloromethane) to give the title compound (0.85 g). e) 1 '-(1-methylethyl)spiro[benzofuran-3( 2 H),4'-piperidin]-5-amine A solution of the compound of Preparation 2(d) (0.78 g, 2.8 mmol) in 10 methanol (250 mL) containing 10% palladium-on-carbon (0.375 g) was shaken in a hydrogen atmosphere (40 psi) for 40 min, filtered, and concentrated in vacuo to afford the title compound (0.6 g). Preparation 3 Preparation of 7-Amino-3,4-dihydro-N,N-bis(1 -methylethyl)- 1(2H) 15 quinolineethanamine a) 3,4-dihydro-N,N-bis(1-methylethyl)-7-nitro-1(2H)-quinolineethanamine Sodium carbonate (2.9 g, 27 mmol) was added to a mixture of 7-nitro 1, 2 ,3,4-tetrahydroquinoline (1.2 g, 6.7 mmol) (United States Patent 5696133), 2 (diisopropylamino)ethyl chloride hydrochloride (4.0 g, 20 mmol), and ethanol (25 20 mL). The mixture was heated at reflux for 3 h, filtered, and concentrated in vacuo. The crude product was purified by chromatography (silica gel, dichloromethane followed by 5% methanol:dichloromethane) to afford 1.4 g (68%) of the title compound as a yellow oil. MS(ES) m/e 306.1 [M+H]+. b) 7-amino-3,4-dihydro-N,N-bis(1-methylethyl)-1( 2 H)-quinolineethanamine 25 A mixture of the compound of Preparation 3(a) and 5% palladium-on-carbon in ethanol was hydrogenated at 50 psi. The mixture was filtered and concentrated in vacuo to afford the title compound. Preparation 4 Preparation of 2 -(Phenylmethyl)-4-thiazolecarboxylic Acid 30 A solution of benzeneethanethioamide (1.0 g, 6.6 mmol) in dioxane (25 mL) was treated with bromopyruvic acid (1.1 g, 6.6 mmol) and heated to 90'C for 4 h. The mixture was diluted with water and the tan crystals which formed were collected by filtration to afford the title compound. Example 1 35 Preparation of N-r 3
-[
2 -(Diethylamino)ethoxyl-4-methoxyphenyll-4 phenoxybenzamide a) 3
-[
2 -(diethylamino)ethoxy]- 4 -methoxyaniline/[4-formyl-3,5 (dimethoxy)phenoxy]-Merrifield resin adduct 28 WO 00/06146 PCT/US99/17121 A mixture of [ 4 -formyl-3,5-(dimethoxy)phenoxy]-Merrifield resin (Boojamra et al., J. Org. Chem. 1995, 60, 5742-3), 3-[2-(diethylamino)ethoxy]-4 methoxyaniline (WO 95/15954), and sodium triacetoxyborohydride in dimethylformamide containing 1% acetic acid was shaken to afford the title adduct. 5 b) N-[ 3
-[
2 -(diethylamino)ethoxy]-4-methoxyphenyl]-4 phenoxybenzamide/[4-formyl-3,5-(dimethoxy)phenoxy]-Merrifield resin adduct The resin of Example 1(a) was placed in an Irori MicroKan and treated with a ten-fold molar excess of an equimolar mixture of 4-chlorocinnamic acid, N bromosuccinimide, and triphenylphosphine in dichloromethane, followed by 10 addition of a ten-fold excess of pyridine. The mixture was gently agitated for 48 h after which the resin was washed three-times, sequentially with dimethylformamide, dichloromethane, and methanol to afford the title adduct. c) N-[ 3
-[
2 -(diethylamino)ethoxy]-4-methoxyphenyl]-4-phenoxybenzamide The resin of Example 1(b) was stirred in a mixture of trifluoroacetic 15 acid:dichloromethane:water (50:48:2), filtered, and the filtrate concentrated in vacuo to afford the title compound. MS (ES) m/e 435.0 (M+H)+. Examples 2-30 Following the procedure of Example 1 (a)-(c), except using 4-[(2 diisopropylamino)ethoxy]aniline (WO 99/01127), 4 -[2-(diethylamino)ethoxy]aniline 20 (J. Med. Chem. 1995, 38, 1657-65), 3
-[(
2 -diisopropylamino)ethoxy]aniline (WO 99/01127), 3
-[(
2 -diisopropylamino)ethoxy]-4-methoxyaniline (WO 95/15954), 3-[2
(
2 ,2,6,6-tetramethyl- 1 -piperidinyl)ethoxy]-4-methoxyaniline (WO 99/01127), and 3
[(
3 -diisopropylamino)propyl]-4-methoxyaniline (WO 99/01127) in addition to 3-[2 (diethylamino)ethoxy]-4-methoxyaniline, and except using 3-phenoxybenzoic acid, 25 4-(phenylmethyl)benzoic acid, 4-benzoylbenzoic acid, 4-[(4 chlorophenyl)sulfonyl]benzoic acid, 5-butylamino-4-phenoxy-3-(sulfamoyl)benzoic acid, 4
-[(
4 -chlorophenyl)oxy]-3-nitrobenzoic acid, 2-[(4 carboxyphenyl)amino]quinoxaline, and 4
-[(
4 -methylphenyl)sulfonyl]-3-nitrobenzoic acid in addition to 4 -phenoxybenzoic acid, gave the title compounds: 30 N-[4-[2-[bis(1-methylethyl)amino]ethoxy]phenyl]]-4-phenoxybenzamide: MS (ES) m/e 433.2 (M+H)+;
N-[
4
-[
2 -(diethylamino)ethoxy]phenyl]-4-phenoxybenzamide: MS (ES) n/e 405.2 (M+H)+; N-[3-[2-[bis(1-methylethyl)amino]ethoxy]phenyl]-4-phenoxybenzanmide: 35 MS (ES) m/e 433.2 (M+H)+;
N-[
3
-[
2 -(diethylamino)ethoxy]-4-methoxyphenyl]-3-phenoxybenzamide: MS (ES) m/e 435.0 (M+H)+; 29 WO 00/06146 PCTIUS99/17121 N-[4-[2-[bis(1-methylethyl)arnino]ethoxyphenyl]-3-phenoxybenzamide: MS (ES) m/e 433.2 (M+H)+; N-[4-[2-[bis(1 -methylethyl)amino]ethoxy]phenyl]-4 (phenylmethyl)benzamide: MS (ES) m/e 431.2 (M+H)+; 5 N-[ 2
-[
2 -(diethylamino)ethoxy]phenyl]-4-(phenylmethyl)benzamide: MS (ES) m/e 403.0 (M+H)+; N-[3-[3-[bis(1-methylethyl)anino]propyl]-4-methoxyphenyl]-3 phenoxybenzamide: MS (ES) m/e 460.9 (M+H)+;
N-[
3
-[
2 -(2,2,6,6-tetramethyl- 1-piperidinyl)ethoxy]-4-methoxyphenyl]-3 10 phenoxybenzamide: MS (ES) m/e 502.9 (M+H)+; N-[3-[ 2
-(
2
,
2 ,6,6-tetramethyl-1-piperidinyl)ethoxy]-4-methoxyphenyl]-4 phenoxybenzamide: MS (ES) m/e 503.3 (M+H)+; N-[3-[3-[bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-4 benzoylbenzamide: MS (ES) m/e 473.3 (M+H)+; 15 N-[ 3 -[2-(2,2,6,6-tetramethyl-1-piperidinyl)ethoxy]-4-methoxyphenyl]-4 benzoylbenzamide: MS (ES) m/e 515.3 (M+H)+; N-[3-[3-[bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-4 (phenylmethyl)benzamide: MS (ES) m/e 459.3 (M+H)+;
N-[
3
-[
2 -(2,2,6,6-tetramethyl-1-piperidinyl)ethoxy]-4-methoxyphenyl]-4 20 (phenylmethyl)benzamide: MS (ES) m/e 501.3 (M+H)+; N-[3-[2-[bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4 chlorophenyl)sulfonyl]benzamide: MS (ES) m/e 545.2 (M+H)+; N-[3-[3-[bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-4-[(4 chlorophenyl)sulfonyl]benzamide: MS (ES) m/e 543.2 (M+H)+; 25 N-[ 3
-[
2
-(
2
,
2
,
6 ,6-tetramethyl-1 -piperidinyl)ethoxy]-4-methoxyphenyl]-4-[(4 chlorophenyl)sulfonyl]benzanide: MS (ES) m/e 585.2 (M+H)+; N-[3-[2-[bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-5-butylamino 4-phenoxy-3-(sulfamoyl)benzamide: MS (ES) m/e 613.3 (M+H)+; N-[3-[3-[bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-5-butylamino 30 4 -phenoxy-3-(sulfamoyl)benzamide: MS (ES) n/e 611.3 (M+H)+;
N-[
3
-[
2
-(
2
,
2
,
6 ,6-tetramethyl-1-piperidinyl)ethoxy]-4-methoxyphenyl]-5 butylamino-4-phenoxy-3-(sulfamoyl)benzamide: MS (ES) m/e 653.3 (M+H)+; N-[3-[2-[bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(4 chlorophenoxy)-3-nitrobenzamide: MS (ES) n/e 542.2 (M+H)+; 35 N-[3-[3-[bis(1 -methylethyl)amino]propyl]-4-methoxyphenyl]-4-(4 chlorophenoxy)-3-nitrobenzamide: MS (ES) n/e 540.2 (M+H)+;
N-[
3
-[
2
-(
2 ,2,6,6-tetramethyl- 1 -piperidinyl)ethoxy]-4-methoxyphenyl]-4-(4 chlorophenoxy)-3-nitrobenzamide: MS (ES) m/e 582.2 (M+H)+; 30 WO 00/06146 PCT/US99/17121 N-[3-[2-[bis(1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(2 quinoxalinylamino)benzamide: MS (ES) nie 514.4 (M+H)+; N-[3-[3-[bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-4-(2 quinoxalinylamino)benzamide: MS (ES) ne 512.4 (M+H)+; 5 N-[3-[2-(2,2,6,6-tetramethyl-1-piperidinyl)ethoxy]-4-methoxyphenyl]-4-(2 quinoxalinylamino)benzamide: MS (ES) m/e 554.2 (M+H)+; N-[3-[2-[bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4 methylphenyl)sulfonyl]-3-nitrobenzamide: MS (ES) n/e 570.2 (M+H)+; N-[3-[3-[bis(1 -methylethyl)amino]propyl]-4-methoxyphenyl]-4-[(4 10 methylphenyl)sulfonyl]-3-nitrobenzamide: MS (ES) m/e 568.3 (M+H)+; and N-[3-[2-(2,2,6,6-tetramethyl- 1 -piperidinyl)ethoxy]-4-methoxyphenyl]-4-[(4 methylphenyl)sulfonyl]-3-nitrobenzamide: MS (ES) m/e 610.3 (M+H)+. Example 31 Preparation of N-f3-[2-[Bis(1-methylethyl)aminolethoxyl-4-methoxyphenyll-3 15 phenoxybenzamide 3-Phenoxybenzoyl chloride, prepared from 3-phenoxybenzoic acid (0.11 g, 0.5 mmol) and thionyl chloride ( 5 mL) heated to reflux for 30 min, concentrated in vacuo and concentrated in vacuo from dichloromethane, was dissolved in dichloromethane (5 mL) and treated with 3-[(2 diisopropylamino)ethoxy]-4-methoxyaniline (0.14 g, 0.5 mmol) and 20 diisopropylethylamine (0.07 g, 0.5 mmol). The mixture was stirred at RT for 16 h, and washed twice with 5% sodium carbonate and with water. The organic phase was dried (MgSO 4 ) and concentrated in vacuo to afford a residue that was chromatographed (silica gel, 1:1 ethyl acetate:hexane) to give the title compound (0.12 g). MS (ES) m/e 463.2 (M+H)+. 25 Example 32-35 Following the procedure of Example 31 except substituting 4 phenoxybenzoic acid, 4-(phenylmethyl)benzoic acid, 4-(phenylthio)benzoic acid, and 4 -(phenylsulfonyl)benzoic acid (Chim. Ther. 1973, 8, 340-1) for 3 phenoxybenzoic acid, gave the title compounds: 30 N-[3-[2-[bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 phenoxybenzamide: MS (ES) ne 463.0 (M+H)+; N-[3-[2-[bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (phenylmethyl)benzamide: MS (ES) m/e 460.9 (M+H)+; N-[3-[2-[bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 35 (phenylthio)benzamide: MS (ES) m/e 478.9 (M+H)+; and N-[3-[2-[bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (phenylsulfonyl)benzamide: MS (ES) m/e 510.7 (M+H)+. Example 36 31 WO 00/06146 PCT/US99/17121 Preparation of N-[3-[2- Bis( 1-methvlethvl)aminolethoxl-4-methoxyphenyl-4(3 hydroxyphenoxy)benzamide A solution of 4-(3-hydroxyphenoxy)benzoic acid (0.23 g, 1 mmol), 3
-[(
2 -diisopropylamino)ethoxy]-4-methoxyaniline (0.27 g, 1 mmol), and BOP reagent (0.44 g, 1 mmol) in acetonitrile (20 mL) was treated with 5 triethylamine (0.2 g, 2 mmol) and stirred at RT for 16 h. The mixture was diluted with dichloromethane and filtered. The filtrate was washed with water, dried (MgSO 4 ), and concentrated in vacuo to afford a residue that was purified by HPLC (ODS-A, 20 X 50 mm, A:acetonitrile B:water-0.1% trifluoroacetic acid, 10-90% during 10 min, UV detection at 254 nm) to afford the title compound. MS (ES) m/e 10 478.8 (M+H)+. Examples 37-43 Following the procedure of Example 36, except substituting 4-[(4 chlorophenyl)sulfinyl]-3-nitrobenzoic acid, 4 -[(2,4-dichlorophenyl)sulfinyl]-3 nitrobenzoic acid, 4 -benzoylbenzoic acid, 3-benzoylbenzoic acid, the compound of 15 Preparation 1, 4 -(phenylamino)benzoic acid, and 4 -(phenylsulfinyl)benzoic acid (Synthesis 1990, 847-9) for 4
-(
3 -hydroxyphenoxy)benzoic acid, afforded the title compounds: N-[3-[2-[bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4 chlorophenyl)sulfinyl]-3-nitrobenzamide: MS (ES) m/e 573.7 (M+H)+; 20 N-[3-[2-[bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(2,4 dichlorophenyl)sulfinyl]-3-nitrobenzamide: MS (ES) m/e 607.7 (M+H)+; N-[3-[2-[bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 benzoylbenzamide: MS (ES) m/e 475.3 (M+H)+; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 25 benzoylbenzamide: MS (ES) m/e 474.9 (M+H)+; N-[3-[2-[bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (methylphenylamino)benzamide: MS (ES) m/e 475.9 (M+H)+; N-[3-[2-[bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (phenylamino)benzamide: MS (ES) m/e 462.0 (M+H)+; and 30 N-[3-[2-[bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (phenylsulfinyl)benzamide: MS (ES) m/e 494.7 (M+H)+. Example 44 Preparation of N-r3-[3-[Bis(1-methylethyl)aminolpropvll-4-methoxyphenyll-4 phenoxybenzamide Following the procedure of Example 36, except substituting 35 4 -phenoxybenzoic acid for 4 -(3-hydroxyphenoxy)benzoic acid and 3-[(3 diisopropylamino)propyl]-4-methoxyaniline for 3
-[(
2 -diisopropylamino)ethoxy]-4 methoxyaniline, afforded the title compound. MS (ES) m/e 461.3 (M+H)+. Example 45 32 WO 00/06146 PCT/US99/17121 Preparation of N-[3-[2-[Bis(I-methylethvl)aminolethoxyl-4-methoxyphenyl-4 [(hydroxvimino)phenylmethyllbenzamide A solution of the compound of Example 39 (0.24 g, 0.5 mmol), hydroxylamine hydrochloride (0.17 g), and triethylamine (0.24 mL) in ethanol (10 mL) was heated to reflux for 20 h. The 5 mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water to give the title compound. MS (ES) m/e 490.0 (M+H)+. Example 46 Preparation of N-[3-r2-rBis(1-methylethyl)aminoethoxyl-4-methoxyphenyll-4 (hydroxyphenvlmethyl)benzamide A mixture of the compound of Example 39 10 (0.24 g, 0.5 mmol), ethanol (21 mL), water (7 mL), methanol (5 mL), and dichloromethane (5 mL) was treated with sodium borohydride (0.13 g, 3.5 mmol) and stirred at RT for 2 h. The mixture was diluted with water, reduced in volume in vacuo, and extracted three times with dichloromethane. The combined organic phase was washed with brine, dried (MgSO 4 ), and concentrated in vacuo to give the 15 title compound (40 mg). MS (ES) m/e 477.2 (M+H)+. Example 47 Preparation of N-[l '-(1-Methylethvl)spirofbenzofuran-3(2H)4'5-piperidinl-5-vll-4 benzovlbenzamide trifluoroacetate A solution of 4-benzoylbenzoic acid (55 mg, 0.254 mmol), the compound of Preparation 2(e) (60 mg, 0.24 mmol), and BOP 20 reagent (108 mg, 0.24 mmol) in acetonitrile (5 mL) was treated with triethylamine (50 mg, 0.5 mmol) and stirred at RT for 16 h. The mixture was quenched with brine and extracted with ethyl acetate. The organic extract was washed with 5% sodium carbonate and with brine, dried (MgSO 4 ), and concentrated in vacuo. The residue was purified by HPLC (ODS-A, 20 X 50 mm, A:acetonitrile B:water-0. 1% 25 trifluoroacetic acid, 10-90% during 10 min, UV detection at 254 nm) to give the title compound. MS (ES) m/e 455.1 (M+H)+. Examples 48-49 Preparation of N-r 1'-(1 -Methylethyl)spirobenzofuran-3(2H),4'5-piperidinl-5-yvl-4 Pheno'benzamide and N-r1'-(1-Methylethyl)spirobenzofuran-3(2H),4'5-piperidinl 30 5-vll-4-(phenvlthio)benzamide Following the procedure of Example 47, except substituting 4 phenoxybenzoic acid and 4-(phenylthio)benzoic acid for 4-benzoylbenzoic acid, gave the title compounds: N-[l'-(1-methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4 35 phenoxybenzamide: MS (ES) m/e 443.1 (M+H)+; and N-[l'-(1-methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4 (phenylthio)benzamide: MS (ES) m/e 459.1 (M+H)+. Example 50 33 WO 00/06146 PCT/US99/17121 Preparation of N-r-[2-[Bis(1-methylethyl)aminolethyll-1,2,3,4-tetrahydroquinol-7-: yll-4-phenoxybenzamide Following the procedure of Example 31, except substituting 4-phenoxybenzoic acid for 3-phenoxybenzoic acid and substituting the compound of Preparation 3(b) for 3
-[(
2 -diisopropylamino)ethoxy]-4 5 methoxyaniline, gave the title compound. MS (ES) m/e 472.2 (M+H)+. Example 51 Preparation of N-[3-r2-[Bis(1-methvlethvl)aminolethoxvl-4-methoxyphenyll-4 phenoxybenzamide Methiodide The compound of Example 32 (93 mg, 0.2 mmol) in methanol (3 mL) was treated with iodomethane (8 mL), maintained at RT for 4 d, 10 concentrated in vacuo, and the residue was triturated with ethyl acetate and then with :1 ethyl acetate:ether. The residue was stirred with 1:1 ethyl acetate:ether for several hours and filtered to afford the title compound. MS (ES) m/e 477 (M+H)+. Example 52 Preparation of N-[3-t2-rBis(1-mehylethyl)aminolethoxvl-4-methoxyphenyll-2 15 (phenylmethyl)thiazole-4-carboxamide hydrochloride Following the procedure of Example 31, except substituting the compound of Preparation 4 for 3-phenoxybenzoic acid, afforded the title compound. MS (ES) m/e 468.0 (M+H)+. 20 Biological Data: CCR5 Receptor Binding Assay.CHO cell membranes (0.25 x10 6 cell equivalents) derived from CHO cells stably transfected with CCR5 were incubated with 0.3 'I-RANTES in a 96 well plate for 45 min at room temperature (final reaction volume 200 ul). The reaction was terminated by filtration and the filters (GF/C) were washed twelve times with a 25 solution of phosphate buffered saline containing 0.1 % bovine serum albumin and 0.05 % NaN 3 . The radioactivity bound to filters was measured by liquid scintillation spectrometry. Non-specific binding was determined in the presence of unlabelled RANTES (10 or 30 nM) and averages 30-50% of total binding. 30 CCR5 Receptor Functional Assay The cellular functional assay used to assess antagonist activity of compounds was RANTES-induced Ca 2 + mobilization in RBL 2H3 cells stably expressing the hCCR5 receptor (RBL 2H3 hCCR5). Agonist activity is determined by Ca 2 + mobilization in the same cells which is inhibitable by a selective CCR5 antagonist. Cells were grown to 80 35 100% confluency in T- 150 flasks and washed with phosphate-buffered saline. Cells were lifted from the flasks by treating with 3 mL of 1 mM EDTA for 3 min at room temperature and diluting to 2 X 106 cells/mL with Krebs Ringer Henseleit buffer (KRH; 118 mM NaCl, 4.6 mM KCL, 25 mM NaHCO 3 , 1 mM KH 2
PO
4 and I mM glucose) containing 5 34 WO 00/06146 PCT/US99/17121 mM HEPES (pH 7.4), 1 mM CaCl 2 , 1 mM MgC1 2 and 0.1% BSA and centrifuged a 200g for 3 min. Cells were resuspended at 2 X 106 cells/mL in the same buffer with 2 pM Fura 2AM, and incubated for 35 min at 370 C. Cells were centrifuged at 200 x g for 3 min and resuspended in the same buffer without Fura-2AM, then incubated for 15 min at 370 C to 5 complete the hydrolysis of intracellular Fura-2AM, and then centrifuged as before. Cells (106 cells/mL) were resuspended in cold KRH with 5 mM HEPES (pH 7.4), 1 mM CaCl 2 , 1 mM MgCl 2 and 0.1% gelatin and maintained on ice until assayed. For antagonist studies, aliquots (2 mL) of cells were prewarmed at 370 C for 5 min in 3 mL plastic cuvettes and fluorescence measured in a fluorometer (Johnson Foundation Biomedical 10 Group, Philadelphia, PA, USA) with magnetic stirring and temperature maintained at 370 C. Excitation was set at 340 nm and emission set at 510 nm. Various concentrations of antagonists or vehicle were added and fluorescence monitored for -15 sec to ensure that there was no change in baseline fluorescence, followed by the addition of 33 nM RANTES. Maximal Ca 2 + attained after 33 nM RANTES stimulation was calculated as described by 15 Grynkiewicz et al., (1985). The percent of maximal RANTES-induced Ca 2 + was determined for each concentration of antagonist and the IC 50 , defined as the concentration of test compound that inhibits 50% of the maximal 33 nM RANTES response, obtained from the concentration-response curves (5-7 concentrations of antagonists). The compounds of this invention show CCR5 receptor modulator activity having 20 IC 50 values in the range of 0.000 1 to 100 p.M. The full structure/activity relationship has not yet been established for the compounds of this invention. However, given the disclosure herein, one of ordinary skill in the art can utilize the present assays in order to determine which compounds of this invention are modulators of the CCR5 receptor and which bind thereto with an IC 50 value in the range of 0.0001 to 100 p.M. 25 All publications, including, but not limited to, patents and patent applications cited in this specification, are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. The above description fully discloses the invention including preferred 30 embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration it is believed that one skilled in the art can, given the preceding description, utilize the present invention to its fullest extent. Therefore any examples are to be construed as merely illustrative and not a limitation on the scope of the present invention in any way. 35 The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows. 35

Claims (2)

1. A method of treating a CCR5-mediated disease state in mammals which comprises administering to a mammal in need of such treatment, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof: (FF) (R 3 ')b, R 1 r2 A P L-E Formula I wherein: the basic nitrogen in moiety E may be optionally quaternized with C1 6 alkyl or is optionally present as the N-oxide; P 1 and P 2 are independently phenyl, fused bicyclic aryl, a monocyclic heterocyclic ring of 5- to 7-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, or a fused bicyclic heterocyclic ring of 8 to
11-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur; A is C(R 4 ') 2 , CR 4 '(OR 5 '), CO, C=NOR 6 ', NR 7 ', oxygen, or S(O)c'; L is a group of formula -C(=V)-DR 8 '-, -DR 9 '-C(=V)-, -CH 2 NH-, or NHCH 2 -; V is oxygen or sulfur; D is nitrogen, carbon, or a CH group, R ' and R 2 ' are independently hydrogen, C 1 -6alkyl, C2-6alkenyl, C 2 6alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, aryl, (CH2)d'NR1O'R 11', (CH2)d'NR10'COR 1 2', (CH2)d'NR 10 'CO 2 R 1 3', (CH2)d'NR 0 'SO 2 R14', (CH 2 )d'CONR 1 5 'R 16 ', hydroxyC 1-6alkyl, C1-4alkoxyalkyl (optionally substituted by a C1- 4 alkoxy or hydroxy group), (CH2)d'CO 2 C 1 - 6 alkyl, (CH2)e'OC(O)R 1 7', CR 18 '=NOR 1 9', CNR 20 '=NOR 1 9', COR 2 'I, CONR 1 5 'R 1 6', CONR 1 5 '(CH 2 )f'OC 1 -4alkyl, CONR 15 '(CH2)d'CO 2 R 2 2 ' CONHNR 2 3 'R 2 4 ', CONR 1 5 'S0 2 R 2 5 ', C0 2 R 2 6 , cyano, trifluoromethyl, NR 10 'R Il', NR 10 'COR 1 2', NR 2 7 'CO(CH 2 )d'NR 2 7 'R28', NR 2 7 'CONR 2 7 'R 2 8 ', NR 1 0 'CO 2 R 1 3', NR 10 'SO 2 R 1 4', N=CNR 2 7 'NR 2 7 'R 2 8 ', nitro, hydroxy, C -6alkoxy, hydroxyC l-6alkoxy, C1-6alkoxyC l-6alkoxy, OC(O)NR 29 'R 30 ', SR 3 1 ', SOR 3 2 ', S0 2 R 32 , S0 2 NR 3 3 'R 3 4 ', halogen, C 1 _ 6alkanoyl, CO2(CH2)d'OR 3 5', or R 1 ' is an optionally substituted 5 to 7 36 WO 00/06146 PCTIUS99/17121 membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; R 3 'is hydrogen, C 1 - 6 alkyl, C3-6cycloalkyl, C 3 -6cycloalkenyl, hydroxyCl-6alkyl, C 1 -6alkylOCl-6alkyl, CONR 36 'R 37 ', C0 2 R 3 8 ', cyano, aryl, trifluoromethyl, NR 3 9 'R 4 0 ', nitro, hydroxy, C1-6alkoxy, C1-6alkanoyl, acyloxy, or halogen; R 4 ', R 5 ', R 6 ', R 7 ', R 18 ', R 19 ', R 20 ', R 2 1 ', R 2 2 ', R 2 3 ', R 2 4 ', R 27 ', R 2 8 ', R 3 1 ', R 3 5 ', R 36 ', R 3 7 ', R 3 8 ', R 3 9 ', and R 4 0 ' are independently hydrogen or C 1- 6 alkyl; R 8 ' is hydrogen or Cl-6alkyl, providing that D is nitrogen or a CH group; R 9 'is hydrogen or C 1 -6alkyl, providing that D is nitrogen or a CH group; R 10 ' and R 1 ' are independently hydrogen or C 1 - 6 alkyl, or R 10 ' and R I' together with the nitrogen to which they are attached, forms a 5- to 6 membered heterocyclic ring, which may optionally be substituted by an oxo group, and, when there are six members, may optionally contain in the ring one oxygen or one sulfur atom; R 12 'is hydrogen, C 1 -6alkyl, or Ci-4alkoxyalkyl; R 13 ', R 2 5 ', and R 3 2 ' are independently C 1 -6alkyl; R 14 'is C1-6alkyl or phenyl; R 15 ' and R 16 ' are independently hydrogen or C 1 - 6 alkyl, or R 15 ' and R 1 6 ' together with the nitrogen to which they are attached form a 5- to 6 membered saturated heterocyclic ring which, when there are 6 ring members, may optionally contain in the ring one oxygen or one sulfur atom; R 17 'is Cl- 4 alkyl, optionally substituted by Cl- 6 alkoxy; R 26 'is hydrogen or C1-6alkyl optionally substituted with one or two substituents selected from C1- 6 alkyl, C1-6alkoxy, hydroxy, or NR 10 'R 1'; R 29 ' and R 30 ' are independently hydrogen or C 1 - 6 alkyl, or R 2 9 ' and R 30 ' together with the nitrogen to which they are attached form a 5- to 6 membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring one oxygen or sulfur atom; R 3 3 ' and R 34 ' are independently hydrogen or C 1 - 6 alkyl, or R 3 3 ' and R 34 ' together with the nitrogen to which they are attached form 5- to 6 membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring one oxygen or one sulfur atom; a'and b' are independently 1, 2, or 3; c' is 0, 1, or 2; 37 WO 00/06146 PCTIUS99/17121 d'is 1, 2, 3, or 4; e'is 0, 1, 2, or 3; f is 1, 2, or 3; E represents (a): B- (CR1R 2 )a -NR3R4 (R 5 )b R 6 (a); in which B is oxygen, S(O)c, CR 7 =CR 8 , or CR 7 R 8 , or B is NR 9 ; R I and R 2 are independently hydrogen or C1-6alkyl; alternatively B(CR IR 2 )a is OCR 1 R 2 CR 1 (OH)CR 1 R 2 or OCR 1 R 2 CR 1 (OCOCH 3 )CR 1 R 2 ; R 3 and R 4 are independently hydrogen, Cl- 6 alkyl, C3- 7 cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C 1 - 6 alkyl, aryl, CONR 10 R 1, NR 10 R 11, hydroxy, OCOR 12 , NHCOC 0 - 6 alkyl where alkyl is optionally substituted by OH, NHCOCF 3 , NHSO 2 R 13 , and NHCO 2 R 14 ; R 5 is hydrogen, C 1 - 6 alkyl, aryl, CN, CONR 15 R 16 , C0 2 R 17 , trifluoromethyl, NHCO 2 R 18 , hydroxy, Cl-6alkoxy, benzyloxy, OCH2CO 2 Cl- 6 alkyl, OCF 3 , S(O)dR1 9 , S0 2 NR 20 R 2 1 or halogen; R 6 is hydrogen, Cl-6alkyl, aryl, trifluoromethyl, hydroxy, Cl-6alkoxy or halogen, or R 6 taken together with R 8 ' forms a group D where D is (CR 22 R 2 3 )e or D is (CR 22 R 2 3 )f-G where G is oxygen, sulfur or CR 22 =CR 2 3 , CR 2 2 =N, =CR 2 2 0, =CR 22 S, or =CR22-NR23; R 7 , R 8 , R 10 , R 1, R 12 , R 15 , R 16 , R 17 , R 20 , R 2 1 , R 22 , and R 2 3 are independently hydrogen or C 1 - 6 alkyl; R 9 is hydrogen, C 1 - 6 alkyl, or phenylC 1 - 6 alkyl; R 13 , R 14 , R 18 , and R 19 are independently C1-6alkyl; a is 1, 2, 3, or 4; b is 1 or 2; c and d are independently 0, 1 or 2; e is 2, 3 or 4; f is 0, 1, 2 or 3; alternatively, E represents (b): 38 WO 00/06146 PCT/US99/17121 R 28 R29C R 2 6 R 27 C NR 30 -(CR 24 R 2 5 )g JCR 3 1R 32 )h R33 (b); R 24 , R 25 , R 2 6 , R 2 7 , R 2 8 , R 2 9 , R 3 1 , and R 32 are independently hydrogen or C 1 -6alkyl; R 30 is hydrogen, Cl- 6 alkyl, or C3-7cycloalkyl; R 33 is hydrogen, Cl-6alkyl, trifluoromethyl, hydroxy, or halogen, or R 3 3 and R 8 ' together form a group -K- where K is (CR 34 R 3 5 )i or K is (CR 34 R 3 5 )j -M and M is oxygen, sulfur, CR 3 4 =CR 3 5 , CR 3 4 =N, or N=N; J is oxygen, CR 3 6 R 37 , or NR 3 8 , or J is a group S(O)k; R 34 , R 35 , R 3 6 , R 3 7 , and R 38 are independently hydrogen or Cl 6alkyl; g is 1, 2 or 3; his 1,2or3; i is 2, 3, or 4; j is 0, 1, 2, or 3; k is 0, 1 or 2; alternatively, E represents (c): aQ- (CR 39 R4) 1 -R41 (R 42 )m R43 (c); in which: Q is oxygen, S(O)n, CR 44 =CR 4 5 , CR 4 4 R 4 5 , or Q is NR 4 6 ; R 3 9 and R 4 0 are independently hydrogen or C 1 - 6 alkyl; R 4 1 is a group of formula (d): (CH 2 )o (CH 2 )p (CH 2 )q N (d) or R 4 1 is a group of formula (e): CH 2 ), N/ R 47 (e) 39 WO 00/06146 PCT/US99/17121 R 4 2 is hydrogen, C 1 - 6 alkyl, aryl, CN, CONR 4 8 R 4 9 , C0 2 R 5 0 , trifluoromethyl, NHCO 2 R 5 1 , hydroxy, C1-6alkoxy, benzyloxy, OCH 2 CO 2 Cl-6alkyl, OCF 3 , S(O)sR 52 , S0 2 NR 5 3 R 54 , or halogen; R 4 3 is hydrogen or R 4 3 together with R 8 ' forms a group R where R is CR 5 5 =CR 56 , CR55=CR 5 6 CR55R56, or (CR 55 R 5 6 )t; R 4 4 , R 4 5 , R 4 6 , R 4 8 , R 4 9 , R 50 , R 53 , R 54 , R 5 5 , and R 5 6 are independently hydrogen or CI-6alkyl; R 4 7 is hydrogen, C 1 - 6 alkyl, or C 3 - 7 cycloalkyl; R 5 1 and R 5 2 are independently C 1 - 6 alkyl; l is 0, 1, 2, or 3; mis 1 or2; n is 0, 1, or 2 o, p, and q are independently integers having the value 1, 2, or 3; r is 0,1, 2, or 3; s is 0, 1, or 2; t is 2 or 3; alternatively, E represents (f): W-(CR 57 R 58 ) t- NR 59 R 60 0 T (f); R 5 7 and R 58 are independently hydrogen or C1-6alkyl; R 5 9 and R 6 0 are independently hydrogen, Cl- 6 alkyl, C3- 7 cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C-6alkyl, aryl, CONR 6 1 R 62 , NR 6 1 R 6 2 , hydroxy, OCOR 6 3 , NHCOC 0 - 6 alkyl where alkyl is optionally substituted by OH, NHCOCF 3 , NHSO 2 R 64 , and NHCO 2 R 6 5 ; T is -(CR 6 6 R 6 7 )v- or -O(CR66R67) W is oxygen, S(O)x, NR 6 8 , or W is CR 69 =CR 7 0 or CR69R70; R 6 1 , R 6 2 , R 6 3 , R 6 6 , R 6 7 R 68 , R 6 9 , and R 7 0 are independently hydrogen or C 1 - 6 alkyl; R 64 and R 65 are independently C 1 - 6 alkyl; u is 1 to 4; v is 2 or 3; w is 1, 2, or 3; x is 0, 1 or 2; 40 WO 00/06146 PCT/US99/17121 alternatively, E represents a group (g): R71 R73 (R 72 )y(g); R 7 1 is an optionally substituted 5 to 7-membered saturated or partially saturated heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur or R 7 1 is an optionally substituted 6,6 or 6,5 bicyclic ring containing a nitrogen atom and optionally a further heteroatom selected from oxygen, nitrogen or sulfur; R 7 2 is hydrogen, Cl- 6 alkyl, aryl, CN, CONR 74 R 7 5 , C0 2 R 7 6 , trifluoromethyl, NHCO 2 R 7 7 , hydroxy, C1-6alkoxy, benzyloxy, OCH 2 CO 2 C 1 - 6 alkyl, OCF 3 , S(O)zR 7 8 , S0 2 NR 7 9 R 80 , or halogen; R 7 3 is hydrogen, C1- 6 alkyl, hydroxy, Cl- 6 alkoxy or halogen, or R73 and R 8 ' taken together from a group -X- where X is (CR 8 1R 8 2 )aa or X is (CR 8 1 R 8 2 )ab-Y and Y is oxygen, sulfur or CR 8 1 =CR 82 ; R 74 , R 7 5 , R 7 6 , R 7 9 , R 80 , R 8 1 , and R 8 2 are independently hydrogen or C1-6alkyl; R 7 7 and R 7 8 are independently C1-6alkyl; y is 1 or 2; z is 0, 1, or 2; aa is 2, 3 or 4; ab is 0, 1, 2 or 3; alternatively, E represents group (h): aZ (CR 83 RB4)a- NR85R 8 6 R 8 7 (h); R 8 3 and R 8 4 are independently hydrogen or C1-6alkyl; R 8 5 and R 8 6 are independently hydrogen, Cl- 6 alkyl, C3-7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C 1 - 6 alkyl, aryl, CONR 88 R 89 , NR 9 0 R 9 1 , hydroxy, OCOR 9 2 , NHCOC 0 - 6 alkyl where alkyl is optionally substituted by OH, NHCOCF 3 , NHSO 2 R 9 3 , and NHCO 2 R 94 ; R 87 is hydrogen or C 1 - 6 alkyl, C 1 -6alkoxy, or halogen, or R87 together with R 8 ' forms a group -AA- where AA is (CR 9 5 R 9 6 )ad or AA is (CR 9 5 =CR 9 6 )ae-AB and AB is oxygen, sulfur, CR 9 5 =CR 9 6 , CR 9 5 =N, CR 9 5 NR 96 or N=N; 41 WO 00/06146 PCT/US99/17121 Z is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur; R 8 8 , R 89 , R 9 0 , R 9 1 , R 9 2 , R 9 5 , and R 9 6 are independently hydrogen or C1- 6 alkyl; R 9 3 and R 94 are independently C 1 -6alkyl; ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2; alternatively, E represents group (i): (CH 2 )afNR 97 R 98 (CH 2 )ag 4(CR9R100)ah R101 A 6 (i); R 97 and R 9 8 are independently hydrogen, C 1 - 6 alkyl, C3-7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C1- 6 alkyl, aryl, CONR 10 2 R 10 3 , NR 104 R 10 5 , hydroxy, OCOR 10 6 , NHCOC 0 - 6 alkyl where alkyl is optionally substituted by OH, NHCOCF 3 , NHSO 2 R 10 7 , and NHCO 2 R1 0 8 ; R 9 9 and R1 00 are independently hydrogen or C1- 6 alkyl; R 10 1 is hydrogen or Cl- 6 alkyl or R 10 1 and R 8 ' together form a group -AD- where AD is (CR 10 9 R 1 1 0)ai or AD is (CR10 9 R 11)aj-AE and AE is oxygen, sulfur or CR 10 9 =CR 1 10. AC is oxygen, CR 11 1 R 1 12 or NR113 or AC is a group S(O)ak; R 10 2 , R1 0 3 , R 10 4 , R 10 5 , R 10 6 , R1 0 9 , R 1 10, R 1 1 1, R 1 12, and R 1 13 are independently hydrogen or C1- 6 alkyl; R 10 7 and R 10 8 are independently Cl- 6 alkyl; af is 0, 1, 2, 3, or 4; ag is 1, 2, or 3; ah is 1, 2, 3 or 4; ai is 2, 3 or 4; aj is 0, 1, 2, or 3; and ak is 0, 1 or 2. 42 WO 00/06146 PCT/US99/17121 2. The method of claim 1 wherein the compound of formula (I) is selected from a subgenus of formula (Ia) or a pharmaceutically acceptable salt thereof: (R 2 ')a, (R 3 ')b. R 28 R29C R 26 R 27 C NR30 -(CR 2 4 R 2 5 )g R 1 P2 A P 1 L CR31R32) R 33 Formula (Ia) wherein: Rl', R 2 ', R 3 ', pI, p 2 , A, a', b', L, R 2 4 , R 2 5 , R 2 6 , R 2 7 , R 2 8 , R 2 9 , R 3 0 , R 3 1 , R 3 2 , R 3 3 , J, g, and h are defined in claim 1. 3. The method as claimed in claim 1 wherein the compound is selected from: N-[ 4 -[2-(Dimethylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl) 4-phenoxybenzamide; N-[ 3 -[ 2 -(Diethylamino)ethoxy]-4-methoxyphenyl]-4 phenoxybenzamide; N-[4-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]]-4-phenoxybenzamide; N-[ 4 -[ 2 -(Diethylamino)ethoxy]phenyl]-4-phenoxybenzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxyphenyl]-4-phenoxybenzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 phenoxybenzamide; N-[ 3 -[ 2 -(Diethylarino)ethoxy]-4-methoxyphenyl]-3 phenoxybenzamide; N-[4-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-3 phenoxybenzamide; N-[4-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-4 (phenylmethyl)benzamide; N-[ 2 -[ 2 -(Diethylamino)ethoxy]phenyl]-4-(phenylmethyl)benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 phenoxybenzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (phenylmethyl)benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2 (phenylmethyl)thiazole-4-carboxamide hydrochloride; 43 WO 00/06146 PCT/US99/17121 N-[3-12-IIBis(I1-methylethy)amino]ethoxy]-4-methoxyphenyly4 phenoxybenzamide Methiodide; N-[ 1-[2-[Bis(l1-methylethyl)amino]ethyl]- 1,2,3 ,4-tetrahydroquinol-7 yl]-4-phenoxybenzamide; N-[3- [2-[Bis(I1-methylethyl)aminolethoxy-4methoxyphenyl-4-(3 hydroxyphenoxy)benzamide; N-[3-[2- [Bis(l1-methylethy)amino]ethoxy]-4-methoxyphenyl]A4[(4 c~rpey~ufnl--irbnaie N-[3- [2-[Bis(l1-methylethyl)am-ino]ethoxy]-4-methoxyphenylp4-[(2,4 dihoohnlsliyl--irbnaie N-[3-[3-[Bis( 1 -methylethyI)amiinolpropyl]-4-methoxyphenyl]y3 phenoxybenzamide; N-[ 3 -1 2 -(2,2,6,6-Tetramethyl. 1 -piperidinyl)ethoxy]-4 methoxyphenyl1-3-phenoxybenzanmjde; N-[3-[3-[Bis(l1-methylethy1)amino]propyl]-4methoxyphenylI]A phenoxybenzamide; N-[ 3 -[ 2 -(2,2,6,6-Tetramethyl- 1 -piperidinyl)ethoxy]-4 mehxpeyl4phnxbnaie N-[3-[2-[Bis(l1-methylethyl)amino]ethoxy]-4-methoxyphenyllA4 benzoylbenzamide; N-[3-113-[Bis(l1-methylethy1)amino]propy1]-4methoxyphenylI]A benzoylbenzamide; N-[ 3 -[2-(2,2,6,6-Tetramethylp 1-piperidinyl)ethoxy]-4 methoxypheny1]-4-benzoylbenzanmjde; N-[3- [3- [Bis(l1-methylethyl)aminolpropyl-4-methoxyphenyl]A4 (phenylmethyl)benzamide; N-[ 3 -1 2 -(2,2,6,6-Tetramethyl. 1 -piperidinyl)ethoxy]-4 methoxyphenyl]-4-(phenylmethy)benzmide; N-[3-[2- [Bis(I1-methylethyl)amino]ethoxy-4-methoxyphenyl]-4-[(4 chlorophenyl)sulfonyl]benzamide; N-[3-[3- [Bis(l1-methylethy1)amino]propyl]-4methoxyphenyl]p4-[(4 chlorophenyl)sulfonyl]benzamide; N-[ 3 -[ 2 -(2,2,6,6-Tetramethyl. 1 -piperidinyl)ethoxy]-4 methoxyphenyl]-4- [( 4 -chlorophenyl)sulfonyl]benzamide; N-[3- [2-[B is(I -methylethy1)amino]ethoxy-4-methoxyphenyl-5 butylamino-4-phenoxy-3.(sulfamoyl)benzamide; N-[3-[3- [Bis(I -methylethyl)amino]propyly4-methoxyphenyl-5 butylamnino-4-phenoxy-3-(sufamoy)benzaide; 44 WO 00/06146 PCT/US99/17121 N-[ 3 -[ 2 -(2,2,6,6-Tetramethyl- 1-piperidinyl)ethoxy]-4 methoxyphenyl]- 5 -butylamino-4-phenoxy-3-(sulfamoyl)benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(4 chlorophenoxy)-3-nitrobenzamide; N-[3-[3-[Bis(1 -methylethyl)amino]propyl]-4-methoxyphenyl]-4-(4 chlorophenoxy)-3-nitrobenzarnide; N-[ 3 -[ 2 -(2,2,6,6-Tetramethyl- 1-piperidinyl)ethoxy]-4 methoxyphenyl]-4-(4-chlorophenoxy)-3-nitrobenzamide; N-[3-[2-[Bis(1-methylethy)amino]ethoxy]-4-methoxyphenyl]-4-(2 quinoxalinylamino)benzamide; N-[3-[3-[Bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-4-(2 quinoxalinylamino)benzamide; N-[ 3 -[ 2 -(2,2,6,6-Tetramethyl- 1-piperidinyl)ethoxy]-4 methoxyphenyl]-4-(2-quinoxalinylamino)benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4 methylphenyl)sulfonyl]-3-nitrobenzamide; N-[3-[3-[Bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-4-[(4 methylphenyl)sulfonyl]-3-nitrobenzamide; N-[ 3 -[ 2 -(2,2,6,6-Tetramethyl-1 -piperidinyl)ethoxy]-4 methoxyphenyl]-4-[(4-methylphenyl)sulfonyl]-3-nitrobenzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 benzoylbenzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (methylphenylamino)benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (phenylamino)benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (phenylthio)benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (phenylsulfonyl)benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (phenylsulfinyl)benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 [(hydroxyimino)phenylmethyl]benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (hydroxyphenylmethyl)benzamide; N-[ l'-(1-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl] 4-benzoylbenzamide trifluoroacetate; 45 WO 00/06146 PCT/US99/17121 N-[l'-(1-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4 phenoxybenzamide; and N-['1 -(1-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4 (phenylthio)benzamide; or a pharmaceutically acceptable salt thereof. 4. The method of claim 1 wherein the CCR5-mediated disease state is selected from COPD, asthma and atopic disorders, rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic disease, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIV. 5. A compound of formula (I) selected from: N-[ 4 -[ 2 -(Dimethylamino)ethyl]-3,4-dihydro-2H- 1,4-benzoxazin-6-yl) 4-phenoxybenzamide; N-[ 3 -[ 2 -(Diethylamino)ethoxy]-4-methoxyphenyl]-4 phenoxybenzamide; N-[4-[2-[Bis(1 -methylethyl)amino]ethoxy]phenyl]]-4-phenoxybenzamide; N-[ 4 -[ 2 -(Diethylamino)ethoxy]phenyl]-4-phenoxybenzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-4-phenoxybenzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 phenoxybenzamide; N-[ 3 -[ 2 -(Diethylamino)ethoxy]-4-methoxyphenyl]-3 phenoxybenzamide; N-[4-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-3 phenoxybenzamide; N-[4-[2-[Bis(1 -methylethyl)amino]ethoxy]phenyl]-4 (phenylmethyl)benzamide; N-[ 2 -[ 2 -(Diethylamino)ethoxy]phenyl]-4-(phenylmethyl)benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 phenoxybenzamide; N-[3-[2-[Bis(1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 (phenylmethyl)benzamide; N-[3-[2-[Bis(1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-2 (phenylmethyl)thiazole-4-carboxamide hydrochloride; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 phenoxybenzamide Methiodide; N-[1-[2-[Bis(I-methylethyl)amino]ethyl]-1,2,3,4-tetrahydroquinol-7 yl]-4-phenoxybenzamide; 46 WO 00/06146 PCT/US99/17121 N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl)-4-(3 hydroxyphenoxy)benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4 chlorophenyl)sulfinyl]-3-nitrobenzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(2,4 dichlorophenyl)sulfinyl]-3-nitrobenzamide; N-[3-[3-[Bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-3 phenoxybenzamnide; N-[3-[2-(2,2,6,6-Tetramethyl- 1 -piperidinyl)ethoxy]-4 methoxyphenyl]-3-phenoxybenzamide; N-[3-[3-[Bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-4 phenoxybenzamide; N-[ 3 -[ 2 -(2,2,6,6-Tetramethyl- 1 -piperidinyl)ethoxy]-4 methoxyphenyl]-4-phenoxybenzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4 benzoylbenzamide; N-[3-[3-[Bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-4 benzoylbenzamide; N-[3-[2-(2,2,6,6-Tetramethyl- 1 -piperidinyl)ethoxy]-4 methoxyphenyl]-4-benzoylbenzamide; N-[3-[3-[Bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-4 (phenylmethyl)benzamide; N-[ 3 -[2-(2,2,6,6-Tetramethyl- 1 -piperidinyl)ethoxy]-4 methoxyphenyl]-4-(phenylmethyl)benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4 chlorophenyl)sulfonyl]benzamide; N-[3-[3-[Bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-4-[(4 chlorophenyl)sulfonyl]benzamide; N-[3-[2-(2,2,6,6-Tetramethyl- 1 -piperidinyl)ethoxy]-4 methoxyphenyl]-4-[(4-chlorophenyl)sulfonyl]benzamide; N-[3-[2-[Bis(1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-5 butylamino-4-phenoxy-3-(sulfamoyl)benzamide; N- [3- [3-[Bis(1 -methylethyl)amino]propyl]-4-methoxyphenyl]-5 butylamino-4-phenoxy-3-(sulfamoyl)benzamide; N-[ 3 -[ 2 -(2,2,6,6-Tetramethyl-1 -piperidinyl)ethoxy]-4 methoxyphenyl]-5-butylamino-4-phenoxy-3-(sulfamoyl)benzamide; N-[3-[2-[Bis(1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(4 chlorophenoxy)-3-nitrobenzamide; 47 WO 00/06146 PCT/US99/17121 N-[3-[3-[Bis(l1-methylethyl)amino]propyl]-4-methoxyphenyl]A.(4-. chlorophenoxy)-3-nitrobenzamide; N-[3.-[2-(2,2,6,6-Tetramethyl- 1 -piperidinyl)ethoxy]-4 methoxyphenyl]-4-(4-chorophenoxy-3-nitrobenzanmjde; N-[3-[2-[Bis(I1-methylethyl)amino]ethoxy]-4-methoxyphenyly4-(2 quinoxalinylamino)benzamide; N-[3-[3-[Bis(l1-methylethyl)aminolpropyl]-4-methoxyphenylp4-(2 quinoxalinylam-ino)benzamide; N-[3-[2-(2,2,6,6-Tetramethyl- 1 -piperidinyl)ethoxy]-4 methoxyphenyl]-4-(2-quinoxalinylanmino)benzamide; N-[3-[2-[Bis(l1-methylethyl)amnino]ethoxy]-4-methoxyphenyl].4-[(4 methylphenyl)sulfonyl]-3-nitrobenzamide; N- [3- [3-[Bis(I1-methylethy1)amino]propyl]-4methoxyphenyI-4-[(4 methylphenyl)sulfony1]-3-nitrobenzanmjde; N-[3-[2-(2,2,6,6-Tetramethyl- 1 -piperidinyl)ethoxy]-4 methoxypheny1I-4-[(4-methylphenyl)sulfonyly3-nitrobenzide; N-[3-[2-[Bis(l1-methylethyl)amino]ethoxy]-4-methoxyphenyl]y3 benzoylbenzaxnide; N-[3-[2-[Bis(l1-methylethyl)amiinolethoxy]-4-methoxyphenyly4 (methylphenylamino)benzamide; N-[3-[2-[Bis(l1-methylethyl)amino]ethoxy]-4-methoxyphenylp4 (phenylamino)benzamide; N-[3-[2-[Bis(I1-methylethyl)amino]ethoxy]-4-methoxyphenyl-4 (phenylthio)benzamide; N-[3-[2-[Bis(I1-methylethyl)arnino]ethoxy]-4-methoxyphenyly4 (phenylsulfonyl)benzamide; N-[3-[2-[Bis(l1-methylethyl)aminolethoxy]-4-methoxyphenyl-4 (phenylsulfinyl)benzamide; N-[3-[2-[Bis(l1-methylethyl)amino]ethoxy]-4-methoxyphenyly4 [(hydroxyimino)phenylmethyl]benzarnide; N-[3-[2-[Bis(l1-methylethyl)am-ino]ethoxy]-4-methoxyphenyly4 (hydroxyphenylmethyl)benzamide; N-[ 1 '-(1 -Methylethyl)spiro[benzofuran-3(2H),45piperidin-5-yl]p 4-benzoylbenzamide trifluoroacetate; N-[l1'-(1 -Methylethyl)spiro[benzofuran3(2H),4'5piperidin-5-yly4 phenoxybenzamide; and N-[l 1 '(1-Methylethy)spiro[benzofuran3(2H),4'5piperidin] -5-yl]-4 (phenylthio)benzamide. 48
AU52392/99A 1998-07-28 1999-07-28 Substituted anilide compounds and methods Abandoned AU5239299A (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US9440698P 1998-07-28 1998-07-28
US60094406 1998-07-28
US13415799P 1999-05-14 1999-05-14
US60134157 1999-05-14
PCT/US1999/017121 WO2000006146A1 (en) 1998-07-28 1999-07-28 Substituted anilide compounds and methods

Publications (1)

Publication Number Publication Date
AU5239299A true AU5239299A (en) 2000-02-21

Family

ID=26788834

Family Applications (1)

Application Number Title Priority Date Filing Date
AU52392/99A Abandoned AU5239299A (en) 1998-07-28 1999-07-28 Substituted anilide compounds and methods

Country Status (13)

Country Link
EP (1) EP1100485A4 (en)
JP (1) JP2002521436A (en)
KR (1) KR20010074779A (en)
CN (1) CN1310621A (en)
AU (1) AU5239299A (en)
BR (1) BR9912406A (en)
CA (1) CA2338764A1 (en)
HU (1) HUP0102752A3 (en)
IL (1) IL141028A0 (en)
NO (1) NO20010446D0 (en)
PL (1) PL345713A1 (en)
TR (1) TR200100267T2 (en)
WO (1) WO2000006146A1 (en)

Families Citing this family (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MXPA03000923A (en) * 2000-07-31 2003-06-09 Smithkline Beecham Plc Carboxamide compounds and their use as antagonists of a human 11cby receptor.
AU2002235277A1 (en) * 2000-10-23 2002-05-06 Smith Kline Beecham Corporation Compounds and methods
US7507767B2 (en) 2001-02-08 2009-03-24 Schering Corporation Cannabinoid receptor ligands
US7067539B2 (en) 2001-02-08 2006-06-27 Schering Corporation Cannabinoid receptor ligands
KR20050044417A (en) 2001-11-14 2005-05-12 쉐링 코포레이션 Cannabinoid receptor ligands
JP2005533809A (en) 2002-06-19 2005-11-10 シェーリング　コーポレイション Cannabinoid receptor agonist
TW201018661A (en) 2003-03-14 2010-05-16 Ono Pharmaceutical Co Heterocyclic rinf having nitrogen atom derivatives and medicament containing the derivatives as active ingredient
AR043633A1 (en) 2003-03-20 2005-08-03 Schering Corp CANABINOID RECEIVERS LINKS
US7498323B2 (en) 2003-04-18 2009-03-03 Ono Pharmaceuticals Co., Ltd. Spiro-piperidine compounds and medicinal use thereof
CN1925854A (en) * 2003-11-14 2007-03-07 沃泰克斯药物股份有限公司 Thiazoles and oxazoles useful as modulators of ATP-binding cassette transporters
US7544803B2 (en) * 2004-01-23 2009-06-09 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7786141B2 (en) 2004-08-19 2010-08-31 Vertex Pharmaceuticals Incorporated Dihydrospiroindene modulators of muscarinic receptors
RU2007109794A (en) 2004-08-19 2008-09-27 Вертекс Фармасьютикалз, Инкорпорейтед (Us) MUSCARINE RECEPTOR MODULATORS
EP2546234A1 (en) 2004-09-13 2013-01-16 Ono Pharmaceutical Co., Ltd. Nitrogeneous heterocyclic derivative and medicine containing the same as an active ingredient
US7863449B2 (en) 2004-11-29 2011-01-04 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
WO2006129679A1 (en) 2005-05-31 2006-12-07 Ono Pharmaceutical Co., Ltd. Spiropiperidine compound and medicinal use thereof
CA2628863A1 (en) * 2005-10-06 2007-04-19 University Of Massachusetts Composition and synthesis of new reagents for inhibition of hiv replication
EP2657235A1 (en) 2005-10-28 2013-10-30 Ono Pharmaceutical Co., Ltd. Compound containing basic group and use thereof
JP5217438B2 (en) 2005-11-18 2013-06-19 小野薬品工業株式会社 COMPOUND CONTAINING BASIC GROUP AND USE THEREOF
WO2007076070A2 (en) 2005-12-22 2007-07-05 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US8263605B2 (en) 2006-02-22 2012-09-11 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
CA2643320A1 (en) 2006-02-22 2007-09-07 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
JPWO2007105637A1 (en) 2006-03-10 2009-07-30 小野薬品工業株式会社 Nitrogen-containing heterocyclic derivatives and drugs containing them as active ingredients
US8618122B2 (en) 2006-05-16 2013-12-31 Ono Pharmaceutical Co., Ltd. Compound having acidic group which may be protected, and use thereof
CN101500565A (en) 2006-06-29 2009-08-05 弗特克斯药品有限公司 Modulators of muscarinic receptors
US20090325992A1 (en) 2006-07-31 2009-12-31 Ono Pharmaceutical Co., Ltd. Compound having cyclic group bound thereto through spiro binding and use thereof
JP2010500412A (en) 2006-08-15 2010-01-07 バーテックス ファーマシューティカルズ インコーポレイテッド Modulator of muscarinic receptor
CA2660974A1 (en) 2006-08-18 2008-02-21 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
GB0625523D0 (en) * 2006-12-21 2007-01-31 Ge Healthcare Ltd In vivo imaging agents
WO2009045519A1 (en) 2007-10-03 2009-04-09 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
WO2010129351A1 (en) 2009-04-28 2010-11-11 Schepens Eye Research Institute Method to identify and treat age-related macular degeneration
EP2741777B1 (en) 2011-08-12 2017-01-18 INSERM - Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical compositions for treatment of pulmonary hypertension
FR2984323B1 (en) 2011-12-16 2019-08-30 L'oreal STRUCTURE COUPLER 7 AMINO-1,2,3,4-TETRAHYDROQUINOLINES, TINCTORIAL COMPOSITION COMPRISING THE SAME, METHODS AND USES
FR2984318B1 (en) 2011-12-16 2014-06-27 Oreal CATIONIC AMINO-1,2,3,4-TETRAHYDROQUINOLINE 7 STRUCTURE COUPLER, TINCTORIAL COMPOSITION COMPRISING THE SAME, METHODS AND USES
FR3072286B1 (en) 2017-10-13 2022-08-12 Oreal PARTICULAR 7-AMINO-1,2,3,4-TETRAHYDROQUINOLEINS, METHOD AND COMPOSITION

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK189677A (en) * 1976-05-07 1977-11-08 Sumitomo Chemical Co M-PHENOXYBENZAMIDE DERIVATORS
ZA985542B (en) * 1997-07-03 1999-04-07 Smithkline Beecham Corp Substituted benzanilides as CCR5 receptor ligands antiinflammatory agents and antiviral agents

Also Published As

Publication number Publication date
HUP0102752A2 (en) 2001-12-28
IL141028A0 (en) 2002-02-10
CN1310621A (en) 2001-08-29
BR9912406A (en) 2001-04-24
NO20010446L (en) 2001-01-26
NO20010446D0 (en) 2001-01-26
HUP0102752A3 (en) 2002-11-28
TR200100267T2 (en) 2001-09-21
JP2002521436A (en) 2002-07-16
WO2000006146A1 (en) 2000-02-10
KR20010074779A (en) 2001-08-09
CA2338764A1 (en) 2000-02-10
EP1100485A4 (en) 2004-06-09
EP1100485A1 (en) 2001-05-23
WO2000006146A9 (en) 2000-08-03
PL345713A1 (en) 2002-01-02

Similar Documents

Publication Publication Date Title
AU5239299A (en) Substituted anilide compounds and methods
US6399656B1 (en) Compounds and methods
US6515027B1 (en) Substituted benzanilides as CCR5 receptors ligands, antiinflammatory agents and antiviral agents
CA2338804A1 (en) Propenamides as ccr5 modulators
WO2004011427A2 (en) Substituted benzanilides as modulators of the ccr5 receptor
EP1313477A1 (en) Compounds and methods
US6476028B1 (en) Compounds and methods
JP2002535256A (en) Compounds and methods
WO2004010942A2 (en) Substituted heterocyclic compounds as modulators of the ccr5 receptor
WO2001064213A1 (en) Compounds and methods
EP1140072B1 (en) Compounds and methods
EP1156801B1 (en) SUBSTITUTED BENZO(1,2-b:5,4-b')DIPYRAN-4-AMINES AS CCR5 MODULATORS
US20040038982A1 (en) Compounds and methods
WO2002034760A2 (en) Compounds and methods
MXPA01001023A (en) Substituted anilide compounds and methods
MXPA00000148A (en) Compounds and methods
CZ474999A3 (en) Pharmaceutical preparation for treating pathological states mediated by CCR5

Legal Events

Date Code Title Description
MK5 Application lapsed section 142(2)(e) - patent request and compl. specification not accepted