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US20040010008A1 - Piperidine derivatives useful as CCR5 antagonists - Google Patents

Piperidine derivatives useful as CCR5 antagonists Download PDF

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Publication number
US20040010008A1
US20040010008A1 US10/229,466 US22946602A US2004010008A1 US 20040010008 A1 US20040010008 A1 US 20040010008A1 US 22946602 A US22946602 A US 22946602A US 2004010008 A1 US2004010008 A1 US 2004010008A1
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alkyl
group
aryl
compounds
cycloalkyl
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Inventor
Anandan Palani
Michael Miller
Jack Scott
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Merck Sharp and Dohme LLC
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Schering Corp
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Priority to US10/229,466 priority Critical patent/US20040010008A1/en
Assigned to SCHERING CORPORATION reassignment SCHERING CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MILLER, MICHAEL W., SCOTT, JACK D., PALANI, ANANDAN
Priority to US10/629,466 priority patent/US7442703B2/en
Priority to US10/628,933 priority patent/US7384948B2/en
Publication of US20040010008A1 publication Critical patent/US20040010008A1/en
Priority to US12/104,914 priority patent/US8034933B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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

Definitions

  • the present invention relates to piperidine derivatives useful as selective CCR5 antagonists, pharmaceutical compositions containing the compound of this invention, and methods of treatment using the inventive compounds.
  • the invention also relates to the use of a combination of the compound of this invention and one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus (HIV).
  • HIV Human Immunodeficiency Virus
  • the invention further relates to the use of the compound of this invention, alone or in combination with another agent, in the treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis.
  • CCR5 gene plays a role in resistance to HIV infection. HIV infection begins by attachment of the virus to a target cell membrane through interaction with the cellular receptor CD4 and a secondary chemokine co-receptor molecule, and proceeds by replication and dissemination of infected cells through the blood and other tissue.
  • chemokine receptors There are various chemokine receptors, but for macrophage-tropic HIV, believed to be the key pathogenic strain that replicates in vivo in the early stages of infection, the principal chemokine receptor required for the entry of HIV into the cell is CCR5. Therefore, interfering with the interaction between the viral receptor CCR5 and HIV can block HIV entry into the cell.
  • the present invention relates to small molecules which are CCR5 antagonists.
  • CCR5 receptors have been reported to mediate cell transfer in inflammatory diseases such as arthritis, rheumatoid arthritis, atopic dermatitis, psoriasis, asthma and allergies. Inhibitors of such receptors are expected to be useful in the treatment of such diseases, and in the treatment of other inflammatory diseases or conditions such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft v. host disease.
  • piperidine derivatives which are muscarinic antagonists useful in the treatment of cognitive disorders such as Alzheimer's disease, are disclosed in U.S. Pat. Nos. 5,883,096, 6,037,352, 5,889,006, 5,952,349, and 5,977,138.
  • HAART Highly Active Antiretroviral Therapy
  • NRTI nucleoside reverse transcriptase inhibitors
  • NRTI non-nucleoside reverse transcriptase inhibitors
  • PI HIV protease inhibitors
  • the present invention provides a novel class of compounds as antagonists of the CCR5 receptor, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, and methods of treatment, prevention or amelioration of one or more diseases associated with the CCR5 receptor.
  • One aspect of the invention relates to a compound having the general structure shown in Formula I:
  • R 1 is
  • R 2 is selected from the group consisting of H, alkyl, aryl, arylalkyl, heteroarylalkyl, alkylketone, arylketone, alkyl, haloalkyl, cycloalkyl, cycloheteroalkyl, cycloalkylalkyl, alkylsulfonyl, arylsulfonyl, alkoxyalkyl, or amide;
  • R 3 is selected from the group consisting of aryl, 6-membered heteroaryl, fluorenyl; and diphenylmethyl, 6 membered heteroaryl-N-oxide,
  • aryl, fluorenyl, diphenyl or heteroaryl is optionally substituted with 1-4 substituents which can be the same or different and are independently selected from the group consisting of R 11 , R 12 , R 13 , R 14 and R 15 ;
  • R 4 is 1-3 substituents selected from the group consisting of H, halo, alkyl, haloalkyl, alkoxy, cycloalkyl, cycloheteroalkyl, amide, CF 3 , OCF 3 , aryl, heteroaryl, —XR 7 , —C(O)C 3 -C 8 cycloalkyl, —C(O)C 3 -C 8 cycloheteroalkyl, —(C 1 -C 6 )alkyl-N(R 21 )SO 2 R 22 , —(C 1 -C 6 )alkyl-C(O)NR 20 R 21 , —CN, —CO 2 H, —CO 2 R 22 , R 8 -aryl(C 1 -C 6 )alkyl-, R 8 -heteroaryl(C 1 -C 6 )alkyl-, —C(O)—(C 1 -C 6 )—(O
  • R 5 is selected from the group consisting of H, arylalkyl, (C 1 -C 6 )alkyl, R 8 -aryl(C 1 -C 6 )alkyl-, R 8 -heteroaryl(C 1 -C 6 )alkyl-, —SO 2 —(C 1 -C 6 )alkyl, —SO 2 —(C 3 -C 6 )cycloalkyl, —SO 2 -aryl, R 8 -aryl-SO 2 —, —C(O)—(C 1 -C 6 )alkyl, —C(O)—(C 4 -C 6 )cycloalkyl, R 8 -aryl-C(O)—, —C(O)NR 21 R 22 , and —SO 2 NR 21 R 22 ;
  • R 6 is H, —(C 1 -C 6 )alkyl, or —(C 1 -C 6 )haloalkyl;
  • R 7 is selected from the group consisting of aryl, substituted aryl, heteroaryl, alkyl, haloalkyl and cycloalkyl;
  • R 8 is 1, 2 or 3 substituents selected from the group consisting of H, halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, —CF 3 , —OCF 3 , CH 3 C(O)—, —CN, CH 3 SO 2 —, CF 3 SO 2 — and —NH 2 , wherein R 8 can be the same or different and is independently selected when there are more than one R 8 present;
  • R 9 , R 10 and B can be the same or different and are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, and —(C 1 -C 6 )haloalkyl;
  • R 11 and R 12 can be the same or different and are each independently selected from the group consisting of (C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, halogen, —NR 19 R 20 , —OH, CF 3 , —OCH 3 , —O-acyl, and —OCF 3 ;
  • R 13 is selected from the group consisting of hydrogen, R 11 , H, phenyl, —NO 2 , —CN, —CH 2 F, —CHF 2 , —CHO, —CH ⁇ NOR 19 , pyridyl-N-oxide, pyrimidinyl, pyrazinyl, N(R 20 )CONR 20 R 21 , —NHCONH(chloro-(C 1 -C 6 )alkyl), —NHCONH((C 3 -C 10 )-cycloalkyl(C 1 -C 6 )alkyl), —NHCO(C 1 -C 6 )alkyl, —NHCOCF 3 , —NHCOCF 3 , —NHSO 2 N((C 1 -C 6 )alkyl) 2 , —NHSO 2 (C 1 -C 6 )alkyl, —N(SO 2 CF 3 ) 2 , —NHCO 2 (C 1 , —
  • R 14 is selected from the group consisting of (C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl —NH 2 and R 15 -phenyl;
  • R 15 is 1-3 substituents selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —CF 3 , —CO 2 R 20 , —CN, (C 1 -C 6 )alkoxy and halogen; wherein R 15 can be the same or different and is independently selected when there are more than one R 15 present;
  • R 16 and R 17 can each be the same or different and are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, or
  • R 16 and R 17 together are a C 2 -C 5 alkylene group and with the carbon to which they are attached from a spiro ring of 3 to 6 carbon atoms;
  • R 19 , R 20 and R 21 can each be the same or different and are each independently selected from the group consisting of H, (C 1 -C 6 )alkyl and (C 3 -C 6 )cycloalkyl;
  • R 22 is selected from the group consisting of (C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, (C 2 -C 6 )hydroxyalkyl, (C 2 -C 6 )alkylene, (C 3 -C 6 )cycloalkyl, aryl and aryl(C 1 -C 6 )alkyl-;
  • A is selected from the group consisting of H, (C 1 -C 6 )alkyl, and (C 2 -C 6 ) alkenyl.
  • M is aryl or heteroaryl optionally substituted with R 4 ;
  • Q is CH or N
  • X is selected from the group consisting of CH 2 , SO 2 , SO, S, and O, with the following proviso:
  • R 1 is phenyl, pyridyl, thiophenyl or naphthyl
  • R 2 cannot be H, —(C 1 -C 6 )alkyl or —C(O)—(C 1 -C 6 )alkyl.
  • Another aspect of the invention relates to a pharmaceutical composition for treatment of HIV comprising one or more compounds of formula I.
  • Yet another aspect of the invention relates to a method of treating Human Immunodeficiency Virus comprising administering to a patient in need of such treatment a therapeutically effective amount of one or more compounds of formula I.
  • a further aspect of the invention relates to a method of treating solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis comprising administering to a patient in need of such treatment a therapeutically effective amount of one or more compounds of formula I.
  • Still another aspect of this invention relates to a method of treating Human Immuno-deficiency Virus comprising administering to a patient in need of such treatment the one or more compounds of formula I in combination with one or more antiviral or other agents useful in the treatment.
  • a further aspect of this invention relates to a method of treating solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma or allergies comprising administering to a patient in need of such treatment one or more compounds of formula I in combination with one or more antiviral or other agents useful in the treatment.
  • CCR5 and antiviral or other agents which are components of the combination can be administered in a single dosage or administered separately.
  • a kit comprising separate dosage forms of the actives is also contemplated.
  • the present invention relates to a compound having the general structure shown in Formula I:
  • R 1 , R 2 , R 3 , R 9 , R 10 , A and B are defined as above.
  • Q is preferably CH or N, and R 2 is preferably alkyl, aryl or benzyl.
  • R 1 is M-R 4
  • R2 is preferably benzyl, phenyl or cyclopropylmethly.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain 1 to about 6 carbon atoms in the chain. Branched alkyl means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. “Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Preferred alkyl groups in the present invention are lower alkyl groups.
  • Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, trifluoromethyl and cyclopropylmethyl.
  • Halo means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.
  • Halogen means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine.
  • Haloalkyl or “halogenated alkyl” means alkyl having one or more halo atom substituents.
  • the haloalkyl is a haloalkyl.
  • Non-limiting examples include —CH 2 Cl, —CHCl 2 , —CCl 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 —CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 and —CF 2 CF 3 .
  • Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of aryl, heteroaryl, aralkyl, alkylamino, arylamino, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, aralkyloxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl,
  • Cycloalkyl means a non-aromatic mono- or multicyclic fused ring system comprising 3 to 10 ring carbon atoms, preferably 3 to 7 ring carbon atoms, more preferably 3 to 6 ring carbon atoms.
  • the cycloalkyl can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • suitable multicyclic cycloalkyls include 1-decalinyl, norbornenyl, adamantyl and the like.
  • Cycloheteroalkyl means a non-aromatic mono- or multicyclic fused ring system comprising 3 to 10 ring carbon atoms, preferably 3 to 7 ring carbon atoms, more preferably 3 to 6 ring carbon atoms, wherein the cycloheteroaryl has 1 or 2 heteroatoms independently selected from O, S or N, said heteroatom(s) interrupting a carbocyclic ring structure provided that the rings do not contain adjacent oxygen and/or sulfur atoms.
  • the cycloheteroalkyl can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined above.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising 6 to 14 ring carbon atoms, preferably 6 to 10 ring carbon atoms.
  • the aryl group can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined herein.
  • suitable aryl groups include phenyl and naphthyl.
  • Heteroaryl represents cyclic aromatic groups of 5 or 6 ring atoms or bicyclic groups of 11 to 12 ring atoms having 1 or 2 heteroatoms independently selected from O, S or N, said heteroatom(s) interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, provided that the rings do not contain adjacent oxygen and/or sulfur atoms.
  • Preferred heteroaryls contain 5 to 6 ring atoms.
  • the “heteroaryl” can be optionally substituted by one or more “ring system substituents” which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • Nitrogen atoms can form an N-oxide. All regioisomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl.
  • Useful 6-membered heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and the like and the N-oxides thereof.
  • Useful 5-membered heteroaryl rings include furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, isoxazolyl and the like.
  • Useful bicyclic groups include benzo-fused ring systems derived from the heteroaryl groups named above, e.g. quinolyl, phthalazinyl, quinazolinyl, benzofuranyl, benzothienyl, indolyl and the like.
  • Amide is represented by RCONH 2 wherein one or both of the hydrogen atoms in RCONH 2 can be substituted by an alkyl group and alkyl has the same meaning as defined above.
  • Arylalkyl or aralkyl represents a moiety containing an aryl group linked to the main group or ring via an alkyl.
  • Alkylketone represents a moiety containing an alkyl group linked to the main group or ring via a ketone.
  • Arylketone represents a moiety containing an aryl group linked to the main group or ring via a ketone.
  • Alkylaryl represents a moiety containing an alkyl linked to the main group or ring via an aryl group.
  • Heteroarylalkyl represents a moiety containing a heteroaryl group linked to the main group or ring via an alkyl.
  • the term “optionally substituted” means optional substitution with the specified groups, radicals or moieties.
  • solvate as used herein means an aggregate that consists of a solute ion or molecule with one or more solvent molecules, for example, a hydrate containing such ions.
  • composition and “formulation” are intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combination of the specified ingredients.
  • “Patient” includes mammals and other animals.
  • “Mammal” includes humans and other mammalian animals.
  • terapéuticaally effective amount is intended to mean an amount of a therapeutic agent of the compound of formula I that will have an effect on a tissue, system, animal or patient that is being sought by the administrator (such as a researcher, doctor or veterinarian), which includes alleviation of the symptoms of the condition or disease being treated and the prevention, slowing or halting of progression of the disease or condition, for example, the inflammatory, immunomodulatory or respiratory diseases discussed herein.
  • Prodrugs and solvates of the compounds of the invention are also contemplated within the scope of this invention.
  • the term “prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I or a salt and/or solvate thereof.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.
  • the compounds of formula I can form salts, solvates and prodrugs which are also within the scope of this invention.
  • Reference to a compound of formula I herein is understood to include reference to salts, solvates and prodrugs thereof, unless otherwise indicated.
  • salt(s) denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • a compound of formula I contains both a basic moiety, such as, but not limited to, a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein.
  • Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful.
  • Salts of the compounds of the formula I may be formed, for example, by reacting a compound of formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulforiates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphat
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g.
  • dialkyl sulfates e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides
  • aralkyl halides e.g. benzyl and phenethyl bromides
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the use of the terms “salt”, “solvate” “prodrug” and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds.
  • NRTI nucleoside and nucleotide reverse transcriptase inhibitors
  • Typical suitable NRTIs include zidovudine (AZT) available under the RETROVIR tradename from Glaxo-Wellcome Inc., Research Triangle, NC 27709; didanosine (ddl) available under the VIDEX tradename from Bristol-Myers Squibb Co., Princeton, N.J. 08543; zalcitabine (ddC) available under the HIVID tradename from Roche Pharmaceuticals, Nutley, N.J. 07110; stavudine (d4T) available under the ZERIT trademark from Bristol-Myers Squibb Co., Princeton, N.J.
  • BCH-10652 a reverse transcriptase inhibitor (in the form of a racemic mixture of BCH-10618 and BCH-10619) under development by Biochem Pharma, Laval, Quebec H7V, 4A7, Canada; emitricitabine [( ⁇ )-FTC] licensed from Emory University under Emory Univ. U.S. Pat. No. 5,814,639 and under development by Triangle Pharmaceuticals, Durham, N.C. 27707; beta-L-FD4 (also called beta-L-D4C and named beta-L-2′, 3′-dicleoxy-5-fluoro-cytidene) licensed by Yale University to Vion Pharmaceuticals, New Haven Conn.
  • beta-L-FD4 also called beta-L-D4C and named beta-L-2′, 3′-dicleoxy-5-fluoro-cytidene
  • DAPD the purine nucleoside, ( ⁇ )-beta-D-2,6,-diamino-purine dioxolane disclosed in EP 0656778 and licensed by Emory University and the University of Georgia to Triangle Pharmaceuticals, Durham, N.C. 27707; and Iodenosine (FddA), 9-(2,3-dideoxy-2-fluoro-b-D-threo-pentofuranosyl)adenine, an acid stable purine-based reverse transcriptase inhibitor discovered by the NIH and under development by U.S. Bioscience Inc., West Conshohoken, Pa. 19428.
  • NRTI non-nucleoside reverse transcriptase inhibitors
  • Typical suitable NNRTIs include nevirapine (BI-RG-587) available under the VIRAMUNE tradename from Boehringer Ingelheim, the manufacturer for Roxane Laboratories, Columbus, Ohio 43216; delaviradine (BHAP, U-90152) available under the RESCRIPTOR tradename from Pharmacia & Upjohn Co., Bridgewater N.J. 08807; efavirenz (DMP-266) a benzoxazin-2-one disclosed in WO94/03440 and available under the SUSTIVA tradename from DuPont Pharmaceutical Co., Wilmington, Del. 19880-0723; PNU-142721, a furopyridine-thio-pyrimide under development by Pharmacia and Upjohn, Bridgewater N.J.
  • protease inhibitor means inhibitors of the HIV-1 protease, an enzyme required for the proteolytic cleavage of viral polyprotein precursors (e.g., viral GAG and GAG Pol polyproteins), into the individual functional proteins found in infectious HIV-1.
  • HIV protease inhibitors include compounds having a peptidomimetic structure, high molecular weight (7600 daltons) and substantial peptide character, e.g. CRIXIVAN (available from Merck) as well as nonpeptide protease inhibitors e.g., VIRACEPT (available from Agouron).
  • Typical suitable PIs include saquinavir (Ro 31-8959) available in hard gel capsules under the INVIRASE tradename and as soft gel capsules under the FORTOVASE tradename from Roche Pharmaceuticals, Nutley, N.J. 07110-1199; ritonavir (ABT-538) available under the NORVIR tradename from Abbott Laboratories, Abbott Park, Ill. 60064; indinavir (MK-639) available under the CRIXIVAN tradename from Merck & Co., Inc., West Point, Pa. 19486-0004; nelfnavir (AG-1343) available under the VIRACEPT tradename from Agouron Pharmaceuticals, Inc., LaJolla Calif.
  • amprenavir 141W94
  • tradename AGENERASE a non-peptide protease inhibitor under development by Vertex Pharmaceuticals, Inc., Cambridge, Mass. 02139-4211 and available from Glaxo-Wellcome, Research Triangle, N.C. under an expanded access program
  • lasinavir BMS-234475
  • DMP-450 a cyclic urea discovered by Dupont and under development by Triangle Pharmaceuticals
  • BMS-2322623 an azapeptide under development by Bristol-Myers Squibb, Princeton, N.J.
  • antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607.
  • Hydroyurea (Droxia), a ribonucleoside triphosphate reductase inhibitor, the enzyme involved in the activation of T-cells, was discovered at the NCI and is under development by Bristol-Myers Squibb; in preclinical studies, it was shown to have a synergistic effect on the activity of didanosine and has been studied with stavudine.
  • IL-2 is disclosed in Ajinomoto EP-0142268 , Takeda EP-0176299, and Chiron U.S. Pat. Nos.
  • IL-12 is disclosed in WO96/25171 and is available from Roche Pharmaceuticals, Nutley, N.J. 07110-1199 and American Home Prodocts, Madison, N.J.
  • Pentafuside DP-178, T-20
  • Pentafuside a 36-amino acid synthetic peptide,disclosed in U.S. Pat. No. 5,464,933 licensed from Duke University to Trimeris which is developing pentafuside in collaboration with Duke University; pentafuside acts by inhibiting fusion of HIV-1 to target membranes.
  • Pentafuside (3-100 mg/day) is given as a continuous sc infusion or injection together with efavirenz and 2 PI's to HIV-1 positive patients refractory to a triple combination therapy; use of 100 mg/day is preferred. Yissum Project No.
  • Ribavirin 1- ⁇ -D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif.; its manufacture and formulation are described in U.S. Pat. No. 4,211,771.
  • anti-HIV-1 therapy means any anti-HIV-1 drug found useful for treating HIV-1 infections in man alone, or as part of multidrug combination therapies, especially the HAART triple and quadruple combination therapies.
  • Typical suitable known anti-HIV-1 therapies include, but are not limited to multidrug combination therapies such as (i) at least three anti-HIV-1 drugs selected from two NRTIs, one PI, a second PI, and one NNRTI; and (ii) at least two anti-HIV-1 drugs selected from NNRTIs and PIs.
  • Typical suitable HAART—multidrug combination therapies include:
  • triple combination therapies such as two NRTIs and one PI
  • two NRTIs and one NNRTI it is preferred to start anti-HIV-1 treatment with the triple combination therapy; the use of two NRTIs and one PI is prefered unless there is intolerance to PIs.
  • Drug compliance is essential.
  • the CD4 + and HIV-1-RNA plasma levels should be monitored every 3-6 months. Should viral load plateau, a fourth drug, e.g., one PI or one NNRTI could be added. See the table below wherein typical therapies are further described:
  • R 1 , R 2 and R 3 are as defined in the following table: TABLE 1 # R 1 R 2 R 3 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 CH 3 112 113
  • TABLE 1A # R 1 R 2 R 3 1 2 6 10 11 12 13 14 16 17 28 29 31 36 37 39 40 47 49 50 56 57 61 68 69 70 71 80 81 82 90 91 93 96 99 100 101 102
  • the compound of the present invention also referred to herein as the inventive compound, is particularly useful as a CCR5 antagonist.
  • solvents and reagents may be referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1-hydroxy-benzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA); triethylamine (Et 3 N); diethyl ether (Et 2 O); tert-butoxy-carbonyl (BOC); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); dimethyl-sulfoxide (DMSO); p-toluene sulfonic acid (p-TSA); potassium bis(trimethylsilyl)-amide (KHMDA);
  • the keto-amide 8 is reacted with a substituted 4-amino piperidine 7 in the presence of sodium triacetoxy borohydride to give the amine 8.
  • the free amine in 8 can be functionalized either by reductive amination (RCHO/Na(AcO) 3 BH) or alkylation (NaH or Cs 2 CO 3 /R 2 X) to furnish compounds of formula IA.
  • the keto-amide 5 is reacted with an amine 10 in the presence of sodium triacetoxyborohydride to furnish the functionalized amine 11.
  • the amine 11 can be alkylated either with NaH, Cs 2 CO 3 /R 2 X or Na(AcO) 3 BH/RCHO to furnish the tertiary amine 12.
  • the Boc group in 12 can be removed with an acid such as HCl or TFA, and the resulting piperidine can be coupled to acids to furnish compounds of formula IB.
  • N-Boc-4-piperidone 2 is reacted with and amine (R 2 NH 2 ) in the presence of Na(AcO) 3 BH to furnish the amine 13.
  • the amine 13 can be reacted with either aryl or heteroaryl halides/triflates under palladium catalysis or Cu(OAc) 2 /(R 4 M) 3 Bi to furnish the arylated amines 14.
  • the Boc group in 14 can be removed, and the second piperidine ring can be added according to the procedure previously discussed (Scheme 1; Steps 1 and 2) to furnish the piperidine 15.
  • the Boc group in 15 is removed with an acid such as TFA or HCL, and the amine is coupled to an acid represented by R 3 CO 2 H to furnish the compounds of formula IB.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.
  • Liquid form preparations include solutions, suspensions and emulsions.
  • An example of this includes, but is not limited to, water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions.
  • Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. nitrogen.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • the compound of the invention may also be deliverable transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compounds of this invention may also be deliverable subcutaneously.
  • the compound is administered orally.
  • the pharmaceutical preparation is in a unit dosage form.
  • the preparation is subdivided into suitably sized unit doses containing a therapeutically effective amount of the compound having formula I.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 10 mg to about 500 mg, preferably from about 25 mg to about 300 mg, more preferably from about 50 mg to about 250 mg, and most preferably from about 55 mg to about 200 mg, according to the particular application.
  • the actual dosage of the inventive compound employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
  • a typical recommended daily dosage regimen for oral administration can range from about 100 mg/day to about 300 mg/day, preferably 150 mg/day to 250 mg/day, more preferably about 200 mg/day, in two to four divided doses.
  • the doses and dosage regimens of the NRTIs, NNRTIs, PIs and other agents used in combination with the compounds of this invention will be determined by the attending clinician inview of the approved doses and dosage regimens in the package inserts or as set forth in the protocols, taking into consideration the age, sex and condition of the patient and the severity of the condition treated.
  • the compound of the present invention can be used to treat Human Immunodeficiency Virus by administering to a patient in need of such treatment a therapeutically effective amount of one or more compounds having formula I, preferably in combination with one or more pharmaceutically acceptable carriers.
  • One or more, preferably one to four, antiviral agents useful in anti-HIV-1 therapy can be used in combination with the compound of the present invention.
  • the antiviral agent or agents can be combined with one or more compounds of the present invention in a single dosage form, or the one or more compounds of the present invention and the antiviral agent or agents may be administered simultaneously or sequentially as separate dosage forms.
  • antiviral agents contemplated for use in combination with the compound of the present invention comprise nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and other antiviral drugs listed below not falling within these classifications.
  • antiviral agents include, but are not limited to, zidovudine, lamivudine, zalcitabine, didanosine, stavudine, abacavir, adefovir dipivoxil, lobucavir, BCH-10652, emitricitabine, beta-L-FD4, DAPD, Iodenosine, nevirapine, delaviridine, efavirenz, PNU-142721, AG-1549, MKC-442, (+)-calanolide A and B, saquinavir, indinavir, ritonavir, nelfinavir, lasinavir, DMP-450, BMS-2322623, ABT-378, amprenavir, hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, Yissum No. 11607 and AG-1549.
  • the combinations known as HAART are contemplated for use in combination with the
  • the active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.
  • Another aspect of the invention provides a method of treating solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis comprising administering to a patient in need of such treatment a therapeutically effective amount of one or more compounds of formula I, preferably in combination with one or more pharmaceutically acceptable carriers.
  • the method for treating solid organ transplant rejection, graft v. host disease, rheumatoid arthritis, inflammatory bowel disease or multiple sclerosis further comprises administering one or more other agents useful in the treatment of said diseases in combination with one or more compounds of formula I.
  • Agents known in the treatment of rheumatoid arthritis, transplant and graft v. host disease, inflammatory bowel disease and multiple sclerosis which can be administered in combination with the compound of the present invention are as follows:
  • immune suppressants such as cyclosporine and Interleukin-10 (IL-10), tacrolimus, antilymphocyte globulin, OKT-3 antibody, and steroids;
  • inflammatory bowel disease IL-10 (see U.S. Pat. No. 5,368,854), steroids and azulfidine;
  • rheumatoid arthritis methotrexate, azathioprine, cyclophosphamide, steroids and mycophenolate mofetil;
  • multiple sclerosis interferon-beta, interferon-alpha, and steroids.
  • kits comprising in separate containers in a single package pharmaceutical composition for use in combination to treat Human Immunodeficiency Virus.
  • a pharmaceutical composition comprises one or more compounds of formula I in one or more pharmaceutically acceptable carriers, and in separate containers, one or more pharmaceutical compositions comprising an effective amount of one or more antiviral agents or other agents useful in the treatment of Human Immunodeficiency Virus in one or more pharmaceutically acceptable carriers.
  • the goal of the HIV-1 therapy of the present invention is to reduce the HIV-1-RNA viral load below the detectable limit.
  • the “detectable limit of HIV-1-RNA” in the context of the present invention means that there are fewer than about 200 to fewer than about 50 copies of HIV-1-RNA per ml of plasma of the patient as measured by quantitative, multi-cycle reverse transcriptase PCR methodology. HIV-1-RNA is preferably measured in the present invention by the methodology of Amplicor-1 Monitor 1.5 (available from Roche Diagnsotics) or of Nuclisens HIV-1 QT-1.
  • a high throughput screen utilizing a CCR5 membrane binding assay identifies inhibitors of RANTES binding.
  • This assay utilizes membranes prepared from NIH 3T3 cells expressing the human CCR5 chemokine receptor which have the ability to bind to RANTES, a natural ligand for the receptor.
  • membrane preparations are incubated with 125 I-RANTES in the presence or absence of compound for one hour.
  • Compounds are serially diluted over a wide range of 0.001 ug/ml to 1 ug/ml and tested in triplicates. Reaction cocktails are harvested through glass fiber filters, and washed thoroughly. Total counts for replicates are averaged and data reported as the concentration required to inhibit 50 percent of total 125 I-RANTES binding.
  • Compounds with potent activity in the membrane binding assay are further characterized in seconday cell-based HIV-1 entry and replication assays.
  • Replication defective HIV-1 reporter virions are generated by cotransfection of a plasmid encoding the NL4-3 strain of HIV-1 (which has been modified by mutation of the envelope gene and introduction of a luciferase reporter plasmid) along with a plasmid encoding one of several HIV-1 envelope genes as described by Connor et al, Virology, 206 (1995), p. 935-944. Following transfection of the two plasmids by calcium phosphate precipitation, the viral supernatants are harvested on day 3 and a functional viral titer determined.
  • This assay uses primary peripheral blood mononuclear cells or the stable U87-CCR5 cell line to determine the effect of anti-CCR5 compounds to block infection of primary HIV-1 strains.
  • the primary lymphocytes are purified from normal healthy donors and stimulated in vitro with PHA and IL-2 three days prior to infection.
  • cells are pretreated with drug for 1 hour at 37° C. and subsequently infected with an M-tropic HIV-1 isolates. Following infection, the cells are washed to remove residual inoculum and cultured in the presence of compound for 4 days. Culture supernatants are harvested and viral replication measured by determination of viral p24 antigen concentration.
  • Cells expressing the HIV coreceptor CCR5 are loaded with calcium sensitive dyes prior to addition of compound or the natural CCR5 ligand.
  • Compounds with agonist properties will induce a calcium flux signal in the cell, while the compounds of this invention are identified as compounds which do not induce signaling by themselves but are capable of blocking signaling by the natural ligand RANTES.
  • a GTP S binding assay measures receptor activation by CCR5 ligands. This assay measures the binding of 35 S labeled-GTP to receptor coupled G-proteins that occurs as a result of receptor activation by an appropriate ligand.
  • the CCR5 ligand, RANTES is incubated with membranes from CCR5 expressing cells and binding to the receptor activation (or binding) is determined by assaying for bound 35 S label.
  • the assay quantitatively determines if compounds exhibit agonist characteristics by inducing activation of the receptor or alternatively antagonist properties by measuring inhibition of RANTES binding in a competitive or non-competitive fashion.
  • the chemotaxis assay is a functional assay which characterizes the agonist vs. antagonist properties of the test compounds.
  • the assay measures the ability of a non-adherent murine cell line expressing human CCR5 (BaF-550) to migrate across a membrane in response to either test compounds or natural ligands (i.e., RANTES, MIP-1 ⁇ ). Cells migrate across the permeable membrane towards compounds with agonist activity.
  • Compounds that are antagonists not only fail to induce chemotaxis, but are also capable of inhibiting cell migration in response to known CCR5 ligands.
  • Plasmids encoding the full length genome of HIV-1 pNL-4-Luc with the gp 120 V-3 loop replaced by the Bgl II fragment of HIV-1 ADA, YU-2 or HxB are obtained from Dr. Susan Pontow (Washington University, St. Louis Mo.).
  • Replication-competent luciferase reporter virus stocks are generated by transfection of plasmids into 293T cells using Superfect (Qiagen) or Mirus transfection reagents. Viral stocks are collected 48 hours following transfection and titered for luciferase production on U-87-CCR5 or CXCR4 cells.
  • U87-CD4-CCR5 cells (10 4/ well) are plated in 96-well cell culture plates and incubated overnight. Media is removed and replaced with 50 ⁇ l of fresh culture media (DMEM, 10% FCS) and 50 ⁇ l of compound diluted in culture medium. Cells are incubated with compound at 37° C. for 1 hour. The resultant supernatant is removed and replaced with 20 ⁇ l of media containing compound and infected with an equal volume of diluted or undiluted virus stock at 37° C. for 3-4 hours. The cells are washed once with DMEM, and 200 ⁇ l of media containing compound is added.
  • DMEM fresh culture media
  • FCS 50 ⁇ l of compound diluted in culture medium.
  • the resultant supernatant is removed and replaced with 20 ⁇ l of media containing compound and infected with an equal volume of diluted or undiluted virus stock at 37° C. for 3-4 hours.
  • the cells are washed once with DMEM, and 200 ⁇ l of media containing compound is
  • the cultures are incubated for 3 days, the cells lysed in luciferase lysis buffer (Promega, Madison, Wis.) and transferred to Immulon plates (Dynex Technologies, Chantilly Va.). An equal volume of luciferase substrate (Promega, Madison Wis.) is added to lysates and the plates read immediately in a Wallac Luminometer. Fifty and ninety percent inhibitory concentrations are determined using GraphPad PRISM software.
  • DMSO 0.9 mL, 12.6 mmol
  • Oxalyl chloride 1.1 mL, 12.6 mmol
  • the solution was stirred at that temperature for 20 minutes.
  • the alcohol from step 2 2.5 g, 8.39 mmol
  • Triethyl amine 3.5 mL, 25.2 mmol was added to the solution at ⁇ 40° C., and the resulting slurry was warmed to rt.
  • Boc-piperidine (2.0 g, 6.7 mmol) was taken up in CH 2 Cl 2 and TFA (7 mL) was added. The solution was stirred at rt for 1 h. The solution was concentrated. The resulting salt was taken up in H 2 O and basified with NaOH. The solution was extracted with CH 2 Cl 2 . The aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were dried (Na 2 SO 4 ), filtered, and concentrated to furnish 1.1 g (85%) of deprotected piperidine.
  • step 3 The product of step 3 was treated as described above for Example 5 (steps 3 and 4) to furnish the crude pyrimidine amide. Purification via preparative, thin-layer chromagotraphy (99:1 95/5 CH 2 Cl 2 /MeOH:7 N NH 3 in MeOH) gave 8 mg (53%) of Compound 111. The amide was taken up in EtOAc and was precipitated as the HCl salt upon addition of 2.0 M HCl in Et 2 O. m.p. (HCl salt): 164-167° C. (decomposition). HRMS (MH+) calc'd 507.2639; found: 507.2634.

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US9624199B2 (en) 2013-12-19 2017-04-18 Bayer Pharma Aktiengesellschaft Substituted bipiperidinyl derivatives
US9944621B2 (en) 2013-12-19 2018-04-17 Bayer Pharma Aktiengesellschaft Substituted piperidinyl tetrahydroquinolines

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