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WO2000006146A1 - Substituted anilide compounds and methods - Google Patents

Substituted anilide compounds and methods Download PDF

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Publication number
WO2000006146A1
WO2000006146A1 PCT/US1999/017121 US9917121W WO0006146A1 WO 2000006146 A1 WO2000006146 A1 WO 2000006146A1 US 9917121 W US9917121 W US 9917121W WO 0006146 A1 WO0006146 A1 WO 0006146A1
Authority
WO
WIPO (PCT)
Prior art keywords
methoxyphenyl
ethoxy
amino
methylethyl
bis
Prior art date
Application number
PCT/US1999/017121
Other languages
French (fr)
Other versions
WO2000006146A9 (en
Inventor
Thomas W. Ku
William E. Bondinell
Michael J. Neeb
Original Assignee
Smithkline Beecham Corporation
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 Corporation filed Critical Smithkline Beecham Corporation
Priority to EP99937589A priority Critical patent/EP1100485A4/en
Priority to IL14102899A priority patent/IL141028A0/en
Priority to KR1020017001173A priority patent/KR20010074779A/en
Priority to BR9912406-8A priority patent/BR9912406A/en
Priority to JP2000562001A priority patent/JP2002521436A/en
Priority to CA002338764A priority patent/CA2338764A1/en
Priority to AU52392/99A priority patent/AU5239299A/en
Priority to HU0102752A priority patent/HUP0102752A3/en
Publication of WO2000006146A1 publication Critical patent/WO2000006146A1/en
Publication of WO2000006146A9 publication Critical patent/WO2000006146A9/en
Priority to NO20010446A priority patent/NO20010446D0/en

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    • 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
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    • 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
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • 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
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    • 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
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    • 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
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    • C07D491/10—Spiro-condensed systems

Definitions

  • This invention relates to substituted anilide compounds which are 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.
  • 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 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.
  • T cells as well as other inflammatory cells, will migrate into tissues in response to the production of a variety of chemotactic factors.
  • chemokines 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.
  • R ANTES 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 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, monocytes and mast cells.
  • RANTES was originally identified as gene product induced late after antigen activation of T-cells (TJ. 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 epithelial and endothelial cells (C. Stellato, L.A. Beck, G.A. Gorgone, D. Proud, et _ al., J. Immunol.
  • RANTES rriRNA is rapidly upregulated in response to LL-1 or TNF*.
  • RANTES rnRNA 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.
  • RANTES mRNA was visualized using in situ hybridization in renal allografts undergoing rejection (J.M. Pattison, P.J. Nelson, and 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. T presenteda-Barata, Q. Meng, M. Humbert, et al., J. Exp. Med.
  • 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 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.
  • 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, . atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease, all in mammals, preferably humans.
  • CCR5 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 potential therapeutic in the treatment of COPD.
  • selective receptor modulators may be useful in the treatment of HIV infection.
  • this class of non-peptide compounds function as CCR5 receptor modulators, and therefore, have utility in the treatment and prevention of disease states mediated by CCR5 receptor mechanisms.
  • the present invention is to novel compounds of formula (I), or pharmaceutically active salts thereof, and their novel use in treating the above-mentioned CCR5 -mediated disease states:
  • the basic nitrogen in moiety E may be optionally quaternized with Ci .galkyl or is optionally present as the N-oxide;
  • pl and P ⁇ 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;
  • V is oxygen or sulfur
  • D is nitrogen, carbon, or a CH group
  • NR 27 CO(CH 2 ) d 'NR 27 R 28 ', NR 27 'CONR 27 R 28' , NRlO'c ⁇ 2 R 13 ', NR 10 'SO R 14' , N CNR 27 'NR 27 R 28 ', nitro, hydroxy, C ⁇ _ 6 alkoxy, hydroxyCi.
  • R ' is hydrogen, C galkyl, C3_6cycloalkyl, C3_6cycloalkenyl, hydroxyCj. 6 alkyl, .ealkylOC ⁇ galkyl, CONR 36 R 37' , CO 2 R 38 ', cyano, aryl, trifluoromethyl, NR 39 R 4 0 ' , nitro, hydroxy, C ⁇ alkoxy, C ⁇ .galkanoyl, acyloxy, or halogen;
  • R 35' , R 36 ', R 37' , R 38 ', R 39' , and R 40' are independently hydrogen or C ⁇ galkyl
  • R 8 ' is hydrogen or Ci.galkyl, providing that D is nitrogen or a CH group;
  • R 9 ' is hydrogen or C ⁇ alkyl, providing that D is nitrogen or a CH group;
  • RIO' and R ⁇ ' are independently hydrogen or C ⁇ alkyl, or RlO' and R ⁇ l' 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 2 ' is hydrogen, Ci. ⁇ alkyl, or C _4alkoxyalkyl;
  • R13' S R25' ) an R32' are independently C 1 . galkyl
  • R* ' is C ⁇ galkyl or phenyl
  • R 15 ' and R 6 ' are independently hydrogen or C ⁇ .galkyl, or R x ⁇ ' and 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* 7 ' is Cl ⁇ 4 alkyl, optionally substituted by Cj.galkoxy;
  • R ° is hydrogen or Ci .galkyl optionally substituted with one or two substituents selected from C ⁇ alkyl, Cj.galkoxy, hydroxy, or NRIO'RI I ';
  • R 29 ' and R 3 ⁇ ' are independently hydrogen or Ci .galkyl, or R 29 ' and R 3 ⁇ ' 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 33' and R 34' are independently hydrogen or Ci .galkyl, or R 33' 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 iri the ring one oxygen or one sulfur atom; a' and b' are independently 1 , 2, or 3 ; c' is O, l, or 2; d'is 1, 2, 3, or 4; e'is O, 1, 2, or 3; f is 1, 2, or 3; E represents (a):
  • R! and R 2 are independently hydrogen or Ci.galkyl; alternatively B(CR!R 2 ) a is OCR ⁇ CR ⁇ OH ⁇ R ⁇ R 2 or OCR 1 R 2 CR 1 (OCOCH 3 )CR 1 R 2 ;
  • R 3 and R 4 are independently hydrogen, C ⁇ _5alkyl, 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 galkyl, aryl, CONR ⁇ R 1 1 , NR 10 R! 1, hydroxy, OCOR 12 , NHCOCQ. galkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO 2 R 13 , and NHCO 2 R 14 ;
  • R 5 is hydrogen, C ⁇ galkyl, aryl, CN, CONR 15 Rl 6 , CO 2 R 17 , trifluoromethyl, NHCO 2 R 18 , hydroxy, C ⁇ alkoxy, benzyloxy, OCH CO 2 C ⁇ _ 6 alkyl, OCF3, S(O) R 19 , SO 2 NR 20 R 21 or halogen;
  • R 9 is hydrogen, Ci.galkyl, or phenylCi . ⁇ alkyl;
  • R 13 , R 14 , R 18 , and R 19 are independently Ci.galkyl;
  • 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 O, 1, 2 or 3; alternatively, E represents
  • R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 31 , and R 32 are independently hydrogen or C ⁇ _6alkyl
  • R 3 ⁇ is hydrogen, Cj.galkyl, or C3_7cycloalkyl
  • J is oxygen, CR 36 R 37 , or NR 38 , or J is a group S(O)k;
  • R 34 , R 35 , R 36 , R 37 , and R 38 are independently hydrogen or C galkyl; g is 1, 2 or 3; h is 1, 2 or 3; i is 2, 3, or 4; j is O, 1, 2, or 3; k is 0, 1 or 2; alternatively, E represents (c):
  • Q is oxygen, S(O) n , CR ⁇ CR 45 , CR 44 R 45 , or Q is NR 46 ;
  • R 39 and R 4 ⁇ are independently hydrogen or C ⁇ .galkyl;
  • R 1 is a group of formula (d):
  • R 4 ⁇ is a group of formula (e):
  • R 42 is hydrogen, C ⁇ alkyl, aryl, CN, CONR 48 R 49 , CO 2 R 50 , trifluoromethyl, NHCO R 51 , hydroxy, C ⁇ alkoxy, benzyloxy, OCH 2 CO 2 Cj.
  • R 43 is hydrogen or R 43 together with R 8' forms a group R where R is
  • R 47 is hydrogen, C ⁇ .galkyl, or C3.7 cycloalkyl;
  • R ⁇ l and R ⁇ 2 are independently C galkyl;
  • l is O, 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;
  • r is 0,1, 2, or 3;
  • s is O, l, or 2;
  • t is 2 or 3; alternatively, E represents (f):
  • R ⁇ 7 and R ⁇ 8 are independently hydrogen or C ⁇ alkyl
  • R59 and R ⁇ O are independently hydrogen, Cj.galkyl, 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 i ⁇ alkyl, aryl, CONR 61 R 62 , NR 61 R 62 , hydroxy, OCOR 63 , NHCOCo-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO R 64 and NHCO2R 65 ;
  • T is -(CR 66 R 67 ) V - or -O(CR66R67) W _ ;
  • R 61 , R 62 , R6 , R66 R 67 R68 ( R69 ; an d R are independently hydrogen or
  • R" 4 and R ⁇ 5 are independently C galkyl; u is 1 to 4; v is 2 or 3; w is 1, 2, or 3; x is 0, 1 or 2; alternatively, E represents a group (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 * 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 72 is hydrogen, C galkyl, aryl, CN, CONR 74 R 7 5, CO 2 R 76 , trifluoromethyl, NHCO2R 77 , hydroxy, Cj ⁇ alkoxy, benzyloxy, OCH2CO2C1. galkyl, OCF3, S(O) z R 78 , SO 2 NR 79 R 8 0, or halogen;
  • R 74 , R 75 , R 76 , R 79 , R 80 , R 81 , and R 82 are independently hydrogen or C ⁇ . 6alkyl;
  • R 77 and R 7 are independently C galkyl; y is 1 or 2; z is 0, 1, or 2; aa is 2, 3 or 4; ab is O, 1, 2 or 3; alternatively, E represents group (h):
  • R 83 and R 84 are independently hydrogen or C ⁇ alkyl;
  • R 8 5 an d R 8 ⁇ are independently hydrogen, C ⁇ galkyl, 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 ⁇ alkyl, aryl, CONR 88 R 89 , NR 90 R 91 , hydroxy, OCOR 92 , NHCOC ⁇ -6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO 2 R 93 , and NHCO 2 R 94 ;
  • R 87 is hydrogen or C ⁇ .galkyl, C ⁇ alkoxy, or halogen, or R 87 together with- R 8 ' forms a group -AA- where AA is (CR 95 R 9 6) ad or AA is (CR
  • Z is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;
  • R 88 , R 89 , R 90 , R 91 , R 92 , R 95 , and R 96 are independently hydrogen or C . galkyl;
  • R 93 and R 94 are independently C galkyl; ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2; alternatively, E represents group (i):
  • R 97 and R 98 are independently hydrogen, C ⁇ .galkyl, 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 ⁇ alkyl, aryl, CONR 102 R 103 , NR 104 R 105 , hydroxy, OCOR 106 , NHCOC ⁇ -6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO 2 Rl° 7 , and NHCO 2 R 108 ;
  • R 99 and R!°0 are independently hydrogen or C ⁇ .galkyl;
  • RlOl is hydrogen or C galkyl or
  • AC is oxygen, GR! 11R1 l2 or NRl I 3 or AC is a group S(O)a ;
  • R!° and Rl° are independently C galkyl; af is O, 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 O, 1, 2, or 3; and ak is 0, 1 or 2.
  • 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, sarco dosis and other fibrotic disease, psoriasis, autoimmune diseases such as multiple sclerosis, and 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.
  • the present invention is to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier therefor.
  • 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 humans.
  • substituted anilides of formula (I) are CCR5 receptor modulators. It has also now been discovered that selective inhibition of CCR5 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, 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.
  • alkyl is used herein at all occurrences to mean a straight or branched 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.
  • 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- fused ring systems which may additionally include unsaturation, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like.
  • halo or halogen are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.
  • 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[_ 6 lkyl or C3_7cycloalkyl. Examples of such rings include, but are not limited to, piperidine, tetrahydropyridine, and piperazine.
  • heterocyclic ring 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-l,4-benzoxazine and 1,2,3,4-tetrahydroquinoline, which may be optionally substituted by Cj.galkyl or oxo.
  • 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 C ⁇ alkyl.
  • CCR5 mediated disease state is used herein at all occurrences to mean any disease state which is mediated (or modulated) by CCR5.
  • 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, and pyridyl.
  • 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.
  • 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.
  • 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 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.
  • various embodiments are as follows. It will be understood that the basic nitrogen in moiety E may be optionally quaternized with C ⁇ _ galkyl or is optionally present as the N-oxide.
  • p and P 2 are suitably 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.
  • pl is phenyl and P 2 is phenl or quinoxalinyl. More preferably pl and P 2 are phenyl.
  • ' 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 are also within the scope of the invention, in particular rings including an oxo or thioxo moiety such as lactams and thiolactams.
  • 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 attached to pl meta or para to L, more preferably, A is attached to pl para to L.
  • V is suitably oxygen or sulfur. V is preferably oxygen.
  • D is suitably nitrogen, carbon or a CH group. D is preferably nitrogen.
  • Rl' and R 2 ' are suitably independently hydrogen, C ⁇ .galkyl, C 2 _galkenyl, C 2 .galkynyl, C3_7cycloalkyl, C3_7cycloalkenyl, aryl, (CH2)d'NRl° ' RH ' , (CH 2 )d'NRl°'CORl 2 ', (CH 2 ) d 'NRlO ' CO 2 Rl 3 ', (CH 2 ) d .NR 10 'SO 2 R 14 ',
  • NR 2 ' CO(CH 2 ) d 'NR 27 'R 28' , NR 27' CONR 27 'R 28' , NR 10' C O 2 R1 3 ', NR 1 0 , SO 2 R 14' , N CNR 27 'NR 27' R 28' , nitro, hydroxy, Cj.galkoxy, hydroxyCj. 6alkoxy, C 1 . 6 alkoxyC 1 .
  • R 1 ' is an optionally _ substituted 5 to 7 : membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur.
  • R 1 ' and R 2 ' are preferably hydrogen, C j .galkyl, - hydroxy, or halogen.
  • R 3' is suitably hydrogen, C ⁇ alkyl, C3_6cycloalkyl, C3_6cycloalkenyl, hydroxyC ⁇ alkyl, Ci.galkylOCi.galkyl, CONR 3 6'R 37 ', CO 2 R 38 ', cyano, aryl, trifluoromethyl, NR 3 R 40 ', nitro, hydroxy, C galkoxy, Cj.galkanoyl, acyloxy, or halogen.
  • R 3 ' is preferably hydrogen, nitro, sulfamoyl or C ⁇ ⁇ alkylamino.
  • R 4 ', R5', R6', R 7 ', Rl8', R19', R20' R 21 ', R 22', R 23', R 24', R 27', R 28', R 31', R 35' , R 36' , R 37 ', R 38 ', R 39 ', and R 40 ' are suitably independently hydrogen or C galkyl;
  • R 8' is suitably hydrogen or Cj.galkyl, providing that D is nitrogen or a CH group.
  • R 8' is preferably hydrogen.
  • R 9 ' is suitably hydrogen or C ⁇ _galkyl, providing that D is nitrogen or a CH group.
  • RIO ' and R 1 1 ' are suitably independently hydrogen or C ⁇ alkyl, or RlO' 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.
  • R 12 ' is suitably hydrogen, C ⁇ galkyl, or Cj ⁇ alkoxyalkyl.
  • R13' 5 R25' ; and R 32 ' are suitably independently C ⁇ .galkyl.
  • R! 4 is suitably C galkyl or phenyl.
  • Rl5' and R 16' are suitably independently hydrogen or C galkyl, or R ⁇ ' and Rl6 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! 7 ' is suitably Cl" alkyl, optionally substituted by C ⁇ _galkoxy.
  • R 26 is suitably hydrogen or Cj ⁇ alkyl optionally substituted with one or two substituents selected from Cj.gaikyl, .galkoxy, hydroxy, or NRIO R 1 ' .
  • R 29 and R 30 ' re suitably independently hydrogen or C ⁇ .galkyl, or R 29 and R30 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 33 and R 34' are suitably independently hydrogen or Ci. ⁇ alkyl, or R 33 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 sulfur atom.
  • 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.
  • f is suitably 1, 2, or 3.
  • E suitably represents (a):
  • B is preferably CR R 8 , or oxygen. More preferably, B is CH 2 or oxygen.
  • R 1 and R 2 are suitably independently hydrogen or Cj.galkyl; alternatively B(CR R 2 ) a is or OCR 1 R 2 CR 1 (OCOCH 3 )CR 1 R 2 .
  • R 1 and R 2 are hydrogen.
  • R 3 and R 4 are suitably independently hydrogen, C galkyl, 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 galkyl, aryl, CONR ⁇ R 1 l , NR 10 R! 1, hydroxy, OCOR 12 , NHCOCo-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2 R 13 , and NHCO 2 R 14 .
  • R 3 and R 4 are both C galkyl, 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 C3_6alkyl, or together with the nitrogen to which they are attached form a 6-membered ring, optionally substituted with one or more of Cj.galkyl, N-acetamido, or hydroxy.
  • 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), l-(4-acetamido-2,2,6,6-tetramethylpiperidinyl), l-(4- hydroxy-2,2,6,6-tetramethylpiperidinyl), or 1 -(4-hydroxy-2,2,4,6,6- pentamethylpiperidinyl).
  • B-(CR 1 R 2 ) a -NR R 4 is ortho to R 5 , meta to L, and para to R 6 , and R-> is para to L.
  • R 5 is suitably hydrogen, C ⁇ galkyl, aryl, CN, CONR 15 R 16 , CO 2 R 17 , trifluoromethyl, NHCO2R 18 , hydroxy, C ⁇ alkoxy, benzyloxy, OCH2CO2C1. 6 alkyl, OCF3, S(O) d R 19 , SO 2 NR 20 R 21 , or halogen.
  • R5 is preferably C ⁇ alkoxy, SC ⁇ galkyl, or halogen; more preferably methoxy, methylthio, or iodo, most preferably methoxy. When R ⁇ is methoxy, it is preferably para to L.
  • R 6 is hydrogen.
  • R 7 , R 8 , RiO, Rl 1, Rl5, R 6 , R 17, R20 ( R 21 , R 22 an d R 23 are independently hydrogen or C ⁇ .galkyl.
  • R 9 is hydrogen, Cj.galkyl, or phenylC galkyl.
  • R 12 , R 13 , R 14 , R 18 , and R 19 are independently C galkyl.
  • a is suitably 1, 2, 3, or 4.
  • a is 2 or 3, more preferably, a is 2 or 3 when B is oxygen and a is 2 when B is CH , most preferably, a is 2 when B is oxygen.
  • b is suitably 1 or 2.
  • b is 1.
  • 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 re
  • R 24 , R 2 5, R26 5 R27, R 28 ( R29, R31 f and R 32 are suitably independently hydrogen or .galkyl.
  • R 24 R 25 , R 26 , R 27 , R 28 , R 29 , R 31 , and R 32 are preferably hydrogen.
  • R 30 is suitably hydrogen, C galkyl, or C3_7cycloalkyl.
  • R 30 is C ⁇ galkyl, more preferably, R 30 is C3_6alkyl, most preferably, R 30 is isopropyl.
  • R 33 is hydrogen.
  • J is suitably oxygen, CR 36 R 37 , or NR 38 , or J is a group 8(0) ⁇ , Preferably, J is oxygen. Preferably, J is para to L.
  • R 34 , R 3 ⁇ , R 3 6 ( R37 ; R38 a re suitably independently hydrogen or C ⁇ alkyl.
  • g is suitably 1, 2, or 3.
  • g is 2 or 3, more preferably 2.
  • h is suitably 1, 2, or 3.
  • h is 1.
  • i is suitably 2, 3, or 4.
  • j is suitably 0, 1, 2, or 3.
  • k is. suitably 0, 1 or 2.
  • E may be optionally quaternized with C galkyl 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 24 , R 5, R 26 , R27 ; R 28, R29 ; R 31 t a d R 32 are hydrogen;
  • R 30 is hydrogen or C galkyl;
  • R 33 is hydrogen, C galkyl, trifluoromethyl, or halogen;
  • L is CONR 8' or NR CO;
  • R 8' and R 9' are independently hydrogen or C ⁇ alkyl;
  • P and P 2 are phenyl;
  • A is CO, O or S(O) ⁇ -2;
  • R ' is hydrogen;
  • R 2 ' is hydrogen or 1, 2, or 3 of hydroxy, C ⁇ alkyl, cyano, halogen, or trifluoromethyl;
  • R 3' is hydrogen or 1 or 2 of hydroxy, cyano, halogen, trifluor
  • the basic nitrogen in moiety E may be optionally quaternized with Cj.galkyl 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 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 31 , and R 32 are hydrogen;
  • R 30 is hydrogen or C galkyl;
  • R 33 is hydrogen, C ⁇ alkyl, trifluoromethyl, or halogen;
  • L is CH2NH;
  • 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, pyr
  • R 1 * is an optionally substituted heterocyclic ring selected from furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl;
  • R 2 * is hydrogen or 1, or 2 of hydroxy, cyano, halogen, trifluoromethyl, NR 10 *COR 12 *, NR 1 0*CO 2 R 13 *, NR 27 *CONHR 28 *, NHS(O)
  • R 38 * are independently hydrogen or C ⁇ alkyl
  • R 13 * and R 32 * are independently Cj.galkyl
  • R 14 * is Cj.galkyl or phenyl
  • R 26 * is hydrogen or C j.gal yl optionally substituted with one or two of hydroxy, has been 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 (la) in which R 1 ' , R 2 ', R 3' , P 1 , P 2 , A, a', b', L, R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R31, R 32 , R 33 , J, g, and h are defined as above:
  • the pharmaceutically effective compounds of this invention 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, 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.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • the preparation can be tableted, placed in a hard gelatin capsule in 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.
  • the preparation 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.
  • 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 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.
  • topical administration non-systemic administration and includes the application of the active ingredient externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream.
  • systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.
  • an active ingredient may be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
  • the active 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.
  • topical formulations of the present invention 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 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.
  • 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 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.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), 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 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 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 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.
  • 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 materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • the active ingredient may also be administered by inhalation.
  • 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 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 1 mg to about 10 mg per day.
  • 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 H1N 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.
  • atopic disorders for example, atopic dermatitis and allergies
  • sarcoidosis and other fibrotic diseases for example, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and H1N infection
  • a CCR5 receptor modulator for example, atopic dermatitis and allergies
  • rheumatoid arthritis for example, atopic dermatitis and allergies
  • treating is meant either prophylactic or therapeutic therapy.
  • Such compound can be administered to such mammal in a conventional dosage form 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 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 HIN infection, in an amount sufficient to decrease symptoms associated with these disease states.
  • atopic disorders for example, atopic dermatitis and allergies
  • rheumatoid arthritis for example, atopic dermatitis and allergies
  • rheumatoid arthritis for example, atopic dermatitis and allergies
  • atherosclerosis for example, atopic dermatitis and allergies
  • sarcoidosis and other fibrotic diseases for example, atopic dermatitis and allergies
  • psoriasis autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIN infection
  • the route of administration may be oral
  • parenteral as used herein includes intravenous, intramuscular, subcutaneous, intra-rectal, intravaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generally 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.
  • the optimal quantity and spacing of individual dosages of a compound of this invention will be determined by 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 skilled in the art using conventional course of treatment determination tests.
  • 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 dichloromethane, to give compounds of formula (I).
  • a suitable base such as diisopropylethylamine
  • a suitable solvent such as dichloromethane
  • 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.
  • dimethylformamide may be added to the resulting mixture to increase the solubility of the 3-aryl- or heteroaryl carboxylic acid.
  • Example 1(a) The resin of Example 1(a) was placed in an Irori Micro Kan and treated with a ten-fold molar excess of an equimolar mixture of 4-chlorocinnamic acid, N- bromosuccinimide, and triphenylphosphine in dichloromethane, followed by 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.
  • Example 2-30 Following the procedure of Example l(a)-(c), except using 4-[(2- diisopropylamino)ethoxy]aniline (WO 99/01127), 4-[2-(diethylamino)ethoxy]aniline (J. Med. Chem. 1995, 38, 1657-65), 3-[(2-diisopropylamino)ethoxy]aniline (WO 99/01127), 4-[2-(diethylamino)ethoxy]aniline (J. Med. Chem. 1995, 38, 1657-65), 3-[(2-diisopropylamino)ethoxy]aniline (WO
  • Example 44 Preparation of N-r3-r3-rBis(l-methylethyl)amino1propyl1-4-methoxyphenyll-4- phenoxybenzamide Following the procedure of Example 36, except substituting 4-phenoxybenzoic acid for 4-(3-hydroxyphenoxy)benzoic acid and 3-[(3- diisopro ⁇ ylamino)propyl]-4-methoxyaniline for 3-[(2-diisopropylamino)ethoxy]-4- methoxyaniline, afforded the title compound. MS (ES) m/e 461.3 (M+H) + .
  • Example 45 Preparation of N-f3-r2-rBis( l-methylethyl)aminolethoxy1-4-methoxyphenyll-4- [(hydroxyimino)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 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-f3-r2-rBis( l-methylethyl)amino1ethoxy1-4-methoxyphenyll-4- (hydroxyphenylmethyl)benzamide
  • a mixture of the compound of Example 39 (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 (MgSO4), and concentrated in vacuo to give the title compound (40 mg).
  • MS (ES) m/e 477.2 (M+H)+.
  • Example 50 Preparation of N-f 1 -[2-rBis( l-methylethyl)aminolethvn- 1 ,2.3,4-tetrahydroquinol-7- ⁇ y 1] -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- methoxyaniline, gave the title compound. MS (ES) m/e 472.2 (M+H) + .
  • Example 51 Preparation of N-[3-r2-fBis( l-methylethyl)amino1ethoxyl-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, concentrated in vacuo, and the residue was triturated with ethyl acetate and then withl:l 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) + .
  • CCR5 Receptor Binding Assay CHO cell membranes (0.25 xlO 6 cell equivalents) derived from CHO cells stably transfected with CCR5 were incubated with 0.3 125 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 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.
  • the cellular functional assay used to assess antagonist activity of compounds was RANTES-induced Ca + 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- 100% confluency in T-150 flasks and washed with phosphate-buffered saline.
  • Cells were resuspended at 2 X 10 ⁇ cells/mL in the same buffer with 2 ⁇ -M Fura- 2AM, and incubated for 35 min at 37° 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 37° C to complete the hydrolysis of intracellular Fura-2AM, and then centrifuged as before. Cells (10 6 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.
  • the percent of maximal RANTES -induced Ca 2+ was determined for each concentration of antagonist and the IC50 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 IC50 values in the range of 0.0001 to 100 ⁇ M.
  • the full structure/activity relationship has not yet been established for the compounds of this invention.
  • 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 IC50 value in the range of 0.0001 to 100 ⁇ M.
  • 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.

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Abstract

This invention relates to substituted anilide compounds which are modulators, agonists or antagonists, of the CCR5 receptor. In addition, this invention relates to the treatment and prevention of disease states mediated by CCR5.

Description

SUBSTITUTED ANILIDE COMPOUNDS AND METHODS
FIELD OF THE INVENTION
This invention relates to substituted anilide compounds which are 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 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 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 atherosclerosis (R. Ross, Annu. Rev. Phvsiol. 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. R ANTES, 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 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, monocytes and mast cells. RANTES was originally identified as gene product induced late after antigen activation of T-cells (TJ. 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 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, O. Devergne, G. Gorgone, A. Portier, et al., J. Immunol. 154: 1870-1878, 1994), synovial fibroblasts- (P. Rathanaswami, M. Hachicha, M. Sadick, TJ. Schall, et al., J. Biol. Chem. 268: 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 rriRNA is rapidly upregulated in response to LL-1 or TNF*. Although RANTES rnRNA 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 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 (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 (CM. Gelder, P.S. Thomas, D.H. Yates, I.M. Adcock, et al., Thorax 50: 1033-1037, 1995). 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 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. 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, . 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 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 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 pharmaceutically active salts thereof, and their novel use in treating the above-mentioned CCR5 -mediated disease states:
Figure imgf000005_0001
Formula I
wherein: the basic nitrogen in moiety E may be optionally quaternized with Ci .galkyl or is optionally present as the N-oxide; pl and P^ 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(R4')2, CR4'(OR5'), CO, C=NOR6', NR7', oxygen, or S(O)c';
L is a group of formula -C(=V)-DR8'-, -DR9'-C(=V)-, -CH2NH-, or - NHCH2-;
V is oxygen or sulfur;
D is nitrogen, carbon, or a CH group,
Rl' and R2' are independently hydrogen, C1.galkyl, C _galkenyl, C2_ galkynyl, C3_7cycloalkyl, C3_7cycloalkenyl, aryl, (CH2)cj ,NRlO,R1 1', (CH2)d'NR10'CORl2, ; (CH2)d'NRl0'co2Rl ', (CH2)d'NR10'SO2R14', (CH2)d<X>NR15 R16', hydroxyCi.galkyl, (optionally substituted _ by a Ci _4alkoxy or hydroxy group), (C^Jd^^Ci.galkyl, (CH )e C(O)R17', CR18 =NOR19', CNR20'=NOR19', COR21', CONR^ R^', CONR15'(CH2)fOCi_- 4alkyl, CONR15'(CH2)d< θ2R22', CONHNR23 R24', CONR15'SO2R25', CO2R26', cyano, trifluoromethyl, NR10!*11 ', NR10COR12',
NR27 CO(CH2)d'NR27 R28', NR27'CONR27 R28', NRlO'cθ2R13', NR10'SO R14', N=CNR27'NR27 R28', nitro, hydroxy, Cι_6alkoxy, hydroxyCi. 6alkoxy, C galkoxyCμgalkoxy, OC(O)NR 9 R30', SR31', SOR32', SO R32', SO2NR33 R34', halogen, Ci .galkanoyl, CO2(CH2)d R35', or R1' is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;
R ' is hydrogen, C galkyl, C3_6cycloalkyl, C3_6cycloalkenyl, hydroxyCj. 6alkyl, .ealkylOCμgalkyl, CONR36 R37', CO2R38', cyano, aryl, trifluoromethyl, NR39 R40', nitro, hydroxy, C^alkoxy, C^.galkanoyl, acyloxy, or halogen;
R4', R5', R6', R7', RlS', Rl9', R20'f R21', R22', R23'f R24', R27', R28't R31',
R35', R36', R37', R38', R39', and R40' are independently hydrogen or Cμgalkyl;
R8' is hydrogen or Ci.galkyl, providing that D is nitrogen or a CH group;
R9' is hydrogen or C^alkyl, providing that D is nitrogen or a CH group; RIO' and R^' are independently hydrogen or C^alkyl, or RlO' and R^ l' 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 2' is hydrogen, Ci.βalkyl, or C _4alkoxyalkyl;
R13'S R25') an R32' are independently C1 .galkyl;
R* 'is Cμgalkyl or phenyl;
R 15 ' and R 6 ' are independently hydrogen or C \ .galkyl, or R x ^ ' and 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*7' is Cl~4alkyl, optionally substituted by Cj.galkoxy;
R ° is hydrogen or Ci .galkyl optionally substituted with one or two substituents selected from C^alkyl, Cj.galkoxy, hydroxy, or NRIO'RI I '; R29' and R3^' are independently hydrogen or Ci .galkyl, or R29' and R3^' 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; R33' and R34' are independently hydrogen or Ci .galkyl, or R33' and R34' - 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; a' and b' are independently 1 , 2, or 3 ; c' is O, l, or 2; d'is 1, 2, 3, or 4; e'is O, 1, 2, or 3; f is 1, 2, or 3; E represents (a):
Figure imgf000007_0001
R6 (a); in which
B is oxygen, S(O)c, CR7=CR8, or CR7R8, or B is NR9; R! and R2 are independently hydrogen or Ci.galkyl; alternatively B(CR!R2)a is OCR^CR^OH^RΪR2 or OCR1R2CR1(OCOCH3)CR1R2;
R3 and R4 are independently hydrogen, Cι_5alkyl, 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 galkyl, aryl, CONR^R1 1, NR10R! 1, hydroxy, OCOR12, NHCOCQ. galkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2R13, and NHCO2R14;
R5 is hydrogen, Cμgalkyl, aryl, CN, CONR15Rl6, CO2R17, trifluoromethyl, NHCO2R18, hydroxy, C^alkoxy, benzyloxy, OCH CO2Cι_ 6alkyl, OCF3, S(O) R19, SO2NR20R21 or halogen;
R° is hydrogen, Cι _6alkyl, aryl, trifluoromethyl, hydroxy, Ci .βalkoxy or halogen, or R^ taken together with R8' forms a group D where D is (CR22R2 )e or D is (CR2 R23)f-G where G is oxygen, sulfur or CR22=CR23, CR22=N, =CR22O, =CR22S, or =CR2 -NR23; R7, R8, RlO, Rl 1, R12, R15, R16f R17, R20, R21, R22, and R23 ^ independently hydrogen or C^galkyl;
R9 is hydrogen, Ci.galkyl, or phenylCi .βalkyl; R13, R14, R18, and R19 are independently Ci.galkyl; 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 O, 1, 2 or 3; alternatively, E represents
Figure imgf000008_0001
R24, R25, R26, R27, R28, R29, R31, and R32 are independently hydrogen or Cι_6alkyl;
R3^ is hydrogen, Cj.galkyl, or C3_7cycloalkyl;
R33 is hydrogen, C^.galkyl, trifluoromethyl, hydroxy, or halogen, or R33 and R8' together form a group -K- where K is (CR 4R35)j or K is (CR34R35)j -M and M is oxygen, sulfur, CR34=CR35, CR34=N, or N=N;
J is oxygen, CR36R37, or NR38, or J is a group S(O)k;
R34, R35, R36, R37, and R38 are independently hydrogen or C galkyl; g is 1, 2 or 3; h is 1, 2 or 3; i is 2, 3, or 4; j is O, 1, 2, or 3; k is 0, 1 or 2; alternatively, E represents (c):
Figure imgf000008_0002
in which:
Q is oxygen, S(O)n, CR^CR45, CR44R45, or Q is NR46; R39 and R4^ are independently hydrogen or C^.galkyl; R 1 is a group of formula (d):
Figure imgf000008_0003
(CH2)0 (CH2 2)lDp (C "H '2Z)/q
N - (d)
or R4^ is a group of formula (e):
Figure imgf000009_0001
R42 is hydrogen, C^alkyl, aryl, CN, CONR48R49, CO2R50, trifluoromethyl, NHCO R51, hydroxy, C^alkoxy, benzyloxy, OCH2CO2Cj.
6alkyl, OCF3, S(O)sR52, SO2NR53R54, or halogen; R43 is hydrogen or R43 together with R8' forms a group R where R is
CR55=CR56, CR55=CR56CR55R56, or (CR55R56)t;
R44, R45, R46, R48, R49, R50; R53> R54; R55( and R56 ^ independently hydrogen or C^alkyl;
R47 is hydrogen, C^.galkyl, or C3.7 cycloalkyl; R^l and R^2 are independently C galkyl; l is O, 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; r is 0,1, 2, or 3; s is O, l, or 2; t is 2 or 3; alternatively, E represents (f):
Figure imgf000009_0002
R^7 and R^8 are independently hydrogen or C ^alkyl;
R59 and R^O are independently hydrogen, Cj.galkyl, 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 i^alkyl, aryl, CONR61R62, NR61R62, hydroxy, OCOR63, NHCOCo-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO R64 and NHCO2R65;
T is -(CR66R67)V- or -O(CR66R67)W_; W is oxygen, S(O)x, NR68, or W is CR69=CR70 or CR69R70; R61, R62, R6 , R66 R67 R68( R69; and R are independently hydrogen or
Cι_6alkyl;
R"4 and R^5 are independently C galkyl; u is 1 to 4; v is 2 or 3; w is 1, 2, or 3; x is 0, 1 or 2; alternatively, E represents a group (g):
Figure imgf000010_0001
R71 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 R7* 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;
R72 is hydrogen, C galkyl, aryl, CN, CONR74R75, CO2R76, trifluoromethyl, NHCO2R77, hydroxy, Cj^alkoxy, benzyloxy, OCH2CO2C1. galkyl, OCF3, S(O)zR78, SO2NR79R80, or halogen;
R73 is hydrogen, C^.galkyl, hydroxy, C galkoxy or halogen, or R73 and R8' taken together from a group -X- where X is (CR81R82)aa or X is (CR81R82)ab- Y and Y is oxygen, sulfur or CR81=CR82;
R74, R75, R76, R79, R80, R81, and R82 are independently hydrogen or C\. 6alkyl;
R77 and R7 are independently C galkyl; y is 1 or 2; z is 0, 1, or 2; aa is 2, 3 or 4; ab is O, 1, 2 or 3; alternatively, E represents group (h):
Figure imgf000010_0002
R87 (h);
R83 and R84 are independently hydrogen or C^alkyl; R85 and R8^ are independently hydrogen, Cμgalkyl, 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^alkyl, aryl, CONR88R89, NR90R91, hydroxy, OCOR92, NHCOCυ-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2R93, and NHCO2R94; R87 is hydrogen or C^.galkyl, C^alkoxy, or halogen, or R87 together with- R8' forms a group -AA- where AA is (CR95R96)ad or AA is (CR95=CR96)ae-AB." and AB is oxygen, sulfur, CR95=CR96, CR95=N, CR 5NR96 or N=N;
Z is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;
R88, R89, R90, R91, R92, R95, and R96 are independently hydrogen or C . galkyl;
R93 and R94 are independently C galkyl; ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2; alternatively, E represents group (i):
Figure imgf000011_0001
R97 and R98 are independently hydrogen, C^.galkyl, 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^alkyl, aryl, CONR102R103, NR104R105, hydroxy, OCOR106, NHCOCυ-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2 Rl°7, and NHCO2R108;
R99 and R!°0 are independently hydrogen or C^.galkyl; RlOl is hydrogen or C galkyl or R 101 and R8' together form a group -AD- where AD is (CR °9R1 l°)ai or AD is (CR1°9R1 l°)aj-AE and AE is oxygen, sulfur or CRl09=CR 0; AC is oxygen, GR! 11R1 l2 or NRl I3 or AC is a group S(O)a ;
R102, R103, R104f R105f R106 R109, Rl 10, Rl 11^112, an Rl 13 ^ independently hydrogen or C^alkyl;
R!° and Rl° are independently C galkyl; af is O, 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 O, 1, 2, or 3; and ak is 0, 1 or 2. 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, sarco dosis and other fibrotic disease, psoriasis, autoimmune diseases such as multiple sclerosis, and 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. 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 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 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, 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 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- 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. 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[_ 6 lkyl 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-l,4-benzoxazine and 1,2,3,4-tetrahydroquinoline, which may be optionally substituted by Cj.galkyl or oxo. 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 C^alkyl. Examples of such ring systems include, but are not limited to, tropane, isoquinuclidine and granatane rings. 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 P2 including thienyl, furyl, pyrrolyl, 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. 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. 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 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. 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\_ galkyl or is optionally present as the N-oxide. p and P2 are suitably 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. Preferably, pl is phenyl and P2 is phenl or quinoxalinyl. More preferably pl and P2 are phenyl. When R! ' 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 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 R3 . A is C(R4 )2, CR4'(OR5'), CO, C=NOR6', NR7', oxygen, or S(O)c>. Preferably A is C(R4') , CO, C=NOR6', NR7', oxygen, or sulfur. More preferably, A is CH2, CO, C=NOH, oxygen or sulfur. Most preferably, A is CH2, CO, oxygen or sulfur. Preferably, A is attached to pl meta or para to L, more preferably, A is attached to pl para to L.
L is suitably a group of formula -C(=V)-DR8'-, -DR9'-C(=V)-, -CH2NH-, or -NHCH -. L is preferably -C(=V)-DR8'-.
V is suitably oxygen or sulfur. V is preferably oxygen. D is suitably nitrogen, carbon or a CH group. D is preferably nitrogen. Rl' and R2' are suitably independently hydrogen, C^.galkyl, C2_galkenyl, C2.galkynyl, C3_7cycloalkyl, C3_7cycloalkenyl, aryl, (CH2)d'NRl°'RH', (CH2)d'NRl°'CORl2', (CH2)d'NRlO'CO2Rl3', (CH2)d.NR10'SO2R14',
(CH2)d'CONRl5'Rl6', hydroxyCi.galkyl, C^alkoxyalkyl (optionally substituted by a C^alkoxy or hydroxy group), (CH2)d'CO2C1.6alkyl, (CH2)eOC(O)Rl7', CRl8'=NORl9', CNR 0'=NORl9', COR2!', CONRIS'RIO', CONR15'(CH2)fOC1. 4alkyl, CONRl5'(CH2)d'CO2R22', CONHNR 3 R24', CONR15'SO2R25', CO2R26', cyano, trifluoromethyl, NR10^1 r, NRlO'COR12',
NR2 'CO(CH2)d'NR27'R28', NR27'CONR27'R28', NR 10'CO2R13', NR10,SO2R14', N=CNR27'NR27'R28', nitro, hydroxy, Cj.galkoxy, hydroxyCj. 6alkoxy, C1.6alkoxyC1.6alkoxy, OC(O)NR2 'R30', SR3 !', SOR32', SO R32', SO2NR33'R34', halogen, C^galkanoyl, CO2(CH2) OR35', or R1' is an optionally _ substituted 5 to 7:membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur. R 1 ' and R2' are preferably hydrogen, C j .galkyl, - hydroxy, or halogen. R3' is suitably hydrogen, C^alkyl, C3_6cycloalkyl, C3_6cycloalkenyl, hydroxyC^alkyl, Ci.galkylOCi.galkyl, CONR36'R37', CO2R38', cyano, aryl, trifluoromethyl, NR3 R40', nitro, hydroxy, C galkoxy, Cj.galkanoyl, acyloxy, or halogen. R3' is preferably hydrogen, nitro, sulfamoyl or Cγ ^alkylamino.
R4', R5', R6', R7', Rl8', R19', R20' R21 ', R22', R23', R24', R27', R28', R31', R35', R36', R37', R38', R39', and R40' are suitably independently hydrogen or C galkyl;
R8' is suitably hydrogen or Cj.galkyl, providing that D is nitrogen or a CH group. R8' is preferably hydrogen.
R9' is suitably hydrogen or Cι_galkyl, providing that D is nitrogen or a CH group.
RIO' and R11' are suitably independently hydrogen or C^alkyl, or RlO' 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.
R12' is suitably hydrogen, Cμgalkyl, or Cj^alkoxyalkyl. R13'5 R25'; and R32' are suitably independently C^.galkyl. R!4 is suitably C galkyl or phenyl.
Rl5' and R 16' are suitably independently hydrogen or C galkyl, or R^' and Rl6 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!7' is suitably Cl" alkyl, optionally substituted by Cι_galkoxy. R26 is suitably hydrogen or Cj^alkyl optionally substituted with one or two substituents selected from Cj.gaikyl, .galkoxy, hydroxy, or NRIO R 1'.
R29 and R30' re suitably independently hydrogen or C^.galkyl, or R29 and R30 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. R33 and R34' are suitably independently hydrogen or Ci.βalkyl, or R33 and
R34 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. 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. f is suitably 1, 2, or 3.
E suitably represents (a):
Figure imgf000016_0001
in which
B is suitably oxygen, S(O)c, CR7=CR8- or CR7R8, or B is NR9. B is preferably CR R8, or oxygen. More preferably, B is CH2 or oxygen.
R1 and R2 are suitably independently hydrogen or Cj.galkyl; alternatively B(CR R2)a is
Figure imgf000016_0002
or OCR1R2CR1(OCOCH3)CR1R2. Preferably, R1 and R2 are hydrogen.
R3 and R4 are suitably independently hydrogen, C galkyl, 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 galkyl, aryl, CONR^R1 l, NR10R! 1, hydroxy, OCOR12, NHCOCo-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2 R13, and NHCO2R14. Preferably R3 and R4 are both C galkyl, 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, R3 and R4 are C3_6alkyl, or together with the nitrogen to which they are attached form a 6-membered ring, optionally substituted with one or more of Cj.galkyl, N-acetamido, or hydroxy.
Most preferably, R3 and R4 are isopropyl or R3 is isopropyl and R4 is tert-butyl, or together with the nitrogen to which they are attached are 1 -(2,2,6,6- tetramethylpiperidinyl), l-(4-acetamido-2,2,6,6-tetramethylpiperidinyl), l-(4- hydroxy-2,2,6,6-tetramethylpiperidinyl), or 1 -(4-hydroxy-2,2,4,6,6- pentamethylpiperidinyl).
Preferably, B-(CR1R2)a-NR R4 is ortho to R5, meta to L, and para to R6, and R-> is para to L.
R5 is suitably hydrogen, C^galkyl, aryl, CN, CONR15R16, CO2R17, trifluoromethyl, NHCO2R18, hydroxy, C^alkoxy, benzyloxy, OCH2CO2C1. 6alkyl, OCF3, S(O)dR19, SO2NR20R21, or halogen. R5 is preferably C^alkoxy, SC^galkyl, or halogen; more preferably methoxy, methylthio, or iodo, most preferably methoxy. When R^ is methoxy, it is preferably para to L.
R6 is suitably hydrogen, .galkyl, aryl, trifluoromethyl, hydroxy, C\_ galkoxy, or halogen, or R6 taken together with R8' forms a group D where D is (CR22R23)e or D is (CR22R23)f-G where G is oxygen, sulfur, or CR22=CR23, CR22=N, =CR22O, =CR22S, or =CR22-NR23. Preferably, R6 is hydrogen.
R7, R8, RiO, Rl 1, Rl5, R 6, R17, R20( R21 , R22 and R23 are independently hydrogen or C^.galkyl.
R9 is hydrogen, Cj.galkyl, or phenylC galkyl. R12, R13, R14, R18, and R19 are independently C galkyl. 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 , most preferably, a is 2 when B is oxygen. b is suitably 1 or 2. Preferably, b is 1. 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 re
Figure imgf000017_0001
R24, R25, R265 R27, R28( R29, R31 f and R32 are suitably independently hydrogen or .galkyl. R24 R25, R26, R27, R28, R29, R31, and R32 are preferably hydrogen.
R30 is suitably hydrogen, C galkyl, or C3_7cycloalkyl. Preferably, R30 is Cμgalkyl, more preferably, R30 is C3_6alkyl, most preferably, R30 is isopropyl. R33 is suitably hydrogen, C^.galkyl, trifluoromethyl, hydroxy, or halogen, or R33 and R8' together form a group -K- where K is (CR3 R35)j or K is (CR34R35)j -M and M is oxygen, sulfur, CR34=CR35, CR34=N, or N=N. Preferably, R33 is hydrogen.
J is suitably oxygen, CR36R37, or NR38, or J is a group 8(0)^, Preferably, J is oxygen. Preferably, J is para to L.
R34, R3^, R36( R37; R38 are suitably independently hydrogen or C^alkyl. 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. j is suitably 0, 1, 2, or 3. 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 optionally quaternized with C galkyl or is optionally present as the N-oxide; E is (b); J is CH2; g is 1, 2, or 3; h is 1, 2, or 3; R24, R 5, R26, R27; R28, R29; R31t a d R32 are hydrogen; R30 is hydrogen or C galkyl; R33 is hydrogen, C galkyl, trifluoromethyl, or halogen; L is CONR8' or NR CO; R8' and R9' are independently hydrogen or C^alkyl; P and P2 are phenyl; A is CO, O or S(O)ø-2; R ' is hydrogen; R2' is hydrogen or 1, 2, or 3 of hydroxy, C^alkyl, cyano, halogen, or trifluoromethyl; R3' is hydrogen or 1 or 2 of hydroxy, cyano, halogen, trifluoromethyl, CONR36*R37*, COC^alkyl, CO2R38*, C^alkoxy, or phenyl; and R36*, R37*, and R38* are independently hydrogen or C galkyl, has been described in WO 98/25604, published 18 June 1998, as chemokine receptor modulators.
Further, a subgenus of formula (I) wherein: the basic nitrogen in moiety E may be optionally quaternized with Cj.galkyl or is optionally present as the N- oxide; E is (b); J is CH2; g is 1, 2, or 3; h is 1, 2, or 3; R24, R25, R26, R27, R28, R29, R31, and R32 are hydrogen; R30 is hydrogen or C galkyl; R33 is hydrogen, C^alkyl, trifluoromethyl, or halogen; L is CH2NH; P1 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, O or S(O)Q-2; P^ is phenyl; R1* is hydrogen or one of hydroxy, cyano, halogen, trifluoromethyl, NR 0*COR12*,
NR10*CO2R13*, NR 7*CONHR28*, NHS(O)0-2R14*, CONR^R16*, cOC 5alkyl, CO2R26*, Cμgalkoxy, SR31*, SOR32*, SO2R32*, or phenyl, or R1* is an optionally substituted heterocyclic ring selected from furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl; R2* is hydrogen or 1, or 2 of hydroxy, cyano, halogen, trifluoromethyl, NR10*COR12*, NR10*CO2R13*, NR27*CONHR28*, NHS(O)0-2R14*, CONR^R16*, C0Cι_ 5alkyl, CO2R26*, C ^alkoxy, SR31*, SOR32*, SO R32*, or phenyl; R3' is hydrogen or 1 or 2 of hydroxy, cyano, halogen, trifluoromethyl, CONR36*R37*, COC^alkyl, CO2R38*, C^galkoxy, or phenyl; R10*, R12*, R^*, R16*, R27*, R28*? R31 *> R36*5 R37*5 and R38* are independently hydrogen or C^alkyl; R13* and R32* are independently Cj.galkyl; R14* is Cj.galkyl or phenyl; and R26* is hydrogen or C j.gal yl optionally substituted with one or two of hydroxy, has been 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 (la) in which R1 ', R2', R3', P1, P2, A, a', b', L, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, J, g, and h are defined as above:
Figure imgf000019_0001
Formula (la)
Among the preferred compounds of the invention are the following compounds:
N-[4-[2-(Dimethylamino)ethyl]-3,4-dihydro-2H-l,4-benzoxazin-6-yl)-4- phenoxybenzamide ;
N- [3 - [2-(Diethy lamino)ethoxy ] -4-methoxypheny 1] -4-phenoxybenzamide ; N-[4-[2-[Bis(l-methylethyl)amino]ethoxy]phenyl]]-4-phenoxybenzamide;
N-[4-[2-(Diethylamino)ethoxy]phenyl]-4-phenoxybenzamide; N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]phenyl]-4-phenoxybenzamide; N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3- phenoxybenzamide ; N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-3-phenoxybenzamide;
N-[4-[2-[Bis(l-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( l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- phenoxybenzamide ;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (pheny lmethy l)benzamide ;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2- (phenylmethyl)thiazole-4-carboxamide hydrochloride;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- phenoxybenzamide Methiodide;
N-[l-[2-[Bis(l-methylethyl)amino]ethyl]-l,2,3,4-tetrahydroquinol-7-yl]-4- phenoxybenzamide ; N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(3- hydroxyphenoxy )benzamide ;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4- chlorophenyl)sulfinyl]-3-nitrobenzamide; N-[3-[2-[Bis(l-methylethyl)"amino]ethoxy]-4-methoxyphenyl]-4-[(2,4- dichlorophenyl)sulfιnyl] -3 -nitrobenzamide ;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-3- phenoxybenzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-3- phenoxybenzamide;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4- phenoxybenzamide ;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4- phenoxybenzamide ; N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- benzoy lbenzamide ;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4- benzoylbenzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-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-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4- (pheny lmethy l)benzamide ; N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4- chlorophenyl)sulfonyl]benzamide ;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4-[(4- chlorophenyl)sulfonyl]benzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4-[(4- chlorophenyl)sulfonyl]benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-5-butylamino- 4-phenoxy-3-(sulfamoyl)benzamide;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-5-butylamino- 4-phenoxy-3-(sulfamoyl)benzamide; N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-5- butylamino-4-phenoxy-3-(sulfamoyl)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(4- chlorophenoxy)-3-nitrobenzamide; N- [3 - [3 - [B is ( 1 -methy lethyl)amino]propy 1] -4-methoxypheny l]-4-(4- chlorophenoxy)-3-nitrobenzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4-(4-- chlorophenoxy)-3-nitrobenzamide; N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(2- quinoxalinylamino)benzamide;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4-(2- quinoxalinylamino)benzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4-(2- quinoxalinylamino)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4- methylphenyl)sulfonyl]-3-nitrobenzamide;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4-[(4- methylphenyl)sulfonyl]-3-nitrobenzamide; N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4-[(4- methylphenyl)sulfonyl]-3-nitrobenzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3- benzoylbenzamide ;
N-[3-[2-[Bis( 1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (methy lphenylamino)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (phenylamino)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (phenylthio)benzamide ; N-[3-[2-[Bis( l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-
(phenylsulfonyl)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (pheny lsulfinyl)benzamide ;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- [(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; N-[l'-(l-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4- phenoxybenzamide; and
N-[l'-(l-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4- (pheny lthio)benzamide . Among the more preferred compounds of this invention are the following compounds:
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3- phenoxybenzamide ; N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-
(phenylmethyl)benzamide ;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- phenoxybenzamide methiodide
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-3- phenoxybenzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-3- phenoxybenzamide;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4- phenoxybenzamide; N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4- phenoxybenzamide ;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- benzoylbenzamide;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4- benzoylbenzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4- benzoy lbenzamide ;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4- (phenylmethyl)benzamide; N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4-
(pheny lmethyl)benzamide ;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4-methoxyρhenyl]-5- butylamino-4-phenoxy-3-(sulfamoyl)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4- chlorophenyl)oxy]-3-nitrobenzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4-[(4- chlorophenyl)oxy]-3-nitrobenzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (phenylthio)benzamide; N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-
[(hydroxyimino)phenylmethyl]benzamide;
N-[l'-(l-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]- 4-benzoylbenzamide trifluoroacetate; N-[l'-(l-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. Among the most preferred compounds of this invention are the following compounds:
N- [ l'-( 1 -Methy lethy l)spiro [benzof uran-3 (2H) ,4 '5 -piperidin] -5-y 1]- 4-benzoylbenzamide trifluoroacetate;
N-[l'-(l-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4- phenoxybenzamide; and
N-[ 1 '-( l-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4- (phenylthio)benzamide.
Among compounds excluded from this invention are the following compounds: N-[2-[2-[Bis(l-methylethyl)amino]ethoxy]phenyl]-4-phenoxybenzamide;
N- [2- [2-(Diethy lamino)ethoxy ]pheny 1] -4-phenoxybenzamide ; N-[4-[2-(Diethylamino)ethoxy]phenyl]-3-phenoxybenzamide; N-[2-[2-[Bis(l-methylethyl)amino]ethoxy]phenyl]-3-phenoxybenzamide ; N- [2- [2-(Diethy lamino)ethoxy ]pheny 1] -3-phenoxybenzamide ; N-[4-[2-(Diethylamino)ethoxy]phenyl]-4-(phenylmethyl)benzamide; and
N-[2-[2-[Bis(l-methylethyl)amino]ethoxy]phenyl]-4- (phenylmethyl)benzamide. Formulation of Pharmaceutical Compositions
The pharmaceutically effective compounds of this invention (and the 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, 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. 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 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 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. 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 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 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 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 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 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. 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 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%), 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 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 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 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 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 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 1 mg to about 10 mg per day. 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 H1N 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 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 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 HIN infection, in an amount sufficient to decrease symptoms 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 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 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 skilled in the art using conventional course of treatment determination tests.
Methods of Preparation 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 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 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 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, 1-1, according to the procedures 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 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- 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. 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 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:
Figure imgf000028_0001
a) C1(CH2)2NR3R4, K2CO3, CH3COCH3; (b) H2, 5% Pd C, MeOH; (c) Merrifield resin bound aldehyde (3); NaBH(OAc)3, 1% HOAc, DMF; (d) aryl/heteroaryl carboxylic acid, NBS, Ph3P, pyridine; (e) TFA, CH2C12, H2O.
The invention will now be described by reference to the following examples 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 Preparation 1
Preparation of 4-(Methylphenylamino)benzoic acid 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, 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 Preparation of 1 '-( l-Methylethyl)spirorbenzofuran-3(2H).4'-piperidinl-5-amine a) 5- and 7-nitrospiro[benzofuran-3(2H),4'-piperidine]
A solution of l'-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 mmol) at RT, stirred for 1 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 was extracted with dichloromethane (2 X 50 mL). The combined organic phase was dried (Na2SO4) and concentrated to afford the title compound (2. 65 g). b) -(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) 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 [benzof uran-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, 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 SO4) ancl concentrated in vacuo to give the title compound (1.45 g). MS(ES) m/e 235.1 [+H]+. d) 1 '-( l-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) 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°C for 2 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and water (20 mL). The organic phase was washed, dried (MgSO4), concentrated in vacuo, and the residue was chromatographed (silica gel, 5% methanol: dichloromethane) to give the title compound (0.85 g). e) 1 '-( l-methylethyl)spiro[benzofuran-3(2H),4'-piperidin]-5-amine A solution of the compound of Preparation 2(d) (0.78 g, 2.8 mmol) in 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(l-methylethyl)-l(2H)- quinolineethan amine 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 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 (2H)-quinolineethanamine 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 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 Preparation of N-r3-r2-(Diethylamino)ethoxy1-4-methoxyphenyll-4- phenoxybenzamide a) 3-[2-(diethylamino)ethoxy]-4-methoxyaniline/[4-formyl-3,5- (dimethoxy)phenoxy]-Merrifield resin adduct 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]- - methoxyaniline (WO 95/15954), and sodium triacetoxyborohydride in dimethylformamide containing 1% acetic acid was shaken to afford the title adduct. 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 Micro Kan and treated with a ten-fold molar excess of an equimolar mixture of 4-chlorocinnamic acid, N- bromosuccinimide, and triphenylphosphine in dichloromethane, followed by 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 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 l(a)-(c), except using 4-[(2- diisopropylamino)ethoxy]aniline (WO 99/01127), 4-[2-(diethylamino)ethoxy]aniline (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-l-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, 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: N-[4-[2-[bis( l-methylethyl)amino]ethoxy]phenyl]]-4-phenoxybenzamide: MS
(ES) m/e 433.2 (M+H)+;
N-[4-[2-(diethylamino)ethoxy]phenyl]-4-phenoxybenzamide: MS (ES) m e 405.2 (M+H)+;
N-[3-[2-[bis(l-methylethyl)amino]ethoxy]phenyl]-4-phenoxybenzamide: 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)+; N-[4-[2-[bis(l-methylethyl)amino]ethoxy]phenyl]-3-phenoxybenzamide: MS (ES) m/e 433.2 (M+H)+;
N-[4-[2-[bis(l-methylethyl)amino]ethoxy]phenyl]-4- (phenylmethyl)benzamide: MS (ES) m/e 431.2 (M+H)+; N-[2-[2-(diethylamino)ethoxy]phenyl]-4-(phenylmethyl)benzamide: MS
(ES) m e 403.0 (M+H)+;
N- [3 - [3- [bis( 1 -methy lethyl) amino] propyl] -4-methoxyphenyl] -3 - phenoxybenzamide: MS (ES) m/e 460.9 (M+H)+;
N-[3-[2-(2,2,6,6-tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-3- phenoxybenzamide: MS (ES) m/e 502.9 (M+H)+;
N-[3-[2-(2,2,6,6-tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4- phenoxybenzamide: MS (ES) m/e 503.3 (M+H)+;
N-[3-[3-[bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4- benzoylbenzamide: MS (ES) m/e 473.3 (M+H)+; N-[3-[2-(2,2,6,6-tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4- benzoylbenzamide: MS (ES) m/e 515.3 (M+H)+;
N-[3-[3-[bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4- (phenylmethyl)benzamide: MS (ES) m/e 459.3 (M+H)+;
N-[3-[2-(2,2,6,6-tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4- (phenylmethyl)benzamide: MS (ES) m/e 501.3 (M+H)+;
N-[3-[2-[bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4- chlorophenyl)sulfonyl]benzamide: MS (ES) m/e 545.2 (M+H)+;
N- [3 - [3- [bis( 1 -methy lethy l)amino] propyl] -4-methoxyphenyl] -4- [(4- chlorophenyl)sulfonyl]benzamide: MS (ES) m/e 543.2 (M+H)+; N-[3-[2-(2,2,6,6-tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4-[(4- chlorophenyl)sulfonyl]benzamide: 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(l-methylethyl)amino]propyl]-4-methoxyphenyl]-5-butylamino- 4-phenoxy-3-(sulfamoyl)benzamide: MS (ES) m/e 611.3 (M+H)+;
N-[3-[2-(2,2,6,6-tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-5- butylamino-4-phenoxy-3-(sulfamoyl)benzamide: MS (ES) m/e 653.3 (M+H)+;
N-[3-[2-[bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(4- chlorophenoxy)-3-nitrobenzamide: MS (ES) m/e 542.2 (M+H)+; N-[3-[3-[bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4-(4- chlorophenoxy)-3-nitrobenzamide: MS (ES) m/e 540.2 (M+H)+;
N-[3-[2-(2,2,6,6-tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4-(4- chlorophenoxy)-3-nitrobenzamide: MS (ES) m/e 582.2 (M+H)+; N- [3 - [2- [bis( 1 -methylethy l)amino] ethoxy] -4-methoxyphenyl] -4-(2- quinoxalinylamino)benzamide: MS (ES) m/e 514.4 (M+H)+;
N- [3 - [3 - [bis( 1 -methy lethy l)amino]propy 1] -4-methoxyphenyl] -4-(2- quinoxalinylamino)benzamide: MS (ES) m/e 512.4 (M+H)+; N-[3-[2-(2,2,6,6-tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4-(2- quinoxalinylamino)benzamide: MS (ES) m/e 554.2 (M+H)+;
N-[3-[2-[bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4- methylphenyl)sulfonyl]-3-nitrobenzamide: MS (ES) m/e 570.2 (M+H)+;
N-[3-[3-[bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4-[(4- methylphenyl)sulfonyl]-3-nitrobenzamide: MS (ES) m/e 568.3 (M+H)+; and
N-[3-[2-(2,2,6,6-tetramethyl-l-piperidinyl)ethoxy]-4-methoxyphenyl]-4-[(4- methylphenyl)sulfonyl]-3-nitrobenzamide: MS (ES) m/e 610.3 (M+H)+.
Example 31 Preparation of N-[3-[2-fBis(l-methylethyl)amino1ethoxy1-4-methoxyphenyll-3- 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 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 (MgSO4) 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)+. 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: N-[3-[2-[bis( 1 -methy lethyl)amino]ethoxy]-4-methoxyphenyl]-4- phenoxybenzamide: MS (ES) m/e 463.0 (M+H)+;
N-[3-[2-[bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (phenylmethyl)benzamide: MS (ES) m/e 460.9 (M+H)+;
N-[3-[2-[bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (phenylthio)benzamide: MS (ES) m/e 478.9 (M+H)+; and
N-[3-[2-[bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (phenylsulfonyl)benzamide: MS (ES) m/e 510.7 (M+H)+.
Example 36 Preparation of N-r3-r2-rBis(l-methylethyl)aminolethoxyl-4-methoxyphenyll-4-(3- hvdroxyphenoxy)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 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 (MgSO4), 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 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 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(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4- chlorophenyl)sulfinyl]-3-nitrobenzamide: MS (ES) m/e 573.7 (M+H)+; N- [3 - [2- [bis( 1 -methy lethyl)amino] ethoxy ] -4-methoxyphenyl] -4- [(2,4- dichlorophenyl)sulfinyl]-3-nitrobenzamide: MS (ES) m/e 607.7 (M+H)+;
N-[3-[2-[bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- benzoylbenzamide: MS (ES) m/e 475.3 (M+H)+;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3- benzoylbenzamide: MS (ES) m/e 474.9 (M+H)+;
N-[3-[2-[bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (methylphenylamino)benzamide: MS (ES) m/e 475.9 (M+H)+;
N-[3-[2-[bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (phenylamino)benzamide: MS (ES) m/e 462.0 (M+H)+; and N-[3-[2-[bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-
(phenylsulfinyl)benzamide: MS (ES) m/e 494.7 (M+H)+
Example 44 Preparation of N-r3-r3-rBis(l-methylethyl)amino1propyl1-4-methoxyphenyll-4- phenoxybenzamide Following the procedure of Example 36, except substituting 4-phenoxybenzoic acid for 4-(3-hydroxyphenoxy)benzoic acid and 3-[(3- diisoproρylamino)propyl]-4-methoxyaniline for 3-[(2-diisopropylamino)ethoxy]-4- methoxyaniline, afforded the title compound. MS (ES) m/e 461.3 (M+H)+.
Example 45 Preparation of N-f3-r2-rBis( l-methylethyl)aminolethoxy1-4-methoxyphenyll-4- [(hydroxyimino)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 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-f3-r2-rBis( l-methylethyl)amino1ethoxy1-4-methoxyphenyll-4- (hydroxyphenylmethyl)benzamide A mixture of the compound of Example 39 (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 (MgSO4), and concentrated in vacuo to give the title compound (40 mg). MS (ES) m/e 477.2 (M+H)+.
Example 47 Preparation of N-IT-(1 -Methylethyl)spirofbenzofuran-3(2H),4'5-piperidinl-5-yl]-4- benzoylbenzamide 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 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 (MgSO4), and concentrated in vacuo. The residue 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 give the title compound. MS (ES) m/e 455.1 (M+H)+.
Examples 48-49 Preparation of N-fl '-(1 -Methylethyl)spirofbenzofuran-3(2H),4'5-piperidin]-5-yl1-4- phenoxybenzamide and N-fl'-d -Methy lethyl)spirorbenzofuran-3(2H),4'5-piperidinl- 5-yl]-4-fphenylthio)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'-(l-methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4- phenoxybenzamide: MS (ES) m/e 443.1 (M+H)+; and
N-[l'-(l-methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4- (phenylthio)benzamide: MS (ES) m/e 459.1 (M+H)+.
Example 50 Preparation of N-f 1 -[2-rBis( l-methylethyl)aminolethvn- 1 ,2.3,4-tetrahydroquinol-7-~ y 1] -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- methoxyaniline, gave the title compound. MS (ES) m/e 472.2 (M+H)+.
Example 51 Preparation of N-[3-r2-fBis( l-methylethyl)amino1ethoxyl-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, concentrated in vacuo, and the residue was triturated with ethyl acetate and then withl:l 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-r3-r2-rBis(l-methylethyl)amino]ethoxyl-4-methoxyphenyl1-2- (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)+.
Biological Data:
CCR5 Receptor Binding Assay CHO cell membranes (0.25 xlO6 cell equivalents) derived from CHO cells stably transfected with CCR5 were incubated with 0.3 125I-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 solution of phosphate buffered saline containing 0.1 % bovine serum albumin and 0.05 % NaN3. 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.
CCR5 Receptor Functional Assay
The cellular functional assay used to assess antagonist activity of compounds was RANTES-induced Ca + mobilization in RBL 2H3 cells stably expressing the hCCR5 receptor (RBL 2H3 hCCR5). Agonist activity is determined by Ca2+ mobilization in the same cells which is inhibitable by a selective CCR5 antagonist. Cells were grown to 80- 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 NaHCO3, 1 mM KH Pθ4 and 11 mM glucose) containing 5 mM HEPES (pH 7.4), 1 mM CaCl2, 1 mM MgCl2 and 0.1% BSA and centrifuged at 200g for 3 min. Cells were resuspended at 2 X 10^ cells/mL in the same buffer with 2 μ-M Fura- 2AM, and incubated for 35 min at 37° 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 37° C to 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 CaCl2, 1 mM MgCl2 and 0.1% gelatin and maintained on ice until assayed. For antagonist studies, aliquots (2 mL) of cells were prewarmed at 37° C for 5 min in 3 mL plastic cuvettes and fluorescence measured in a fluorometer (Johnson Foundation Biomedical Group, Philadelphia, PA, USA) with magnetic stirring and temperature maintained at 37° 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 Ca2+ attained after 33 nM RANTES stimulation was calculated as described by Grynkiewicz et al., (1985). The percent of maximal RANTES -induced Ca2+ was determined for each concentration of antagonist and the IC50 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 IC50 values in the range of 0.0001 to 100 μM. 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 IC50 value in the range of 0.0001 to 100 μM. 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 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. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims

What is claimed is:
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 ally acceptable salt thereof:
Figure imgf000038_0001
Formula I
wherein: the basic nitrogen in moiety E may be optionally quaternized with C\. galkyl or is optionally present as the N-oxide;
P1 and P2 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(R4')2, CR4'(OR5'), CO, C=NOR6', NR7', oxygen, or S(O)c>;
L is a group of formula -C(=V)-DR8 '-, -DR9'-C(=V)-, -CH2NH-, or - NHCH2-;
V is oxygen or sulfur;
D is nitrogen, carbon, or a CH group,
R1 ' and R2' are independently hydrogen, C^.galkyl, C2-6alkenyl, C2_ galkynyl, C3_7cycloalkyl, C3_7cycloalkenyl, aryl, (CH2)d'NR10'R11', (CH2)d-NR10'COR12', (CH2)d.NR10'CO2R13', (CH2)d'NR10'SO2R14', (CH2)d'CONR15'R16', hydroxyCi .galkyl, C^alkoxyalkyl (optionally substituted by a C 1.4 alkoxy or hydroxy group), (CH2) 'CO2C╬╣_6alkyl, (CH2)eOC(O)R17', CR^NOR1^, CNR^NOR1?', COR21',
Figure imgf000038_0002
CONHNR23'R24', CONR15'sO2R25', CO2R26', cyano, trifluoromethyl, NRiO'R11', NRiO'cOR12', NR27'C0(CH2)d.NR27'R28', NR27'CONR27'R28', NRiO'cOsR13', NR10'SO2R14', N=CNR27'NR27'R28', nitro, hydroxy, C^alkoxy, hydroxyC╬╣_6alkoxy, C galkoxyCj.galkoxy, OC(O)NR29'R 0', SR31 ', SOR32', SO2R32', SO2NR R34', halogen, C╬╣_ galkanoyl, C02(CH2)d R35', or R1' is an optionally substituted 5 to 7- membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;
R3' is hydrogen, C galkyl, C3_6cycloalkyl, C3_6cycloalkenyl, hydroxyC╬╣_6alkyl, Chalky IOC ╬╣_6 lkyl, CONR36'R37', CO R38', cyano, aryl, trifluoromethyl, NR39'R 0', nitro, hydroxy, .galkoxy, C galkanoyl, acyloxy, or halogen;
R4', R5', R6', R7', R18'( R19'; R20', R21 ', R22', R23', R24*, R27', R28',
R31', R35', R36', R37', R38', R39'; and R40' are independently hydrogen or C╬╣_6alkyl;
R ' is hydrogen or C^.galkyl, providing that D is nitrogen or a CH group;
R9' is hydrogen or Ci.╬▓alkyl, providing that D is nitrogen or a CH group;
R1^' and R !' are independently hydrogen or Cj.galkyl, or R1(^' and R1 !' 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;
R12' is hydrogen, C^^yl, or C^alkoxyalkyl; R 3', R2^', and R32' are independently Cj.^alkyl; R1 is Ci.╬▓alkyl or phenyl;
R1^' and R1^' are independently hydrogen or C galkyl, or R ^' and R!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^' is C1_4alkyl, optionally substituted by Cj.galkoxy; R2^' is hydrogen or C galkyl optionally substituted with one or two substituents selected from C galkyl, C galkoxy, hydroxy, or NR^' I I ';
R2" and R3" are independently hydrogen or C j.galkyl, or R2" and R30' 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;
R33 and R34' are independently hydrogen or Cj.galkyl, or R33' and R34 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 O, l, or 2; d' is 1, 2, 3, or 4; e' is O, 1, 2, or 3; f is 1, 2, or 3; E represents (a):
Figure imgf000040_0001
in which
B is oxygen, S(O)c, CR7=CR8, or CR7R8, or B is NR9;
R1 and R2 are independently hydrogen or C^.galkyl; alternatively B(CR1R2)a is OCR1R2CR1(OH)CR1R2 or
Figure imgf000040_0002
R3 and R4 are independently hydrogen, C^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 Cμgalkyl, aryl, CONR^R1 1, NR^R1 1, hydroxy, OCOR12, NHCOCg-όalkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2R13, and NHCO2R14;
R5 is hydrogen, C^alkyl, aryl, CN, CONR^R16, CO2R17, trifluoromethyl, NHCO2R18, hydroxy, C╬╝╬▓alkoxy, benzyloxy, OCH2CO2C╬╣_6alkyl, OCF3, S(O)dR19, SO2NR20R21 or halogen;
R^ is hydrogen, C^alkyl, aryl, trifluoromethyl, hydroxy, C galkoxy or halogen, or R" taken together with R┬░ forms a group D where D is (CR22R23)e or D is (CR22R23)f-G where G is oxygen, sulfur or CR22=CR23, CR22=N, =CR22O, =CR22S, or =CR22-NR23;
R7, R8, R10, R11, R125 R15? RIO, R17, R20> R21, R22f md R23 are independently hydrogen or Cj.galkyl;
R9 is hydrogen, C^alkyl, orphenylCi.galkyl;
R13, R14, R18, and R19 are independently C galkyl; 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 O, 1, 2 or 3; alternatively, E represents (b):
Figure imgf000041_0001
R24, R25, R26, R2 , R28; R29, R31f and R32 ^ independently hydrogen or C╬╝galkyl;
R30 is hydrogen, C galkyl, or C3_7cycloalkyl;
R33 is hydrogen, C galkyl, trifluoromethyl, hydroxy, or halogen, or R33 and R8' together form a group -K- where K is (CR34R35)j or K is (CR34R35)j -M and M is oxygen, sulfur, CR34=CR35, CR 4=N, or N=N;
J is oxygen, CR36R37, or NR38, or J is a group S(O)k;
R34, R35, R36, R37, and R38 are independently hydrogen or C\_ ╬▓alkyl; g is 1, 2 or 3; 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):
Figure imgf000041_0002
in which:
Q is oxygen, S(O)n, CR44=CR45, CR^R45, or Q is NR46; R39 and R4^ are independently hydrogen or Cj.galkyl; R41 is a group of formula (d):
Figure imgf000041_0003
or R41 is a group of formula (e):
Figure imgf000041_0004
R42 is hydrogen, C galkyl, aryl, CN, CONR48R49, CO2R50, trifluoromethyl, NHOI^R^1, hydroxy, C^.galkoxy, benzyloxy, OCH2CO2C1.6alkyl, OCF3, S(O)sR52, SO2NR53R54( or halogen;
R43 is hydrogen or R43 together with R8' forms a group R where R is CR55=CR56, CR55=CR56CR55R56, or (CR55R56)t;
R44, R 5, R46, R48, R49, R50, R53, R54, R55, md R56 ^ independently hydrogen or Cj.galkyl;
R47 is hydrogen, C galkyl, or C3.7 cycloalkyl;
R^1 and R^2 are independently .galkyl; l is O, 1, 2, or 3; m is 1 or 2; n is O, 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):
Figure imgf000042_0001
R57 and R^8 are independently hydrogen or .galkyl;
R^ and R^0 are independently hydrogen, C^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 Cj.galkyl, aryl, CONR61R62, NR61R62, hydroxy, OCOR^3, NHCOC()-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2R64 and NHCO2R65;
T is -(CR66R67)V- or -O(CR66R67)W-;
W is oxygen, S(O)x, NR08, or W is CR69=CR70 0r CR6 R70;
R61, R62, R63, R66, R67 R68> R69> and R70 ^ independently hydrogen or C^.^alkyl;
R^4 and R^5 are independently C^alkyl; u is 1 to 4; v is 2 or 3; w is 1, 2, or 3; x is 0, 1 or 2; alternatively, E represents a group (g):
Figure imgf000043_0001
R71 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 R71 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;
R72 is hydrogen, C galkyl, aryl, CN, CONR74R75; CO2R76, trifluoromethyl, NHCO2R7 , hydroxy, C╬╣_galkoxy, benzyloxy, OCH2CO2C1.6alkyl, OCF3, S(O)zR78, SO2NR79R80, 0r halogen;
R73 is hydrogen, Cj.galkyl, hydroxy, Ci.galkoxy or halogen, or R73 and R8' taken together from a group -X- where X is (CR8 R8 )aa or X is (CR81R82)aD-Y and Y is oxygen, sulfur or CR81=CR82;
R74, R75, R76f R79? R805 81, and R82 ^ independently hydrogen or C galkyl;
R77 and R7 re independently C galkyl; y is 1 or 2; z is O, 1, or 2; aa is 2, 3 or 4; ab is 0, 1, 2 or 3; alternatively, E represents group (h):
Figure imgf000043_0002
R87 (h);
R83 and R84 are independently hydrogen or Cj.galkyl;
R85 an R86 ^g independently hydrogen, C╬╝galkyl, 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^galkyl, aryl, CONR88R89, NR 0R91, hydroxy, OCOR92, NHCOCo_galkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2R93, and NHCO2R94;
R 7 is hydrogen or Cj.galkyl, C╬╣_galkoxy, or halogen, or R87 together with R8 forms a group -AA- where AA is (CR95R96)a or AA is (CR95=CR96)ae-AB and AB is oxygen, sulfur, CR95=CR96, CR95=N, CR95NR96 or N=N; Z is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;
R88, R89, R90, R91, R92, R95, and R96 are independently hydrogen or C╬╝galkyl;
R93 and R94 are independently C^.galkyl; ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2; alternatively, E represents group (i):
Figure imgf000044_0001
R9 and R98 are independently hydrogen, C galkyl, 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 galkyl, aryl, CONR102R103, NR10 R105, hydroxy, OCOR106, NHCOCo-galkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2 R107, and NHCO2R108;
R99 and R 00 are independently hydrogen or C^.galkyl;
R101 is hydrogen or C galkyl or R101 and R8' together form a group -AD- where AD is (CR^R1 !0)ai or AD is (CR10^110)aj-AE and AE is oxygen, sulfur or CR^CR1 10;
AC is oxygen, CR11 lRl 12 or NR1 13 or AC is a group S(O)ak;
R102, R103, R104 R105, R106, R109 Rl 10, Rl 11, Rl 12 md Rl 13 are independently hydrogen or C╬╣_galkyl;
R107 and R108 are independently C^.galkyl; af is O, 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.
2. The method of claim 1 wherein the compound of formula (I) is selected from a subgenus of formula (la) or a pharmaceutically acceptable salt thereof:
Figure imgf000045_0001
Formula (la) wherein:
Rl', R2', R3', Pl, P2, A, a', b', L, R24, R25, R26, R27, R28; R29, R30; R31, R32, R33, 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-l,4-benzoxazin-6-yl)- 4-phenoxybenzamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-4- phenoxybenzamide ;
N-[4-[2-[Bis(l-methylethyl)amino]ethoxy]phenyl]]-4-phenoxybenzamide;
N-[4-[2-(Diethylamino)ethoxy]phenyl]-4-phenoxybenzamide;
N- [3 - [2- [B is( 1 -methy lethy l)amino]ethoxy ]phenyl] -4-phenoxybenzamide ;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3- phenoxybenzamide ;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-3- phenoxybenzamide ;
N- [4- [2- [B is( 1 -me thy lethy l)amino]ethoxy ]pheny 1] -3 - phenoxybenzamide ;
N-[4-[2-[Bis(l-methylethyl)amino]ethoxy]phenyl]-4- (phenylmethy l)benzamide ;
N-[2-[2-(Diethylamino)ethoxy]phenyl]-4-(phenylmethyl)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- phenoxybenzamide ;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (phenylmethyl)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2- (phenylmethyl)thiazole-4-carboxamide hydrochloride; N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- phenoxybenzamide Methiodide;
N-[ 1 -[2-[Bis( 1 -methylethyl)amino]ethyl]- 1 ,2,3,4-tetrahydroquinol-7- yl] -4-phenoxy benzamide ;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(3- hydroxyphenoxy)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4- chloropheny l)sulfiny 1] -3 -nitrobenzamide ;
N- [3 - [2- [B is( 1 -methylethy l)amino] ethoxy ] -4-methoxyphenyl] -4- [(2,4- dichlorophenyl)sulf╬╣nyl]-3-nitrobenzamide;
N-[3-[3-[Bis( 1 -methylethyl)amino]propyl]-4-methoxyphenyl]-3- phenoxy benzamide ;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4- methoxyphenyl]-3-ρhenoxybenzamide;
N-[3-[3-[Bis(l-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(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4- benzoylbenzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4- methoxyphenyl]-4-benzoylbenzamide;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4- (phenylmethy l)benzamide ;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4- methoxyphenyl]-4-(phenylmethyl)benzamide;
N- [3 - [2- [B is( 1 -methylethyl)amino] ethoxy] -4-methoxyphenyl] -4- [(4- chlorophenyl)sulfonyl]benzamide;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4-[(4- chlorophenyl)sulfonyl]benzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4- methoxyphenyl]-4-[(4-chlorophenyl)sulfonyl]benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-5- butylamino-4-phenoxy-3-(sulfamoyl)benzamide;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-5- butylamino-4-phenoxy-3-(sulfamoyl)benzamide; N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4- methoxyphenyl]-5-butylamino-4-phenoxy-3-(sulfamoyl)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(4- chlorophenoxy)-3-nitrobenzamide;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4-(4- chlorophenoxy)-3-nitrobenzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4- methoxyphenyl]-4-(4-chlorophenoxy)-3-nitrobenzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(2- quinoxalinylamino)benzamide;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4-(2- quinoxalinylamino)benzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4- methoxyphenyl] -4-(2-quinoxaliny lamino)benzamide ;
N-[3-[2-[Bis(l -methy lethyl) amino]ethoxy] -4-methoxyphenyl] -4- [(4- methylphenyl)sulfonyl]-3-nitrobenzamide;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4-[(4- methylphenyl)sulfonyl]-3-nitrobenzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-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(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (methylphenylamino)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (phenylamino)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (phenylthio)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (phenylsulf onyl)benzamide ;
N- [3- [2- [B is( 1 -methy lethy 1) amino] ethoxy] -4-methoxyphenyl] -4- (phenylsulfinyl)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- [(hydroxyimino)phenylmethyl]benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (hydroxyphenylmethyl)benzamide;
N-[l'-(l-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]- 4-benzoylbenzamide trifluoroacetate; N-[ 1 '-( 1 -Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4- phenoxybenzamide; and
N-[r-(l-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 HTV.
5. A compound of formula (I) selected from: N-[4-[2-(Dimethylamino)ethyl]-3,4-dihydro-2H-l,4-benzoxazin-6-yl)-
4-phenoxy benzamide ;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-4- phenoxybenzamide ;
N-[4-[2-[Bis(l-methylethyl)amino]ethoxy]phenyl]]-4-phenoxybenzamide;
N-[4-[2-(Diethylamino)ethoxy]phenyl]-4-phenoxybenzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]phenyl]-4-phenoxybenzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3- phenoxybenzamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-3- phenoxybenzamide ;
N-[4-[2-[Bis(l-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(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- phenoxybenzamide ;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (phenylmethyl)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2- (phenylmethyl)thiazole-4-carboxamide hydrochloride;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- phenoxybenzamide Methiodide;
N-[l-[2-[Bis(l-methylethyl)amino]ethyl]-l,2,3,4-tetrahydroquinol-7- yl]-4-phenoxy benzamide ; N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(3- hydroxyphenoxy )benzamide ;
N- [3- [2- [B is( 1 -methylethy l)amino] ethoxy] -4-methoxyphenyl]-4- [(4- chlorophenyl)sulfinyl]-3-nitrobenzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(2,4- dichlorophenyl)sulfinyl]-3-nitrobenzamide;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-3- phenoxybenzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4- methoxyphenyl]-3-phenoxybenzamide;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4- phenoxybenzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4- methoxyphenyl]-4-phenoxybenzamide;
N-[3-[2-[Bis( 1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- benzoy lbenzamide ;
N-[3-[3-[Bis( 1 -methylethyl)amino]propyl]-4-methoxyphenyl]-4- benzoylbenzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4- methoxyphenyl] -4-benzoy lbenzamide ;
N-[3-[3-[Bis(l-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(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4- chlorophenyl)sulfonyl]benzamide;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4-[(4- chlorophenyl)sulfonyl]benzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4- methoxyphenyl]-4-[(4-chlorophenyl)sulfonyl]benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-5- butylamino-4-phenoxy-3-(sulfamoyl)benzamide;
N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-5- butylamino-4-phenoxy-3-(sulfamoyl)benzamide;
N-[3-[2-(2,2,6,6-Tetramethyl-l-piperidinyl)ethoxy]-4- methoxyphenyl]-5-butylamino-4-phenoxy-3-(sulfamoyl)benzamide;
N- [3 - [2- [B is( 1 -methy lethy l)amino] ethoxy ]-4-methoxy phenyl] -4-(4- chlorophenoxy)-3-nitrobenzamide; N-[3-[3-[Bis(l-methylethyl)amino]propyl]-4-methoxyphenyl]-4-(4- chlorophenoxy)-3-nitrobenzamide;
N-[3-[2-(2,2,6,6-Tetramethyl- 1 -piperidinyl)ethoxy]-4- methoxyphenyl]-4-(4-chlorophenoxy)-3-nitrobenzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(2- quinoxalinylamino)benzamide;
N-[3-[3-[Bis(l-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(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-[(4- methylphenyl)sulfonyl]-3-nitrobenzamide;
N-[3-[3-[Bis(l-methylethyl)amino]proρyl]-4-methoxyphenyl]-4-[(4- methylphenyl)sulf onyl] -3 -nitrobenzamide ;
N-[3-[2-(2,2,6,6-Tetramethyl- 1 -piρeridinyl)ethoxy]-4- methoxyphenyl]-4-[(4-methylphenyl)sulfonyl]-3-nitrobenzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3- benzoy lbenzamide ;
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- (pheny lthio)benzamide ;
N-[3-[2-[Bis( 1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (phenylsulfonyl)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- (phenylsulfinyl)benzamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4- [(hydroxyimino)phenylmethyl]benzamide;
N- [3 - [2- [B is( 1 -methy lethyl)amino] ethoxy] -4-methoxyphenyl] -4- (hy droxyphenylmethy l)benzamide ;
N- [ 1 '-( 1 -Methy lethy l)spiro [benzof uran-3 (2H) ,4 '5 -piperidin] -5 -yl] - 4-benzoylbenzamide trifluoroacetate;
N-[l'-(l-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4- phenoxybenzamide; and
N-[l'-(l-Methylethyl)spiro[benzofuran-3(2H),4'5-piperidin]-5-yl]-4- (phenylthio)benzamide.
PCT/US1999/017121 1998-07-28 1999-07-28 Substituted anilide compounds and methods WO2000006146A1 (en)

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EP99937589A EP1100485A4 (en) 1998-07-28 1999-07-28 Substituted anilide compounds and methods
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KR1020017001173A KR20010074779A (en) 1998-07-28 1999-07-28 Substituted anilide compounds and methods
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CA002338764A CA2338764A1 (en) 1998-07-28 1999-07-28 Substituted anilide compounds and methods
AU52392/99A AU5239299A (en) 1998-07-28 1999-07-28 Substituted anilide compounds and methods
HU0102752A HUP0102752A3 (en) 1998-07-28 1999-07-28 Substituted anilide compounds
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WO2002010146A1 (en) * 2000-07-31 2002-02-07 Smithkline Beecham P.L.C. Carboxamide compounds and their use as antagonists of a human 11cby receptor
EP1343796A2 (en) * 2000-10-23 2003-09-17 SmithKline Beecham Corporation Compounds and methods
US7067539B2 (en) 2001-02-08 2006-06-27 Schering Corporation Cannabinoid receptor ligands
US7071213B2 (en) 2001-11-14 2006-07-04 Schering Corporation Cannabinoid receptor ligands
WO2006129679A1 (en) 2005-05-31 2006-12-07 Ono Pharmaceutical Co., Ltd. Spiropiperidine compound and medicinal use thereof
WO2007049771A1 (en) 2005-10-28 2007-05-03 Ono Pharmaceutical Co., Ltd. Compound containing basic group and use thereof
US7217732B2 (en) 2002-06-19 2007-05-15 Schering Corporation Cannabinoid receptor agonists
WO2007058322A1 (en) 2005-11-18 2007-05-24 Ono Pharmaceutical Co., Ltd. Basic group-containing compound and use thereof
WO2007105637A1 (en) 2006-03-10 2007-09-20 Ono Pharmaceutical Co., Ltd. Nitrogenated heterocyclic derivative, and pharmaceutical agent comprising the derivative as active ingredient
WO2007132846A1 (en) 2006-05-16 2007-11-22 Ono Pharmaceutical Co., Ltd. Compound having acidic group which may be protected, and use thereof
WO2008016006A1 (en) 2006-07-31 2008-02-07 Ono Pharmaceutical Co., Ltd. Compound having cyclic group bound thereto through spiro binding and use thereof
WO2008075040A2 (en) 2006-12-21 2008-06-26 Ge Healthcare Limited In vivo imaging agents
US7507767B2 (en) 2001-02-08 2009-03-24 Schering Corporation Cannabinoid receptor ligands
US7544803B2 (en) * 2004-01-23 2009-06-09 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7642272B2 (en) 2003-03-20 2010-01-05 Schering Corporation Cannabinoid receptor ligands
US7696201B2 (en) 2006-08-15 2010-04-13 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7754773B2 (en) * 2005-10-06 2010-07-13 University Of Massachusetts Composition and synthesis of new reagents for inhibition of HIV replication
US7786107B2 (en) 2006-08-18 2010-08-31 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7786141B2 (en) 2004-08-19 2010-08-31 Vertex Pharmaceuticals Incorporated Dihydrospiroindene modulators of muscarinic receptors
US7858635B2 (en) 2005-12-22 2010-12-28 Vertex Pharmaceuticals Incorporated Spiro compounds as modulators of muscarinic receptors
US7858790B2 (en) 2006-06-29 2010-12-28 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7863449B2 (en) 2004-11-29 2011-01-04 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7879834B2 (en) 2004-08-19 2011-02-01 Vertex Pharmaceuticals Incorporated Spiroindoline modulators of muscarinic receptors
US7973162B2 (en) 2007-10-03 2011-07-05 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US8003660B2 (en) 2006-02-22 2011-08-23 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
EP2364982A1 (en) 2003-04-18 2011-09-14 ONO Pharmaceutical Co., Ltd. Spiro-piperidine compounds as chemokine receptor antagonists and medicinal use thereof
EP2385040A1 (en) 2003-03-14 2011-11-09 ONO Pharmaceutical Co., Ltd. Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient
US8263605B2 (en) 2006-02-22 2012-09-11 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
EP2546234A1 (en) 2004-09-13 2013-01-16 Ono Pharmaceutical Co., Ltd. Nitrogeneous heterocyclic derivative and medicine containing the same as an active ingredient
WO2013024022A1 (en) 2011-08-12 2013-02-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for treatment of pulmonary hypertension
WO2013087931A1 (en) 2011-12-16 2013-06-20 L'oreal Coupler with cationic 7-amino-1,2,3,4-tetrahydroquinoline structure, dyeing composition comprising same, processes and uses
WO2013087932A1 (en) 2011-12-16 2013-06-20 L'oreal Coupler with 7-amino-1,2,3,4-tetrahydroquinoline structure, dyeing composition comprising same, processes and uses
US10117931B2 (en) 2009-04-28 2018-11-06 Kameran Lashkari Methods for treatment of age-related macular degeneration
WO2019072697A1 (en) 2017-10-13 2019-04-18 L'oreal Specific 7-amino-1,2,3,4-tetrahydroquinolines, method, and composition
WO2021222069A1 (en) 2020-04-27 2021-11-04 Incelldx, Inc. Methods and compositions for treating cytokine storm infections, including covid-19, by inhibiting ccr5/ccl5 interaction

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Publication number Priority date Publication date Assignee Title
WO2002010146A1 (en) * 2000-07-31 2002-02-07 Smithkline Beecham P.L.C. Carboxamide compounds and their use as antagonists of a human 11cby receptor
EP1343796A2 (en) * 2000-10-23 2003-09-17 SmithKline Beecham Corporation Compounds and methods
EP1343796A4 (en) * 2000-10-23 2005-01-12 Smithkline Beecham Corp 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
US7718702B2 (en) 2001-02-08 2010-05-18 Schering Corporation Cannabinoid receptor ligands
US7645774B2 (en) 2001-11-14 2010-01-12 Schering Corporation Cannabinoid receptor ligands
US7071213B2 (en) 2001-11-14 2006-07-04 Schering Corporation Cannabinoid receptor ligands
US7217732B2 (en) 2002-06-19 2007-05-15 Schering Corporation Cannabinoid receptor agonists
EP2385040A1 (en) 2003-03-14 2011-11-09 ONO Pharmaceutical Co., Ltd. Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient
US7642272B2 (en) 2003-03-20 2010-01-05 Schering Corporation Cannabinoid receptor ligands
EP2364982A1 (en) 2003-04-18 2011-09-14 ONO Pharmaceutical Co., Ltd. Spiro-piperidine compounds as chemokine receptor antagonists and medicinal use thereof
US7544803B2 (en) * 2004-01-23 2009-06-09 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US8367691B2 (en) 2004-08-19 2013-02-05 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US8258148B2 (en) 2004-08-19 2012-09-04 Vertex Pharmaceutical Incorporated Spiroindoline modulators of muscarinic receptors
US8497295B2 (en) 2004-08-19 2013-07-30 Vertex Pharmaceuticals Incorporated Spiroindoline modulators of muscarinic receptors
US7879834B2 (en) 2004-08-19 2011-02-01 Vertex Pharmaceuticals Incorporated Spiroindoline modulators of muscarinic receptors
US7786141B2 (en) 2004-08-19 2010-08-31 Vertex Pharmaceuticals Incorporated Dihydrospiroindene modulators of muscarinic receptors
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
US7754773B2 (en) * 2005-10-06 2010-07-13 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
WO2007049771A1 (en) 2005-10-28 2007-05-03 Ono Pharmaceutical Co., Ltd. Compound containing basic group and use thereof
WO2007058322A1 (en) 2005-11-18 2007-05-24 Ono Pharmaceutical Co., Ltd. Basic group-containing compound and use thereof
US7858635B2 (en) 2005-12-22 2010-12-28 Vertex Pharmaceuticals Incorporated Spiro compounds as modulators of muscarinic receptors
US8003660B2 (en) 2006-02-22 2011-08-23 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US8263605B2 (en) 2006-02-22 2012-09-11 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US8304423B2 (en) 2006-02-22 2012-11-06 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
WO2007105637A1 (en) 2006-03-10 2007-09-20 Ono Pharmaceutical Co., Ltd. Nitrogenated heterocyclic derivative, and pharmaceutical agent comprising the derivative as active ingredient
WO2007132846A1 (en) 2006-05-16 2007-11-22 Ono Pharmaceutical Co., Ltd. Compound having acidic group which may be protected, and use thereof
US7858790B2 (en) 2006-06-29 2010-12-28 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
WO2008016006A1 (en) 2006-07-31 2008-02-07 Ono Pharmaceutical Co., Ltd. Compound having cyclic group bound thereto through spiro binding and use thereof
US7696201B2 (en) 2006-08-15 2010-04-13 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7786107B2 (en) 2006-08-18 2010-08-31 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
WO2008075040A2 (en) 2006-12-21 2008-06-26 Ge Healthcare Limited In vivo imaging agents
CN101678129B (en) * 2006-12-21 2013-01-16 通用电气健康护理有限公司 Radioactive pet agents for imaging CCR5 in vivo
JP2010513441A (en) * 2006-12-21 2010-04-30 ジーイー・ヘルスケア・リミテッド InVivo contrast agent
WO2008075040A3 (en) * 2006-12-21 2009-11-05 Ge Healthcare Limited Radioactive pet agents for imaging ccr5 in vivo
US7973162B2 (en) 2007-10-03 2011-07-05 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US10117931B2 (en) 2009-04-28 2018-11-06 Kameran Lashkari Methods for treatment of age-related macular degeneration
WO2013024022A1 (en) 2011-08-12 2013-02-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for treatment of pulmonary hypertension
WO2013087931A1 (en) 2011-12-16 2013-06-20 L'oreal Coupler with cationic 7-amino-1,2,3,4-tetrahydroquinoline structure, dyeing composition comprising same, processes and uses
WO2013087932A1 (en) 2011-12-16 2013-06-20 L'oreal Coupler with 7-amino-1,2,3,4-tetrahydroquinoline structure, dyeing composition comprising same, processes and uses
US9107848B2 (en) 2011-12-16 2015-08-18 L'oreal Coupler with cationic 7-amino-1,2,3,4-tetrahydroquinoline structure, dyeing composition comprising same, processes and uses
US9233060B2 (en) 2011-12-16 2016-01-12 L'oreal Coupler with 7-amino-1,2,3,4-tetrahydroquinoline structure, dyeing composition comprising same, processes and uses
WO2019072697A1 (en) 2017-10-13 2019-04-18 L'oreal Specific 7-amino-1,2,3,4-tetrahydroquinolines, method, and composition
WO2021222069A1 (en) 2020-04-27 2021-11-04 Incelldx, Inc. Methods and compositions for treating cytokine storm infections, including covid-19, by inhibiting ccr5/ccl5 interaction

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AU5239299A (en) 2000-02-21
HUP0102752A3 (en) 2002-11-28
CN1310621A (en) 2001-08-29
CA2338764A1 (en) 2000-02-10
NO20010446D0 (en) 2001-01-26
JP2002521436A (en) 2002-07-16
PL345713A1 (en) 2002-01-02
KR20010074779A (en) 2001-08-09
BR9912406A (en) 2001-04-24
TR200100267T2 (en) 2001-09-21
IL141028A0 (en) 2002-02-10
WO2000006146A9 (en) 2000-08-03
HUP0102752A2 (en) 2001-12-28

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