WO2000042852A1 - Compounds and methods - Google Patents

Compounds and methods Download PDF

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Publication number
WO2000042852A1
WO2000042852A1 PCT/US2000/001908 US0001908W WO0042852A1 WO 2000042852 A1 WO2000042852 A1 WO 2000042852A1 US 0001908 W US0001908 W US 0001908W WO 0042852 A1 WO0042852 A1 WO 0042852A1
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Prior art keywords
galkyl
methoxyphenyl
carboxamide
diisopropylamino
ethoxy
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PCT/US2000/001908
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French (fr)
Inventor
William E. Bondinell
Michael J. Neeb
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Smithkline Beecham Corporation
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Priority to JP2000594326A priority Critical patent/JP2002535256A/en
Priority to EP00909984A priority patent/EP1146790A4/en
Priority to AU32155/00A priority patent/AU3215500A/en
Publication of WO2000042852A1 publication Critical patent/WO2000042852A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates to substituted heterocyclic 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. Lab. Sci.
  • 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.
  • RANTES which stands for Regulated upon Activation Normal T cell Expressed and Secreted, is an 8 kDa protein member of CC branch of the chemokine family. These proteins recruit and activate immune and inflammatory cells through an interaction with G-protein coupled receptors.
  • the CC branch is defined by the absence of an intervening amino acid residue between the first two cysteine residues and members 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 (T.J. Schall, J. Jongstra, B.J. Dyer, J. Jorgensen, et al., J. Immunol. 141:1018-1025, 1988), however, RANTES has been shown to be synthesized and secreted by a diverse group of cells that include 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.
  • RANTES mRNA is rapidly upregulated in response to IL-1 or TNFa.
  • RANTES mRNA is not usually detected in normal tissues (J.M. Pattison, P.J. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-8, 1995), increased mRNA or protein has been found in diseases characterized by a mononuclear infiltrate.
  • RANTES mRNA was visualized using in situ hybridization in renal allografts undergoing rejection (J.M. Pattison, P.J. Nelson, and A.M. Krensky, Clin.
  • 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 of T cells into inflammatory lesions and provide a novel therapeutic approach for the treatment of atopic and autoimmune disorders.
  • T cells 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.
  • CD8+ T cells 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.
  • a subset of compounds included in formula (I) have been reported to have
  • the present invention is to novel compounds of formula (I) and their novel use as CCR5 modulators for the treatment of certain disease states, including, but not limited to, 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, all in mammals, preferably humans.
  • the preferred compounds for use as CCR5 modulators are those compounds of Formula (I) as noted herein.
  • the present invention is directed to methods for making and using the compounds of formula (I), as well as pharmaceutical compositions of formula (I) or a pharmaceutically acceptable salt thereof.
  • substituted 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, 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.
  • atopic disorders for example, atopic dermatitis and allergies
  • rheumatoid arthritis for example, atopic dermatitis and allergies
  • sarcoidosis and other fibrotic diseases for example, atopic dermatitis and allergies
  • atherosclerosis for example, atopic dermatitis and allergies
  • psoriasis
  • 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.
  • Compounds of formula (I) for use herein as CCR5 modulators include those compounds as described in FR 2758328, published 17 July 1998, FR 2761069, published 25 September 1998, WO 94/07496, published 14 April 1994, and WO95/25443, published 28 September 1995. Each of these references is incorporated herein in their entirety.
  • Preferred compounds for use as CCR5 modulators are those compounds of formula (I) as noted herein.
  • a preferred group of compounds for use herein are those compounds of the formula (I) or a pharmaceutically acceptable salt thereof:
  • A' is aryl, heteroaryl, or tetrahydronaphthyl, each of which is optionally substituted with one or more of R* ;
  • Ri is hydrogen, Cj.galkyl, C 2 -6a ⁇ kenyl, C 2 _6alkynyl, C3_7cycloalkyl, C3. 6cycloalkenyl, CH CF 3 , aryl, aralkyl, (CH 2 ) a NR 2 R 3 , (CH 2 ) a NR 2 COR 4 , (CH 2 ) a NR 2 CO 2 R 5 , (CH 2 ) a NR2sO 2 R 6 , (CH 2 ) a CONR7R8, hydroxy .galkyl, C ⁇ _4alkoxy alkyl (optionally substituted by a C ⁇ _- ⁇ alkoxy or hydroxy group), (CH 2 ) a CO 2 C!.
  • R 7 and R 8 are independently hydrogen or Cj.galkyl, or R 7 and R 8 together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring, wherein when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom;
  • R 9 is C]_4alkyl, optionally substituted by a Cj.galkoxy;
  • RIO and R 1 1 are independently hydrogen or C1 _6alkyl;
  • Ri 2 is hydrogen or C ⁇ .galkyl;
  • R 13 is hydrogen or Ci .galkyl;
  • R i4 and R 1 ⁇ are independently hydrogen or C galkyl;
  • Rl6 is hydrogen or C ⁇ alkyl;
  • Ri 7 is hydrogen or Ci .galkyl optionally substituted with one or more substituents selected from C ⁇ galkyl, C ⁇ .galkoxy, hydroxy, or NR 2 R 3 ;
  • R ! 8 and R 1 9 are independently hydrogen or C _6alkyl;
  • R 2 ⁇ and R 21 are independently hydrogen or Ci .galkyl, or R 2 ⁇ and R 2 ⁇ together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which, when the ring is 6-membered, may optionally contain in the ring one oxygen or one sulfur atom.
  • R 22 is hydrogen or C ⁇ .galkyl;
  • R 23 is C ⁇ _ 6 a ⁇ kyl;
  • D' is either a bond or represents [C(R 24 ) 2 ] a >, [C(R 24 ) ] a CO, CO,
  • R 24 is hydrogen or C ⁇ .galkyl;
  • R 2 ⁇ is hydrogen or C galkyl;
  • R 2 ⁇ is hydrogen or C ⁇ .galkyl
  • R 27 is hydrogen, OR 28 , NHR 28 , CN, NO 2 , R 28 , SR 29 , COR 29 , CHOHR 29 , CO 2 R 29 , NHCOR 29 , NHCO 2 R 29 , NHSO 2 R 29 , or OCONHR 29 ;
  • R is hydrogen, Ci_5alkyl, aryl or aralkyl;
  • R 29 is C ⁇ alkyl, aryl or aralkyl;
  • R is one or more of hydrogen or C j.galkyl, or R is oxo;
  • J' is CO or SO 2 ;
  • L' is NR 30 , O or C(R 30 ) 2 ;
  • R ⁇ is hydrogen or Ci .galkyl; E represents group (a):
  • R 3 1 and R 32 are independently hydrogen or C ⁇ alkyl;
  • R 33 is hydrogen, C galkyl, CO 2 R 37 , NHCO 2 R 38 , hydroxy, C ⁇ galkoxy or halogen, wherein R 37 is hydrogen or Cj-galkyl and R 3 8 is C ⁇ .galkyl;
  • d is 1 to 4;
  • e is 1 or 2;
  • R 34 and R 3 ⁇ are independently hydrogen, Ci .galkyl, C3_ cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring containing one to two heteroatoms selected from oxygen, nitrogen or sulfur;
  • R 4 ⁇ is hydrogen or C galkyl
  • R 4 ⁇ and R 47 are independently hydrogen or Ci- alkyl
  • J is oxygen, CR 50 R 51 , or NR 52 , wherein R 50 , R 51 and R 52 are independently hydrogen or C galkyl, or J is a group S(O) m wherein m is 0, 1 or 2; i is 1, 2 or 3; and j is 1, 2 or 3; alternatively, E represents group (c):
  • R ⁇ 3 and R ⁇ 4 are independently hydrogen or C ⁇ .galkyl
  • R 55 is hydrogen, C galkyl, CO 2 R 61 , NHCO 2 R 62 , hydroxy, C galkoxy or halogen, wherein R"l is hydrogen or Cj.galkyl, and R ⁇ 2 is C galkyl;
  • R57 is a group of formula (d):
  • R ⁇ 7 is a group of formula (e), which may be optionally substituted by one or more of C galkyl:
  • R66 an( j 67 are independently hydrogen or Chalky!
  • R6 8 and R ⁇ 9 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 containing one to two heteroatoms selected from oxygen, nitrogen or sulfur
  • T is -(CR 70 R 71 ) W - or -O(CR 70 R 1 ) X -, wherein R 70 and R 71 are independently hydrogen or C ⁇ .galkyl, wherein w is 2 or 3, and x is 1, 2 or 3; v is 1 to 4; and
  • R 76 is hydrogen, C galkyl, CO 2 R 80 , NHCO 2 R 81 , hydroxy, Ci ⁇ alko y or halogen, wherein R 8 ⁇ is hydrogen or Cj-galkyl, and R 81 is C .galkyl; z is 1 or 2; and
  • R 77 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 77 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; alternatively, E represents group (h):
  • R82 (h); in which: R 82 is hydrogen, C galkyl, Cj -galkoxy or halogen, or R8 2 together with
  • R 83 and R 84 are independently hydrogen or Ci .galkyl
  • R 8 ⁇ and R 8 ⁇ are independently hydrogen, C j .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 containing one to two heteroatoms selected from oxygen, nitrogen or sulfur; ac is 0 to 4; and
  • Z is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur; alternatively, E is group (i):
  • R 9 ⁇ and R 9 ⁇ 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 containing one to two heteroatoms selected from oxygen, nitrogen or sulfur;
  • R 92 and R 93 are independently hydrogen or C galkyl; AC is oxygen, CR 96 R 97 or NR 98 wherein R 9 6, R 97 and R 98 are independently hydrogen or C].galkyl or AC is a group S(O)aj wherein aj is 0, 1 or 2; af is 1, 2 or 3; ag is 1, 2, 3, or 4; and ah is O, 1, 2, 3 or 4.
  • A' is an aryl ring, a heteroaryl ring, or tetrahydronaphthyl.
  • A' is optionally substituted by one or more substituents R 1 .
  • R 1 is hydrogen, C galkyl, C 2 _6alkenyl, C 2 _galkynyl, C3.
  • cycloalkyl C3_6cycloalkenyl, CH 2 CF 3 , aryl, aralkyl, (CH 2 ) a NR 2 R 3 , (CH 2 ) a NR 2 COR 4 , (CH 2 ) a NR 2 CO 2 R 5 , (CH 2 ) a NR 2 SO 2 R 6 , (CH 2 ) a CONR 7 R 8 , hydroxyCi.galkyl, C _4alkoxy alkyl (optionally substituted by a C ⁇ _4alkoxy or hydroxy group), (CH 2 ) a CO 2 C 1 .
  • R 1 is a 5- to 7-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, optionally substituted with hydrogen, Ci.galkyl, C3_7cycloalkyl.
  • R 2 and R 3 are independently hydrogen or Cj.galkyl, or suitably, R 2 and R 3 together with the nitrogen to which they are attached, form a 5- to 6- membered heterocyclic ring.
  • the ring may be optionally substituted by an oxo group, or, when R 2 and R 3 form a 6-membered ring, the ring may optionally contain one oxygen or one sulfur atom.
  • the oxygen or sulfur atom are preferably in the 4-position.
  • R 4 is hydrogen, Cj.galkyl or C ⁇ alkoxyalkyl, or, when R is NR 2 COR 4 , R 4 is (CH 2 ) 3 and forms a ring with A'.
  • R5 is Ci.galkyl.
  • R ⁇ is C galkyl or phenyl.
  • R 7 and R 8 are independently hydrogen or C j.galkyl, or suitably, R 7 and R 8 together with the nitrogen to which they are attached form a 5- to 6- membered saturated heterocyclic ring.
  • the ring may optionally contain one oxygen or one sulfur atom.
  • R 9 is C1_.4a.kyl, wherein the C ⁇ galkyl is optionally substituted by a C ⁇ _galkoxy.
  • R 1 ⁇ and R 1 1 are independently hydrogen or Ci.galkyl.
  • R 12 is hydrogen or C ⁇ _galkyl.
  • R 13 is hydrogen or C .galkyl.
  • R 14 and R 1 ⁇ are independently hydrogen or C -galkyl.
  • R 1 ⁇ is hydrogen or Chalky!
  • R 17 is hydrogen or Ci.galkyl, wherein the Ci.galkyl is optionally substituted with one or more substituents selected from Ci.galkyl, C ⁇ _ 6alkoxy, hydroxy, or NR 2 R 3 .
  • R 18 and R 19 are independently hydrogen or Ci.galkyl.
  • R 2 ⁇ and R 2 are independently hydrogen or C galkyl, or suitably, R 2 ⁇ and R 21 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 22 is hydrogen or Ci.galkyl.
  • R 23 is Chalky.
  • R 24 is hydrogen or Ci.galkyl.
  • R 2 ⁇ is hydrogen or Ci.galkyl.
  • R 2 ⁇ is hydrogen or Ci-galkyl.
  • R 27 is hydrogen, OR 28 , NHR 28 , CN, NO 2 , R 28 , SR 29 , COR 29 , CHOHR 29 , CO 2 R 29 , NHCOR 29 , NHCO 2 R 29 , NHSO 2 R 29 , or OCONHR 29 .
  • R 28 is hydrogen, Ci-galkyl, aryl or aralkyl.
  • R 29 is Ci ⁇ alkyl, aryl or aralkyl.
  • R is one or more of hydrogen or C ⁇ _galkyl, or R is oxo.
  • J' is CO or SO 2 .
  • L' is NR 30 , O, or C(R 3 0) 2 .
  • R 3 ⁇ is hydrogen or Ci.galkyl.
  • substituent E is selected from the following groups:
  • E is selected from group (a), (b) and (g).
  • R 44 is hydrogen or Cigalkyl
  • R 4 ⁇ is hydrogen or C galkyl;
  • R 4 ⁇ and R 47 are independently hydrogen or Ci-galkyl;
  • J is oxygen, CR50R51 ?
  • R ⁇ 0, R51 a nd R ⁇ 2 are independently hydrogen or C ⁇ _galkyl, or J is a group S(O) m wherein m is 0, 1 or 2; and suitably, i is an integer from 1 to 3, and j is an integer from 1-3.
  • the point of attachment of group (b) is para to substituent J.
  • R"° and R ⁇ 7 re independently hydrogen or Cigalkyl;
  • R ⁇ 8 and R ⁇ 9 are independently hydrogen, Cigalkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring containing one to two heteroatoms selected from oxygen, nitrogen or sulfur;
  • T is -(CR 7 0R 7 1 ) W - or -O(CR 70 R 71 ) X -, wherein R 70 and R 71 are independently hydrogen or C galkyl, wherein w is 2 or 3, and x is 1, 2 or 3;
  • R 77 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 77 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; and suitably, z is an integer from 1-2.
  • R 82 is hydrogen, Cigalkyl, Ci.galkoxy or halogen, or R 82 together with RTM form a group -AA-, wherein AA is
  • R 90 and R 91 are independently hydrogen, Cigalkyl, C _ 7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring containing one to two heteroatoms selected from oxygen, nitrogen or sulfur;
  • R 92 and R 93 are independently hydrogen or Ci.galkyl;
  • AC is oxygen, CR 9 ⁇ R 97 or NR 98 wherein R 9 ⁇ , R 97
  • A' is phenyl
  • R is one or more of Ci-galkyl, (CH 2 ) a NR 2 COR 4 , CF 3 , Ci.galkoxy, or halogen
  • D' is a bond
  • E' and G' together are NC(R 26 ) 2
  • R is hydrogen
  • J' is CO
  • L' is NR 30
  • E is group (a), (b), (c), (f), (g), (h), or (i).
  • A' is phenyl
  • R 1 is one or more of Cigalkyl, CF3, or halogen
  • D' is a bond
  • E' and G' together are NCH 2
  • R is hydrogen
  • J' is CO
  • L' is NH
  • E is group (a), (b), (c), (f), (g), (h), or (i).
  • E is group (a)
  • L' is attached to group (a) meta to B-(CR 31 R 32 ) c j-NR 3 R 35 and para to (R 3 ) e
  • B is oxygen or CR 3 R 4
  • R 1 and R 32 are hydrogen
  • R 33 is methoxy or iodo
  • R 34 and R-" are independently C3_galkyl
  • R 34 and R 3 ⁇ taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring optionally substituted with one or more of Cigalkyl
  • R 3 ⁇ is hydrogen
  • d is 2 or 3
  • e is 1.
  • E is group (b)
  • L' is attached to group (b) para to J
  • J is oxygen
  • R 44 is hydrogen
  • R 4 ⁇ nd R 47 are hydrogen
  • R 4 ⁇ is C3_galkyl
  • i is 2 and j is 1.
  • A' is phenyl
  • R 1 is two methyl or chloro groups substituted in the 2,3-positions
  • D' is a bond
  • E' and G' together are NCH 2
  • R is hydrogen
  • J' is CO
  • L' is NH
  • E is group (a) or (b).
  • L' is attached to group (a) meta to B-(CR 31 R 32 )d-NR 34 R 35 and para to (R 3 ) e , wherein B is oxygen or CH 2 , R 31 and R 32 are hydrogen, R 33 is methoxy, R 34 and R 3 ⁇ are independently isopropyl, tert-butyl, or R 34 and R ⁇ taken together with the nitrogen to which they are attached are 1 -(2,2,4,4- tetramethylpiperidinyl), R 3 ⁇ is hydrogen, d is 2 or 3, and e is 1.
  • E group (b)
  • L' is attached to group (b) para to J, J is oxygen, R 44 is hydrogen, R 4 ⁇ and R 47 are hydrogen, R 4 ⁇ is isopropyl, i is 2 and j is 1.
  • Ci.galkyl 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.
  • halo or “halogen” are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.
  • 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, 1,2,3,4- tetrahydronaphthyl, and the like.
  • alkenyl is used herein at all occurrences to mean a straight or branched chain radical of 2 to 6 carbon atoms, unless the length is limited thereto, wherein there is at least one double bond between two of the carbon atoms in the chain, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl, and the like.
  • cycloalkenyl is used herein to mean cyclic radicals, preferably of 5 to 8 carbons, which have at least one double bond between two of the carbon atoms in the ring, including but not limited to cyclopentenyl, cyclohexenyl, and the like.
  • alkynyl is used herein at all occurrences to mean a straight or branched chain radical of 2 to 8 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1- propylene, 2-propylene, and the like.
  • aryl is used herein at all occurrences to mean 6-14-membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems, including, but not limited to phenyl, naphthyl, biphenyl, phenanthryl, anthracenyl, and the like.
  • heteroaryl is used herein at all occurrences to mean a 5-14- membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems, which ring or ring systems contain 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, including, but not limited to, indolyl, benzofuranyl, thianaphthenyl, quinolyl, isoquinolyl, pyrrolyl, furanyl, thienyl, pyridyl, and the like.
  • aralkyl is used herein at all occurrences to mean an aryl moiety as defined above, which is connected to an alkyl moiety as defined above, for example, benzyl or phenethyl, and the like.
  • alkoxy 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, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, and the like.
  • oxo is used herein at all occurrences to mean a double bonded oxygen atom attached to a chemical moiety as a substituent.
  • hydroxyCi .galkyl and “hydroxyalkyl” are used herein interchangeably to mean an hydroxyl group bonded to a Ci.galkyl group as defined above, including, but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, and the like.
  • C ⁇ alkoxyalkyl is used herein at all occurrences to mean a C ⁇ _4alkoxy group as defined above bonded to an alkyl group as defined above, such as an ether, e.g., CH 3 -CH 2 -O-CH -CH 2 -CH 3 .
  • hydroxyC .galkoxy is used herein at all occurrences to mean an hydroxyl group bonded to an alkoxy group as defined above, e.g., HO-CH 2 -CH(OH)CH 3 .
  • C ⁇ _galkoxyC ⁇ _galkoxy is used herein at all occurrences to mean an alkoxy group as defined above, substituted with an alkoxy group as defined above.
  • acyloxy is used herein at all occurrences to mean a moiety
  • R is hydrogen or Ci.galkyl
  • C ⁇ _4alkanoyl is used herein at all occurrences to mean a C(O)Ci-4alkyl group wherein the alkyl portion is as defined above.
  • heteroatom is used herein at all occurrences to mean an oxygen atom, a sulfur atom or a nitrogen atom. It will be recognized that when the heteroatom is nitrogen, it may form an NR a R b moiety, wherein R a and R b are, independently, hydrogen or C j to Cg alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6- or 7-membered ring, including, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, pyridine, and the like. It will be recognized that the saturated or unsaturated 5-, 6- or 7-membered ring may optionally have one or more additional heteroatoms in the ring.
  • heterocyclic is used herein at all occurrences to mean a saturated or wholly or partially unsaturated 5-10-membered ring system (unless the cyclic ring system is otherwise limited) in which one or more rings contain one or more heteroatoms, including, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, pyrazolidine, and the like.
  • optionally substituted is used herein at all occurrences to mean an optionally substituted 5- to 7-membered heterocyclic ring wherein the optional substituents are one or more of Ci-galkyl.
  • CCR5 mediated disease state is used herein at all occurrences to mean any disease state which is mediated (or modulated) by CCR5.
  • 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.
  • the solvated forms 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.
  • the preferred compounds of the invention are the following compounds:
  • compositions are administered in conventional dosage forms prepared by combining a compound of formula (I) ("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.
  • 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 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 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.
  • 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.
  • 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 HIV infection, all in mammals, preferably humans, which comprises administering to such mammal an effective amount of a CCR5 receptor modulator, in particular, a compound as depicted in formula (I).
  • treating is meant either prophylactic or therapeutic therapy.
  • Such formula (I) compound can be administered to such mammal in a conventional dosage form prepared by combining the formula (I) compound 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 formula (I) compound is administered to a mammal in need of treatment for asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIV 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
  • atherosclerosis for example, atopic dermatitis and allergies
  • psoriasis rheumatoid arthritis
  • psoriasis autoimmune diseases
  • autoimmune diseases such as multiple sclerosis
  • inflammatory bowel disease inflammatory bowel disease
  • HIV infection HIV infection
  • 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 formula (I) compound 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.
  • the compounds of formula (I) can be prepared by art-recognized procedures from known or commercially available starting materials. If the starting materials are unavailable from a commercial source, their synthesis is described herein, or they can be prepared by procedures known in the art.
  • compounds of formula (I) are prepared by treating a suitably substituted aniline with triphoshene followed by treatment with a suitably substituted 4-(phenyl)piperazine, 4-(phenyl)piperidine, 4-phenyl-2,3,4,6- tetrahydropyrdine, etc.
  • Suitably substituted anilines used to prepare compounds of formula (I) where E is a group of formula (a) are prepared according to the methods of international application publication number WO 95/15954, published 15 June 1995, international application publication number WO 95/17398, published 29 June 1995, international application publication number WO 95/26328, published 5 October 1995, and international application publication number WO 96/06079, published 29 February 1996.
  • Suitably substituted anilines used to prepare compounds of formula (I) where E is a group or formula (f) are prepared according to the methods of international application publication number WO 95/17401, published 29 June 1995.
  • Suitably substituted anilines used to prepare compounds of formula (I) where E is a group or formula (g) are prepared according to the methods of international application publication number WO 96/31508 published 10 October 1996.
  • Suitably substituted anilines used to prepare compounds of formula (I) where E is a group or formula (h) are prepared according to the methods of international application publication number WO 95/32967, published 7 December 1995 and WO 97/07120, published 27 February 1997.WO 97/07120, published 27 February 1997.
  • Suitably substituted anilines used to prepare compounds of formula (I) where E is a group or formula (i) are prepared according to the methods of international application publication number WO 97/19070 published 29 May 1997.
  • Triphosgene (74 mg, 0.25 mmol) was added to a solution of 3-(2- diisopropylamino)ethoxy-4-methoxyaniline (WO 95/15954)(200 mg, 0.75 mmol) and dichloromethane (3 mL) and maintained at RT for 30 min.
  • Triethylamine (0.30 g, 0.42 mL, 3.0 mmol) was added and the resulting mixture was stirred for 1 h, treated with l-(2,3-dimethylphenyl)piperazine (0.11 g, 0.60 mmol), and the mixture stirred at RT for 16 h. The mixture was washed with water, dried (MgSO4) and concentrated in vacuo.
  • Examples 3-13 Following the procedure of Example 2, except substituting phenylpiperazine, 2-methylphenylpiperazine, 2-(acetamidomethyl)phenyl- piperazine(GB 2309458), 3-(trifluoromethyl)phenylpiperazine, 2- methoxyphenylpiperazine, 2-, 3- and 4-chlorophenylpiperazines, 2,6- dimethylphenylpiperazine, 2,3-dichlorophenylpiperazine and 3,4- dichlorophenylpiperazine for 2,3-dimethylphenylpiperazine, gave the following compounds:
  • Example 24 Following the procedure of Example 2, except substituting l'-(l- methylethyl)spiro[benzofuran-3(2H),4'-piperidin]-5-amine for 3-(2- diisopropylamino)ethoxy-4-methoxyaniline, gave the following compound:
  • 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 % 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 2+ mobilization in RBL 2H3 cells stably expressing the hCCR5 receptor (RBL 2H3 hCCR5). Agonist activity is determined by Ca 2+ mobilization in the same cells which is inhibitable by a selective CCR5 antagonist.
  • Cells were grown to 80-100% 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.
  • 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 formula (I) are modulators of the CCR5 receptor and which bind thereto with an IC50 value in the range of 0.0001 to 100 ⁇ M.

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Abstract

This invention relates to substituted heterocyclic 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, including, but no 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, by the use of substituted heterocyclic compounds which are CCR5 receptor antagonists. Furthermore, since CD8+ T cells 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.

Description

COMPOUNDS AND METHODS
FIELD OF THE INVENTION
This invention relates to substituted heterocyclic 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. Physiol. 57: 791- 804, 1995).
T cells, as well as other inflammatory cells, will migrate into tissues in response to the production of a variety of chemotactic factors. Among these factors are a superfamily of 8-12 kDa proteins known as the chemokines. These proteins share structural features such as the presence of 3-4 conserved cysteine residues. RANTES, which stands for Regulated upon Activation Normal T cell Expressed and Secreted, is an 8 kDa protein member of CC branch of the chemokine family. These proteins recruit and activate immune and inflammatory cells through an interaction with G-protein coupled receptors. The CC branch is defined by the absence of an intervening amino acid residue between the first two cysteine residues and members 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 (T.J. Schall, J. Jongstra, B.J. Dyer, J. Jorgensen, et al., J. Immunol. 141:1018-1025, 1988), however, RANTES has been shown to be synthesized and secreted by a diverse group of cells that include 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, T.J. 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 mRNA is rapidly upregulated in response to IL-1 or TNFa. Although RANTES mRNA is not usually detected in normal tissues (J.M. Pattison, P.J. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-8, 1995), increased mRNA or protein has been found in diseases characterized by a mononuclear infiltrate. For example, RANTES mRNA was visualized using in situ hybridization in renal allografts undergoing rejection (J.M. Pattison, P.J. Nelson, and 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 of T cells into inflammatory lesions and provide a novel therapeutic approach for the treatment of atopic and autoimmune disorders.
Since T cells 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 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. A subset of compounds included in formula (I) have been reported to have
5-HT1 D/IB receptor antagonist activity (FR 2758328, published 17 July 1998, and FR 2761069, published 25 September 1998), or tocolytic oxytocin receptor antagonist activity (WO 94/07496, published 14 April 1994, and WO95/25443, published 28 September 1995). Surprisingly, it has now been discovered that this class of non-peptide compounds, in particular substituted heterocyclic compounds of formula (I), 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
The present invention is to novel compounds of formula (I) and their novel use as CCR5 modulators for the treatment of certain disease states, including, but not limited to, 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, all in mammals, preferably humans. The preferred compounds for use as CCR5 modulators are those compounds of Formula (I) as noted herein.
Further, the present invention is directed to methods for making and using the compounds of formula (I), as well as pharmaceutical compositions of formula (I) or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION
It has now been discovered that substituted 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, 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 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 entry into cells, selective receptor modulators may be useful in the treatment of HIV infection. Compounds of formula (I) for use herein as CCR5 modulators include those compounds as described in FR 2758328, published 17 July 1998, FR 2761069, published 25 September 1998, WO 94/07496, published 14 April 1994, and WO95/25443, published 28 September 1995. Each of these references is incorporated herein in their entirety. Preferred compounds for use as CCR5 modulators are those compounds of formula (I) as noted herein.
A preferred group of compounds for use herein are those compounds of the formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000006_0001
Formula (I) in which: the basic nitrogen in moiety E may be optionally quaternized with C^_ galkyl or is optionally present as the N-oxide;
A' is aryl, heteroaryl, or tetrahydronaphthyl, each of which is optionally substituted with one or more of R* ;
Ri is hydrogen, Cj.galkyl, C2-6aιkenyl, C2_6alkynyl, C3_7cycloalkyl, C3. 6cycloalkenyl, CH CF3, aryl, aralkyl, (CH2)aNR2R3, (CH2)aNR2COR4, (CH2)aNR2CO2R5, (CH2)aNR2sO2R6, (CH2)aCONR7R8, hydroxy .galkyl, Cι _4alkoxy alkyl (optionally substituted by a Cι _-ιalkoxy or hydroxy group), (CH2)aCO2C!.6alkyl, (CH2)bOC(O)R9, CR^NOR1 1, CNR^NOR1 1, COR12, CONR7R8, CONR7(CH2)cOCι_4alkyl, CONR7(CH2)aCO2R13, CONHNR14R15, CONR7SO2R16, CO2R17, cyano, trifluoromethyl, NR2R3, NR2COR4, NR18CO(CH2)aNR18R19, NR!8CONR1 8R19, NR2CO2R5, NR2SO2R6, N=CNR18NR18R19, nitro, hydroxy, C galkoxy, OCF3, hydroxyCι_6alkoxy, Ci .galkoxyCi .galkoxy, OC(O)NR20R21, SR22, SOR23, SO2R23, SO2NR ^R ^ or halogen, or R1 is a 5- to 7-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, optionally substituted with hydrogen, C^alkyl, C3_7cycloalkyl, C3_6cycloalkenyl, hydroxyCi .galkyl, (Cι_6alkyl)Cι_6alkyl, CONR7R8, CO2R17, cyano, aryl, trifluoromethyl, nitro, hydroxy, C1 _6alkoxy, acyloxy, or halogen; a is 1, 2, 3 or 4; b is O, 1, 2 or 3; c is 1, 2 or 3; R2 and R3 are independently hydrogen or C i-galkyl, or R2 and R3 together with the nitrogen to which they are attached, form a 5- to 6-membered heterocyclic ring which ring may be optionally substituted by an oxo group, or, when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom; R4 is hydrogen, CT .galkyl or C^^alkoxyalkyl, or, when Ri is NR2COR4, R4 is (CH2)ι_3 and forms a ring with A'; R5 is Cι_6alkyl; R6 is C galkyl or phenyl;
R7 and R8 are independently hydrogen or Cj.galkyl, or R7 and R8 together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring, wherein when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom;
R9 is C]_4alkyl, optionally substituted by a Cj.galkoxy; RIO and R11 are independently hydrogen or C1 _6alkyl; Ri2 is hydrogen or C^.galkyl; R13 is hydrogen or Ci .galkyl;
Ri4 and R1^ are independently hydrogen or C galkyl; Rl6 is hydrogen or C^alkyl;
Ri7 is hydrogen or Ci .galkyl optionally substituted with one or more substituents selected from Cμgalkyl, C^.galkoxy, hydroxy, or NR2R3; R ! 8 and R 19 are independently hydrogen or C _6alkyl;
R2^ and R21 are independently hydrogen or Ci .galkyl, or R2^ and R2^ together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which, when the ring is 6-membered, may optionally contain in the ring one oxygen or one sulfur atom. R22 is hydrogen or C\ .galkyl; R23 is Cι _6aιkyl; D' is either a bond or represents [C(R24)2]a>, [C(R24) ]aCO, CO,
CO[C(R24)2]a% O[C(R24)2]a>, S[C(R24)2]a>, O[C(R24)2]aCO, [C(R24)2]C CO, NR25[C(R24)2]a', NR25[C(R24)2]aCO, [C(R24)2]c>NR25cO, NR25cO[C(R24)2]a', NR25SO2[C(R24)2]a>, [C(R24)2]c>NR 5sO2, CR2 =CR24CO, C≡CCO, (C(R24)2)c>SO2, SO2[C(R24) ]a>, NR25[C(R24)2]a'SO2, NR25sO2[C(R24)2]a>SO2, O[C(R24)2]a>SO2, SO2NR25[C(R24)2] !_2, [C(R24)2]bCOO[C(R24)2]2, [C(R24)2]b€ONR25[C(R24)2]ι_2; and when E' and G' together are CR27- C(R26)2, then D' may further be O, NR25, CONR25, SO2NR25, OCONR25, NR25cOO, NR25CONR25, [C(R24)2]a>NR25[C(R24)2]b>, [C(R24)2]a [C(R24)2]b>, CO[C(R2 )2]aNR 5, NR25[C(R24)2]a ,
NR25[C(R24)2]a'NR 5, O[C(R24)2)]a'NR 5, O[C(R 4)2]a , CO[C(R24)2]a , SO2[C(R24)2]a>NR25, SO2[C(R24)2]a , [C(R24)2]a>SO2NR25, [C(R24)2]aCONR25, O[C(R24)2]a'SO2NR25, O[C(R24)2]aCONR25, NR25[C(R24)2]a'SO NR25, NR25[C(R24)2]aCONR25, NR25cO[C(R24)2]a'NR25, NR 5sO2[C(R24)2]a'NR25,
(C(R24)2)a'S(C(R24)2)b', COO, CR24OH, C(R 4)aCR24OH; and when E' and G' together are CR27-C(R26)2 or C=CR26, D' may further be CR24=CR24 or C≡C; and a' is 1-6, b' is 0-1, c' is 0-2;
R24 is hydrogen or C\ .galkyl; R2^ is hydrogen or C galkyl;
E' and G' together are NC(R26)2, NC(R26)2C(R26)2, CR27C(R26)2 or C=CR26;
R2^ is hydrogen or C^.galkyl;
R27 is hydrogen, OR28, NHR28, CN, NO2, R28, SR29, COR29, CHOHR29, CO2R29, NHCOR29, NHCO2R29, NHSO2R29, or OCONHR29; R is hydrogen, Ci_5alkyl, aryl or aralkyl; R29 is C^alkyl, aryl or aralkyl; R is one or more of hydrogen or C j.galkyl, or R is oxo; J' is CO or SO2; L' is NR30, O or C(R30) 2;
R ^ is hydrogen or Ci .galkyl; E represents group (a):
Figure imgf000009_0001
R36 (a); in which
R31 and R32 are independently hydrogen or C^alkyl; R33 is hydrogen, C galkyl, CO2R37, NHCO2R38, hydroxy, Cμgalkoxy or halogen, wherein R37 is hydrogen or Cj-galkyl and R38 is C^.galkyl; d is 1 to 4; e is 1 or 2;
R34 and R3^ are independently hydrogen, Ci .galkyl, C3_ cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring containing one to two heteroatoms selected from oxygen, nitrogen or sulfur;
B is oxygen, S(O)f, CR39=CR40 , C=C, or CR39R40 wherein R39 and R4^ are independently hydrogen or Ci.galkyl, and wherein f is 0, 1 or 2, or B is NR41 wherein R4^ is hydrogen, C^alkyl or phenylCι_galkyl; and R ^ is hydrogen or R3° taken together with R3" forms a group D, wherein
D is (CR42R43)g, wherein g is 2, 3 or 4, and R42 and R43 are independently hydrogen or Ci-^alkyl, or D is (CR4 R4 )b-G wherein h is 0, 1, 2 or 3, and G is oxygen, sulfur or CR42=CR43; alternatively, E represents group (b):
Figure imgf000009_0002
in which:
R44 is hydrogen or C^alkyl, or R44 and R3^ together form a group -K-, wherein K is (CR48R49)k, wherein k is 2, 3, or 4, and R48 and R49 are independently hydrogen or Cj.galkyl, or K is (CR48R49)j -L, wherein 1 is 0, 1, 2, or 3, and L is oxygen, sulfur or CR48=CR49;
R4^ is hydrogen or C galkyl;
R4^ and R47 are independently hydrogen or Ci- alkyl;
J is oxygen, CR50R51, or NR52, wherein R50, R51 and R52 are independently hydrogen or C galkyl, or J is a group S(O)m wherein m is 0, 1 or 2; i is 1, 2 or 3; and j is 1, 2 or 3; alternatively, E represents group (c):
Figure imgf000010_0001
in which:
M is oxygen, S(O)p, CR58=CR59, C=C or CR58R59, wherein p is 0, 1 or 2, and R^8 and R*9 are independently hydrogen or C^.galkyl, or M is NR^O wherein R^O is hydrogen or alkyl;
R^3 and R^4 are independently hydrogen or C^.galkyl;
R55 is hydrogen, C galkyl, CO2R61, NHCO2R62, hydroxy, C galkoxy or halogen, wherein R"l is hydrogen or Cj.galkyl, and R^2 is C galkyl;
R56 is hydrogen, or together with R™ forms a group -Q-, wherein Q is CR63=CR64, CR63=CR64CR6 R64, or (CR63R64)q, wherein q is 2 or 3, and R^3 and R^4 are independently hydrogen or Cj.gaikyl; n is O, 1, 2 or 3; o is 1 or 2; and
R57 is a group of formula (d):
(
Figure imgf000010_0002
wherein r, s and t are independently integers having the value 1, 2 or 3; or R^7 is a group of formula (e), which may be optionally substituted by one or more of C galkyl:
Figure imgf000010_0003
wherein u is 0,1, 2 or 3 and R° is hydrogen or Cj.galkyl; alternatively, E represents group (f):
Figure imgf000010_0004
in which: R66 an(j 67 are independently hydrogen or Chalky!; R68 and R^9 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 containing one to two heteroatoms selected from oxygen, nitrogen or sulfur; T is -(CR70R71)W- or -O(CR70R 1)X-, wherein R70 and R71 are independently hydrogen or C^.galkyl, wherein w is 2 or 3, and x is 1, 2 or 3; v is 1 to 4; and
W is oxygen, S(O)v, wherein y is 0, 1 or 2, or W is NR72, wherein R72 is hydrogen or Chalky., or W is CR73=CR74, C=C, or CR73R74, wherein R73 and R74 are independently hydrogen or Cj.galkyl; alternatively, E represents group (g):
Figure imgf000011_0001
in which:
R7^ is hydrogen, halogen, hydroxy, C galkyl or Cj.galkoxy, or R ^ and R3^ taken together from a group -X-, wherein X is (CR78R79)aa, wherein aa is 2, 3 or 4, and R78 and R79 are independently hydrogen or Cj.galkyl, or X is (CR7 R79)ab-Y, wherein ab is 0, 1, 2 or 3, and Y is oxygen, sulfur or CR78=CR79;
R76 is hydrogen, C galkyl, CO2R80, NHCO2R81, hydroxy, Ci^alko y or halogen, wherein R8^ is hydrogen or Cj-galkyl, and R81 is C .galkyl; z is 1 or 2; and
R77 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 R77 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; alternatively, E represents group (h):
Figure imgf000011_0002
R82 (h); in which: R82 is hydrogen, C galkyl, Cj -galkoxy or halogen, or R82 together with
R 0 form a group -AA-, wherein AA is (CR87R88)ad, wherein ad is 1, 2 or 3, and R87 and R8 are independently hydrogen or Cμgalkyl, or AA is (CR87CR88)ae- AB, wherein ae is 0, 1 or 2, and AB is oxygen, sulfur, CR87=CR88, CR87=N, CR87NR88 or N=N;
R83 and R84 are independently hydrogen or Ci .galkyl;
R8^ and R8^ 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 containing one to two heteroatoms selected from oxygen, nitrogen or sulfur; ac is 0 to 4; and
Z is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur; alternatively, E is group (i):
Figure imgf000012_0001
in which:
R89 is hydrogen or Cι_6alkyl or R89 and R3^ together form a group -AD- wherein AD is (CR94R95)ah wherein ah is 2, 3 or 4 and R94 and R95 are independently hydrogen or Cι_6alkyl or AD is (CR94R9^)ai-AE wherein ai is 0, 1, 2 or 3 and AE is oxygen, sulfur or CR94=CR9^;
R9^ and R9^ 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 containing one to two heteroatoms selected from oxygen, nitrogen or sulfur;
R92 and R93 are independently hydrogen or C galkyl; AC is oxygen, CR96R97 or NR98 wherein R96, R97 and R98 are independently hydrogen or C].galkyl or AC is a group S(O)aj wherein aj is 0, 1 or 2; af is 1, 2 or 3; ag is 1, 2, 3, or 4; and ah is O, 1, 2, 3 or 4.
For 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.
Suitably, A' is an aryl ring, a heteroaryl ring, or tetrahydronaphthyl. Suitably A' is optionally substituted by one or more substituents R1. Preferably A' is an optionally substituted phenyl. Suitably, R1 is hydrogen, C galkyl, C2_6alkenyl, C2_galkynyl, C3. cycloalkyl, C3_6cycloalkenyl, CH2CF3, aryl, aralkyl, (CH2)aNR2R3, (CH2)aNR2COR4, (CH2)aNR2CO2R5, (CH2)aNR2SO2R6, (CH2)aCONR7R8, hydroxyCi.galkyl, C _4alkoxy alkyl (optionally substituted by a Cι_4alkoxy or hydroxy group), (CH2)aCO2C1.6alkyl, (CH2)bOC(O)R9, CR^NOR11, CNR10=NOR1 1, COR12, CONR7R8, CONR7(CH2)cOC1.4alkyl, CONR7(CH2)aCO2R13, CONHNR14R15, CONR7SO2R16, CO2R17, cyano, trifluoromethyl, NR2R3, NR COR4, NR18CO(CH2)aNR18R19, NR18CONR18R19, NR2CO2R5, NR2SO2R6, N=CNR18NR 8R19, nitro, hydroxy, Cj.galkoxy, OCF3, hydroxyCi.galkoxy, Ci-galkoxyCi-galkoxy,
OC(O)NR20R21, SR22, SOR23, SO2R23, SO2NR20R21 or halogen, or R1 is a 5- to 7-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, optionally substituted with hydrogen, Ci.galkyl, C3_7cycloalkyl. C _ gcycloalkenyl, hydroxyC galkyl, (Ci.galkyFlCi-galkyl, CONR7R8, CO2R17, cyano, aryl, trifluoromethyl, nitro, hydroxy, C galkoxy, acyloxy, or halogen.
Suitably, R2 and R3 are independently hydrogen or Cj.galkyl, or suitably, R2 and R3 together with the nitrogen to which they are attached, form a 5- to 6- membered heterocyclic ring. Suitably, the ring may be optionally substituted by an oxo group, or, when R2 and R3 form a 6-membered ring, the ring may optionally contain one oxygen or one sulfur atom. When the ring is a 6-membered ring substituted by an oxygen or sulfur atom, the oxygen or sulfur atom are preferably in the 4-position.
Suitably, R4 is hydrogen, Cj.galkyl or C^alkoxyalkyl, or, when R is NR2COR4, R4 is (CH2) 3 and forms a ring with A'. Suitably R5 is Ci.galkyl.
Suitably, R^ is C galkyl or phenyl.
Suitably, R7 and R8 are independently hydrogen or C j.galkyl, or suitably, R7 and R8 together with the nitrogen to which they are attached form a 5- to 6- membered saturated heterocyclic ring. Suitably, when the ring is 6-membered, the ring may optionally contain one oxygen or one sulfur atom.
Suitably, R9 is C1_.4a.kyl, wherein the Cμgalkyl is optionally substituted by a Cι_galkoxy.
Suitably, R1^ and R1 1 are independently hydrogen or Ci.galkyl. Suitably, R12 is hydrogen or Cι_galkyl. Suitably, R13 is hydrogen or C .galkyl.
Suitably, R14 and R1^ are independently hydrogen or C -galkyl. Suitably, R1^ is hydrogen or Chalky! Suitably, R17 is hydrogen or Ci.galkyl, wherein the Ci.galkyl is optionally substituted with one or more substituents selected from Ci.galkyl, Cι_ 6alkoxy, hydroxy, or NR2R3. Preferably, when there is more than one substituent, there are two substituents. Suitably, R18 and R19 are independently hydrogen or Ci.galkyl.
Suitably, R2^ and R2 are independently hydrogen or C galkyl, or suitably, R2^ and R21 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. Suitably, R22 is hydrogen or Ci.galkyl.
Suitably, R23 is Chalky..
Suitably, D' is either a bond or represents [C(R24)2]a', [C(R24)2]aCO, CO, CO[C(R24)2]a>, O[C(R24)2]a>, S[C(R24)2]a>, O[C(R24)2]a€O, [C(R24)2]C CO, NR25[C(R24)2]a NR25[C(R24)2]aCO, [C(R24)2]c>NR25cO, NR25cO[C(R24)2]a', NR 5sO2[C(R24)2]a', [C(R24)2]c'NR25sO2, CR24=CR24CO, C≡CCO, (C(R 4)2)CSO2, SO2[C(R24)2]a', NR25[C(R2 )2]a'SO2, NR25sO2[C(R24)2]a>SO2, O[C(R2 )2]aSO2, SO2NR25[C(R24)2]ι_2, [C(R24)2]bCOO[C(R24)2]2, [C(R24)2]bCONR25[C(R24)2] ι_2; and when E' and G' together are CR27- C(R26)2, then D' may further be O, NR25, CONR25, SO NR 5, OCONR25, NR 5cOO, NR25CONR25, [C(R 4)2]a'NR25[C(R24)2]b>, [C(R24)2]a [C(R24)2]b', CO[C(R24)2]a>NR25, NR25[C(R24)2]a , NR25[C(R24)2]a>NR25, O[C(R24)2)]a'NR25, O[C(R24)2]a , CO[C(R24)2]a , SO2[C(R24)2]a>NR25, SO2[C(R24)2]a , [C(R24)2]a'SO2NR25, [C(R24)2]aCONR25, O[C(R24)2]a'SO2NR25, O[C(R24)2]aCONR25, NR25[C(R24)2]a'SO2NR25, NR25[C(R24)2]a ONR25, NR25cO[C(R24)2]a'NR25, NR25SO2[C(R24)2]a'NR25,
(C(R24)2)a'S(C(R24)2)b', COO, CR24OH, C(R24)aCR24OH; and when E' and G' together are CR27-C(R26)2 or C=CR26, D' may further be CR24=CR24 or C≡C; and a' is 1-6, b' is 0-1, c' is 0-2.
Suitably, R24 is hydrogen or Ci.galkyl. Suitably, R2^ is hydrogen or Ci.galkyl. Suitably, E' and G' together are NC(R26)2, NC(R26) C(R26)2, CR2 C(R26)2 or C=CR26. Suitably, R2^ is hydrogen or Ci-galkyl.
Suitably, R27 is hydrogen, OR28, NHR28, CN, NO2, R28, SR29, COR29, CHOHR29, CO2R29, NHCOR29, NHCO2R29, NHSO2R29, or OCONHR29. Suitably, R28 is hydrogen, Ci-galkyl, aryl or aralkyl. Suitably, R29 is Ci^alkyl, aryl or aralkyl. Suitably, R is one or more of hydrogen or Cι_galkyl, or R is oxo. Suitably, J' is CO or SO2. Suitably, L' is NR30, O, or C(R30)2. Suitably, R3^ is hydrogen or Ci.galkyl. Suitably, substituent E is selected from the following groups:
Figure imgf000015_0001
Preferably, E is selected from group (a), (b) and (g).
Suitably, when E is group (a), suitably, R31 and R32 are independently hydrogen or Ci-galkyl; suitably, R33 is hydrogen, Ci-galkyl, CO2R37, NHCO2R38, hydroxy, Ci.galkoxy or halogen, wherein R37 is hydrogen or Ci-galkyl and R38 is Ci.galkyl; suitably, R34 and R3^ are independently hydrogen, Ci-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 containing one to two heteroatoms selected from oxygen, nitrogen or sulfur; suitably, B is oxygen, S(O)f, CR3 =CR 0 , C=C, or CR39R40 wherein R39 and R4^ are independently hydrogen or Ci.galkyl, and wherein f is 0, 1 or 2, or B is NR41 wherein R41 is hydrogen, C galkyl or phenylCi.galkyl; and suitably, R3 is hydrogen or R3° taken together with R3^ forms a group D, wherein D is (CR42R 3)g, wherein g is 2, 3 or 4, and R42 and R43 are independently hydrogen or Cμgalkyl, or D is (CR42R43)n-G wherein h is 0, 1, 2 or 3, and G is oxygen, sulfur or CR42=CR43. Suitably, d is an integer from 1 to 4; and e is an integer from 1 to 2.
Suitably, when E is group (b), suitably, R44 is hydrogen or Cigalkyl, or R44 and R30 together form a group -K-, wherein K is (CR48R49)j , wherein k is 2, 3, or 4, and R48 and R49 are independently hydrogen or Ci-galkyl, or K is (CR48R49)j -L, wherein 1 is 0, 1 , 2, or 3, and L is oxygen, sulfur or CR48=CR49; suitably, R4^ is hydrogen or C galkyl; suitably, R4^ and R47 are independently hydrogen or Ci-galkyl; suitably, J is oxygen, CR50R51? or NR52; w erein suitably, R^0, R51 and R^2 are independently hydrogen or Cι_galkyl, or J is a group S(O)m wherein m is 0, 1 or 2; and suitably, i is an integer from 1 to 3, and j is an integer from 1-3. Preferably, the point of attachment of group (b) is para to substituent J.
Suitably, when E is group (c), suitably, M is oxygen, S(O)p, CR58=CR59, C=C ,or CR58R59, wherein p is 0, 1 or 2, and R58 and R59 are independently hydrogen or Ci-galkyl, or suitably, M is NR°0 wherein R"0 is hydrogen or alkyl; suitably, R^3 and R^ are independently hydrogen or Cigalkyl; suitably, R^5 is hydrogen, Cμgalkyl, CO2R6 , NHCO2R62, hydroxy, C galkoxy or halogen, wherein R^1 is hydrogen or Cμgalkyl, and R^2 is Ci-galkyl; suitably, R^6 is hydrogen, or together with R3" forms a group -Q-, wherein Q is CR63=CR64, CR63=CR64CR6 R64, or (CR63R64)q, wherein q is 2 or 3, and suitably, R63 and R^4 are independently hydrogen or C galkyl; suitably, R^7 is selected from a group of formula (d) or (e); suitably, n is 0, 1, 2 or 3, o is an integer from 1-2, and u is 0, 1, 2 or 3.
Suitably, when E is group (f), R"° and R^7 re independently hydrogen or Cigalkyl; suitably, R^8 and R^9 are independently hydrogen, Cigalkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring containing one to two heteroatoms selected from oxygen, nitrogen or sulfur; suitably, T is -(CR70R7 1)W- or -O(CR70R71)X-, wherein R70 and R71 are independently hydrogen or C galkyl, wherein w is 2 or 3, and x is 1, 2 or 3; suitably, W is oxygen, S(O)y, wherein y is 0, 1 or 2, or W is NR72, wherein R72 is hydrogen or Cigalkyl, or W is CR7 =CR74, C=C, or CR73R74, wherein R73 and R74 are independently hydrogen or C galkyl; and suitably, v is an integer from 1- 4.
Suitably, when E is group (g), R ^ is hydrogen, halogen, hydroxy, Ci-galkyl or Ci-galkoxy, or R7^ and R3^ taken together from a group -X-, wherein X is (CR78R79)aa, wherein aa is 2, 3 or 4, and R78 and R79 are independently hydrogen or Cigalkyl, or X is (CR78R79)a -Y, wherein ab is 0, 1, 2 or 3, and Y is oxygen, sulfur or CR78=CR79; suitably, R7^ is hydrogen, C\. galkyl, CO2R80, NHCO R81, hydroxy, C galkoxy or halogen, wherein R80 is hydrogen or Cigalkyl, and R81 is Cigalkyl; suitably, R77 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 R77 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; and suitably, z is an integer from 1-2.
Suitably, when E is group (h), R82 is hydrogen, Cigalkyl, Ci.galkoxy or halogen, or R82 together with R™ form a group -AA-, wherein AA is
(CR87R88)ad, wherein ad is 1, 2 or 3, and R87 and R88 are independently hydrogen or C galkyl, or AA is (CR87CR88)ae-AB, wherein ae is 0, 1 or 2, and AB is oxygen, sulfur, CR87=CR88, CR87=N, CR87NR88 or N=N; suitably, R83 and R84 are independently hydrogen or Ci .galkyl; suitably, R8^ and R8^ are independently hydrogen, Ci -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 containing one to two heteroatoms selected from oxygen, nitrogen or sulfur; suitably, Z is an optionally substituted 5- to 7- membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur; and suitably ac is 0-4.
Suitably, when E is group (i), R89 is hydrogen or Ci -galkyl or R89 and R30 together form a group -AD- wherein AD is (CR94R9^)ah wherein ah is 2, 3 or 4 and R94 and R ^ are independently hydrogen or Ci-galkyl or AD is (CR94R95)aj-AE wherein ai is 0, 1, 2 or 3 and AE is oxygen, sulfur or CR9 =CR95; suitably, R90 and R91 are independently hydrogen, Cigalkyl, C _ 7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring containing one to two heteroatoms selected from oxygen, nitrogen or sulfur; suitably, R92 and R93 are independently hydrogen or Ci.galkyl; suitably, AC is oxygen, CR9^R97 or NR98 wherein R9^, R97 and R98 are independently hydrogen or Cigalkyl or AC is a group S(O)aj wherein aj is 0, 1 or 2; suitably, af is an integer from 1-3, ag is an integer from 1-4, and ah is 0-4. Preferably, A' is phenyl, R is one or more of Ci-galkyl, (CH2)aNR2COR4, CF3, Ci.galkoxy, or halogen, D' is a bond, E' and G' together are NC(R26)2, R is hydrogen, J' is CO, L' is NR30, and E is group (a), (b), (c), (f), (g), (h), or (i). More preferably, A' is phenyl, R1 is one or more of Cigalkyl, CF3, or halogen, D' is a bond, E' and G' together are NCH2, R is hydrogen, J' is CO, L' is NH, and E is group (a), (b), (c), (f), (g), (h), or (i). More preferably, when E is group (a), L'is attached to group (a) meta to B-(CR31R32)cj-NR3 R35 and para to (R3 )e, wherein B is oxygen or CR3 R40, R 1 and R 32 are hydrogen, R33 is methoxy or iodo, R34 and R-" are independently C3_galkyl, or R34 and R3^ taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring optionally substituted with one or more of Cigalkyl, R3^ is hydrogen, d is 2 or 3, and e is 1. Most preferably, when E is group (b), L' is attached to group (b) para to J, J is oxygen, R44 is hydrogen, R4^ nd R47 are hydrogen, R4^ is C3_galkyl, i is 2 and j is 1.
Most preferably, A' is phenyl, R1 is two methyl or chloro groups substituted in the 2,3-positions, D' is a bond, E' and G' together are NCH2, R is hydrogen, J' is CO, L' is NH, and E is group (a) or (b). Most preferably, when E is group (a), L' is attached to group (a) meta to B-(CR31R32)d-NR34R35 and para to (R3 )e, wherein B is oxygen or CH2, R31 and R 32 are hydrogen, R33 is methoxy, R34 and R3^ are independently isopropyl, tert-butyl, or R34 and R ^ taken together with the nitrogen to which they are attached are 1 -(2,2,4,4- tetramethylpiperidinyl), R3^ is hydrogen, d is 2 or 3, and e is 1. Most preferably, when E is group (b), L' is attached to group (b) para to J, J is oxygen, R44 is hydrogen, R4^ and R47 are hydrogen, R4^ is isopropyl, i is 2 and j is 1.
The term "Ci.galkyl" 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 "halo" or "halogen" are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.
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, 1,2,3,4- tetrahydronaphthyl, and the like. The term "alkenyl" is used herein at all occurrences to mean a straight or branched chain radical of 2 to 6 carbon atoms, unless the length is limited thereto, wherein there is at least one double bond between two of the carbon atoms in the chain, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl, and the like.
The term "cycloalkenyl" is used herein to mean cyclic radicals, preferably of 5 to 8 carbons, which have at least one double bond between two of the carbon atoms in the ring, including but not limited to cyclopentenyl, cyclohexenyl, and the like. The term "alkynyl" is used herein at all occurrences to mean a straight or branched chain radical of 2 to 8 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1- propylene, 2-propylene, and the like. The term "aryl" is used herein at all occurrences to mean 6-14-membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems, including, but not limited to phenyl, naphthyl, biphenyl, phenanthryl, anthracenyl, and the like.
The term "heteroaryl" is used herein at all occurrences to mean a 5-14- membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems, which ring or ring systems contain 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, including, but not limited to, indolyl, benzofuranyl, thianaphthenyl, quinolyl, isoquinolyl, pyrrolyl, furanyl, thienyl, pyridyl, and the like. The term "aralkyl" is used herein at all occurrences to mean an aryl moiety as defined above, which is connected to an alkyl moiety as defined above, for example, benzyl or phenethyl, and the like.
The term "alkoxy" 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, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, and the like.
The term "oxo" is used herein at all occurrences to mean a double bonded oxygen atom attached to a chemical moiety as a substituent.
The terms "hydroxyCi .galkyl" and "hydroxyalkyl" are used herein interchangeably to mean an hydroxyl group bonded to a Ci.galkyl group as defined above, including, but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, and the like. The term "C^alkoxyalkyl" is used herein at all occurrences to mean a Cι_4alkoxy group as defined above bonded to an alkyl group as defined above, such as an ether, e.g., CH3-CH2-O-CH -CH2-CH3.
The term "hydroxyC .galkoxy" is used herein at all occurrences to mean an hydroxyl group bonded to an alkoxy group as defined above, e.g., HO-CH2-CH(OH)CH3.
The term "Cι_galkoxyCι_galkoxy" is used herein at all occurrences to mean an alkoxy group as defined above, substituted with an alkoxy group as defined above. The term "acyloxy" is used herein at all occurrences to mean a moiety
-O-C(O)-R, wherein R is hydrogen or Ci.galkyl.
The term " Cι_4alkanoyl " is used herein at all occurrences to mean a C(O)Ci-4alkyl group wherein the alkyl portion is as defined above.
The term "heteroatom" is used herein at all occurrences to mean an oxygen atom, a sulfur atom or a nitrogen atom. It will be recognized that when the heteroatom is nitrogen, it may form an NRaRb moiety, wherein Ra and Rb are, independently, hydrogen or Cj to Cg alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6- or 7-membered ring, including, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, pyridine, and the like. It will be recognized that the saturated or unsaturated 5-, 6- or 7-membered ring may optionally have one or more additional heteroatoms in the ring.
The term "heterocyclic" is used herein at all occurrences to mean a saturated or wholly or partially unsaturated 5-10-membered ring system (unless the cyclic ring system is otherwise limited) in which one or more rings contain one or more heteroatoms, including, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, pyrazolidine, and the like.
The term "optionally substituted" is used herein at all occurrences to mean an optionally substituted 5- to 7-membered heterocyclic ring wherein the optional substituents are one or more of Ci-galkyl.
The term "CCR5 mediated disease state" is used herein at all occurrences to mean any disease state which is mediated (or modulated) by CCR5.
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. Among the preferred compounds of the invention are the following compounds:
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-phenyl- 1,2,3,6- tetrahydropyridine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-phenylpiperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- methylphenyl)piperazine- 1 -carboxamide ;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2-acetamido- methylphenyl) piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-
4-(3-trifluoromethylphenyl)piperazine-l -carboxamide;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- methoxyphenyl)piperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(2-chlorophenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3-chlorophenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(4-chlorophenyl)piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,6- dimethylphenyl)piperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3 ,4-dichlorophenyl)piperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-3-methyl-4-(3- methylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- methoxyphenyl)piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,4- dimethylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]~3-methyl-4- phenylpiperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,4-dihydro-
2(1 H)-quinolinone-6-yl)piperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,5- dimethylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3- cyanophenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- ethoxycarbonylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- ethoxycarbonylphenyl)piperazine- 1 -carboxamide; and N-[2,3-dihydro-l'-isopropyl-spiro[benzofuran-5-yl-3,4'-piperidine]]-4-(2,3- dimethylphenyl)piρerazine- 1 -carboxamide.
Among the more preferred compounds of the invention are the following compounds: N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dimethy lphenyl)piperazine- 1 -carboxamide;and
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dichlorophenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,4- dimethylphenyl)piρerazine- 1 -carboxamide; and
N-[2,3-dihydro-l'-isopropyl-spiro[benzofuran-5-yl-3,4'-piperidine]]-4-(2,3- dimethylphenyl)piperazine- 1 -carboxamide.
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 formula (I) ("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 HIV infection, all in mammals, preferably humans, which comprises administering to such mammal an effective amount of a CCR5 receptor modulator, in particular, a compound as depicted in formula (I). By the term "treating" is meant either prophylactic or therapeutic therapy.
Such formula (I) compound can be administered to such mammal in a conventional dosage form prepared by combining the formula (I) compound 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 formula (I) compound is administered to a mammal in need of treatment for asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIV 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 formula (I) compound 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 formula (I) 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
The compounds of formula (I) can be prepared by art-recognized procedures from known or commercially available starting materials. If the starting materials are unavailable from a commercial source, their synthesis is described herein, or they can be prepared by procedures known in the art.
For example, compounds of formula (I) are prepared by treating a suitably substituted aniline with triphoshene followed by treatment with a suitably substituted 4-(phenyl)piperazine, 4-(phenyl)piperidine, 4-phenyl-2,3,4,6- tetrahydropyrdine, etc.
Suitably substituted anilines used to prepare compounds of formula (I) where E is a group of formula (a) are prepared according to the methods of international application publication number WO 95/15954, published 15 June 1995, international application publication number WO 95/17398, published 29 June 1995, international application publication number WO 95/26328, published 5 October 1995, and international application publication number WO 96/06079, published 29 February 1996.
Suitably substituted anilines used to prepare compounds of formula (I) where E is a group or formula (b) are prepared according to the methods of international application publication number WO 95/11934, published 25 April
1995, and WO 95/19477, published 27 June 1995. Four other applications relate to the spiro compounds WO 97/17350 published 15 May 1997; WO 97/34900 published 25 September 1997; WO 97/34901 published 25 September 1997; WO 97/35862 published 2 October 1997. Suitably substituted anilines used to prepare compounds of formula (I) where E is a group or formula (c) are prepared according to the methods of international application publication number WO 95/30675, published 16 November 1995.
Suitably substituted anilines used to prepare compounds of formula (I) where E is a group or formula (f) are prepared according to the methods of international application publication number WO 95/17401, published 29 June 1995. Suitably substituted anilines used to prepare compounds of formula (I) where E is a group or formula (g) are prepared according to the methods of international application publication number WO 96/31508 published 10 October 1996. Suitably substituted anilines used to prepare compounds of formula (I) where E is a group or formula (h) are prepared according to the methods of international application publication number WO 95/32967, published 7 December 1995 and WO 97/07120, published 27 February 1997.WO 97/07120, published 27 February 1997. Suitably substituted anilines used to prepare compounds of formula (I) where E is a group or formula (i) are prepared according to the methods of international application publication number WO 97/19070 published 29 May 1997.
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 Example 1
Preparation of N-13-(2-Diisopropylamino)ethoxy-4-methoxyphenyll-4-phenyl- 1.2.3.6-tetrahvdropyridine-l-carboxamide
A solution of triphosgene (0.23 g, 0.77 mmol) in dichloromethane (25 mL) was stirred in an ice bath and treated with a solution of 4-phenyl- 1,2,3,6- tetrahydropyridine hydrochloride (0.5 g, 2.6 mmol) and triethylamine (1 g, 10.2 mmol) in dichloromethane added dropwise. The ice bath was removed and the mixture was stirred for 30 min, treated with 3-(2-diisopropylamino)ethoxy-4- methoxyaniline (WO 95/15954)(0.68 g, 2.55 mmol), and stirred for 16 h. The mixture was diluted with dichloromethane (50 mL), extracted with 5% sodium carbonate, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed (silica gel, 8% methanol/dichloromethane saturated with ammonia) to give the title compound. MS(ES) m/e 452.0 [M+H]+.
Example 2 Preparation of N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyll-4-(2,3- dimethy lpheny 1) piperazine- 1 -carboxamide ;
Triphosgene (74 mg, 0.25 mmol) was added to a solution of 3-(2- diisopropylamino)ethoxy-4-methoxyaniline (WO 95/15954)(200 mg, 0.75 mmol) and dichloromethane (3 mL) and maintained at RT for 30 min. Triethylamine (0.30 g, 0.42 mL, 3.0 mmol) was added and the resulting mixture was stirred for 1 h, treated with l-(2,3-dimethylphenyl)piperazine (0.11 g, 0.60 mmol), and the mixture stirred at RT for 16 h. The mixture was washed with water, dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography (silica gel, 20: 1:0.04 dichloromethane:methanol:triethylamine) to give 205 mg (70%) of the title compound as an off-white powder. MS(ES) m/e 483.1 [M+H] +.
Examples 3-13 Following the procedure of Example 2, except substituting phenylpiperazine, 2-methylphenylpiperazine, 2-(acetamidomethyl)phenyl- piperazine(GB 2309458), 3-(trifluoromethyl)phenylpiperazine, 2- methoxyphenylpiperazine, 2-, 3- and 4-chlorophenylpiperazines, 2,6- dimethylphenylpiperazine, 2,3-dichlorophenylpiperazine and 3,4- dichlorophenylpiperazine for 2,3-dimethylphenylpiperazine, gave the following compounds:
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-phenylpiperazine-l- carboxamide: MS(ES) m/e 454. 9 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- methylphenyl)piperazine- 1 -carboxamide: MS(ES) m/e 469.1 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2-acetamido- methylphenyl) piperazine- 1 -carboxamide: MS(ES) m/e 525.9 [M+H] +; N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-
4-(3-trifluoromethylphenyl)piperazine-l -carboxamide: MS(ES) m/e 522.8 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- methoxyphenyl)piperazine- 1 -carboxamide: MS(ES) m/e 485.0 [M+H]+; N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-
4-(2-chlorophenyl)piperazine-l -carboxamide: MS(ES) m/e 488.9 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3-chlorophenyl)piperazine-l -carboxamide: MS(ES) m/e 488.8 [M+H]+; N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(4-chlorophenyl)piperazine-l -carboxamide: MS(ES) m/e 488.8 [M+H]+; N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,6- dimethylphenyl)piperazine-l -carboxamide: MS(ES) m/e 483.1 [M+H]+; N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dichlorophenyl)piperazine-l -carboxamide: MS(ES) m/e 522.9 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3,4-dichlorophenyl)piperazine-l -carboxamide: MS(ES) m/e 522.7 [M+H]+; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-3-methyl-4-(3- methylphenyl)piperazine- 1 -carboxamide: MS(ES) m/e 483.2 [M+H]+;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- methoxyphenyl)piperazine-l -carboxamide: MS(ES) m/e 499.2 [M+H]+; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,4- dimethylphenyl)piperazine-l -carboxamide: MS (ES) m e 483.2 [M+H]+; N- [3 - (2-Diisopropylamino)ethoxy-4-methoxy phenyl] -3 -methy 1-4- phenylpiperazine- 1 -carboxamide: MS(ES) m/e 469.2 [M+H]+;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,4-dihydro- 2(lH)-quinolinone-6-yl)piperazine-l -carboxamide: MS(ES) m e 524.2 [M+H]+; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,5- dimethylphenyl)piperazine-l -carboxamide: MS(ES) m e 483.2 [M+H]+;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3- cyanophenyl)piperazine-l -carboxamide: MS(ES) m/e 480.2 [M+H]+; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- ethoxycarbonylphenyl)piperazine-l -carboxamide: MS(ES) m/e 527.2 [M+H]+; and
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- ethoxycarbonylphenyl)piperazine-l -carboxamide: MS(ES) m/e 527.2 [M+H]+.
Example 23
Preparation of 1 '-(l-Methylethyl)spiro[benzofuran-3(2H),4'-piperidinl-5-amine a) 5- and 7-nitrospirorbenzofuran-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 (Na SO4) and concentrated to afford the title compound (2. 65 g). b) -(tert-butoxycarbonyl)-5-nitrospirorbenzofuran-3(2H),4'-piperidinel 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 fbenzof 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 (Na2SO4) and concentrated in vacuo to give the title compound (1.45 g). MS(ES) m/e 235.1 [+H]+. d) 1 '-( 1 -methylethyl)-5-nitrospirorbenzofuran-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) r-(l-methylethyl)spiro[benzofuran-3(2H).4'-piperidin1-5-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).
Example 24 Following the procedure of Example 2, except substituting l'-(l- methylethyl)spiro[benzofuran-3(2H),4'-piperidin]-5-amine for 3-(2- diisopropylamino)ethoxy-4-methoxyaniline, gave the following compound:
N-[2,3-dihydro-l'-isopropyl-spiro[benzofuran-5-yl-3,4'-piperidine]]-4-(2,3- dimethylphenyl)piperazine-l -carboxamide: MS(ES) m/e 463.1 [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 Ca2+ 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 10^ cells/mL with Krebs Ringer Henseleit buffer (KRH; 118 mM NaCl, 4.6 mM KC1, 25 mM NaHCO3, 1 mM KH2PO4 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 lθ6 cells/mL in the same buffer with 2 μM 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" 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 formula (I) 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 of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000033_0001
Formula I in which: the basic nitrogen in moiety E may be optionally quaternized with Cι_ galkyl or is optionally present as the N-oxide;
A' is aryl, heteroaryl, or tetrahydronaphthyl, optionally substituted with one or more of R1;
R1 is hydrogen, Ci -galkyl, C2-galkenyl, C2-galkynyl, C3_7cycloalkyl, C3- gcycloalkenyl, CH2CF3, aryl, aralkyl, (CH2)aNR2R3, (CH2)aNR2COR4,
(CH2)aNR CO2R5, (CH2)aNR2SO2R6, (CH2)aCONR7R8, hydroxyCi -galkyl, Cι_4alkoxyalkyl (optionally substituted by a Cι_4alkoxy or hydroxy group), (CH2)aCO2Cι .galkyl, (CH2) OC(O)R9, CR^NOR1 1, CNR^NOR1 1, COR12, CONR7R8, CONR7(CH2)cOC!.4alkyl, CONR7(CH2)aCO2R13, CONHNR14R15, CONR7SO2R16, CO2R17, cyano, trifluoromethyl, NR2R3, NR2COR4, NR18CO(CH )aNR18R19, NR18CONR18R19, NR2CO2R5, NR2SO2R6, N=CNR18NR18R19, nitro, hydroxy, Ci-galkoxy, OCF3, hydroxyCi-galkoxy, Ci-galkoxyCi-galkoxy, OC(O)NR20R21, SR22, SOR23, SO2R23, SO2NR20R21 or halogen, or R1 is a 5- to 7-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, optionally substituted with hydrogen, Ci -galkyl, C3-7cycloalkyl, C3-gcycloalkenyl, hydroxy Ci -galkyl, (Cι-galkyl)Cι. galkyl, CONR7R8, CO2R17, cyano, aryl, trifluoromethyl, nitro, hydroxy, Ci-galkoxy, acyloxy, or halogen; a is 1, 2, 3 or 4; b is 0, 1, 2 or 3; c is 1, 2 or 3;
R2 and R3 are independently hydrogen or Ci -galkyl, or R2 and R3 together with the nitrogen to which they are attached, form a 5- to 6-membered heterocyclic ring which ring may be optionally substituted by an oxo group, or, when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom; R4 is hydrogen, Ci -galkyl or Ci^alkoxyalkyl, or, when R1 is NR2COR4, R4 is (CH2)ι_3 and forms a ring with A'; R5 is Ci alkyl; R" is C j .galkyl or phenyl;
R7 and R8 are independently hydrogen or Ci -galkyl, or R7 and R8 together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring, wherein when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom; R9 is Cι-4alkyl, optionally substituted by a Ci-galkoxy;
R1^ and R1 1 are independently hydrogen or Ci-galkyl; R 2 is hydrogen or Ci.galkyl; R13 is hydrogen or Ci -galkyl;
R14 and R ^ are independently hydrogen or Ci -galkyl; R 1 ^ is hydrogen or C i .galkyl ;
R17 is hydrogen or Ci -galkyl optionally substituted with one or more substituents selected from Ci -galkyl, Cι_galkoxy, hydroxy, or NR R3; R18 and R19 are independently hydrogen or Ci -galkyl; R2^ and R21 are independently hydrogen or Ci .galkyl, or R2^ and R2 together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which, when the ring is 6-membered, may optionally contain in the ring one oxygen or one sulfur atom. R22 is hydrogen or Ci -galkyl; R23 is Ci -galkyl; D' is either a bond or represents [C(R24)2]a', [C(R24)2]a€O, CO,
CO[C(R24)2]a', O[C(R24)2]a% S[C(R24)2]a>, O[C(R2 )2]a€O, [C(R24)2]C CO, NR25[C(R24)2]a<, NR25[C(R24)2]aCO, [C(R24)2]C>NR25C0, NR25cO[C(R24)2]a', NR25sO2[C(R24)2]a>, [C(R24)2]c'NR25sO2, CR24=CR2 CO, C≡CCO, (C(R24)2)C'S02, SO2[C(R24)2]a', NR25[C(R24)2]a'SO2, NR25sO2[C(R24)2]a>SO2, O[C(R2 )2]a>SO2, SO2NR25[C(R24)2] ι_2, [C(R24)2]b€OO[C(R24)2]2, [C(R24)2] CONR25[C(R24)2]i-2; and when E' and G' together are CR27- C(R26)2, then D' may further be O, NR25, CONR25, SO2NR25, OCONR25, NR25COO, NR25CONR25, [C(R24)2]a'NR25[C(R24)2]b>, [C(R24)2]a [C(R 4)2]b', CO[C(R24)2]a>NR25, NR 5[C(R24)2]a ,
NR25[C(R24)2]a'NR25, O[C(R24)2)]a>NR25, O[C(R2 )2]a , CO[C(R24)2]aO, SO2[C(R24)2]a'NR25, SO2[C(R24)2]aO, [C(R2 )2]a'SO2NR25, [C(R24)2]aCONR25, O[C(R2 )2]a'SO2NR25, O[C(R24)2]aCONR25,
NR25[C(R24)2]a'SO2NR25, NR25[C(R24)2]a€ONR25,
NR25CO[C(R24)2]aNR25, NR25SO2[C(R24)2]a>NR25,
(C(R24)2)a'S(C(R 4)2)b>, COO, CR24OH, C(R24)aGR24OH; and when E' and G' together are CR27-C(R26)2 or C=CR26, D' may further be CR24=CR24 or C≡C; and a' is 1-6, b' is 0-1, c' is 0-2;
R24 is hydrogen or Ci -galkyl;
R2^ is hydrogen or Ci -galkyl;
E' and G' together are NC(R26)2, NC(R26)2C(R26) , CR27C(R26)2 or C=CR26;
R26 is hydrogen or Cj -galkyl;
R27 is hydrogen, OR28, NHR28, CN, NO2, R28, SR29, COR29,
CHOHR29, CO R29, NHCOR29, NHCO2R29, NHSO2R29, or OCONHR29;
R28 is hydrogen, Cι-5alkyl, aryl or aralkyl; R29 is Cι-5alkyl, aryl or aralkyl;
R is one or more of hydrogen or Ci -galkyl, or R is oxo;
J' is CO or SO ;
L' is NR30, O or C(R30) 2;
R30 is hydrogen or Cigalkyl; E represents group (a):
Figure imgf000035_0001
R36 (a); in which
R3 and R32 are independently hydrogen or Ci -galkyl; R33 is hydrogen, Cj -galkyl, CO R37, NHCO2R38, hydroxy, Ci-galkoxy or halogen, wherein R37 is hydrogen or Ci-galkyl and R38 is Ci-galkyl; d is 1 to 4; e is 1 or 2;
R34 and R ^ are independently hydrogen, Ci -galkyl, C3-γcycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring containing one to two heteroatoms selected from oxygen, nitrogen or sulfur;
B is oxygen, S(O)f, CR39=CR40 , C=C, or CR39R40 wherein R39 and R4^ are independently hydrogen or Ci-galkyl, and wherein f is 0, 1 or 2, or B is NR41 wherein R4 is hydrogen, Ci-galkyl or phenylCi. galkyl; and R3" is hydrogen or R3° taken together with R3^ forms a group D, wherein D is (CR42R4 )g, wherein g is 2, 3 or 4, and R42 and R43 are independently hydrogen or Ci -galkyl, or D is (CR42R43)b-G wherein h is 0, 1, 2 or 3, and G is oxygen, sulfur or CR42=CR43; alternatively, E represents group (b):
Figure imgf000036_0001
in which:
R44 is hydrogen or Ci -galkyl, or R44 and R3*-* together form a group -K-, wherein K is (CR48R 9)k, wherein k is 2, 3, or 4, and R48 and R49 are independently hydrogen or Ci -galkyl, or K is (CR48R49)ι -L, wherein 1 is 0, 1, 2, or 3, and L is oxygen, sulfur or CR48=CR49;
R45 is hydrogen or Ci.galkyl;
R4^ and R47 are independently hydrogen or Ci -galkyl;
J is oxygen, CR50R51, or NR52, wherein R50, R51 and R52 are independently hydrogen or Ci-galkyl, or J is a group S(O)m wherein m is 0, 1 or 2; i is 1, 2 or 3; and j is 1, 2 or 3; alternatively, E represents group (c):
Figure imgf000036_0002
in which:
M is oxygen, S(O)p, CR58=CR59, C=C, or CR58R59, wherein p is 0, 1 or 2, and R^ and R^9 are independently hydrogen or Ci-galkyl, or M is NR"0 wherein R"0 is hydrogen or alkyl;
R^3 and R^4 are independently hydrogen or Ci -galkyl; R55 is hydrogen, -galkyl, CO2R61, NHCO2R62, hydroxy, Cj.galkoxy or halogen, wherein R^1 is hydrogen or Ci .galkyl, and R^2 is Ci -galkyl;
R56 is hydrogen, or together with R3^ forms a group -Q-, wherein Q is CR6 =CR64, CR63=CR64CR63R64, or (CR63R64)q, wherein q is 2 or 3, and R^3 and R^ are independently hydrogen or Ci -galkyl; n is 0, 1, 2 or 3; o is 1 or 2; and R^ is a group of formula (d):
(
Figure imgf000037_0001
wherein r, s and t are independently integers having the value 1, 2 or 3; or R^7 is a group of formula (e), which may be optionally substituted by one or more of Ci -galkyl:
Figure imgf000037_0002
wherein u is 0,1, 2 or 3 and R"^ is hydrogen or Cj -galkyl; alternatively, E represents group (f):
Figure imgf000037_0003
in which:
R66 and R67 are independently hydrogen or Ci -galkyl; R68 and R^9 are independently hydrogen, Ci -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 containing one to two heteroatoms selected from oxygen, nitrogen or sulfur;
T is -(CR70R71)W- or -O(CR70R71)X-, wherein R70 and R71 are independently hydrogen or Ci -galkyl, wherein w is 2 or 3, and x is 1, 2 or 3; v is 1 to 4; and
W is oxygen, S(O)v, wherein y is 0, 1 or 2, or W is NR72, wherein R72 is hydrogen or C i -galkyl, or W is CR73=CR74 or CR73R74, wherein R73 and R74 are independently hydrogen or Ci-galkyl; alternatively, E represents group (g):
Figure imgf000037_0004
in which: R ^ is hydrogen, halogen, hydroxy, Ci-galkyl or Ci-galkoxy, or R7^ and R 0 taken together from a group -X-, wherein X is (CR78R79)aa, wherein aa is 2, 3 or 4, and R78 and R79 are independently hydrogen or Ci -galkyl, or X is (CR 8R79)ab-Y, wherein ab is 0, 1, 2 or 3, and Y is oxygen, sulfur or CR78=CR79;
R76 is hydrogen, Ci -galkyl, CO2R80, NHCO2R81, hydroxy, Ci-galkoxy or halogen, wherein R8^ is hydrogen or Ci.galkyl, and R81 is Ci-galkyl; z is 1 or 2; and
R77 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 R77 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; alternatively, E represents group (h):
Figure imgf000038_0001
in which:
R82 is hydrogen, Ci -galkyl, Ci-galkoxy or halogen, or R82 together with R3^ form a group -AA-, wherein AA is (CR87R88)ad, wherein ad is 1, 2 or 3, and R87 and R88 are independently hydrogen or Ci -galkyl, or AA is (CR87CR88)ae- AB, wherein ae is 0, 1 or 2, and AB is oxygen, sulfur, CR87=CR88, CR87=N, CR87NR88 or N=N;
R83 and R84 are independently hydrogen or Ci -galkyl;
R8^ and R8^ are independently hydrogen, Ci -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 containing one to two heteroatoms selected from oxygen, nitrogen or sulfur; ac is 0 to 4; and
Z is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur; alternatively, E is group (i):
Figure imgf000038_0002
in which: R89 is hydrogen or Ci -galkyl or R89 and R3^ together form a group - AD- wherein AD is (CR94R95)ah wherein ah is 2, 3 or 4 and R94 and R95 are independently hydrogen or Ci -galkyl or AD is (CR94R9^)aj-AE wherein ai is 0, 1, 2 or 3 and AE is oxygen, sulfur or CR94=CR95; R9^ and R91 are independently hydrogen, Ci -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 containing one to two heteroatoms selected from oxygen, nitrogen or sulfur;
R92 and R93 are independently hydrogen or Ci -galkyl; AC is oxygen, CR96R97 or NR98 wherein R96, R97 and R98 are independently hydrogen or Ci -galkyl or AC is a group S(O)aj wherein aj is 0, 1 or 2; af is 1, 2 or 3; ag is 1, 2, 3, or 4; and ah is 0, 1, 2, 3 or 4.
2. The method as claimed in claim 1 wherein the compound of formula (I) is a compound selected from:
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-phenyl-l, 2,3,6- tetrahydropyridine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-phenylpiperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- methylphenyl)piperazine- 1 -carboxamide; N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2-acetamido- methylphenyl) piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3-trifluoromethylphenyl)piperazine-l -carboxamide;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- methoxyphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(2-chlorophenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3-chlorophenyl)piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-
4-(4-chlorophenyl)piperazine-l -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,6- dimethylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3 ,4-dichlorophenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dimethylphenyl)piperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dichlorophenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-3-methyl-4-(3- methylphenyl)piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- methoxyphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,4- dimethylphenyl)piρerazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-3-methyl-4- phenylpiperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,4-dihydro- 2(lH)-quinolinone-6-yl)piperazine-l -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,5- dimethylphenyl)piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3- cyanophenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- ethoxycarbonylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- ethoxycarbonylphenyl)piperazine-l -carboxamide; and
N-[2,3-dihydro-r-isopropyl-spiro[benzofuran-5-yl-3,4'-piperidine]]-4-(2,3- dimethylphenyl)piperazine- 1 -carboxamide .
3. The method as claimed in claim 1, wherein the disease is selected from COPD, asthma and atopic disorders, rheumatoid arthritis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIV infection.
4. The method of claim 3, wherein the compound is selected from: N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-phenyl-l,2,3,6- tetrahydropyridine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-phenylpiperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- methylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2-acetamido- methylphenyl) piperazine- 1 -carboxamide;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] - 4-(3-trifluoromethylphenyl)piperazine-l-carboxamide;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- methoxyphenyl)piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-
4-(2-chlorophenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3-chlorophenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(4-chlorophenyl)piperazine-l -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,6- dimethylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3,4-dichlorophenyl)piperazine-l -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dimethylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dichlorophenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-3-methyl-4-(3- methylphenyl)piperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- methoxyphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,4- dimethylphenyl)piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-3-methyl-4- phenylpiperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,4-dihydro- 2(lH)-quinolinone-6-yl)piperazine-l -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,5- dimethylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3- cyanophenyl)piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- ethoxycarbonylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- ethoxycarbonylphenyl)piperazine- 1 -carboxamide; and N-[2,3-dihydro-l '-isopropyl-spiro[benzofuran-5-yl-3,4'-piperidine]]-4-(2,3- dimethylphenyl)piperazine- 1 -carboxamide.
PCT/US2000/001908 1999-01-25 2000-01-25 Compounds and methods WO2000042852A1 (en)

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