WO2001009137A1 - Antagonistes de recepteur de chemokine et procedes d'utilisation - Google Patents

Antagonistes de recepteur de chemokine et procedes d'utilisation Download PDF

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Publication number
WO2001009137A1
WO2001009137A1 PCT/US2000/020775 US0020775W WO0109137A1 WO 2001009137 A1 WO2001009137 A1 WO 2001009137A1 US 0020775 W US0020775 W US 0020775W WO 0109137 A1 WO0109137 A1 WO 0109137A1
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group
substituted
aromatic
aliphatic group
ring
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PCT/US2000/020775
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English (en)
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Jay R. Luly
Yoshisuke Nakasato
Etsuo Ohshima
Hiroki Sone
Osamu Kotera
Geraldine C. B. Harriman
Kenneth G. Carson
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Millennium Pharmaceuticals, Inc.
Kyowa Hakko Kogyo Co., Ltd.
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Application filed by Millennium Pharmaceuticals, Inc., Kyowa Hakko Kogyo Co., Ltd. filed Critical Millennium Pharmaceuticals, Inc.
Priority to EP00952317A priority Critical patent/EP1204664A1/fr
Priority to AU65039/00A priority patent/AU6503900A/en
Publication of WO2001009137A1 publication Critical patent/WO2001009137A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • Chemoattractant cyto ines or chemokines are a family of proinflammatory mediators that promote recruitment and activation of multiple lineages of leukocytes and lymphocytes . They can be released by many kinds of tissue cells after activation. Continuous release of chemokines at sites of inflammation mediates the ongoing migration of effector cells in chronic inflammation.
  • the chemokines characterized to date are related in primary structure. They share four conserved cysteines, which form disulfide bonds. Based upon this conserved cysteine motif, the family is divided into two main branches, designated as the C-X-C chemokines
  • ⁇ -chemokines and the C-C chemokines ( ⁇ -chemokines) , in which the first two conserved cysteines are separated by an intervening residue, or adjacent respectively (Baggiolini, M. and Dahinden, C. A., Immunology Today, 15:127-133 (1994) ) .
  • the C-X-C chemokines include a number of potent chemoattractants and activators of neutrophils, such as interleukin 8 (IL-8) , PF4 and neutrophil-activating peptide-2 (NAP-2) .
  • IL-8 interleukin 8
  • PF4 neutrophil-activating peptide-2
  • NAP-2 neutrophil-activating peptide-2
  • the C-C chemokines include RANTES (Regulated on Activation, Normal T Expressed and Secreted) , the macrophage inflammatory proteins l and l ⁇ (MIP-l and MIP-l ⁇ ) , eotaxin, and human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2, MCP-3), which have been characterized as chemoattractants and activators of monocytes or lymphocytes but do not appear to be chemoattractants for neutrophils.
  • Chemokines, such as RANTES and MlP-l ⁇ have been implicated in a wide range of human acute and chronic inflammatory diseases including respiratory diseases, such as asthma and allergic disorders.
  • C-C chemokine receptor 1 also referred to as CCR-1; Neote, K., et al . , Cell , 72:415-425 (1993); Horuk, R. et al . , WO 94/11504, May 26, 1994; Gao, J.-I. et al . , J. Exp. Med . , 177:1421-1427 (1993)).
  • CCR3 mediates binding and signaling of chemokines including eotaxin, RANTES, and MCP-3 (Ponath et al., J " . Exp .
  • CCR4 binds chemokines including RANTES, MlP-l ⁇ , and MCP-1 (Power, et al., J. Biol . Che . , 270:19495 (1995)), and CCR5 binds chemokines including MlP-l ⁇ , RANTES, and MlP-l ⁇ (Samson, et al . , Biochem. 35 : 3362-3367 (1996)).
  • RANTES is a chemotactic chemokine for a variety of cell types, including monocytes, eosinophils, and a subset of
  • T-cells T-cells.
  • the responses of these different cells may not all be mediated by the same receptor, and it is possible that the receptors CCR1 , CCR4 and CCR5 will show some selectivity in receptor distribution and function between leukocyte types, as has already been shown for CCR3 (Ponath et al . ) .
  • the ability of the receptors CCR1 , CCR4 and CCR5 will show some selectivity in receptor distribution and function between leukocyte types, as has already been shown for CCR3 (Ponath et al . ) .
  • RANTES to induce the directed migration of monocytes and a memory population of circulating T-cells (Schall, T. et al., Nature, 347:669-71 (1990)) suggests this chemokine and its receptor (s) may play a critical role in chronic inflammatory diseases, since these diseases are characterized by destructive infiltrates of T cells and monocytes .
  • An antagonist of chemokine receptor function is a molecule which can inhibit the binding and/or activation of one or more chemokines, including C-C chemokines such as RANTES and/or MlP-l ⁇ , to one or more chemokine receptors on leukocytes and/or other cell types.
  • C-C chemokines such as RANTES and/or MlP-l ⁇
  • processes and cellular responses mediated by chemokine receptors can be inhibited with these small organic molecules.
  • a method of treating a subject with a disease associated with aberrant leukocyte recruitment and/or activation is disclosed as well as a method of treating a disease mediated by chemokine receptor function.
  • the method comprises administering to the subject a therapeutically effective amount of a compound or small organic molecule which is an antagonist of chemokine receptor function.
  • Compounds or small organic molecules which have been identified as antagonists of chemokine receptor function are discussed in detail herein below, and can be used for the manufacture of a medicament for treating or for preventing a disease associated with aberrant leukocyte recruitment and/or activation.
  • the invention also relates to the disclosed compounds and small organic molecules for use in treating or preventing a disease associated with aberrant leukocyte recruitment and/or activation.
  • the invention also includes pharmaceutical compositions comprising one or more of the compounds or small organic molecules which have been identified herein as antagonists of chemokine function and a suitable pharmaceutical carrier.
  • the invention further relates to novel compounds which can be used to treat an individual with a disease associated with aberrant leukocyte recruitment and/or activation and methods for their preparation.
  • Figure 1 is a schematic showing the preparation of the compounds represented by Structural Formula (I), ( I I I ) and ( IV) .
  • Figure 2 is a schematic showing the preparation of representative compounds of Structural Formula (I) , (III) and (IV) wherein Z is represented by Structural Formulas (VIII) and wherein Ring A and/or Ring B in Z can be substituted with - (O) u - (CH 2 ) t -COOR 20 ,
  • Figure 3 is a schematic showing the preparation of the compounds represented by Structural Formula (I) .
  • Figure 4 is a schematic showing the preparation of compounds represented by Structural Formulas (I) , (III) and (IV) , wherein Z is represented by Structural Formula (VIII), wherein W is H.
  • Figure 5 is a schematic showing the preparation of compounds represented by Structural Formulas (I) , (III) and (IV) , wherein Z is represented by Structural Formula (VIII), wherein W is H.
  • Figure 6 shows the preparation of compounds represented by Structural Formula (I), where in Z is represented by Structural Formulas (VIII) and wherein Ring A and/or Ring B in Z is substituted with -(0) u -(CH 2 ) t -COOR 20 , u is one.
  • Figure 7 shows the preparation of compounds represented by Structural Formula (I), wherein Z is represented by Structural Formulas (VIII) and wherein Ring A or Ring B in Z is substituted with -(0) u - (CH 2 ) t -COOR 20 , u is zero.
  • Figure 8A is a schematic showing the preparation of 4- (4-chlorophenyl) -4-fluoropiperidine .
  • Figure 8B is a schematic showing the preparation of 4-4-azido-4- (4-chlorophenyl) piperidine .
  • Figure 8C is a schematic showing the preparation of 4- (4-chlorophenyl) -4-methylpiperidine .
  • Figure 9A is a schematic showing the preparation of compounds represented by Structural Formulas (I), (VIII) and (VIII) wherein R 1 is an amine.
  • Figure 9B is a schematic showing the preparation of compounds represented by Structural Formulas (I), (VIII) and (VIII) wherein R 1 is an alkylamine.
  • Figure 9C is a schematic showing the preparation of 2- (4-chlorophenyl) -1- ( N-methyl ) ethylamine.
  • Figure 9D is a schematic showing the preparation of 3- (4-chlorophenyl) -3-chloro-l-hydroxypropane .
  • Figure 9E is a schematic showing the preparation of 3- (4-chlorophenyl) -1-N-methylaminopropane .
  • Figure 10A is a schematic showing the preparation of 3- (4-chlorophenyl) -3-hydroxyl-3-methyl-l-N- methylaminopropane .
  • Figure 10B is a schematic showing the preparation of 1- (4-chlorobenzoyl) -1, 3-propylenediamine .
  • Figure IOC is a schematic showing three procedures for the preparation of compounds represented by Structural Formulas (I), (XVII), (XVIII), (XIX) and (XX) wherein Z is represented by Structural Formulas (VIII)- (X) , (Xa) , (Xb) or (Xc) and wherein Ring A or Ring B in Z is substituted with R 40,
  • R 40 is represented by - (0) u - (CH 2 ) t -C(0) - ⁇ R 21 R 22 , u is one, t is zero.
  • Figure 10D is a schematic showing the preparation of 4- (4-chlorophenyl) -4-pyridine.
  • Figures 11A-11K show the structures of exemplary compounds of the present invention.
  • Figure 12 is a schematic showing the preparation of compounds of formula (XV-b) .
  • Figure 13 is a schematic showing the preparation of compounds of formula (XV-c) .
  • Figure 14 is a schematic showing the preparation of compounds of formula (XV-e) .
  • the present invention relates to small molecule compounds which are modulators of chemokine receptor function.
  • the small molecule compounds are antagonists of chemokine receptor function. Accordingly, processes or cellular responses mediated by the binding of a chemokine to a receptor can be inhibited (reduced or prevented, in whole or in part) , including leukocyte migration, integrin activation, transient increases in the concentration of intracellular free calcium [Ca ++ ]i, and/or granule release of proinflammatory mediators .
  • the invention further relates to a method of treatment, including prophylactic and therapeutic treatments, of a disease associated with aberrant leukocyte recruitment and/or activation or mediated by chemokines or chemokine receptor function, including chronic inflammatory disorders characterized by the presence of RANTES, MlP-l ⁇ , MCP-2, MCP-3 and/or MCP-4 responsive T cells, monocytes and/or eosinophils, including but not limited to diseases such as arthritis (e.g., rheumatoid arthritis), atherosclerosis, arteriosclerosis, restenosis, ischemia/reperfusion injury, diabetes mellitus (e.g., type 1 diabetes mellitus) , psoriasis, multiple sclerosis, inflammatory bowel diseases such as ulcerative colitis and Crohn ' s disease, rejection of transplanted organs and tissues (i.e., acute allograft rejection, chronic allograft rejection) , graft versus host disease, as well as allergies and asthma.
  • HIV Human Immunodeficiency Virus
  • the method comprises administering to the subject in need of treatment an effective amount of a compound (i.e., one or more compounds) which inhibits chemokine receptor function, inhibits the binding of a chemokine to leukocytes and/or other cell types, and/or which inhibits leukocyte migration to, and/or activation at, sites of inflammation.
  • a compound i.e., one or more compounds which inhibits chemokine receptor function, inhibits the binding of a chemokine to leukocytes and/or other cell types, and/or which inhibits leukocyte migration to, and/or activation at, sites of inflammation.
  • the invention further relates to methods of antagonizing a chemokine receptor, such as CCR1 , in a mammal comprising administering to the mammal a compound as described herein.
  • a chemokine receptor such as CCR1
  • chemokine-mediated chemotaxis and/or activation of pro-inflammatory cells bearing receptors for chemokines can be inhibited.
  • pro-inflammatory cells includes but is not limited to leukocytes, since chemokine receptors can be expressed on other cell types, such as neurons and epithelial cells.
  • the method and compounds of the invention can be used to treat a medical condition involving cells which express CCR1 on their surface and which respond to signals transduced through CCR1 , as well as the specific conditions recited above.
  • the antagonist of chemokine receptor function is represented by the structural formula (I) : Z L N M
  • Z is a cycloalkyl or non-aromatic heterocyclic ring group fused to a pyridine ring and to a carbocyclic aromatic or heteroaromatic ring, wherein each ring in Z is independently substituted or unsubstituted.
  • L is a C x -C 18 hydrocarbyl group wherein, optionally one or more of the carbon atoms is replaced by a heteroatom such as nitrogen, oxygen or sulfur.
  • M is >NR 2 or >CR 1 R 2 .
  • R 1 is -H, -OH, -N 3/ a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, -0- (aliphatic group) , -O- (substituted aliphatic group) , -SH, -S- (aliphatic group) , -S- (substituted aliphatic group), -OC (O) - (aliphatic group), -O-C (O) - (substituted aliphatic group), -C (0) O- (aliphatic group), -C (0)0- (substituted aliphatic group), -C00H, -CN, -CO-NR 3 R 4 , -NR 3 R 4 ; or R 1 can be a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M.
  • R 1 is preferably -H or -OH.
  • R 2 is -H, -OH, an acyl group, a substituted acyl group, -NR 5 R 6 , an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, -0- (substituted or unsubstituted aromatic group) or -0- (substituted or unsubstituted aliphatic group) .
  • R 2 is preferably an aromatic group or a substituted aromatic group.
  • R 3 , R 4 , R 5 and R 6 are independently -H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group.
  • R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 taken together with the atom to which they are bonded, can alternatively form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.
  • n is an integer from one to eighteen, more preferably n is an integer from one to about five, most preferably n is three.
  • X is a single covalent bond or -CO-, and the antagonist of chemokine receptor function is represented by Structural Formula (III) : (III)
  • Y, n and X are as described above for Structural Formula (II) .
  • Structural Formula (III) are each a covalent bond and the antagonist of chemokine receptor function is a compound represented by Structural Formula (IV) : / ⁇
  • n is an integer from one to about five. n is preferably three . Z and M are as described above for Structural Formula (I) .
  • X is a covalent bond
  • Y is -CO-
  • the antagonist of chemokine receptor function is a compound represented by Structural Formula (V) :
  • X is a covalent bond
  • Y is a double bond
  • the antagonist of chemokine receptor function is a compound represented by Structural formula (VI) :
  • the antagonist of chemokine function can be represented by Structural Formulas (IVa) and (Via) .
  • Z is a tricyclic ring system comprising a five, six, seven or eight membered cycloalkyl or a non- aromatic heterocyclic ring group fused to a pyridine ring and to a carbocyclic aromatic group or a heteroaryl group.
  • Z is represented by Structural Formula (VII) :
  • the pyridine ring labeled with an "A” , and the phenyl ring labeled with a “B” are herein referred to as “Ring A” and “Ring B” respectively.
  • the central ring labeled with a “C”, is herein referred to as “Ring C” and can be, for example, a five, six, seven or eight membered non-aromatic carbocyclic ring (e.g., a cycloheptane or cyclooctane ring) or a non-aromatic heterocyclic ring.
  • Ring C is a non-aromatic heterocyclic ring, it can contain one or two heteroatoms such as nitrogen, sulfur or oxygen.
  • Z is represented by Structural Formula (VII)
  • the tricyclic ring system can be connected to Y in Structural Formula (III) by a single or double covalent bond between Y and a ring atom in Ring C .
  • Each ring can be unsubstituted or can have one or more substituents . Suitable substituents are as described herein below for substituted aromatic groups. In one example, Ring B is substituted with
  • u is zero or one.
  • t is an integer, such as an integer from zero to about three, and the methylene group -(CH 2 ) t - can be substituted, as described herein for aliphatic groups, or unsubstituted.
  • R 20 , R 21 or R 22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a substituted or unsubstituted non-aromatic heterocyclic group.
  • R 21 and R 22 taken together with the nitrogen atom to which they are bonded, form a non- aromatic heterocyclic ring.
  • Ring B is substituted with R 8 and R 9 , wherein R 8 and R 9 are independently -H, a halogen, alkoxy or alkyl, or, taken together with Ring B, form a naphthyl group
  • Ring C optionally contains one or more additional substituents as described herein below.
  • Ring C is substituted with an electron withdrawing group or is unsubstituted.
  • Ring C is substituted with a group selected from -CH 2 -NR 11 R 12 , -CH 2 -OR 11 , -CHs-NH-CO-NR ⁇ R 12 , -CH 2 -0-CO-NR"R 12 or -CH2 -NHC (O) -O-R 11 .
  • R 11 and R 12 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group. Alternatively, R 11 and R 12 , taken together with the nitrogen atom to which they are bonded, form a non- aromatic heterocyclic ring.
  • Structural Formula (VII) examples of suitable tricyclic ring systems represented by Structural Formula (VII) are provided by Structural Formulas (VIII) - (X) , (Xa) , (Xb) and (Xc) shown below:
  • Xi is a covalent bond, -S-, -CH 2 ' " CH 2 — CH 2 - , - CH 2 — S - ,
  • X x is preferably -CH 2 -CH 2 -, -CH 2 -S- or -CH 2 -0-.
  • R c is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzylic group or a substituted benzylic group.
  • R c is - (CH 2 ) s -C00R 30 , - (CH 2 ) s -C(0) -NR 31 R 32 or - (CH 2 ) S -NHC (0) -O-R 30 .
  • s is an integer from zero to about 3; and R 30 , R 31 or R 32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group.
  • R 31 and R 32 taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring.
  • W is -H, an electron withdrawing group or is selected from -C ⁇ -NR ⁇ R 12 , -CH 2 -0R 11 , -CR ⁇ -NH-CO-NR ⁇ R 12 , -CH 2 -0-CO-NR ll R 12 or -CH 2 -NHC(0) -0-R 11 .
  • R 11 and R 12 are as defined above in Structural Formula (VII) .
  • Ring B in Structural Formulas (VIII) - (X) can be unsubstituted or substituted as described in Structural Formula (VII) .
  • Ring B in Structural Formulas (VIII) - (X) is substituted para to the carbon atom in Ring B which is bonded to X : in Ring C, and the tricyclic ring system is represented by Structural Formulas (XI) - (XIII) shown below:
  • X x and W are as defined above in Structural Formulas (VIII) - (X) .
  • R 40 is a substituent as described herein for aromatic groups.
  • R ' u and t are as described herein.
  • R 40 is an aliphatic group, substituted aliphatic group, -O- (aliphatic group) or -O- (substituted aliphatic group) . More preferably R 40 is an -0-alkyl, such as -0-CH 3 , -0-C 2 H 5 , -0-C 3 H 7 or -0-C 4 H 9 .
  • the antagonist of chemokine receptor function is a compound represented by Structural Formulas (XIV) - (XVI) shown below:
  • n is as defined above in Structural Formula (II) .
  • M is as described above in Structural Formula (I) .
  • X lf W and R 40 are as described above in Structural Formulas (XI) - (XIII) .
  • XIV) -(XVI) X ⁇ is -CH 2 -0-, W is -CN, M is >C(OH)R 2 , R 40 is -0-CH 3 and n is three.
  • R 40 can be represented by - (O) u - (CH 2 ) t -C (O) -NR 21 R 22 , wherein u is one, t is zero, and R 21 and R 22 are as described herein.
  • R 21 and R 22 can each independently be -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, or R 21 and R 22 taken together with the nitrogen atom to which they are bonded form a substituted or unsubstituted nonaromatic heterocyclic ring (e.g., pyrrolidine, piperidine, morpholine) .
  • R 40 can be represented by
  • R 40 can be represented by
  • R 40 is an aliphatic group (e.g., methyl, ethyl, propyl) that is substituted with -NR 24 R 25 or -CONR 24 R 25 , wherein R 24 and R 25 are as described herein.
  • R 40 can be represented by
  • R 40 is -O-C (0) -NR 21 R 26 , wherein R 21 is as described herein, R 26 can be -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromatic heterocyclic group, -C (0) -0- (substituted or unsubstituted aliphatic group), -C (0) -0- (substituted or unsubstituted aromatic group), -S (0) 2 - (substituted or unsubstituted aromatic group), -S (0) 2 - (substituted or unsubstituted aromatic group) or R 21 and R 26 , taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring.
  • R 40 can be -S (0) 2 - R 1 R ⁇ or -N-C
  • the chemokine receptor antagonist can be represented by Structural Formula I wherein n is three, M is C(OH)R 2 , R 2 is a phenyl group or a halophenyl group (e.g., 4-chlorophenyl) and Z is represented by Structural Formula (VI) wherein X ⁇ is -CH 2 -0-.
  • R 40 can be - ⁇ -(substituted aliphatic group), such as, R 40 can be
  • R 40 is
  • the antagonist of chemokine activity can be represented by Structural Formula (XVII)
  • n, Y and X are as described in Structural Formula (I).
  • M is >NR 2 , >CR 1 R 2 , -0-CR x R 2 -0- or -CH 2 -CR 1 R 2 -0- .
  • R 1 and R 2 are as described in Structural Formula (I)
  • Z is as described herein, preferably Z is as described in Structural Formulas (XI) - (XIII) . More preferably, Z is as described in Structural Formula (XI)
  • q 1 is an integer, such as an integer from zero to about three, and q 2 is an integer from zero to about one.
  • the ring containing M can be substituted or unsubstituted.
  • the antagonist of chemokine function can be represent by, for example, Structural Formulas (XVIla) - (XVIIK) :
  • XVIIj (XVIIk) and physiologically acceptable salts thereof, wherein Z, n and M are as described in Structural Formula (XVII) , and the ring which contains M is substituted or unsubstituted.
  • the ring containing M can have one or more suitable substituents which are the same or different. Suitable substituents for the ring which contains M and other nonaromatic heterocyclic rings are as described herein.
  • the ring containing M can be substituted with a methyl, ethyl, propyl, butyl or oxo group .
  • the nitrogen atom in the ring containing M can be a tertiary nitrogen as depicted in Structural Formula (IV) , or the nitrogen atom can be quaternized with a suitable substituent, such as a C x to about C 6 or a C x to about C 3 substituted or unsubstituted aliphatic group.
  • a suitable substituent such as a C x to about C 6 or a C x to about C 3 substituted or unsubstituted aliphatic group.
  • Compounds which comprise a quaternary nitrogen atom can also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like.
  • the antagonist of chemokine function can be represented by Structural Formula (XVII) wherein the heterocyclic ring containing M is substituted with a suitable bivalent group which is bonded to two atoms that are in the ring, thereby forming a bicyclic moiety.
  • suitable bivalent groups include, for example, substituted or unsubstituted bivalent aliphatic groups, such as a C ⁇ Cg alkylene group.
  • the antagonist of chemokine receptor function can comprise a variety of bicyclic moieties.
  • the antagonist of chemokine receptor function can be represented by Structural Formula (XVIII) : (XVIII) and physiologically acceptable salts thereof.
  • M is >NR 2 , >CR X R 2 , -0-CR x R 2 -0- or -CH 2 -CR 1 R 2 -0- .
  • M is >NR 2 or >CR 1 R 2 .
  • R 1 , R 2 and n are as described in Structural Formula (I)
  • Z are as described herein.
  • Z is as described in Structural Formulas (XI) - (XIII) . More preferably, Z is as described in Structural Formula (XI) .
  • the antagonist of chemokine receptor function is represented by Structural Formula (XIX) : z-Y- (cii) n -x- NRF°R 5
  • Z is as described herein, preferably as described in Structural Formulas (XI) - (XIII) . More preferably, Z is as described in Structural Formula (XI) .
  • n is an integer, such as an integer from one to about four. Preferably, n is one, two or three. More preferably n is two. In alternative embodiments, other aliphatic or aromatic spacer groups (L) can be employed for (CH 2 ) rope.
  • R 50 and R 51 are each independently -H, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, -NR 3 R 4 , an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group or a covalent bond between the nitrogen atom an adjacent carbon atom.
  • R 3 and R 4 are independently -H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group.
  • R 3 and R 4 taken together with the atom to which they are bonded, can alternatively form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.
  • R 50 is a substituted aliphatic group, such as a substituted ⁇ to about C 12 alkyl group, and R 51 is -H or a substituted or unsubstituted aliphatic group. More preferably, R 50 is a substituted linear or. branched C 2 to about C 7 aliphatic group wherein one or more carbon atoms can be replaced by a heteroatom, such as nitrogen, oxygen or sulfur, and R 51 is -H or a linear or branched C ⁇ to about C 6 or a C to about C 3 aliphatic group wherein one or more carbon atoms can be replaced by a heteroatom.
  • R 50 and R 51 can be substituted with one or more suitable substituents, as described herein, preferably with an aromatic group (e.g., phenyl , 4-halophenyl) .
  • R 50 can be selected from the group consisting of:
  • the activity of chemokine receptor antagonists represented by Structural Formula XIX can be affected by the character of the nitrogen atom to which R 50 and R 51 are bonded. It is believed that compounds in which said nitrogen atom is basic can have potent chemokine receptor antagonist activity. It is known that the basicity of a nitrogen atom can be decreased when the nitrogen atom is bonded to a carbonyl group, sulfonyl group or a sulfinyl group. Therefore, it is preferred that neither R 50 nor R 51 comprise a carbonyl group, sulfonyl group or sulfinyl group that is directly bonded to the nitrogen atom.
  • the antagonist of chemokine receptor function is represented by Structural Formula (XX) :
  • R 2 is as described in Structural Formula (I) .
  • Z is as described in Structural Formulas (IV) - (VIII) and/or (XI) - (XVII) , (XVIIIa) or (XVIIIb) .
  • Z is as described in Structural Formula (XVIIIa) or (XVIIIb) .
  • a " is a physiologically acceptable anion.
  • a " is Cl “ or Br " .
  • chemokine receptor antagonist described herein can be prepared and administered as active compounds or as prodrugs .
  • prodrugs are analogues of pharmaceutical agents which can undergo chemical conversion by metabolic processes to become fully active.
  • a prodrug of the invention can be prepared by selecting appropriate groups for R 40
  • a prodrug can be represented by Structural Formula (XXI) :
  • R 40 is Q-substituted aliphatic group, and the aliphatic group is substituted with - (O) u - (CH 2 ) t -C (O) OR 20 , wherein Q is -C(0)0-, u is one, t is zero and R 20 is a cyclic aliphatic group.
  • R 40 can be represented by:
  • Such a prodrug can be converted to an active chemokine receptor antagonist represented by Structural Formula (XXI) , wherein R 40 is -COOH.
  • Another embodiment of the invention provides novel compounds employed in these methods .
  • physiologically acceptable salts of the compounds represented by Structural Formulas (I) through (XX) are also included in the present invention.
  • Salts of compounds containing an amine or other basic group can be obtained, for example, by reacting with a suitable organic or inorganic acid, such as hydrogen chloride, hydrogen bromide, acetic acid, citric acid, perchloric acid and the like.
  • a suitable organic or inorganic acid such as hydrogen chloride, hydrogen bromide, acetic acid, citric acid, perchloric acid and the like.
  • Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like.
  • Salts of compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base, for example, a hydroxide base.
  • Salts of acidic functional groups contain a countercation such as sodium, potassium, ammonium, calcium and the like.
  • aliphatic groups include straight chained, branched or cyclic C 1 -C 20 hydrocarbons which are completely saturated or which contain one or more units of unsaturation.
  • Preferred aliphatic groups are C x to about C 10 hydrocarbons . More preferred are C ⁇ to about C 6 or C ⁇ to about C 3 hydrocarbons .
  • One or more carbon atoms in an aliphatic group can be replaced with a heteroatom, such as nitrogen, oxygen or sulfur.
  • suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic Ci-Cso alkyl, alkenyl or alkynyl groups.
  • An aminoalkyl group is an alkyl group substituted with -NR 24 R 25 , R 24 and R 25 are as described herein.
  • the alkyl moiety comprises one to about twelve, more preferably one to about six carbon atoms.
  • the alkyl moiety of an aminoalkyl group can be unsubstituted or substituted as described herein for aliphatic groups.
  • suitable aminoalkyl groups include aminomethyl, 2-aminoethyl , 3-aminopropyl , 4-aminobutyl, dimethylaminoethyl , diethylaminomethyl , methylaminohexyl, aminoethylenyl and the like.
  • a hydrocarbyl group includes straight chain hydrocarbons which are completely saturated or which contain one or more units of unsaturation. Optionally, one or more of the carbon atoms in a hydrocarbyl group may be replaced with a heteroatom such as oxygen, nitrogen or sulfur.
  • An "alkyl group” is a saturated aliphatic group, as defined above.
  • the term “alkoxy” refers to an alkyl ether chain with an alkyl group.
  • Alkanoyl refers to alkyl substituted carbonyl;
  • aralkanoyl refers to phenyl -alkyl -CO- and
  • aroyl refers to arylcarbonyl including benzoyl , naphthoyl and the like.
  • halogen means fluoro, chloro, bromo and iodo .
  • substituted phenyl means phenyl substituted by alkyl, halogen, alkoxy, nitro, amino, acetamido, cyano and trifluoromethyl and naphthyl .
  • Aralkyl means - (CH 2 ) x -aryl, wherein x is an integer from one to four including benzyl .
  • Aromatic or aryl groups include carbocyclic aromatic groups such as phenyl, 1 -naphthyl, 2 -naphthyl, 1-anthracyl and 2-anthracyl, and heterocyclic aromatic or heteroaryl groups such as N-imidazolyl , 2-imidazolyl ,
  • Aromatic groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings. Examples include tetrahydronapthyl, 2-benzothienyl, 3 -benzothienyl, 2 -benzofuranyl , 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl , 3-quinolinyl, 2-benzothiazolyl, 2 -benzooxazolyl , 2-benzimidazolyl, 2-quinolinyl, 3-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl , 1-isoindolyl ,
  • aromatic group is a group in which one or more carbocyclic aromatic rings and/or heteroaromatic rings are fused to a cycloalkyl or non-aromatic heterocyclic ring.
  • aromatic group examples include decalin, phthalimido, benzodiazepines, benzooxazepines, benzooxazines, phenothiazines, and groups represented by the following structural formulas:
  • non-aromatic ring includes non-aromatic carbocyclic rings and non-aromatic heterocyclic rings.
  • Non-aromatic heterocyclic rings are non-aromatic carbocyclic rings which include one or more heteroatoms such as nitrogen, oxygen or sulfur in the ring.
  • the ring can be five, six, seven or eight-membered and/or fused to another ring, such as a cycloalkyl or aromatic ring.
  • non-aromatic rings include, for example, 1, 3-dioxolan-2-yl, 3-lH-benzimidazol-2-one, 3 - 1 -alkyl -benzimidazol-2 -one , 3-l-methyl-benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl , 2-tetrahyrothiophenyl , 3-tetrahyrothiophenyl , 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1 -pyrrolidinyl , 2 -pyrrolidinyl, 3 -pyrrolidinyl, 1-piperazinyl , 2-piperazinyl , 1-piperidinyl, 2-piperidinyl , 3-piperidinyl , 4-piperidinyl, 4-thiazolidinyl , diazolonyl,
  • Heterocyclic ring includes “heteroaryl group” and “non-aromatic heterocylic ring” .
  • heterocyclic rings include imidazole, benzimidazole, pyridine, pyrimidine, thiazole, benzothiazole, thienyl, benzothienyl .
  • Suitable substituents on an alkyl, aliphatic, aromatic, non-aromatic heterocyclic ring or benzyl group include, for example, an electron withdrawing group, an aliphatic group, substituted aliphatic group, azido, -OH, a halogen (-Br, -Cl, -I and -F) , -0- (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group) , -CN, -N0 2 , -COOH, -NH 2 , -NH (aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group) , -N- (aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group) , -COO (aliphatic group, substituted aliphatic, benzyl, substituted benzyl
  • R 20 , R 21 and R 22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromatic heterocyclic group, -NHC (O) -0- (aliphatic group), -NHC (0) -0- (aromatic group) or -NHC (0) -O- (non-aromatic heterocyclic group), or R 21 and R 22 , taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring.
  • R 60 is a -H, -OH, -NH 2 , an aromatic group or a substituted aromatic group.
  • t is an integer from zero to about three, and the methylene group, -(CH 2 ) t -, can be substituted, as described herein for aliphatic groups, or unsubstituted.
  • u is zero or one.
  • Q is -0-, -S-, -S(0)-, -S(0) 2 -, -0S(0) 2 -, -C(0)-,
  • R 23 is -H, an aliphatic group, a benzyl group, an aryl group or non-aromatic heterocyclic group.
  • R 24 and R 25 are independently -H, -OH, an aliphatic group, a substituted aliphatic group, a benzyl group, an aryl group, non-aromatic heterocyclic group, or R 24 and R 25 taken together with the nitrogen atom to which they are bonded can form a substituted or unsubstituted non- aromatic heterocyclic ring.
  • a substituted non-aromatic heterocyclic ring, benzyl group or aromatic group can also have an aromatic group, an aliphatic or substituted aliphatic group, as a substituent .
  • a non-aromatic ring (carbocyclic or heterocyclic) or an aromatic ring (carbocyclic aromatic or heteroaryl) is substituted with another ring, the two rings can be fused.
  • a substituted aliphatic group can also have an oxo group, epoxy group, non-aromatic heterocyclic ring, benzyl group, substituted benzyl group, aromatic group or substituted aromatic group as a substituent.
  • a substituted aliphatic, substituted aromatic, substituted non-aromatic heterocyclic ring or substituted benzyl group can have more than one substituent, which can 'be the same or different.
  • Acyl groups include substituted and unsubstituted aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl and aromatic sulfonyl.
  • the compounds disclosed herein may be obtained as different sterioisomers (e.g., diastereomers and enantiomers) .
  • the antagonist of chemokine receptor function is represented by Structural Formula (III) and Z is represented by Structural Formula (VII)
  • the carbon atom in Ring C which is bonded to Y may be in the R or S sterioconfiguration.
  • the invention includes all isomeric forms and racemic mixtures of the disclosed compounds and a method of treating a subject with both pure isomers and mixtures thereof, including racemic mixtures.
  • the desired isomer can be determined by screening for activity, employing the methods described herein.
  • the single or double bond by which a chemical group or moiety is connected to the remainder of the molecule or compound is indicated by the following symbol :
  • the corresponding symbol in Structural Formula (VIII) or (IX) indicates that the tricyclic ring system, which represent Z in Structural Formula (IV) , is connected to the alkylene group in Structural Formula (IV) by a single covalent bond between the alkylene group and the ring carbon in Ring C which is bonded to W.
  • a "subject” is preferably a bird or a mammal, such as a human, but can also be an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, fowl, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • domestic animals e.g., dogs, cats, and the like
  • farm animals e.g., cows, fowl, sheep, pigs, horses, and the like
  • laboratory animals e.g., rats, mice, guinea pigs, and the like.
  • an "effective amount" of a compound is an amount which results in the inhibition of one or more processes mediated by the binding of a chemokine to a receptor in a subject with a disease associated with aberrant leukocyte recruitment and/or activation. Examples of such processes include leukocyte migration, integrin activation, transient increases in the concentration of intracellular free calcium [Ca 2+ ] ⁇ and granule release of proinflammatory mediators.
  • an "effective amount" of a compound is a quantity sufficient to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in the prevention of or a decrease in the symptoms associated with a disease associated with aberrant leukocyte recruitment and/or activation.
  • an effective amount of the compound can range from about 0.1 mg per day to about 100 mg per day for an adult. Preferably, the dosage ranges from about 1 mg per day to about 100 mg per day.
  • An antagonist of chemokine receptor function can also be administered in combination with one or more additional therapeutic agents, e.g.
  • the compound can be administered by any suitable route, including, for example, orally in capsules, suspensions or tablets or by parenteral administration.
  • Parenteral administration can include, for example, systemic administration, such as by intramuscular, intravenous, subcutaneous, or intraperitoneal injection.
  • the compound can also be administered orally (e.g., dietary), transdermally, topically, by inhalation (e.g., intrabronchial , intranasal, oral inhalation or intranasal drops) , or rectally, depending on the disease or condition to be treated.
  • inhalation e.g., intrabronchial , intranasal, oral inhalation or intranasal drops
  • rectally depending on the disease or condition to be treated.
  • Oral or parenteral administration are preferred modes of administration.
  • the compound can be administered to the individual in conjunction with an acceptable pharmaceutical or physiological carrier as part of a pharmaceutical composition for treatment of HIV infection, inflammatory disease, or the other diseases discussed above.
  • Formulation of a compound to be administered will vary according to the route of administration selected (e.g., solution, emulsion, capsule) .
  • Suitable carriers may contain inert ingredients which do not interact with the compound. Standard formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.
  • Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg/ml benzyl alcohol), phosphate- buffered saline, Hank's solution, Ringer ' s-lactate and the like.
  • Methods for encapsulating compositions are known in the art (Baker, et al . , "Controlled Release of
  • Biological Active Agents John Wiley and Sons, 1986.
  • the activity of compounds of the present invention can be assessed using suitable assays, such as receptor binding assays and chemotaxis assays.
  • suitable assays such as receptor binding assays and chemotaxis assays.
  • small molecule antagonists of RANTES and MlP-l ⁇ binding have been identified utilizing THP-1 cells which bind RANTES and chemotax in response to RANTES and MlP-l ⁇ as a model for leukocyte chemotaxis.
  • a high through-put receptor binding assay which monitors 125 I -RANTES and 125 I-MIP-l ⁇ binding to THP-1 cell membranes, was used to identify small molecule antagonists which block binding of RANTES andMIP-l ⁇ .
  • Compounds of the present invention can also be identified by virtue of their ability to inhibit the activation steps triggered by binding of a chemokine to its receptor, such as chemotaxis, integrin activation and granule mediator release. They can also be identified by virtue of their ability to block RANTES andMIP-l mediated HL-60, T-cell, peripheral blood mononuclear cell, and eosinophil chemotactic response.
  • Figure 1 is a schematic showing the preparation of compounds represented by Structural Formulas (I) and
  • L 1 , L 2 and L 3 in Figure 1 are suitable leaving groups such as halogen; p-toluene sulfonate, mesylate, alkoxy and phenoxy.
  • the other symbols are as defined above.
  • the reduction reaction in Step 1 of Figure 1 is performed with a reducing agent such as sodium borohydride or lithium aluminum hydride (LAH) in an inert solvent such as methanol or tetrahydrofuran (THF) .
  • LAH lithium aluminum hydride
  • THF tetrahydrofuran
  • the reaction is carried out at temperatures ranging from O'C up to the reflux temperature and for 5 minutes to 72 h.
  • Compounds represented by formula II in Figure 1 can be prepared by procedures disclosed in JP 61/152673, U.S. Patent 5089496, WO 89/10369, WO 92/20681 and WO 93/02081, the entire teachings of which are incorporated herein by reference.
  • a chlorination reaction in step 2 of Figure 1 can be performed with reagents such as thionyl chloride.
  • the reaction can be carried out in an inert solvent such as methylene chloride at O'C up to the reflux temperature for 5 minutes to 72 h.
  • the hydroxy group can be also be converted to other leaving groups by methods familiar to those skilled in the art.
  • the cyanation reaction in step 3 of Figure 1 can be carried out using reagents such as copper cyanide, silver cyanide or sodium cyanide in an inert solvent such as benzene or toluene. Reaction temperatures range from O'C up to the reflux temperature for 5 minutes to 72 h.
  • Compounds represented by Formula V in Figure 1 can also be prepared by the procedures described in J. Med. Chem. 1994, 37, 804-810 and U.S. Patent 5672611, the entire teachings of which are incorporated herein by reference.
  • the alkylation reactions in steps 4 and 5 of Figure 1 can be carried out in a solvent such as acetone, methyl ethyl ketone, ethyl acetate, toluene, tetrahydrofuran (THF) or dimethylformamide (DMF) in the presence of a base such as potassium carbonate or sodium hydride and a catalyst such as an alkali metal iodide (when necessary) .
  • a solvent such as acetone, methyl ethyl ketone, ethyl acetate, toluene, tetrahydrofuran (THF) or dimethylformamide (DMF)
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • the reaction temperature can range from room temperature up to the reflux temperature and for 5 minutes to 72 h.
  • the product of the synthetic scheme shown in Figure 1 can be decyanated using a reducing agent such as lithium aluminum hydride (LAH) in an inert solvent such as ether or tetrahydrofuran (THF) at O'C up to the reflux temperature for the solvent used for 5 minutes to 72 h.
  • a reducing agent such as lithium aluminum hydride (LAH)
  • an inert solvent such as ether or tetrahydrofuran (THF)
  • Figure 2 is a schematic showing the preparation of representative compounds of Structural Formula (I) , (III) and (IV) , wherein Z is represented by Structural Formula (VIII) and wherein Ring A and/or Ring B in Z can be substituted with - (0) u - (CH 2 ) t -COOR 20 , - (O) u - (CH 2 ) t -0C (0) R 20 , - (0) u - (CH 2 ) t -C(0) -NR 21 R 22 or - (O) u - (CH 2 ) t -NHC (0) -O-R 20 .
  • the hydrolysis reaction may be carried out in a mixture of aqueous alkali metal hydroxide solution and a solvent such as methanol , ethanol, tetrahydrofuran (THF) or dioxane at room temperature up to the reflux temperature for the solvent used for 5 minutes to 72 h.
  • a solvent such as methanol , ethanol, tetrahydrofuran (THF) or dioxane
  • the acylation reaction can be carried out using dicyclohexylcarbodiimide (DCC) or (l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (DEC) in a solvent such as tetrahydrofuran (THF) , dimethylformamide (DMF) or methylene chloride in the presence of a base such as pyridine or triethylamine (when necessary) at , temperatures of 0 to 100 °C for 5 minutes to 72 h.
  • DCC dicyclohexylcarbodiimide
  • DEC l-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • methylene chloride methylene chloride
  • Figure 3 is a schematic showing the preparation of the compounds represented by Structural Formula (I) , (III) and (IV) wherein Z is represented by Structural Formula (VIII) .
  • the reduction of the cyano group to an amine in Figure 3 can be carried out using metal hydrides or by catalytic reduction processes.
  • Suitable reducing agents include lithium aluminum hydride (LAH) , diisobutyl aluminum hydride (DIBAL-H) , borane-methyl sulfide complex or sodium borohydride .
  • LAH lithium aluminum hydride
  • DIBAL-H diisobutyl aluminum hydride
  • the reduction can be carried out in an inert solvent such as ether, tetrahydrofuran (THF) , methylene chloride or methanol at -78 'C up to the reflux temperature for 5 minutes to 72 h. It is also possible to isolate the corresponding imine intermediate, which can be converted to the amine using similar reduction processes .
  • Figure 4 is a schematic showing the preparation of compounds represented by Structural Formulas (I) , (III) and (IV) , wherein Z is represented by Structural Formula (VIII), wherein W is H.
  • the reduction of the double bond in step 1 of Figure 4 can be carried out using the catalytic reduction process.
  • Suitable catalyst include palladium-carbon, platinum oxide or Ranney-nickel .
  • the reduction can be carried out in an inert solvent such as methanol, ethanol or acetic acid at temperatures of 0 to
  • step 2 of Figure 4 can be carried out using the same as those in step 5 of Figure 1.
  • Figure 5 is a schematic showing the preparation of compounds represented by Structural Formulas (I) , (III) and (IV) , wherein Z is represented by Structural Formula (VIII), wherein W is H.
  • the alkylation reaction in step 1 of Figure 5 can be carried out using the same as those in step 5 of Figure 1.
  • the reduction of the double bond in step 2 of Figure 5 can be carried out using the same as those in step 1 of Figure 4.
  • Figure 6 shows the preparation of compounds represented by Structural Formula (I) , where in Z is represented by Structural Formulas (VIII) and wherein Ring A and/or Ring B in Z is substituted with
  • the alkylation reaction can be carried out in a solvent such as acetone, methyl ethyl ketone, ethyl acetate, toluene, tetrahydrofuran (THF) or dimethylformamide (DMF) in the presence of a base such as potassium carbonate or sodium hydride and a catalyst such as an alkali metal iodide at room temperature up to the reflux temperature for the solvent used for 5 minutes to 72 h.
  • a base such as potassium carbonate or sodium hydride
  • a catalyst such as an alkali metal iodide
  • L4 is a suitable leaving group such as halogen or trifluoromethylsulfonate.
  • a palladium coupling reaction such as Stille coupling, Suzuki coupling, Heck reaction, or carboxylation using carbon monoxide
  • a palladium catalyst such as tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium chloride, and palladium acetate in a solvent such as tetrahydrofuran (THF) , 1,4-dioxane, toluene, dimethylformamide (DMF), or dimethylsufoxide (DMSO) in the presence of additive (when necessary) such as triphenylphosphine,
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • DMSO dimethylsufoxide
  • 1,1' -bis (diphenylphosphino) ferrocene 1,1' -bis (diphenylphosphino) ferrocene, triethylamine, sodium bicarbonate, tetraethylammonium chloride, or lithium chloride at room temperature up to the reflux temperature for the solvent used for 5 minutes to 72 h.
  • Figure 8A shows the preparation of N-benzyl-4- (4- chlorophenyl) -4-hydroxypiperidine .
  • the mixture of 3 and 4 (3.5 g, mixture, ⁇ 35% yield) was purified via silica gel flash chromatography, eluting with 2% Me0H/CH 2 Cl 2 . This mixture proved to be inseparable by silica gel flash chromatography. In order to separate out the desired product, the mixture of 3 and 4 were subjected to osmium tetroxide oxidation.
  • FIG. 8B shows the preparation of 4-azido-4- ( 4- chlorophenyl) piperidine .
  • 1 3.0 g, 14 mmol
  • anhydrous dioxane 15 mL
  • NaN 3 1.0 g, 15.4 mmol
  • BF 3 »OEt 4.4 mL, 35 mmol
  • Figures 9A shows the preparation of compounds represent by Structural Formula (I) wherein R 1 is an amine.
  • the azido functionality can be reduced with a variety of reducing agents such as triphenylphosphine, lithium aluminum hydride, sodium borohydride, in a solvent such as tetrahydrofuran or diethyl ether in reaction temperature ranges from 0°C to reflux with a reaction time of between 5 minutes and 72 hours.
  • Figure 9B shows the preparation of compounds represent by Structural Formula (I) wherein R 1 is -CH 2 NH 2 .
  • Figure 9C shows the preparation of 2- (4- chlorophenyl) -1- (N-methyl ) ethylamine.
  • Step 1 To a solution of A1C1 3 (1.96 g, 14.7 mmol) in anhydrous CH 2 C1 2 (50 mL) , Borane- tert-butyl amine complex (2.57 g, 29.6 mmol) was added at 0°C under argon protection, stirred for 10 minutes and clear solution was formed. 4-Chlorophenacyl bromide (1, 1.11 g, 4.91 mmol) in CH 2 C1 2 (5 mL) was added to the resulted mixture at 0°C .
  • Figure 9D shows the preparation of 3- (4- chlorophenyl) -3-hydroxyl-3-methyl-l-N-methylaminopropane Step 1
  • Figure 10A shows the preparation of 3- (4- chlorophenyl ) -3-hydroxyl-3-methyl-l-N-methylaminopropane .
  • Figure 10b shows the preparation of l-(4- c lorobenzoyl) -1, 2-ethylenediamine Step 1 tert-Butyl N- (2-aminoethyl) carbamate (1, 0.50 g g, 3.12 mmol) was added to the mixture of 4-chlorobenzoic acid chloride (0.547 g, 3.12 mmol) and Et 3 ⁇ (1.74 mL, 12.5 mmol) in CH 2 C1 2 (20 mL) under the protection of argon. Stirring at room temperature for 2 hours.
  • Trifluoroacetic acid (7.5 mL) was added to the solution of tert-Butyl 3- (4-chlorobenzoyl) -1- (2- aminoethyl) carbamate (2, 0.86 g, 2.89 mmol) in CH 2 C1 2 (35 mL) at 0°C. Stirring at room temperature for 30 minutes. Concentration in vacuo provided 0.88 g (95%) of the desired product 1- (4-chlorobenzoyl) -1, 2-ethylenediamine (3) . MS m/z: (M+ 199) .
  • FIG. 10C shows three procedures for the preparation of compounds represented by Structural Formulas (I), (VII), (VIII) and (IX), wherein Z is represented by Structural Formula (III) and wherein Ring A or Ring B in Z is substituted with R 40 -
  • R 40 is represented by
  • a compound containing a phenol can be reacted with a carbonate equivalent, such as a carbamoyl chloride (method A) , an isocyanate (method B) or an acylimidazole (method C) , in the presence of a base such as sodium hydroxide, potassium carbonate or sodium carbonate in a solvent such as dimethylformamide or tetrahydrofuran, at a temperature from 0°C to reflux temperature for a period of about 5 minutes to about 72 hours.
  • a carbonate equivalent such as a carbamoyl chloride (method A) , an isocyanate (method B) or an acylimidazole (method C)
  • a base such as sodium hydroxide, potassium carbonate or sodium carbonate
  • a solvent such as dimethylformamide or tetrahydrofuran
  • FIG 12 shows the preparation of compounds represented by Compound (XV-b) .
  • a Grignard reaction can be carried out in a solvent such as ether, or tetrahydrofuran (THF) at 0°C up to the reflux temperature for the solvent used for 5 minuets to 72 h.
  • Compound XIII is available commercially.
  • bromination can be carried out with brominate agents such as hydrobromic acid, bromotrimethylsil ' ane or boron tribromide-methyl sulfide complex in a solvent such as acetic acid, dichloromethane or dichloroethane at room temperature up to the reflux temperature for the solvent used for 5 minutes to 72 h.
  • Figure 13 shows the preparation of compounds of formula (XV-c) .
  • the Friedel-Crafts acylation can be carried out using an acid chloride in the presence of a Lewis acid, such as aluminum trichloride or titanium tetrachloride, in a solvent such as dichloromethane, dichloroethane, nitrobenzene or carbon disulfide.
  • the acylation reaction can be run at a temperature of about room temperature up to the reflux temperature of the chosen solvent, and for a period of about 5 minutes to about 72 hours.
  • FIG 14 shows the preparation of compounds of formula (XV-e) .
  • a chlorosulfonylation can be carried out using chlorosulfonic acid in a solvent, such as dichloromethane, or in the absence of a solvent at a temperature of about 0°C to about 60 °C for a period of about 5 minutes to about 72 hours.
  • a coupling reaction can be carried out using an amine in the presence of a base, such as triethylamine, in a solvent such as dichloromethane, acetone, ethanol, THF or DMF. The reaction can be carried out at a temperature of about room temperature up to the reflux temperature of the selected solvent, and for a period of about 5 minutes to about 72 hours.
  • Figures 1-7 show the preparation of compounds in which B is a phenyl ring and Figures 12-14 show the preparation of compounds in which Rings A and B are both phenyl rings
  • analogous compounds with heteroaryl groups for Ring A and/or Ring B can be prepared by using the starting materials with heteroaryl groups in the corresponding positions, which can be prepared according to methods disclosed in JP 61/152673, U.S. Patent 5089496, WO 89/10369, WO 92/20681 and WO 93/02081.
  • Step 2 To a solution of the product of step 1 (4.3g) in acetic acid (30ml) was added 48% aqueous HBr (25ml) at 10°C. The reaction mixture was warmed to room temperature, and stirred for 12 hours. Water and ethyl acetate were added to the reaction mixture and neutralized with dilute NaOH solution. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure.
  • step 2 To a solution of the product of step 2 (160mg) in ethanol (3ml) and acetic acid (1ml) were added 10% Pd-C (79mg) was stirred under hydrogen (under a balloon) at room temperature for 24 hour. The mixture was filtered through the celite and distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography eluting with ethyl acetate-hexane (1:2) to give 5- (3-bromopropyl) -5, ll-dihydro-7- methoxypyrido [2 , 3-c] [1] benzoxepine (48mg) .
  • Step 4 To a solution the product of step 3 (45mg) in DMF (lml) were added 4- (4-chlorophenyl) -4-hydroxypiperidine (54mg) and potassium carbonate (19mg) and the mixture was stirred at 50°C for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-methanol (10:1) to give the titled compound (19mg) .
  • Examples 2 - 157 which can be represented by Structural Formulas (XIV) and (XVI) and are presented in Table 1 and Table la, can be prepared by methods set forth in the schemes in Figure 1-5 and the procedures described above.
  • Membranes are prepared from THP-1 cells (ATCC #TIB202) . Cells are harvested by centrifugation, washed twice with PBS (phosphate-buffered saline) , and the cell pellets are frozen at -70 to -85°C.
  • PBS phosphate-buffered saline
  • the frozen pellet is thawed in ice-cold lysis buffer consisting of 5 mM HEPES (N-2- hydroxyethylpiperazine-N' -2-ethane-sulfonic acid) pH 7.5, 2 mM EDTA (ethylenediaminetetraacetic acid) , 5 ⁇ g/ml each aprotinin, leupeptin, and chymostatin (protease inhibitors) , and 100 ⁇ g/ml PMSF (phenyl methane sulfonyl fluoride - also a protease inhibitor) , at a concentration of 1 to 5 x 10 7 cells/ml. This procedure results in cell lysis.
  • HEPES N-2- hydroxyethylpiperazine-N' -2-ethane-sulfonic acid
  • 2 mM EDTA ethylenediaminetetraacetic acid
  • PMSF phenyl methane sulfonyl fluor
  • the suspension is mixed well to resuspend all of the frozen cell pellet. Nuclei and cell debris are removed by centrifugation of 400 x g for 10 minutes at 4°C. The supernatant is transferred to a fresh tube and the membrane fragments are collected by centrifugation at 25,000 x g for 30 minutes at 4°C. The supernatant is aspirated and the pellet is resuspended in freezing buffer consisting of 10 mM HEPES pH 7.5, 300 mM sucrose, l ⁇ g/ml each aprotinin, leupeptin, and chymostatin, and 10 ⁇ g/ml PMSF (approximately 0.1 ml per each 10 8 cells).
  • Binding Assays utilize the membranes described above.
  • Membrane protein (2 to 20 ⁇ g total membrane protein) is incubated with 0.1 to 0.2 nM 125 I-labeled RANTES or MlP-l ⁇ with or without unlabeled competitor (RANTES or MlP-l ⁇ ) or various concentrations of compounds.
  • the binding reactions are performed in 60 to 100 ⁇ l of a binding buffer consisting of 10 mM HEPES pH 7.2 , 1 mM CaCl 2 , 5 mM MgCl 2 , and 0.5% BSA (bovine serum albumin), for 60 min at room temperature.
  • the binding reactions are terminated by harvesting the membranes by rapid filtration through glass fiber filters (GF/B or GF/C, Packard) which are presoaked in 0.3% polyethyleneimine .
  • GF/B or GF/C, Packard glass fiber filters
  • the filters are rinsed with approximately 600 ⁇ l of binding buffer containing 0.5 M NaCl , dried, and the amount of bound radioactivity is determined by scintillation counting in a Topcount beta-plate counter.
  • the activities of test compounds can be reported as IC 50 values or the inhibitor concentration required for 50% inhibition of specific binding in receptor binding assays using 125 I -RANTES or 125 MIP-l ⁇ as ligand and THP-1 cell membranes.
  • Specific binding can be defined as the total binding minus the non-specific binding; nonspecific binding can be the amount of cpm still detected in the presence of excess unlabeled RANTES or 125 MIP-l ⁇ .
  • the title compound was prepared by following the procedure of Example 268, but replacing the solvent with N-methyl pyrrolidone/methanol .

Abstract

L'invention concerne un procédé pour traiter un sujet souffrant d'une maladie associée à la capture et/ou l'activation de leucocytes aberrants. Ce procédé consiste à administrer au sujet une quantité thérapeutiquement efficace d'un composé représenté par: (I) ou Z-Y-(CH2)n -X-NR50R5 et de sels physiologiquement acceptables de ce dernier.
PCT/US2000/020775 1999-07-28 2000-07-28 Antagonistes de recepteur de chemokine et procedes d'utilisation WO2001009137A1 (fr)

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WO2002051809A1 (fr) * 2000-12-22 2002-07-04 Schering Corporation Antagonistes piperidiniques de mch et leur utilisation dans le traitement de l'obesite
JP2006508966A (ja) * 2002-11-13 2006-03-16 ミレニアム・ファーマシューティカルズ・インコーポレイテッド Ｉ．ａ．脱髄炎症疾患の処置のためのｃｃｒ１アンタゴニスト
US7271176B2 (en) * 1998-09-04 2007-09-18 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use thereof
SG165152A1 (en) * 2001-11-21 2010-10-28 Millennium Pharm Inc Chemokine receptor antagonists and methods of use thereof
US7960549B2 (en) 2004-12-17 2011-06-14 Carole Neves Solid forms of a chemokine receptor antagonist and methods of use thereof
US20130045165A1 (en) * 2010-04-30 2013-02-21 Kinentia Biosciences, Llc 4-fluoro-4-arylpiperdin-1-yl derivatives as mu opioid function moderators
US9593113B2 (en) 2013-08-22 2017-03-14 Bristol-Myers Squibb Company Imide and acylurea derivatives as modulators of the glucocorticoid receptor
US9663537B2 (en) 2001-11-21 2017-05-30 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use
US9796720B2 (en) 2013-08-22 2017-10-24 Bristol-Myers Squibb Company Imidazole-derived modulators of the glucocorticoid receptor

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US7271176B2 (en) * 1998-09-04 2007-09-18 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use thereof
US6472394B1 (en) 2000-12-22 2002-10-29 Schering Corporation MCH antagonists and their use in the treatment of obesity
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JP2013209393A (ja) * 2001-11-21 2013-10-10 Millennium Pharmaceuticals Inc ケモカイン受容体アンタゴニストおよびその使用方法
US9663537B2 (en) 2001-11-21 2017-05-30 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use
SG165152A1 (en) * 2001-11-21 2010-10-28 Millennium Pharm Inc Chemokine receptor antagonists and methods of use thereof
JP2016138122A (ja) * 2001-11-21 2016-08-04 ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． ケモカイン受容体アンタゴニストおよびその使用方法
JP2015083577A (ja) * 2001-11-21 2015-04-30 ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． ケモカイン受容体アンタゴニストおよびその使用方法
US9334283B2 (en) 2002-11-13 2016-05-10 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use thereof
JP4644491B2 (ja) * 2002-11-13 2011-03-02 ミレニアム・ファーマシューティカルズ・インコーポレイテッド Ｉ．ａ．脱髄炎症疾患の処置のためのｃｃｒ１アンタゴニスト
JP2006508966A (ja) * 2002-11-13 2006-03-16 ミレニアム・ファーマシューティカルズ・インコーポレイテッド Ｉ．ａ．脱髄炎症疾患の処置のためのｃｃｒ１アンタゴニスト
US8481737B2 (en) 2004-12-17 2013-07-09 Millennium Pharmaceuticals, Inc. Solid forms of a chemokine receptor antagonist and methods of use thereof
US7960549B2 (en) 2004-12-17 2011-06-14 Carole Neves Solid forms of a chemokine receptor antagonist and methods of use thereof
US8859777B2 (en) * 2010-04-30 2014-10-14 Kinentia Biosciences Llc 4-fluoro-4-arylpiperdin-1-yl derivatives as mu opioid function moderators
US20130045165A1 (en) * 2010-04-30 2013-02-21 Kinentia Biosciences, Llc 4-fluoro-4-arylpiperdin-1-yl derivatives as mu opioid function moderators
US9593113B2 (en) 2013-08-22 2017-03-14 Bristol-Myers Squibb Company Imide and acylurea derivatives as modulators of the glucocorticoid receptor
US9796720B2 (en) 2013-08-22 2017-10-24 Bristol-Myers Squibb Company Imidazole-derived modulators of the glucocorticoid receptor

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