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WO1998031364A1 - 3,3-disubstituted piperidines as modulators of chemokine receptor activity - Google Patents

3,3-disubstituted piperidines as modulators of chemokine receptor activity Download PDF

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Publication number
WO1998031364A1
WO1998031364A1 PCT/US1998/001101 US9801101W WO9831364A1 WO 1998031364 A1 WO1998031364 A1 WO 1998031364A1 US 9801101 W US9801101 W US 9801101W WO 9831364 A1 WO9831364 A1 WO 9831364A1
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ring
phenyl
4alkyl
substituted
group
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PCT/US1998/001101
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French (fr)
Inventor
Malcolm Maccoss
Sander G. Mills
Timothy Harrison
Christopher John Swain
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Merck & Co., Inc.
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Publication date
Priority claimed from GBGB9707490.0A external-priority patent/GB9707490D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to EP98905975A priority Critical patent/EP1003743A4/en
Priority to CA002278309A priority patent/CA2278309A1/en
Priority to JP53466298A priority patent/JP2001508798A/en
Priority to AU61330/98A priority patent/AU6133098A/en
Publication of WO1998031364A1 publication Critical patent/WO1998031364A1/en

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/10—Spiro-condensed systems

Definitions

  • Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, Cvtokine. 3, 165-183 (1991) and Murphy, Rev. Immun.. 12, 593-633 (1994)).
  • the -chemokines such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils, whereas ⁇ -chemokines, such as RANTES, MlP-l ⁇ , MIP- l ⁇ , monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al., Nature. 381.661-666 (1996)).
  • IL-8 interleukin-8
  • NAP-2 neutrophil-activating protein-2
  • MGSA melanoma growth stimulatory activity protein
  • ⁇ -chemokines such as RANTES, MlP-l ⁇ , MIP- l ⁇ , monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are
  • chemokines bind specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane- domain proteins (reviewed in Horuk, Trends Pharm. Sci.. 15, 159-165 (1994)) which are termed "chemokine receptors.” On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration.
  • CCR-1 or "CKR-1" or "CC-CKR-1”
  • MlP-l ⁇ , MlP-l ⁇ , MCP-3, RANTES a human chemokine receptor that bind or respond to ⁇ -chemokines with the following characteristic pattern: CCR-1 (or "CKR-1" or "CC-CKR-1") [MlP-l ⁇ , MlP-l ⁇ , MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem.. 270. 22123-22128 (1995); Beote, et al, Cell.
  • CCR- 2A and CCR-2B (or "CKR-2A7"CKR-2A” or “CC-CKR-2A7”CC-CKR- 2A") [MCP-1, MCP-3, MCP-4]; CCR-3 (or “CKR-3” or "CC-CKR-3") [eotaxin, RANTES, MCP-3] (Combadiere, et al., J. Biol. Chem.. 270. 16491-16494 (1995); CCR-4 (or "CKR-4" or "CC-CKR-4") [MlP-l ⁇ , RANTES, MCP-1] (Power, et al., J. Biol. Chem.. 270.
  • ⁇ -chemokines include eotaxin, MIP ("macrophage inflammatory protein”), MCP ("monocyte chemoattractant protein”) and RANTES ("regulation-upon-activation, normal T expressed and secreted").
  • Chemokine receptors such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR-4, have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
  • the chemokine receptor CCR-3 plays a pivotal role in attracting eosinophils to sites of allergic inflammation. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases.
  • HIV-1 human immunodeficiency virus
  • AIDS acute immune deficiency syndrome
  • Certain compounds have been demonstrated to inhibit the replication of HIV, including soluble CD4 protein and synthetic derivatives (Smith, et al., Science. 238. 1704-1707 (1987)), dextran sulfate, the dyes Direct Yellow 50, Evans Blue, and certain azo dyes (U.S. Patent No. 5,468,469). Some of these antiviral agents have been shown to act by blocking the binding of gpl20, the coat protein of HTV, to its target, the CD4 gyycoprotein of the cell.
  • the principal cofactor for entry mediated by the envelope glycoproteins of primary macrophage-trophic strains of HrV-1 is CCR5, a receptor for the ⁇ - chemokines RANTES, MlP-l ⁇ and MlP-l ⁇ (Deng, et al., Nature. 381. 661-666 (1996)).
  • HIN attaches to the CD4 molecule on cells through a region of its envelope protein, gpl20. It is believed that the CD-4 binding site on the gpl20 of HIV interacts with the CD4 molecule on the cell surface, and undergoes conformational changes which allow it to bind to another cell-surface receptor, such as CCR5 and/or CXCR-4.
  • chemokine receptors may be used by some strains of HIN- 1 or may be favored by non-sexual routes of transmission. Although most HlN-l isolates studied to date utilize CCR-5 or fusin, some can use both as well as the related CCR-2B and CCR-3 as co-receptors (Nature Medicine. 2(11), 1240-1243 (1996)). Nevertheless, drugs targeting chemokine receptors may not be unduly compromised by the genetic diversity of HlN-l (Zhang, et al., Nature. 383. 768 (1996)).
  • the ⁇ -chemokine macrophage-derived chemokine has been shown to inhibit H-N-l infection (Pal, et al., Science. 278 (5338), 695-698 (1997).
  • the chemokines RANTES, MlP-l ⁇ , MlP-l ⁇ , vMIP-I, vMIP-II, SDF-1 have also been shown to suppress HIN.
  • a derivative of RANTES, (AOP)-RANTES is a subnanomolar antagonist of CCR-5 function in monocytes (Simmons, et al., Science. 276.276-279 (1997)).
  • Monoclonal antibodies to CCR-5 have been reported to block infection of cells by ⁇ LTV in vitro.
  • an agent which could block chemokine receptors in humans who possess normal chemokine receptors should prevent infection in healthy individuals and slow or halt viral progression in infected patients (see Science. 275. 1261-1264 (1997)).
  • better therapies towards all subtypes of HIN may be provided.
  • peptides eotaxin, RANTES, MlP-l ⁇ , MlP-l ⁇ , MCP-1, and MCP-3 are known to bind to chemokine receptors.
  • the inhibitors of HlN-l replication present in supernatants of CD8+ T cells have been characterized as the ⁇ -chemokines RANTES, MlP-l ⁇ and MlP-l ⁇ .
  • U.S. Patent Nos. 5,340,822., 5,350,852, 5,434,158, 5,559,132, 5,589,489, and 5,635,510 and PCT Patent Publication WO 95/05377 disclose certain compounds as tachykinin antagonists.
  • EP 0 512 901 published Nov.
  • the present invention is directed to compounds which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
  • the invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which chemokine receptors are involved.
  • the present invention is further concerned with compounds which inhibit the entry of human immunodeficiency virus (HIN) into target cells and are of value in the prevention of infection by HIN, the treatment of infection by HIN and the prevention and/or treatment of the resulting acquired immune deficiency syndrome (AIDS).
  • HIN human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • the present invention also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the prevention and treatment of AIDS and viral infection by HIV.
  • the present invention is directed to a compound of formula I:
  • Ar is selected from the group consisting of: unsubstituted phenyl; phenyl which is substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, trifluoromethyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3_7cycloalkyl, C3-7cycloalkylCi-4alkyl, and Ci-6alkoxy; thienyl; benzothienyl; naphthyl; unsubstituted indolyl; and indolyl which is substituted on the nitrogen atom by a C ⁇ _ 4alkyl group;
  • R is selected from the group consisting of: unsubstituted phenyl; and phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, trifluoromethyl, C ⁇ _6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3- 7cycloalkylCi-4alkyl, and Ci-6alkoxy;
  • R is selected from the group consisting of: hydrogen; Cl-6alkyl; Ci-6alkyl substituted by 1 or 2 substituents selected from: hydroxy, -OR 3 , oxo, -NHCOR 3 , -NR 3 R 4 , cyano, halogen, trifluoromethyl, unsubstituted phenyl, and phenyl substituted by 1 or 2 substituents selected from: hydroxy, cyano, halogen and trifluoromethyl; unsubstituted phenyl; phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, -C(O)NR 3 R 4 , -NR 3 R 4 , -NR 3 COR 4 , halogen, trifluoromethyl, C ⁇ -4alkyl, -S(O)pCl-4alkyl and -C(O)R 3 ; unsubstituted aryl; aryl substituted by 1, 2 or 3 substituents selected from
  • R 1 and R 2 are joined together to form a 5- or 6-membered non- aromatic ring which may contain in the ring 1 or 2 groups of the formula -NR -, which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, a phenyl group, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR 3 R 4 , -NR 3 R 4 , -NR 3 COR 4 , halogen, trifluoromethyl, Ci-4alkyl, -S(O) p Cl_4alkyl, and -C(O)R 3 ;
  • R 3 and R 4 are each independently selected from: hydrogen; unsubstituted Ci-6alkyl;
  • R 5 is selected from hhyyddrroosgen, Cl- alkyl, -S(O) 2 Ci-4alkyl, -C(O)R 3 , unsubstituted phenyl and benzyl;
  • R is selected from: hydrogen or Ci-4alkyl; and p is zero, 1 or 2; or a pharmaceutically acceptable salt thereof.
  • halogen means fluorine, chlorine, bromine and iodine.
  • the preferred halogen are fluorine and chlorine of which fluorine is most preferred.
  • alkyl or alkoxy as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i- propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t- butoxy.
  • alkenyl as a group or part of a group means that the group is straight or branched and contains at least one double bond.
  • suitable alkenyl groups include vinyl and allyl.
  • alkynyl as a group or part of a group means that the group is straight or branched and contains at least one triple bond.
  • An example of a suitable alkynyl group is propargyl.
  • Suitable cycloalkyl and cycloalkyl-alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl and cyclobutylmethyl.
  • heteroaryl represents a heteroaromatic ring including furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidyl, benzofuranyl, benzthienyl, indolyl, benzimidazolyl, benzoxazolyl and quinolyl.
  • group NR R forms a saturated heterocylic ring of 4 to 7 ring atoms which may optionally contain in the ring one oxygen
  • heterocylic groups include azetidinyl, pyrrolidino, piperidino, homopiperidino, piperazino, N-methylpiperazino, morpholino and thiomorpholino.
  • Suitable substituents on the saturated heterocyclic ring include -CH2OH, -CH2OCH3, oxo, -CHO, -CO2H, -CO2CH3, and -CO2CH2CH3.
  • Preferred compounds of the present invention include those compounds of formula I, with the exception of:
  • a preferred class of compounds of formula I for use in the present invention is that wherein the sum of m + n is 3.
  • m is preferably 2.
  • n is preferably 1.
  • a preferred group of compounds for use in the present invention is wherein X is:
  • Ar preferably represents unsubstituted phenyl or phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, triflourom ethyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3. 7cycloalkyl, C3-7cycloalkylC ⁇ _4alkyl, and C ⁇ -6alkoxy.
  • Preferred substituents are halogen atoms, most especially chlorine atoms.
  • Ar represents phenyl substituted by two substituents.
  • Ar represents a 3,4-disubstituted phenyl ring.
  • R preferably represents unsubstituted phenyl or phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, trifluoromethyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 7cycloalkyl, C3-7cycloalkylCi-4alkyl, and Ci-6alkoxy.
  • Preferred substituents are halogen atoms, most especially chlorine atoms.
  • R represents an unsubstituted phenyl ring.
  • R preferably represents an unsubstituted phenyl group or a saturated heterocyclic ring of 5 ring atoms which ring contains 1 or 2 nitrogen atoms, one of which is at the point of attachment to the remainder of the molecule, which ring is substituted on any available nitrogen atom by a group R 5 , preferably where R 5 is hydrogen, and which ring is preferably substituted by an oxo group, and which ring has fused thereto a phenyl ring, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR 3 R 4 , -NR 3 R 4 , -NR 3 COR 4 , halogen, trifluoromethyl, Ci-4alkyl, -S(O) p Ci-4alkyl, and -C(O)R 3 .
  • the phenyl ring is unsubstituted.
  • R 2 preferably represents hydrogen or -COR 3 , where R 3 represents Cl-6alkyl, in particular Ci-3alkyl, especially methyl.
  • a further preferred class of compound of formula I for use in the present invention is that wherein R 1 and R 2 are joined together to form a 5-membered non-aromatic ring which may contain in the ring 1 or 2 groups of the formula NR 5 , which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, a phenyl group, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR R , -NR R , -
  • the phenyl ring, where present, is unsubstituted.
  • R and R each independently preferably represent hydrogen or Ci-6alkyl.
  • R preferably represents hydrogen, Ci-4alkyl, -S(O)2Ci-
  • R is preferably hydrogen, -S(O)2CH3 or phenyl.
  • R , R , R and R are selected from: hydrogen and halogen
  • R is an unsubstituted phenyl group or a saturated heterocyclic ring of 5 ring atoms which ring contains 1 or 2 nitrogen atoms, one of which is at the point of attachment to the remainder of the molecule, which ring is substituted on any available nitrogen atom by a group R , and which ring may be substituted by an oxo group, and which ring has fused thereto a phenyl ring, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR 3 R 4 , -NR 3 R 4 , -NR 3 COR 4 , halogen, trifluoromethyl, Ci-4alkyl, -S(0) p Ci_ 4alkyl, and -C(O)R 3 ;
  • R 15 is -COR 3 , where R 3 is Ci- ⁇ alkyl; or R and R are joined together to form a 5-membered non-aromatic ring which may contain in the ring 1 or 2
  • a preferred class of compound of formula (la) for use in the present invention is that wherein:
  • R and R each are chlorine
  • R 12 and R 13 each are hydrogen; R is unsubstituted phenyl;
  • R 15 is -COCH3; or R and R are joined together to form a 5-membered non-aromatic ring which may contain in the ring 1 or
  • Particularly preferred compounds of formula I for use in the present invention are those wherein: m is 2, n is 1 and X is:
  • each phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR 3 R 4 , -NR 3 R 4 , -NR 3 COR 4 , halogen, trifluoromethyl, C ⁇ _4alkyl, -S(0) p Ci-4alkyl and -C(O)R 3 , where R , R and p are as previously defined above.
  • Exemplifying the present invention is the use of a compound selected from the group consisting of: 5-[3- ⁇ 4,4-CN-sulfonamidomethyl-3,3- indolyl)piperidino ⁇ propyl]-5-[3,4-diphenyl]-l-benzylpiperidin-2-one;
  • the salts of the compounds of formula I will be non-toxic pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts such as those formed with hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.
  • suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
  • the pharmaceutically acceptable salts of the present invention may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
  • the present invention includes within its scope solvates of the compounds of formula I and salts thereof, for example, hydrates.
  • the compounds according to the invention may have one or more asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
  • the subject compounds are useful in a method of modulating chemokine receptor activity in a patient in need of such modulation comprising the administration of an effective amount of the compound.
  • Exemplifying the invention is the use of the compounds disclosed in the Examples and elsewhere herein.
  • the present invention is directed to the use of the foregoing compounds as modulators of chemokine receptor activity.
  • these compounds are useful as modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and/or CXCR-4.
  • the present invention is further directed to the use of compounds of this general structure which are disclosed as being antagonists of neurokinin receptors.
  • Such compounds are disclosed, for example, in: U.S. Patent No. 5,317,020; U.S. Patent No. 5,340,822; U.S. Patent No. 5,350,852; U.S. Patent No. 5,411,971; U.S. Patent No. 5,434,158; U.S. Patent No. 5,446,052; U.S. Patent No. 5,534,525; U.S. Patent No. 5,559,132; U.S. Patent No. 5,560,700; U.S. Patent No. 5,589,489; U.S. Patent No. 5,635,510; EP 0 512 901, Nov.
  • the present invention embraces the use of a compound disclosed in these publications as a modulator of chemokine receptor activity.
  • the utility of the compounds in accordance with the present invention as modulators of chemokine receptor activity may be demonstrated by methodology known in the art, such as the assay for CCR-1 and/or CCR-5 binding as disclosed by Van Riper, et al., J. Exp. Med.. 177, 851-856 (1993), and the assay for CCR-2 and/or CCR-3 binding as disclosed by Daugherty, et al., J. Exp. Med.. 183. 2349-2354 (1996).
  • Cell lines for expressing the receptor of interest include those naturally expressing the receptor, such as EOL-3 or THP-1, or a cell engineered to express a recombinant receptor, such as CHO, RBL-2H3, HEK-293.
  • a CCR3 transfected AML14.3D10 cell line has been placed on restricted deposit with American Type Culture Collection in Rockville, Maryland as ATCC No. CRL-12079, on April 5, 1996.
  • the utility of the compounds in accordance with the present invention as inhibitors of the spread of HIN infection in cells may be demonstrated by methodology known in the art, such as the HIN quantitation assay disclosed by ⁇ unberg, et al., J. Virology. 65 (9), 4887-4892 (1991).
  • the compounds of the following examples had activity in binding to either the CCR-5 receptor or the CCR-3 receptor in the aforementioned assays. Such a result is indicative of the intrinsic activity of the compounds in use as modulators of chemokine receptor activity.
  • Mammalian chemokine receptors provide a target for interfering with or promoting eosinophil and/or lymphocyte function in a mammal, such as a human.
  • Compounds which inhibit or promote chemokine receptor function are particularly useful for modulating eosinophil and/or lymphocyte function for therapeutic purposes. Accordingly, the present invention is directed to compounds which are useful in the prevention and/or treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
  • an instant compound which inhibits one or more functions of a mammalian chemokine receptor may be administered to inhibit (i.e., reduce or prevent) inflammation.
  • a mammalian chemokine receptor e.g., a human chemokine receptor
  • one or more inflammatory processes such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, is inhibited.
  • eosinophilic infiltration to inflammatory sites e.g., in asthma
  • inflammatory sites e.g., in asthma
  • an instant compound which promotes one or more functions of a mammalian chemokine receptor is administered to stimulate (induce or enhance) an inflammatory response, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, resulting in the beneficial stimulation of inflammatory processes.
  • a mammalian chemokine receptor e.g., a human chemokine
  • an inflammatory response such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, resulting in the beneficial stimulation of inflammatory processes.
  • eosinophils can be recruited to combat parasitic infections.
  • mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated.
  • the method can also be practiced in other species, such as avian species (e.g., chickens).
  • the disease or condition is one in which the actions of eosinophils and/or lymphocytes are to be inhibited or promoted, in order to modulate the inflammatory response.
  • Diseases or conditions of humans or other species which can be treated with inhibitors of chemokine receptor function include, but are not limited to: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), delayed-type hypersentitivity, interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies; autoimmune diseases, such as rheumatoid arthritis
  • Other diseases or conditions in which undesirable inflammatory responses are to be inhibited can be treated, including, but not limited to, reperfusion injury, atherosclerosis, certain hematologic malignancies, cytokine-induced toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis.
  • Immunosuppression such as that in individuals with immunodeficiency syndromes such as AIDS, individuals undergoing radiation therapy, chemotherapy, therapy for autoimmune disease or other drug therapy (e.g., corticosteroid therapy), which causes immunosuppression; immunosuppression due congenital deficiency in receptor function or other causes; and infectious diseases, such as parasitic diseases, including, but not limited to helminth infections, such as nematodes (round worms); (Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, f ⁇ lariasis); trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tape worms) (Echinococcosis, Taeniasis saginata, Cysticercosis);
  • helminth infections such as nematodes (round worms); (Trichuriasis, Enterobias
  • the compounds of the present invention are accordingly useful in the prevention and treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases.
  • the instant invention may be used to evaluate putative specific agonists or antagonists of chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and CXCR-4.
  • the present invention is directed to the use of these compounds in the preparation and execution of screening assays for compounds which modulate the activity of chemokine receptors.
  • the compounds of this invention are useful for isolating receptor mutants, which are excellent screening tools for more potent compounds.
  • the compounds of this invention are useful in establishing or determining the binding site of other compounds to chemokine receptors, e.g., by competitive inhibition.
  • the compounds of the instant invention are also useful for the evaluation of putative specific modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and CXCR-4.
  • putative specific modulators of the chemokine receptors including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and CXCR-4.
  • the present invention is further directed to a method for the manufacture of a medicament for modulating chemokine receptor activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
  • the present invention is further directed to the use of these compounds in the prevention or treatment of infection by a retrovirus, in particular, the human immunodeficiency virus (HIV) and the treatment of, and delaying of the onset of consequent pathological conditions such as AIDS.
  • Treating AIDS or preventing or treating infection by HIN is defined as including, but not limited to, treating a wide range of states of HIN infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIN.
  • the compounds of this invention are useful in treating infection by HIN after suspected past exposure to HIN by, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
  • a compound of the present invention may be used for the prevention of infection by HIN and the prevention of AIDS, such as in post-coital prophylaxis or in the prevention of maternal transmission of the HIN virus to a fetus or a child upon birth.
  • a subject compound may be used in a method of inhibiting the binding of a human immunodeficiency virus to a chemokine receptor, such as CCR-5 and or CXCR-4, of a target cell, which comprises contacting the target cell with an amount of the compound which is effective at inhibiting the binding of the virus to the chemokine receptor.
  • a chemokine receptor such as CCR-5 and or CXCR-4
  • the subject treated in the methods above is a mammal, preferably a human being, male or female, in whom modulation of chemokine receptor activity is desired.
  • “Modulation” as used herein is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism.
  • therapeutically effective amount means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • administration of and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
  • Combined therapy to modulate chemokine receptor activity and thereby prevent and treat inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and those pathologies noted above is illustrated by the combination of the compounds of this invention and other compounds which are known for such utilities.
  • the present compounds may be used in conjunction with an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine- suppressing antiinflammatory agent, for example with a compound such as acetaminophen, asprin, codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like.
  • the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo- desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine.
  • a pain reliever such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide
  • a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinep
  • compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the pressent invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • active ingredients include, but are not limited to: (a) VLA-4 antagonists such as those described in US 5,510,332, WO97/03094, WO97/02289, WO96/40781, WO96/22966, WO96/20216, WO96/01644, WO96/06108, WO95/15973 and WO96/31206; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapamycin and other FK-506 type immunosuppressants; (d) antihistamines (Hl-histamine antagonists)
  • the weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an ⁇ SAID the weight ratio of the compound of the present invention to the ⁇ SAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the present invention is further directed to combinations of the present compounds with one or more agents useful in the prevention or treatment of AIDS.
  • the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, anti-infectives, or vaccines known to those of ordinary skill in the art.
  • Abacavir (1592U89) Glaxo Wellcome HIV infection, AIDS, ARC (RT inhibitor)
  • Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus
  • Virazole Viratek/ICN asymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC
  • Enkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma
  • Isethionate (IM & IN) (Rosemont, IL)
  • Preferred combinations are simultaneous or alternating treatments of with a compound of the present invention and an inhibitor of HIN protease and/or a non-nucleoside inhibitor of HIN reverse transcriptase.
  • An optional fourth component in the combination is a nucleoside inhibitor of HIN reverse transcriptase, such as AZT, 3TC, ddC or ddl.
  • a preferred inhibitor of HIN protease is indinavir, which is the sulfate salt of ⁇ -(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)- hydroxy-5-(l-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)- piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999.
  • Indinavir is generally administered at a dosage of 800 mg three times a day.
  • Other preferred protease inhibitors are nelfinavir and ritonavir.
  • HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid.
  • Preferred non- nucleoside inhibitors of HIV reverse transcriptase include efavirenz.
  • the preparation of ddC, ddl and AZT are also described in EPO 0,484,071. These combinations may have unexpected effects on limiting the spread and degree of infection of HIN.
  • Preferred combinations include those with the following (1) indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddl and/or ddC; (2) indinavir, and any of AZT and or ddl and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and lamivudine.
  • the compound of the present invention and other active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICN, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, ICN, intracisternal injection or infusion, subcutaneous injection, or implant
  • inhalation spray nasal, vaginal, rectal, sublingual, or topical routes of administration
  • nasal, vaginal, rectal, sublingual, or topical routes of administration may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the compounds of the invention are effective for
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl- pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy- ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbit
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene gly cols.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of The present invention are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
  • compositions and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
  • an appropriate dosage level will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day.
  • compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • R and Z are as defined in relation to formula (I) and LG represents a leaving group such as a halogen atom or an alkyl- or aryl-sulphonyloxy group, e.g. chlorine, bromine or iodine or a methylsulphonate or p-toluenesulphonate group, in the presence of a base.
  • LG represents a leaving group such as a halogen atom or an alkyl- or aryl-sulphonyloxy group, e.g. chlorine, bromine or iodine or a methylsulphonate or p-toluenesulphonate group, in the presence of a base.
  • suitable bases include organic bases such as tertiary amines, e.g. triethylamine, and inorganic bases such as alkali metal carbonates, e.g. sodium carbonate or potassium carbonate.
  • organic bases such as tertiary amines, e.g. triethylamine
  • inorganic bases such as alkali metal carbonates, e.g. sodium carbonate or potassium carbonate.
  • the reaction is effected in a suitable organic solvent, such as dimethylformamide, acetonitrile or dichloromethane, conveniently at a temperature between room temperature and 100°C.
  • suitable bases include alkali metal hydrides, e.g. sodium hydride.
  • the reaction is effected in a suitable organic solvent such as an ether, e.g. tetrahydrofuran, conveniently at a temperature between room temperature and 100°C.
  • compounds of formula (I) may be prepared from compounds of formula (IN):
  • Suitable bases include organic bases such as tertiary amines, e.g. triethylamine, and inorganic bases such as alkali metal carbonates, e.g. sodium carbonate or potassium carbonate.
  • organic bases such as tertiary amines, e.g. triethylamine
  • inorganic bases such as alkali metal carbonates, e.g. sodium carbonate or potassium carbonate.
  • the reaction is effected in a suitable organic solvent, such as dimethylformamide, acetonitrile or dichloromethane, conveniently at a temperature between room temperature and 100°C.
  • LG is as previously defined, and R is a suitable amine protecting group, such as an alkoxycarbonyl group, for example, £ert butoxycarbonyl, by reaction with an amine of formula (N) according to the method of process (B) above, followed by removal of any protecting group where present.
  • R is a suitable amine protecting group, such as an alkoxycarbonyl group, for example, £ert butoxycarbonyl, by reaction with an amine of formula (N) according to the method of process (B) above, followed by removal of any protecting group where present.
  • the desired leaving group is a halogen atom
  • a corresponding halogen acid such as hydrogen bromide or hydrogen iodide
  • the leaving group is an alkyl- or aryl-sulphonyloxy group
  • the compound of formula (Nil) may be reacted with, for example, methanesulfonyl chloride or p-toluenesulfonyl chloride.
  • compounds of formula (IN) may be prepared by the reaction of a compound of formula (NIII):
  • R 30 is a suitable hydroxy protecting group, for example, tetrahydropyran, with a compound of formula (II) according to the method of process (A), above, followed by removal of any protecting group where present.
  • Suitable reducing agents include hydrides such as lithium aluminium hydride in a suitable solvent, for example, tetrahydrofuran, conveniently at a temperature between room temperature and 100°C, for example, at about 60°C.
  • compounds of formula (IX) in which Y is two hydrogen atoms may be prepared in a two-step reaction from a compound of formula (X)
  • R 30 is a suitable hydroxy protecting group as previously defined and R is a Ci-6alkyl group, espeically an ethyl group.
  • Compounds of formula (IX) in which Y is an oxygen atom may also be prepared from a corresponding compound of formula (X), by hydrogenation in the presence of an excess of RaneyTM nickel.
  • a suitable solvent for this reaction is a mixture of ethanol and ammonia.
  • amino moieties may be protected by, for example, the formation of alkoxycarbonyl derivatives, e.g. tert- butoxycarbonyl and trichloroethoxycarbonyl, or benzyl, trityl or benzyloxycarbonyl derivatives. Subsequent removal of the protecting group is achieved by conventional procedures thus, for example, tert- butoxycarbonyl, benzyl or benzyloxycarbonyl groups may be removed by hydrogenolysis in the presence of a catalyst e.g. palladium; a trichloroethoxycarbonyl group may be removed with zinc dust; and a trityl group may be removed under acidic conditions using standard procedures.
  • a catalyst e.g. palladium
  • a trichloroethoxycarbonyl group may be removed with zinc dust
  • a trityl group may be removed under acidic conditions using standard procedures.
  • hydroxyl groups require protection, this may be effected by the formation of esters or trialkylsilyl, tetrahydropyran or benzyl ethers.
  • esters or trialkylsilyl, tetrahydropyran or benzyl ethers Such derivatives may be deprotected by standard procedures thus, for example, a tetrahydropyran ether derivative may be deprotected using hydrochloric acid in methanol.
  • the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • nitrile (Intermediate 1) (30.15g, 0.0919mol) was dissolved in 1,4-dioxane (200ml). Ethyl acrylate (17.56g, 1.7eq) and Triton BTM (5ml, 40wt%, methanol) were added and the solution was stirred at 80°C for 29 hours at room temperature. The reaction was quenched with ammonium chloride and extracted with diethyl ether (x2). The combined organic phase was washed with water (x2), brine (xl) and dried (MgSO4). The solvent and unreacted ethyl acrylate were evaporated to provide the title compound as a viscous yellow oil (37.4g, 95% yield).
  • the THP protected piperidinone (Intermediate 4) (4.11g, 8.65mmol) was deprotected by stirring with 3M hydrochloric acid/methanol (50ml) for 2 hours. The solvent was evaporated and the residue was redissolved in ethyl acetate and washed with sodium bicarbonate (xl), brine (xl) and dried (MgSO4). The solvent was evaporated to afford the title compound as a yellow oil which was used without further purification.
  • nitrile ester (Intermediate 2) (2.07g, 4.84mmol) was dissolved in tetrahydrofuran (10ml) and cooled on a ice-bath, lithium aluminium hydride (IM, THF, 14.5ml, 3eq) was added over 10 minutes. The solution was then stirred at 60°C on an oil bath for 2 hours after which it quenched carefully with sodium, hydroxide (2M, 2ml) and water (2ml). The solution was filtered through a Hyflo filter and the filtrate was dried (MgSO4) and evaporated to provide the title compound (1.71g, 91% yield).
  • IM lithium aluminium hydride
  • Step (A) The amino alcohol of Step (A) (1.70g, 436mmol) was dissolved in anhydrous dichloromethane and triphenyl phosphine (1.26g, l.leq) was added. After stirring for 5 minutes diethyl azodicarboxylate (0.73g, leq) was added and the mixture was stirred for 5 hours. The solution was diluted with water and extracted with dichloromethane (x2). The combined organic phase was washed with water (x2), brine (xl), dried (MgSO4) and the solvent was evaporated.
  • THP protected amide (Intermediate 9) (12.8g, 0.027mol) was deprotected by stirring with 3M hydrochloric acid in methanol (150ml) for 2 hours. The solvent was removed in vacuo and the residue was redissolved in ethyl acetate and washed with sodium bicarbonate (xl), water (xl) and (MgSO4). The solvent was evaporated to provide the title compound. This material was used without further purification.
  • the lactam mesylate (Intermediate 6) (0.433g, 0.923mmol) was dissolved in dimethylformamide (3ml).
  • Potassium carbonate (0.262g, 2eq) and 4,4-[iV-sulfonamidomethyl-3,3-indolyl]-piperidine (0.268g, l.leq) was added and stirred at 60°C on an oil bath for 16 hours.
  • the solution was diluted with water (xl5) and extracted with ethyl acetate (x2).
  • the combined organic phase was washed with water (x2), brine (xl) and dried (MgSO4).
  • the lactam mesylate (Intermediate 6) (0.336g, 0.716mmol) was dissolved in dimethylformamide (5ml). Potassium carbonate (0.198g, 2eq) and 4- [2-keto-l-benzimidazolinyl] -piperidine (0.175g, l.leq) was added and stirred at 60°C on an oil bath for 16 hours. The solution was diluted with water (xl5) and extracted with ethyl acetate (x2). The combined organic phase was washed with water (x2), brine (xl) and dried (MgSO4).
  • the lactam mesylate, (Intermediate 6) (0.437g, 0.932mmol) was dissolved in dimethylformamide (5ml). Potassium carbonate (0.385 g, 3 eq) and 4-acetyl-4-phenylpiperidine hydrochloride (0.248g, l.leq) was added and stirred at 60°C on an oil bath for 16 hours. The solution was diluted with water (xl5) and extracted with ethyl acetate (x2). The combined organic phase was washed with water (x2), brine (xl) and dried (MgSO4).
  • the lactam mesylate (Intermediate 6) (0.420g, 0.896mmol) was dissolved in dimethylformamide (6ml). Potassium carbonate (0.493g, 4eq) and l-phenyl-l,3,8-triazaspiro[4.5]decan-4-one (0.231g, l.leq) was added and stirred at 60°C on an oil bath for 16 hours. The solution was diluted with water (xl5) and extracted with ethyl acetate (x2). The combined organic phase was washed with water (x2), brine (xl) and dried (MgSO4).
  • the amide mesylate (Intermediate 11) (0.70g, 1.49mmol) was dissolved in dimethylformamide (8ml). Potassium carbonate (0.44g, 2eq) and 4,4-(iV-sulfonamido-3,3-indolyl)-piperidine (0.48g, 1.2eq) were added and the mixture was stirred on an oil bath at 60°C for 16 hours. The reaction was diluted with water (xl5) and extracted with ethyl acetate (x2). The organic phase was washed with water (xl), brine (xl) and dried (MgSO4).
  • the amide mesylate (Intermediate 11) (0.660g, 1.41mmol) was dissolved in dimethylformamide (5ml). Potassium carbonate (0.388g, 2eq) and 4-(2-keto-l-benzimidazolinyl)-piperidine (0.366g, 1.2eq) were added and the mixture was stirred on an oil bath at 60°C for 16 hours. The reaction was diluted with water (xl5) and extracted with ethyl acetate (x2). The organic phase was washed with water (xl), brine (xl) and dried (MgSO4).
  • the amide mesylate (Intermediate 11) (0.567g, 1.21mmol) was dissolved in dimethylformamide (8ml). Potassium carbonate (0.333g, 2eq) and 4-acetyl-4-phenylpiperidine (0.270g, l.leq) were added and the mixture was stirred on an oil bath at 60°C for 16 hours. The reaction was diluted with water (xl5) and extracted with ethyl acetate (x2). The organic phase was washed with water (xl), brine (xl) and dried (MgSO4).

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Abstract

The present invention is directed to 3,3-disubstituted piperidines of formula (I), (wherein X, Y, Z, Ar, R, m and n are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and/or CXCR-4.

Description

TITLE OF THE INVENTION
3,3-DISUBSTITUTED PIPERIDINES AS MODULATORS OF
CHEMOKINE RECEPTOR ACTIVITY
BACKGROUND OF THE INVENTION
Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, Cvtokine. 3, 165-183 (1991) and Murphy, Rev. Immun.. 12, 593-633 (1994)). There are two classes of chemokines, C-X-C (α) and C-C (β), depending on whether the first two cysteines are separated by a single amino acid (C-X-C) or are adjacent (C-C). The -chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils, whereas β-chemokines, such as RANTES, MlP-lα, MIP- lβ, monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al., Nature. 381.661-666 (1996)).
The chemokines bind specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane- domain proteins (reviewed in Horuk, Trends Pharm. Sci.. 15, 159-165 (1994)) which are termed "chemokine receptors." On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least seven human chemokine receptors that bind or respond to β-chemokines with the following characteristic pattern: CCR-1 (or "CKR-1" or "CC-CKR-1") [MlP-lα, MlP-lβ, MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem.. 270. 22123-22128 (1995); Beote, et al, Cell. _ , 415-425 (1993)); CCR- 2A and CCR-2B (or "CKR-2A7"CKR-2A" or "CC-CKR-2A7"CC-CKR- 2A") [MCP-1, MCP-3, MCP-4]; CCR-3 (or "CKR-3" or "CC-CKR-3") [eotaxin, RANTES, MCP-3] (Combadiere, et al., J. Biol. Chem.. 270. 16491-16494 (1995); CCR-4 (or "CKR-4" or "CC-CKR-4") [MlP-lα, RANTES, MCP-1] (Power, et al., J. Biol. Chem.. 270. 19495-19500 (1995)); CCR-5 (or "CKR-5" or "CC-CKR-5") [MlP-lα, RANTES, MlP-lβ] (Sanson, et al., Biochemistry. 35, 3362-3367 (1996)); and the Duffy blood- group antigen [RANTES, MCP-1] (Chaudhun, et al., J. Biol. Chem.. 269. 7835-7838 (1994)). The β-chemokines include eotaxin, MIP ("macrophage inflammatory protein"), MCP ("monocyte chemoattractant protein") and RANTES ("regulation-upon-activation, normal T expressed and secreted").
Chemokine receptors, such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR-4, have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example, the chemokine receptor CCR-3 plays a pivotal role in attracting eosinophils to sites of allergic inflammation. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases.
A retrovirus designated human immunodeficiency virus (HIV-1) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV.
Certain compounds have been demonstrated to inhibit the replication of HIV, including soluble CD4 protein and synthetic derivatives (Smith, et al., Science. 238. 1704-1707 (1987)), dextran sulfate, the dyes Direct Yellow 50, Evans Blue, and certain azo dyes (U.S. Patent No. 5,468,469). Some of these antiviral agents have been shown to act by blocking the binding of gpl20, the coat protein of HTV, to its target, the CD4 gyycoprotein of the cell.
Entry of HIN-l into a target cell requires cell-surface CD4 and additional host cell cofactors. Fusin has been identified as a cofactor required for infection with virus adapted for growth in transformed T- cells, however, fusin does not promote entry of macrophagetropic viruses which are believed to be the key pathogenic strains of HIV in vivo. It has recently been recognized that for efficient entry into target cells, human immunodeficiency viruses require the chemokine receptors CCR-5 and CXCR-4, as well as the primary receptor CD4 (Levy, N. Engl. J. Med.. 335(20), 1528-1530 (Nov. 14 1996). The principal cofactor for entry mediated by the envelope glycoproteins of primary macrophage-trophic strains of HrV-1 is CCR5, a receptor for the β- chemokines RANTES, MlP-lα and MlP-lβ (Deng, et al., Nature. 381. 661-666 (1996)). HIN attaches to the CD4 molecule on cells through a region of its envelope protein, gpl20. It is believed that the CD-4 binding site on the gpl20 of HIV interacts with the CD4 molecule on the cell surface, and undergoes conformational changes which allow it to bind to another cell-surface receptor, such as CCR5 and/or CXCR-4. This brings the viral envelope closer to the cell surface and allows interaction between gp41 on the viral envelope and a fusion domain on the cell surface, fusion with the cell membrane, and entry of the viral core into the cell. Macrophage-tropic HIV and SIN envelope proteins have been shown to induce a signal through CCR-5 on CD4+ cells resulting in chemotaxis of T cells which may enhance the replication of the virus (Weissman, et al., Nature. 389. 981-985 (1997)). It has been shown that β- chemokine ligands prevent HPV-l from fusing with the cell (Dragic, et al., Nature. 381. 667-673 (1996)). It has further been demonstrated that a complex of gpl20 and soluble CD4 interacts specifically with CCR-5 and inhibits the binding of the natural CCR-5 ligands MlP-lα and MlP-lβ (Wu, et al., Nature. 384. 179-183 (1996); Trkola, et al, Nature. 384. 184-187 (1996)).
Humans who are homozygous for mutant CCR-5 receptors which do not serve as co-receptors for HlN-l in vitro apper to be unusually resistant to HIV-1 infection, and are not immuno- compromised by the presence of this genetic variant (Nature. 382. 722-725 (1996)). Similarly, an alteration in the CCR-2 gene, CCR2-641, can prevent the onset of full-blown AIDS (Smith, et al., Science. 277.959-965 (1997). Absence of CCR-5 appears to confer protection from HlN-l infection (Nature. 382. 668-669 (1996)). An inherited mutation in the gene for CCR5, Delta 32, has been shown to abolish functional expression of the gene and individuals homozygous for the mutation are apparently not susceptible to HIN infection. Other chemokine receptors may be used by some strains of HIN- 1 or may be favored by non-sexual routes of transmission. Although most HlN-l isolates studied to date utilize CCR-5 or fusin, some can use both as well as the related CCR-2B and CCR-3 as co-receptors (Nature Medicine. 2(11), 1240-1243 (1996)). Nevertheless, drugs targeting chemokine receptors may not be unduly compromised by the genetic diversity of HlN-l (Zhang, et al., Nature. 383. 768 (1996)). The β-chemokine macrophage-derived chemokine (MDC) has been shown to inhibit H-N-l infection (Pal, et al., Science. 278 (5338), 695-698 (1997). The chemokines RANTES, MlP-lα, MlP-lβ, vMIP-I, vMIP-II, SDF-1 have also been shown to suppress HIN. A derivative of RANTES, (AOP)-RANTES, is a subnanomolar antagonist of CCR-5 function in monocytes (Simmons, et al., Science. 276.276-279 (1997)). Monoclonal antibodies to CCR-5 have been reported to block infection of cells by ΕLTV in vitro. Accordingly, an agent which could block chemokine receptors in humans who possess normal chemokine receptors should prevent infection in healthy individuals and slow or halt viral progression in infected patients (see Science. 275. 1261-1264 (1997)). By focusing on the host's cellular immune response to HΣV infection, better therapies towards all subtypes of HIN may be provided. These results indicate that inhibition of chemokine receptors presents a viable method for the prevention or treatment of infection by HIN and the prevention or treatment of AIDS.
The peptides eotaxin, RANTES, MlP-lα, MlP-lβ, MCP-1, and MCP-3 are known to bind to chemokine receptors. As noted above, the inhibitors of HlN-l replication present in supernatants of CD8+ T cells have been characterized as the β-chemokines RANTES, MlP-lα and MlP-lβ. U.S. Patent Nos. 5,340,822., 5,350,852, 5,434,158, 5,559,132, 5,589,489, and 5,635,510 and PCT Patent Publication WO 95/05377 disclose certain compounds as tachykinin antagonists. EPO Patent Publications EP 0 512 901 (published Nov. 11, 1992), EP 0 673 928 (published Sep. 27, 1995) and EP 0 723 959 (published Jul. 31, 1996) disclose certain piperidines as tachykinin antagonists. A poster presentation by T. Harrison, et al. (Gordon Conference on Medicinal Chemistry, Colby Sawyer College, New London, NH, August 4-9, 1996) disclosed certain 3,3-disubstituted piperidines as tachykinin antagonists. SUMMARY OF THE INVENTION
The present invention is directed to compounds which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which chemokine receptors are involved.
The present invention is further concerned with compounds which inhibit the entry of human immunodeficiency virus (HIN) into target cells and are of value in the prevention of infection by HIN, the treatment of infection by HIN and the prevention and/or treatment of the resulting acquired immune deficiency syndrome (AIDS). The present invention also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the prevention and treatment of AIDS and viral infection by HIV.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a compound of formula I:
Figure imgf000007_0001
(I)
wherein: m is zero, 1 or 2; n is 1, 2 or 3, with the proviso that the sum of m + n is 1 to 4; X is:
Figure imgf000008_0001
one of Y and Z is =O whereas the other represents two hydrogen atoms;
Ar is selected from the group consisting of: unsubstituted phenyl; phenyl which is substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, trifluoromethyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3_7cycloalkyl, C3-7cycloalkylCi-4alkyl, and Ci-6alkoxy; thienyl; benzothienyl; naphthyl; unsubstituted indolyl; and indolyl which is substituted on the nitrogen atom by a Cι_ 4alkyl group;
R is selected from the group consisting of: unsubstituted phenyl; and phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, trifluoromethyl, Cι_6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3- 7cycloalkylCi-4alkyl, and Ci-6alkoxy;
R is selected from the group consisting of: hydrogen; Cl-6alkyl; Ci-6alkyl substituted by 1 or 2 substituents selected from: hydroxy, -OR3, oxo, -NHCOR3, -NR3R4, cyano, halogen, trifluoromethyl, unsubstituted phenyl, and phenyl substituted by 1 or 2 substituents selected from: hydroxy, cyano, halogen and trifluoromethyl; unsubstituted phenyl; phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Cχ-4alkyl, -S(O)pCl-4alkyl and -C(O)R3; unsubstituted aryl; aryl substituted by 1, 2 or 3 substituents selected from : hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(O)pCi_4alkyl and -C(O)R3; and a saturated heterocyclic ring of 4, 5 or 6 ring atoms which ring contains 1 or 2 nitrogen atoms, one of which may be at the point of attachment to the remainder of the molecule, and optionally containing in the ring an oxygen atom, which ring is substituted on any available nitrogen atom by a group R and which ring may be further substituted by a group selected from: hydroxyCi-4alkyl, Ci-4alkoxyCi-
3 4alkoxy, oxo and COR , and which ring may have fused thereto a phenyl ring, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Cι_4alkyl, -S(O)pCi-4alkyl, and -C(O)R3;
elected from:
3 Cχ-6alkyl hydroxyCi-6alkyl, hydroxy, OR , halogen, trifluoromethyl, nitro, cyano, -NR3R4, -NHCOR3, -
NR3COR4, -NHCO2R3, -NR3CO2R4, -NHS(O)pR3, - NR3S(O)pR4, -CONR3R4, -COR3, -CO2R3 and -S(O)pR3;
or R 1 and R 2 are joined together to form a 5- or 6-membered non- aromatic ring which may contain in the ring 1 or 2 groups of the formula -NR -, which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, a phenyl group, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(O)pCl_4alkyl, and -C(O)R3;
R 3 and R 4 are each independently selected from: hydrogen; unsubstituted Ci-6alkyl;
Ci-6alkyl substituted by 1 or 2 substituents selected from unsubstituted: phenyl, hydroxy, oxo, cyano, Ci- 4alkoxy and trifluoromethyl; Ci-βalkoxy; unsubstituted phenyl; and phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, Cl-4alkyl, cyano, halogen, and trifluor om ethyl ; or the group -NR R is a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulfur atom or a group selected from: -NR -, -S(O)- or -S(O)2- and which ring may be optionally substituted by one or two groups selected from: hydroxyCi_4alkyl, Cι_4alkoxyCι_4alkyl, oxo,
-COR6 and -CO2R6;
R 5 is selected from hhyyddrroosgen, Cl- alkyl, -S(O)2Ci-4alkyl, -C(O)R3, unsubstituted phenyl and benzyl;
R is selected from: hydrogen or Ci-4alkyl; and p is zero, 1 or 2; or a pharmaceutically acceptable salt thereof.
When used herein the term "halogen" means fluorine, chlorine, bromine and iodine. The preferred halogen are fluorine and chlorine of which fluorine is most preferred. When used herein the term "alkyl" or "alkoxy" as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i- propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t- butoxy.
The term "alkenyl" as a group or part of a group means that the group is straight or branched and contains at least one double bond. Examples of suitable alkenyl groups include vinyl and allyl. The term "alkynyl" as a group or part of a group means that the group is straight or branched and contains at least one triple bond. An example of a suitable alkynyl group is propargyl.
Suitable cycloalkyl and cycloalkyl-alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl and cyclobutylmethyl.
When used herein the term "heteroaryl" represents a heteroaromatic ring including furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidyl, benzofuranyl, benzthienyl, indolyl, benzimidazolyl, benzoxazolyl and quinolyl.
Where the group NR R forms a saturated heterocylic ring of 4 to 7 ring atoms which may optionally contain in the ring one oxygen
5 or sulfur atom or a group selected from -NR -, -S(O)- or -S(O)2-, suitable heterocylic groups include azetidinyl, pyrrolidino, piperidino, homopiperidino, piperazino, N-methylpiperazino, morpholino and thiomorpholino.
Suitable substituents on the saturated heterocyclic ring include -CH2OH, -CH2OCH3, oxo, -CHO, -CO2H, -CO2CH3, and -CO2CH2CH3.
Preferred compounds of the present invention include those compounds of formula I, with the exception of:
5-[3-{4,4-(iV-sulfonamidomethyl-3,3- indolyl)piperidino}propyl]-5-[3,4-diphenyl]-l-benzylpiperidin-2-one; 5- [3- {4-(2-keto- l-benzimidazolinyl)-piperidino}propyl] -5- [3 ,4- dichlorophenyl]-l-benzylpiperidin-2-one;
5-[3-{4-acetyl-4-phenyl-piperidino}propyl]-5-[3,4- dichlorophenyl]-l-benzylpiperidin-2-one; 5-[3-{l-phenyl-l,3,8-triazaspiro[4.5]decan-4-one}propyl]-5-
[3,4-dichlorophenyl]-l-benzylpiperidin-2-one;
5-[3-{4,4-(iV-sulfonamidomethyl-3,3- indolyl)piperidino}propyl]-5-[3,4-diphenyl]-l-benzoylpiperidine;
5- [3-{4-(2-keto- l-benzimidazolinyl)-piperidino}propyl] -5- [3,4- dichlorophenyl]-l-benzoylpiperidine;
5-[3-{4-acetyl-4-phenyl-piperidino}propyl]-5-[3,4- dichlorophenyl]-l-benzoylpiperidine;
5-[3-{l-phenyl-l,3,8-triazaspiro[4.5]decan-4-one}propyl]-5- [3,4-dichlorophenyl]-l-benzoylpiperidine; and 5-[3-{4,4-(l,l-indanyl)piperidino}propyl]-5-[3,4-diphenyl]-l- benzoylpiperidine.
A preferred class of compounds of formula I for use in the present invention is that wherein the sum of m + n is 3. In particular, m is preferably 2. In particular, n is preferably 1. A preferred group of compounds for use in the present invention is wherein X is:
Figure imgf000012_0001
wherein Rl and R^ are defined above. Ar preferably represents unsubstituted phenyl or phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, triflourom ethyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3. 7cycloalkyl, C3-7cycloalkylCι_4alkyl, and Cχ-6alkoxy. Preferred substituents are halogen atoms, most especially chlorine atoms. In particular, Ar represents phenyl substituted by two substituents. Preferably Ar represents a 3,4-disubstituted phenyl ring. R preferably represents unsubstituted phenyl or phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, trifluoromethyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 7cycloalkyl, C3-7cycloalkylCi-4alkyl, and Ci-6alkoxy. Preferred substituents are halogen atoms, most especially chlorine atoms. In particular, R represents an unsubstituted phenyl ring.
R preferably represents an unsubstituted phenyl group or a saturated heterocyclic ring of 5 ring atoms which ring contains 1 or 2 nitrogen atoms, one of which is at the point of attachment to the remainder of the molecule, which ring is substituted on any available nitrogen atom by a group R 5 , preferably where R 5 is hydrogen, and which ring is preferably substituted by an oxo group, and which ring has fused thereto a phenyl ring, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(O)pCi-4alkyl, and -C(O)R3. Preferably the phenyl ring is unsubstituted.
R 2 preferably represents hydrogen or -COR 3 , where R 3 represents Cl-6alkyl, in particular Ci-3alkyl, especially methyl. A further preferred class of compound of formula I for use in the present invention is that wherein R 1 and R 2 are joined together to form a 5-membered non-aromatic ring which may contain in the ring 1 or 2 groups of the formula NR 5 , which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, a phenyl group, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR R , -NR R , -
NR3COR4, halogen, trifluoromethyl, Ci_4alkyl, -S(O)pCi_4alkyl, and -
3 C(O)R . Preferably the phenyl ring, where present, is unsubstituted.
Where present, R and R each independently preferably represent hydrogen or Ci-6alkyl.
5 R preferably represents hydrogen, Ci-4alkyl, -S(O)2Ci-
4alkyl or unsubstituted phenyl. In particular, R is preferably hydrogen, -S(O)2CH3 or phenyl. From the foregoing, it will be appreciated that a particularly preferred sub-group of compounds for use in the present invention include are those of formula (la):
Figure imgf000014_0001
(la)
wherein:
R , R , R and R are selected from: hydrogen and halogen;
R is an unsubstituted phenyl group or a saturated heterocyclic ring of 5 ring atoms which ring contains 1 or 2 nitrogen atoms, one of which is at the point of attachment to the remainder of the molecule, which ring is substituted on any available nitrogen atom by a group R , and which ring may be substituted by an oxo group, and which ring has fused thereto a phenyl ring, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(0)pCi_ 4alkyl, and -C(O)R3;
R15 is -COR3, where R3 is Ci-βalkyl; or R and R are joined together to form a 5-membered non-aromatic ring which may contain in the ring 1 or 2
5 groups of the formula NR , which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, a phenyl group, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR R , - NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci_4alkyl,
-S(O)pCi-4alkyl, and -C(O)R3; and
one of Y and Z is =O whereas the other represents two hydrogen atoms; or a pharmaceutically acceptable salt thereof.
A preferred class of compound of formula (la) for use in the present invention is that wherein:
R and R each are chlorine;
R 12 and R 13 each are hydrogen; R is unsubstituted phenyl;
R15 is -COCH3; or R and R are joined together to form a 5-membered non-aromatic ring which may contain in the ring 1 or
5 2 groups of the formula -NR -, which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, an unsubstituted phenyl group, wherein R is selected from: hydrogen, -S(O)2CH3 and phenyl.
Particularly preferred compounds of formula I for use in the present invention are those wherein: m is 2, n is 1 and X is:
R1
\ /
C
R 2 \
to give a group of the formula:
Figure imgf000016_0001
of which preferred examples are selected from:
Figure imgf000017_0001
Figure imgf000017_0002
wherein each phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Cι_4alkyl, -S(0)pCi-4alkyl and -C(O)R3, where R , R and p are as previously defined above.
Particularly preferred examples of groups for the compounds of use in the present invention which are represented by
Figure imgf000018_0001
include:
Exemplifying the present invention is the use of a compound selected from the group consisting of: 5-[3-{4,4-CN-sulfonamidomethyl-3,3- indolyl)piperidino}propyl]-5-[3,4-diphenyl]-l-benzylpiperidin-2-one;
5-[3-{4-(2-keto-l-benzimidazolinyl)-piperidino}propyl]-5-[3,4- dichlorophenyl]-l-benzylpiperidin-2-one; 5-[3-{4-acetyl-4-phenyl-piperidino}propyl]-5-[3,4- dichlorophenyl]-l-benzylpiperidin-2-one;
5- [3- { 1-phenyl- 1,3 ,8-triazaspiro [4.5] decan-4-one}propyl] -5- [3,4-dichlorophenyl]-l-benzylpiperidin-2-one; 5-[3-{4,4-CN-sulfonamidomethyl-3,3- indolyl)piperidino}propyl]-5-[3,4-diphenyl]-l-benzoylpiperidine;
5-[3-{4-(2-keto-l-benzimidazolinyl)-piperidino}propyl]-5-[3,4- dichlorophenyl]-l-benzoylpiperidine;
5- [3-{4-acetyl-4-phenyl-piperidino}propyl] -5- [3 ,4- dichlorophenyl]-l-benzoylpiperidine;
5-[3-{l-phenyl-l,3,8-triazaspiro[4.5]decan-4-one}propyl]-5- [3,4-dichlorophenyl]-l-benzoylpiperidine;
5-[3-{4,4-(l,l-indanyl)piperidino}propyl]-5-[3,4-diphenyl]-l- benzoylpiperidine; and pharmaceutically acceptable salts thereof.
For use in medicine, the salts of the compounds of formula I will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts such as those formed with hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. The pharmaceutically acceptable salts of the present invention may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
The present invention includes within its scope solvates of the compounds of formula I and salts thereof, for example, hydrates.
The compounds according to the invention may have one or more asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
The subject compounds are useful in a method of modulating chemokine receptor activity in a patient in need of such modulation comprising the administration of an effective amount of the compound. Exemplifying the invention is the use of the compounds disclosed in the Examples and elsewhere herein.
The present invention is directed to the use of the foregoing compounds as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and/or CXCR-4.
The present invention is further directed to the use of compounds of this general structure which are disclosed as being antagonists of neurokinin receptors. Such compounds are disclosed, for example, in: U.S. Patent No. 5,317,020; U.S. Patent No. 5,340,822; U.S. Patent No. 5,350,852; U.S. Patent No. 5,411,971; U.S. Patent No. 5,434,158; U.S. Patent No. 5,446,052; U.S. Patent No. 5,534,525; U.S. Patent No. 5,559,132; U.S. Patent No. 5,560,700; U.S. Patent No. 5,589,489; U.S. Patent No. 5,635,510; EP 0 512 901, Nov. 11, 1992; EP 0 591 040, Apr. 6, 1994; EP 0 673 928, Sep. 27, 1995; EP 0 698 601, Feb. 28, 1996; EP 0 625 509, Nov. 23, 1994; EP 0 630 887, Dec. 28, 1994; EP 0 680 962, Nov. 8, 1995; EP 0 709 375, May 1, 1996; EP 0 709 376, May 1, 1996; EP 0 723 959, Jul. 31, 1996; EP 0 739 891; WO 94/10146, May 11, 1994; WO 94/17045, Aug. 4, 1994; WO 94/26735, Nov. 24, 1994; WO 94/29309, Dec. 22, 1994; WO 95/05377, Feb. 23, 1995; WO 95/12577, May 11, 1995; WO 95/15961, Jun. 15, 1995; WO 95/16682, Jun. 22, 1995; WO 95/21187; WO 95/26335, Oct. 5, 1995; WO 95/26338, Oct. 5, 1995; WO 95/35279; WO 96/06094, Feb. 29, 1996; WO 96/10568, Apr. 11, 1996; WO 96/23787, Aug. 8, 1996; WO 96/24582, Aug. 15, 1996; WO 96/28441; and WO 96/32385. Accordingly, the present invention embraces the use of a compound disclosed in these publications as a modulator of chemokine receptor activity.
The utility of the compounds in accordance with the present invention as modulators of chemokine receptor activity may be demonstrated by methodology known in the art, such as the assay for CCR-1 and/or CCR-5 binding as disclosed by Van Riper, et al., J. Exp. Med.. 177, 851-856 (1993), and the assay for CCR-2 and/or CCR-3 binding as disclosed by Daugherty, et al., J. Exp. Med.. 183. 2349-2354 (1996). Cell lines for expressing the receptor of interest include those naturally expressing the receptor, such as EOL-3 or THP-1, or a cell engineered to express a recombinant receptor, such as CHO, RBL-2H3, HEK-293. For example, a CCR3 transfected AML14.3D10 cell line has been placed on restricted deposit with American Type Culture Collection in Rockville, Maryland as ATCC No. CRL-12079, on April 5, 1996. The utility of the compounds in accordance with the present invention as inhibitors of the spread of HIN infection in cells may be demonstrated by methodology known in the art, such as the HIN quantitation assay disclosed by Νunberg, et al., J. Virology. 65 (9), 4887-4892 (1991).
In particular, the compounds of the following examples had activity in binding to either the CCR-5 receptor or the CCR-3 receptor in the aforementioned assays. Such a result is indicative of the intrinsic activity of the compounds in use as modulators of chemokine receptor activity.
Mammalian chemokine receptors provide a target for interfering with or promoting eosinophil and/or lymphocyte function in a mammal, such as a human. Compounds which inhibit or promote chemokine receptor function, are particularly useful for modulating eosinophil and/or lymphocyte function for therapeutic purposes. Accordingly, the present invention is directed to compounds which are useful in the prevention and/or treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
For example, an instant compound which inhibits one or more functions of a mammalian chemokine receptor (e.g., a human chemokine receptor) may be administered to inhibit (i.e., reduce or prevent) inflammation. As a result, one or more inflammatory processes, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, is inhibited. For example, eosinophilic infiltration to inflammatory sites (e.g., in asthma) can be inhibited according to the present method.
Similarly, an instant compound which promotes one or more functions of a mammalian chemokine receptor (e.g., a human chemokine) is administered to stimulate (induce or enhance) an inflammatory response, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, resulting in the beneficial stimulation of inflammatory processes. For example, eosinophils can be recruited to combat parasitic infections.
In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens).
Diseases and conditions associated with inflammation and infection can be treated using the method of the present invention. In a preferred embodiment, the disease or condition is one in which the actions of eosinophils and/or lymphocytes are to be inhibited or promoted, in order to modulate the inflammatory response.
Diseases or conditions of humans or other species which can be treated with inhibitors of chemokine receptor function, include, but are not limited to: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), delayed-type hypersentitivity, interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet's disease; graft rejection (e.g., in transplantation), including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such an dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinphilic myositis, eosinophilic fasciitis; cancers with leukocyte infiltration of the skin or organs. Other diseases or conditions in which undesirable inflammatory responses are to be inhibited can be treated, including, but not limited to, reperfusion injury, atherosclerosis, certain hematologic malignancies, cytokine-induced toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis.
Diseases or conditions of humans or other species which can be treated with promoters of chemokine receptor function, include, but are not limited to: immunosuppression, such as that in individuals with immunodeficiency syndromes such as AIDS, individuals undergoing radiation therapy, chemotherapy, therapy for autoimmune disease or other drug therapy (e.g., corticosteroid therapy), which causes immunosuppression; immunosuppression due congenital deficiency in receptor function or other causes; and infectious diseases, such as parasitic diseases, including, but not limited to helminth infections, such as nematodes (round worms); (Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, fϊlariasis); trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tape worms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceral worms, visceral larva migrans (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki spp., Phocanema ssp.), cutaneous larva migrans (Ancylostona braziliense, Ancylostoma caninum).
The compounds of the present invention are accordingly useful in the prevention and treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases.
In another aspect, the instant invention may be used to evaluate putative specific agonists or antagonists of chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and CXCR-4. Accordingly, the present invention is directed to the use of these compounds in the preparation and execution of screening assays for compounds which modulate the activity of chemokine receptors. For example, the compounds of this invention are useful for isolating receptor mutants, which are excellent screening tools for more potent compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other compounds to chemokine receptors, e.g., by competitive inhibition. The compounds of the instant invention are also useful for the evaluation of putative specific modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and CXCR-4. As appreciated in the art, thorough evaluation of specific agonists and antagonists of the above chemokine receptors has been hampered by the lack of availability of non-peptidyl (metabolically resistant) compounds with high binding affinity for these receptors. Thus the compounds of this invention are commercial products to be sold for these purposes.
The present invention is further directed to a method for the manufacture of a medicament for modulating chemokine receptor activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
The present invention is further directed to the use of these compounds in the prevention or treatment of infection by a retrovirus, in particular, the human immunodeficiency virus (HIV) and the treatment of, and delaying of the onset of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIN is defined as including, but not limited to, treating a wide range of states of HIN infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIN. For example, the compounds of this invention are useful in treating infection by HIN after suspected past exposure to HIN by, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery. In addition, a compound of the present invention may be used for the prevention of infection by HIN and the prevention of AIDS, such as in post-coital prophylaxis or in the prevention of maternal transmission of the HIN virus to a fetus or a child upon birth.
In a preferred aspect of the present invention, a subject compound may be used in a method of inhibiting the binding of a human immunodeficiency virus to a chemokine receptor, such as CCR-5 and or CXCR-4, of a target cell, which comprises contacting the target cell with an amount of the compound which is effective at inhibiting the binding of the virus to the chemokine receptor. The subject treated in the methods above is a mammal, preferably a human being, male or female, in whom modulation of chemokine receptor activity is desired. "Modulation" as used herein is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism. The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The terms "administration of and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment. Combined therapy to modulate chemokine receptor activity and thereby prevent and treat inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and those pathologies noted above is illustrated by the combination of the compounds of this invention and other compounds which are known for such utilities.
For example, in the treatment or prevention of inflammation, the present compounds may be used in conjunction with an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine- suppressing antiinflammatory agent, for example with a compound such as acetaminophen, asprin, codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly, the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo- desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the pressent invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred.
Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention. Examples of other active ingredients that may be combined with a compound of the present invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) VLA-4 antagonists such as those described in US 5,510,332, WO97/03094, WO97/02289, WO96/40781, WO96/22966, WO96/20216, WO96/01644, WO96/06108, WO95/15973 and WO96/31206; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapamycin and other FK-506 type immunosuppressants; (d) antihistamines (Hl-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydr amine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidal anti-asthmatics such as β2-agonists (terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY- 1005); (f) non-steroidal antiinflammatory agents (NSAIDs) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors of phosphodiesterase type W (PDE-1N); (i) other antagonists of the chemokine receptors, especially CCR-1, CCR- 2, CCR-3 and CCR-5; (j) cholesterol lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, and other statins), sequestrants (cholestyramine and colestipol), nicotinic acid, fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), and probucol; (k) anti-diabetic agents such as insulin, sulfonylureas, biguanides (metformin), α-glucosidase inhibitors (acarbose) and glitazones (troglitazone and pioglitazone); (1) preparations of interferon beta (interferon beta-lα, interferon beta-lβ); (m) other compounds such as 5- aminosalicylic acid and prodrugs thereof, antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxic cancer chemotherapeutic agents. The weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an ΝSAID the weight ratio of the compound of the present invention to the ΝSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
The present invention is further directed to combinations of the present compounds with one or more agents useful in the prevention or treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, anti-infectives, or vaccines known to those of ordinary skill in the art.
ANTIVIRALS
Drug Name Manufacturer Indication
097 Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase (RT) inhibitor)
141 W94 Glaxo Wellcome HIV infection, AIDS, ARC (protease inhibitor)
1592U89 Glaxo Wellcome HIV infection, AIDS, ARC
(protease inhibitor)
Abacavir (1592U89) Glaxo Wellcome HIV infection, AIDS, ARC (RT inhibitor)
Acemannan Carrington Labs ARC (Irving, TX)
Acyclovir Burroughs Wellcome HIV infection, AIDS,
ARC, in combination with AZT
AD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxil Gilead Sciences HIV infection AL-721 Ethigen ARC, PGL
(Los Angeles, CA) HIV positive, AIDS
Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIN in combination w/Retrovir
Ansamycin Adria Laboratories ARC LM 427 (Dublin, OH) Erbamont (Stamford, CT)
Antibody which Advanced Biotherapy AIDS, ARC neutralizes pH Concepts labile alpha aberrant (Rockville, MD) Interferon AR177 Aronex Pharm HIV infection, AIDS,
ARC beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated diseases
BMS-232623 Bristol-Myers Squibb/ HIV infection,
(CGP-73547) Novartis AIDS, ARC
(protease inhibitor)
BMS-234475 Bristol-Myers Squibb/ HIV infection, (CGP-61755) Novartis AIDS, ARC
(protease inhibitor)
(-) 6-Chloro-4(S)- Merck HIV infection, cyclopropylethynyl- AIDS, ARC
4(S)-trifluoro- (non-nucleoside methyl-l,4-dihydro- reverse
2H-3 , 1-benzoxazin- transcriptase
2-one inhibitor)
CI-1012 Warner-Lambert HIV-1 infection
Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus
Curdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus Medlmmune CMV retinitis immune globin Cytovene Syntex sight threatening Ganciclovir CMV peripheral CMV retinitis
Delaviridine Pharmacia-Upjohn HIV infection,
AIDS, ARC
(RT inhibitor)
Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka, positive asymptomatic Japan) ddC Hoffman-La Roche HIV infection, AIDS,
Dideoxycytidine ARC ddl Bristol-Myers Squibb HIN infection, AIDS, Dideoxyinosine ARC; combination with AZT/d4T
DMP-266 DuPont-Merck HIV infection, Pharmaceuticals AIDS, ARC
(non-nucleoside reverse transcriptase inhibitor)
DMP-450 AVID HIV infection, (Camden, NJ) AIDS, ARC
(protease inhibitor)
Efavirenz DuPont Merck HIV infection, (DMP 266) AIDS, ARC
(non-nucleoside RT inhibitor)
EL10 Elan Corp, PLC HIV infection (Gainesville, GA) Famciclovir Smith Kline herpes zoster, herpes simplex FTC Emory University HIV infection,
AIDS, ARC
(reverse transcriptase inhibitor)
GS 840 Gilead HIV infection,
AIDS, ARC
(reverse transcriptase inhibitor)
GW 141 Glaxo Welcome HIN infection,
AIDS, ARC
(protease inhibitor)
GW 1592 Glaxo Welcome HIN infection,
AIDS, ARC
(reverse transcriptase inhibitor)
HBY097 Hoechst Marion HIN infection, Roussel AIDS, ARC
(non-nucleoside reverse transcriptase inhibitor)
Hypericin VIMRx Pharm. HIN infection, AIDS,
ARC
Recombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIN infection, AIDS,
ARC, asymptomatic
HIN positive, also in combination with
AZT/ddl/ddC
ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIN-assoc. diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also with AZT
Lobucavir Bristol-Myers Squibb CMV infection Nelfinavir Agouron HIV infection,
Pharmaceuticals AIDS, ARC (protease inhibitor)
Nevirapine Boeheringer HIV infection, Ingleheim AIDS, ARC (RT inhibitor)
Novapren Novaferon Labs, Inc. HIN inhibitor (Akron, OH)
Peptide T Peninsula Labs AIDS
Octapeptide (Belmont, CA)
Sequence
Trisodium Astra Pharm. CMV retinitis, HIV
Phosphonoformate Products, Inc infection, other CMV infections
PNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (protease inhibitor)
Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIV infection, Tech (Houston TX) AIDS, ARC
Ritonavir Abbott HIV infection, AIDS, ARC (protease inhibitor) Saquinavir Hoffmann- HIV infection, LaRoche AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS,
Didehydrodeoxy- ARC thymidine
Valaciclovir Glaxo Wellcome genital HSV & CMV infections
Virazole Viratek/ICN asymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC
VX-478 Vertex HIN infection, AIDS, ARC
Zalcitabine Hoffmann-La Roche HIV infection, AIDS, ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIN infection, AIDS, ARC, Kaposi's sarcoma, in combination with other therapies
IMMUNO-MODULATORS
Drug Name Manufacturer Indication AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia Upjohn advanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX)
CL246,738 American Cyanamid AIDS, Kaposi's Lederle Labs sarcoma
EL10 Elan Corp, PLC HIV infection (Gainesville, GA)
FP-21399 Fuki ImmunoPharm blocks HIV fusion with CD4+ cells
Gamma Interferon Genentech ARC, in combination w/TNF (tumor necrosis factor) Granulocyte Genetics Institute AIDS
Macrophage Colony Sandoz
Stimulating
Factor
Granulocyte Hoeschst-Roussel AIDS
Macrophage Colony Immunex
Stimulating
Factor
Granulocyte Schering-Plough AIDS, combination
Macrophage Colony w/AZT
Stimulating Factor
HIN Core Particle Rorer seropositive HIV
Immunostimulant
IL-2 Cetus AIDS, in combination
Interleukin-2 w/AZT
IL-2 Hoffman-La Roche AIDS, ARC, HIV, in
Interleukin-2 Immunex combination w/AZT
IL-2 Chiron AIDS, increase in CD4
Interleukin-2 cell counts
(aldeslukin)
Immune Globulin Cutter Biological pediatric AIDS, in
Intravenous (Berkeley, CA) combination w/AZT
(human)
IMREG-1 Imreg AIDS, Kaposi's
(New Orleans, LA) sarcoma, ARC, PGL
IMREG-2 Imreg AIDS, Kaposi's
(New Orleans, LA) sarcoma, ARC, PGL
Imuthiol Diethyl Merieux Institute AIDS, ARC
Dithio Carbamate
Alpha-2 Schering Plough Kaposi's sarcoma
Interferon w/AZT, AIDS
Methionine- TNI Pharmaceutical AIDS, ARC
Enkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma
Muramyl-Tripeptide
Granulocyte Amgen AIDS, in combination
Colony Stimulating w/AZT
Factor
Remune Immune Response immunotherapeutic Corp. rCD4 Genentech AIDS, ARC
Recombinant
Soluble Human CD4 rCD4-IgG AIDS, ARC hybrids
Recombinant Biogen AIDS, ARC
Soluble Human CD4
Interferon Hoffman-La Roche Kaposi's sarcoma
Alfa 2a AIDS, ARC, in combination w/AZT
SK&F106528 Smith Kline HIV infection
Soluble T4
Thymopentin Immunobiology HIV infection Research Institute (Annandale, NJ)
Tumor Necrosis Genentech ARC, in combination
Factor; TNF w/gamma Interferon
ANTI-INFECTIVES
Drug Name Manufacturer Indication
Clindamycin with Pharmacia Upjohn PCP
Primaquine
Fluconazole Pfizer cryptococcal meningitis, candidiasis Pastille Squibb Corp. prevention of
Nystatin Pastille oral candidiasis Ornidyl Merrell Dow PCP Eflornithine
Pentamidine LyphoMed PCP treatment
Isethionate (IM & IN) (Rosemont, IL)
Trimethoprim antibacterial
Trimethoprim/sulfa antibacterial
Piritrexim Burroughs Wellcome PCP treatment
Pentamidine Fisons Corporation PCP prophylaxis isethionate for inhalation
Spiramycin Rhone-Poulenc cryptosporidial diarrhea
Intraconazole- Janssen Pharm. histoplasmosis; R51211 cryptococcal meningitis
Trimetrexate Warner-Lambert PCP
OTHER
Drug Name Manufacturer Indication Daunorubicin NeXstar, Sequus Karposi's sarcoma Recombinant Human Ortho Pharm. Corp. severe anemia Erythropoietin assoc. with AZT therapy
Recombinant Human Serono AIDS-related wasting, Growth Hormone cachexia Megestrol Acetate Bristol-Myers Squibb treatment of anorexia assoc. w/AIDS
Testosterone Alza, Smith Kline AIDS-related wasting Total Enteral Norwich Eaton diarrhea and
Nutrition Pharmaceuticals malabsorption related to AIDS
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Preferred combinations are simultaneous or alternating treatments of with a compound of the present invention and an inhibitor of HIN protease and/or a non-nucleoside inhibitor of HIN reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIN reverse transcriptase, such as AZT, 3TC, ddC or ddl. A preferred inhibitor of HIN protease is indinavir, which is the sulfate salt of Ν-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)- hydroxy-5-(l-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)- piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred protease inhibitors are nelfinavir and ritonavir. Another preferred inhibitor of HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid. Preferred non- nucleoside inhibitors of HIV reverse transcriptase include efavirenz. The preparation of ddC, ddl and AZT are also described in EPO 0,484,071. These combinations may have unexpected effects on limiting the spread and degree of infection of HIN. Preferred combinations include those with the following (1) indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddl and/or ddC; (2) indinavir, and any of AZT and or ddl and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and lamivudine. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICN, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans. The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl- pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy- ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene gly cols. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of The present invention are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
In the treatment or prevention of conditions which require chemokine receptor modulation an appropriate dosage level will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples.
Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. According to one general process, (A), compounds of formula (I) may be prepared from a compound of formula (II)
Figure imgf000043_0001
(ID wherein Ar, X, Y, m and n are as defined in relation to formula (I), by reaction with a compound of the formula (III)
Z
LG Λ' *R
rø wherein R and Z are as defined in relation to formula (I) and LG represents a leaving group such as a halogen atom or an alkyl- or aryl-sulphonyloxy group, e.g. chlorine, bromine or iodine or a methylsulphonate or p-toluenesulphonate group, in the presence of a base.
For compounds wherein Y is two hydrogen atoms and Z is oxygen, suitable bases include organic bases such as tertiary amines, e.g. triethylamine, and inorganic bases such as alkali metal carbonates, e.g. sodium carbonate or potassium carbonate. Conveniently, the reaction is effected in a suitable organic solvent, such as dimethylformamide, acetonitrile or dichloromethane, conveniently at a temperature between room temperature and 100°C.
For compounds wherein Y is oxygen and Z is two hydrogen atoms, suitable bases include alkali metal hydrides, e.g. sodium hydride. Conveniently, the reaction is effected in a suitable organic solvent such as an ether, e.g. tetrahydrofuran, conveniently at a temperature between room temperature and 100°C.
According to another process, (B), compounds of formula (I) may be prepared from compounds of formula (IN):
Figure imgf000045_0001
(IV)
wherein Ar, R Y and Z are as defined in relation to formula (I) and LG is as previously defined, by reaction with an amine of formula (N):
Figure imgf000045_0002
(V)
wherein X, m and n are as defined in relation to formula (I), in the presence of a base.
Suitable bases include organic bases such as tertiary amines, e.g. triethylamine, and inorganic bases such as alkali metal carbonates, e.g. sodium carbonate or potassium carbonate. Conveniently, the reaction is effected in a suitable organic solvent, such as dimethylformamide, acetonitrile or dichloromethane, conveniently at a temperature between room temperature and 100°C.
Compounds of formula (II) may be prepared from compounds of formula (VI):
Figure imgf000045_0003
( D wherein Ar and Y are as defined in relation to formula (I), LG is as previously defined, and R is a suitable amine protecting group, such as an alkoxycarbonyl group, for example, £ert butoxycarbonyl, by reaction with an amine of formula (N) according to the method of process (B) above, followed by removal of any protecting group where present.
Compounds of formula (IN) may be prepared from compounds of formula (Nil):
Figure imgf000046_0001
(VII) by conventional methodology. For instance, where the desired leaving group is a halogen atom, by reaction with a corresponding halogen acid, such as hydrogen bromide or hydrogen iodide. Where the leaving group is an alkyl- or aryl-sulphonyloxy group, the compound of formula (Nil) may be reacted with, for example, methanesulfonyl chloride or p-toluenesulfonyl chloride.
Alternatively, compounds of formula (IN) may be prepared by the reaction of a compound of formula (NIII):
Figure imgf000046_0002
(VIII)
with a compound of formula (II) according to the method of process (A).
Compounds of formula (Nil) may be prepared by the reaction of a compound of formula (IX):
Figure imgf000047_0001
(IX)
where R 30 is a suitable hydroxy protecting group, for example, tetrahydropyran, with a compound of formula (II) according to the method of process (A), above, followed by removal of any protecting group where present.
Compounds of formula (IX) in which Y is two hydrogen atoms may be prepared by reduction of the corresponding compound of formula (IX) in which Y is an oxygen atom. Suitable reducing agents include hydrides such as lithium aluminium hydride in a suitable solvent, for example, tetrahydrofuran, conveniently at a temperature between room temperature and 100°C, for example, at about 60°C.
Alternatively, compounds of formula (IX) in which Y is two hydrogen atoms may be prepared in a two-step reaction from a compound of formula (X)
Figure imgf000047_0002
(X)
wherein R 30 is a suitable hydroxy protecting group as previously defined and R is a Ci-6alkyl group, espeically an ethyl group. Firstly the compound of formula (X) is reduced using, for example, lithium aluminium hydride as described above. The resulting compound of formula (Xa):
Figure imgf000048_0001
(Xa)
is then cyclized by converting the alcohol group to a leaving group using, for example, triphenyl phosphine, followed by the addition of diethyl azodicarboxylate (DEAD) in a suitable organic solvent, for example, dichloromethane, to complete the cyclization, this method being based upon that described by R.C. Bernotas and R.V. Cube in Tetrahedron Letters (1990) 91, 161-164.
Compounds of formula (IX) in which Y is an oxygen atom may also be prepared from a corresponding compound of formula (X), by hydrogenation in the presence of an excess of Raney™ nickel. A suitable solvent for this reaction is a mixture of ethanol and ammonia.
Compounds of formula (X) may be prepared from a compound of formula (XI):
Figure imgf000048_0002
(XI)
by a Michael addition using a compound of the formula H2C=CHCO2R and a suitable base, preferably, iV-benzyltrimethyl-ammonium hydroxide (Triton B™).
Compounds of formula (XI) may be prepared by the alkylation of a compound of formula (XII) with a compound of formula (XIII):
Figure imgf000048_0003
(XII) (XIII) wherein Ar, R 30 and LG are as previously defined, using conventional conditions, for example, using a base such as sodium hydride in a suitable solvent such as tetrahydrofuran, preferably at a temperature between -25°C and room temperature. Compounds of formulae (III), (N), (XII) and (XIII) are commercially available, or may be prepared from commercially available starting materials using conventional procedures well known to those skilled in the art.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective
Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
In particular, amino moieties may be protected by, for example, the formation of alkoxycarbonyl derivatives, e.g. tert- butoxycarbonyl and trichloroethoxycarbonyl, or benzyl, trityl or benzyloxycarbonyl derivatives. Subsequent removal of the protecting group is achieved by conventional procedures thus, for example, tert- butoxycarbonyl, benzyl or benzyloxycarbonyl groups may be removed by hydrogenolysis in the presence of a catalyst e.g. palladium; a trichloroethoxycarbonyl group may be removed with zinc dust; and a trityl group may be removed under acidic conditions using standard procedures.
Where hydroxyl groups require protection, this may be effected by the formation of esters or trialkylsilyl, tetrahydropyran or benzyl ethers. Such derivatives may be deprotected by standard procedures thus, for example, a tetrahydropyran ether derivative may be deprotected using hydrochloric acid in methanol. In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.
INTERMEDIATE 1
3.4-Dichlorotetrahydropyranyloxypropyl- -benzeneacetonitrile
3,4-Dichlorophenylacetonitrile (52.0g, 0.280mol) and 3- bromopropoxy-tetrahydropyrane (68.6g, l.leq) were mixed in tetrahydrofuran (350ml) and cooled to -20°C. Sodium hydride (60% in oil, 30g, 2.7eq) was added during 25 minutes. The solution was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched carefully with water and partitioned with ethyl acetate and the aqueous phase was extracted with ethyl acetate (x2). The combined organic phase was washed with water (x2), brine (xl) and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography using petroleum ether/dichloromethane
(gradient 100:0 to 0:100) as eluant to provide the title compound as a viscous yellow oil (77.0g, 84% yield). 1H NMR (250MHz, CDCI3): δ 7.48 (2H, m) 7.20 (1H, dd, Ji=8.29Hz, J2=2.17Hz) 4.55 (1H, t, J=1.74Hz) 3.92- 3.74 (2H, m) 3.55-3.39 (2H, m) 2.07-1.97 (2H, m) 1.83-1.71 (4H, m) 1.55 (4H, m) 1.26 (1H, t, J=14.29Hz). m z (ES+) 327/329 due to chlorine isotope pattern.
INTERMEDIATE 2
4- [3-Tetrahydropyranyloxypropyl] -4-cyano-4- [3 ,4-dichlorophenyl] - ethylbutanoate
The nitrile (Intermediate 1) (30.15g, 0.0919mol) was dissolved in 1,4-dioxane (200ml). Ethyl acrylate (17.56g, 1.7eq) and Triton B™ (5ml, 40wt%, methanol) were added and the solution was stirred at 80°C for 29 hours at room temperature. The reaction was quenched with ammonium chloride and extracted with diethyl ether (x2). The combined organic phase was washed with water (x2), brine (xl) and dried (MgSO4). The solvent and unreacted ethyl acrylate were evaporated to provide the title compound as a viscous yellow oil (37.4g, 95% yield). 1H NMR (250MHz, CDCI3): δ 7.48 (2H, m) 7.26 (IH, dd, Jl=8.29Hz, J2=2.17Hz) 4.51 (IH, dt, J]=10.23Hz, J2=3.21Hz) 4.17-4.03 (2H, m) 3.86-3.65 (2H, m) 3.51-3.32 (2H, m) 2.54-1.96 (6H, ) 1.77-1.66 (4H, m) 1.51 (4H, m) 1.24 (3H, m). m/z (ES+) 428/430 due to chlorine isotope pattern
INTERMEDIATE 3
5-f3-Tetrahydropyranyloxypropyl1-5-f3.4-dichlorophenyn-piperidin-2-one The ester nitrile (Intermediate 2) (26.66g, 0.062mol) was dissolved in ethanol (140ml) and ammonia (22ml). Raney™ nickel catalyst was added (8 "scoops") and the solution was hydrogenated at 40 psi for 48 hours (the hydrogen was recharged several times the first couple of hours). The solution was filtered, keeping the catalyst wet at all times, the solvent was evaporated under high vacuum and the residue was purified by flash chromatography using ethyl acetate/methanol (gradient 100:0 to 80:20) as eluant to provide the title compound as a clear yellow viscous oil (18.3g, 76% yield). H NMR (360MHz, CDCI3): δ 7.41 (2H, m) 7.15 (IH, dd, Ji=8.45Hz, J2=2.31Hz) 7.10 (IH, s) 4.45 (IH, dt, Jι=10.23Hz, J2=3.21Hz) 3.77 (IH, m) 3.69-3.56 (2H, m) 3.45 (IH, m) 3.36 (IH, dd, Ji=12.71Hz, J2=undetectable) 3.25 (IH, m) 2.16- 2.04 (2H, m) 1.88-1.79 (2H, m) 1.65 (2H, m) 1.51 (4H, ) 1.33-1.18 (3H, m).
INTERMEDIATE 4
5- [3-Tetrahydropyranyloxypropyl] -5- [3,4-dichlorophenyl] - 1- benzylpiperidin-2-one
The piperidinone (Intermediate 3) (4.43g, O.OlOmol) was dissolved in tetrahydrofuran (40ml). Sodium hydride (60% in oil, 0.44g, l.leq) and benzyl bromide (1.88g, l.leq) were added and the mixture stirred at room temperature for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (x3). The combined organic phase was washed with water (xl), brine (xl) and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography using ethyl acetate/petroleum ether (50:50) as eluant to provide the title compound. H NMR (250 MHz, CDCI3) (this spectrum only contains very broad peaks so in the following only the chemical shifts and the integrations are given) δ 7.34 (6H) 7.08 (IH) 6.80 (IH) 4.86 (IH) 4.42 (IH) 3.75 (IH) 3.52 (3H) 3.22 (2H) 2.44 (IH) 2.12 (2H) 1.67 (4H) 1.51 (4H) 1.17 (3H).
INTERMEDIATE 5
5-[3-Hvdroxypropyl1-5-[3.4-dichlorophenyl1-l-benzylpiperidin-2-one
The THP protected piperidinone (Intermediate 4) (4.11g, 8.65mmol) was deprotected by stirring with 3M hydrochloric acid/methanol (50ml) for 2 hours. The solvent was evaporated and the residue was redissolved in ethyl acetate and washed with sodium bicarbonate (xl), brine (xl) and dried (MgSO4). The solvent was evaporated to afford the title compound as a yellow oil which was used without further purification.
INTERMEDIATE 6
5-[3-Methanesulfonyloxypropyl]-5-[3,4-dichlorophenyl]-l-benzylpiperidin- 2-one
The deprotected piperidinone (Intermediate 5) (3.28g, 8.39mmol) was dissolved in dichloromethane (25ml) on a water bath. Triethylamine (1.27g, 1.5eq) was added followed by methanesulfonyl chloride (1.05g, l.leq). The mixture was stirred for 1.5 hours at room temperature and then quenched with sodium bicarbonate. The aqueous phase was extracted with dichloromethane (x2) and the combined organic phase was washed with water (xl), brine (xl) and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography using ethyl acetate/petroleum ether (gradient 50:50 to 100:0) as eluant to provide the title compound as a clear gum. *H NMR (250MHz, CDCI3): δ 7.38-7.26 (6H, m) 7.08 (IH, d, J=2.28Hz) 6.78 (IH, dd, Ji=8.44Hz, J2=2.28Hz) 4.87 (IH, d, J=14.31Hz) 4.36 (IH, d, J=14.31Hz) 4.02 (IH, t, J=6.15Hz) 3.54 (IH, d, J=12.02Hz) 3.27 (IH, d, J=12.02Hz) 2.94 (3H, s) 2.51-2.41 (IH, m) 2.26-1.97 (3H, m) 1.84-1.57 (2H, m) 1.36-1.24 (2H, m).
INTERMEDIATE 7
5-(3-Tetrapyranyloxypropyl)-5- [3.4-dichlorophenyll -piperidine The THP protected piperidinone (Intermediate 3) (13.74g,
0.036mol) was dissolved in tetrahydrofuran (100ml) and IM lithium aluminium hydride (78ml, 2eq) was added. The solution was stirred at 60°C on an oil bath for 2 hours. The reaction was quenched carefully with 2M sodium hydroxide (15ml) and water (15ml). The aqueous phase was extracted with ethyl acetate (x2) and the combined organic phase was washed with water (xl), brine (xl) and dried (MgSO4). The solvent was evaporated to provide the title compound (lO.Og, 76% yield). H NMR (250MHz, CDCI3): δ 7.41-7.38 (2H, m) 7.17 (IH, dd, Ji=8.47Hz, J2=2.23Hz)
4.46 (IH, t, J=3.51Hz) 3.84-3.75 (IH, m) 3.69-3.56 (IH, m) 3.49-3.41 (IH, m) 3.28-3.19 (2H, m) 2.86-2.71 (2H, m) 2.12-2.05 (IH, m) 1.85-1.37 (12H, m) 1.31-1.14 (3H, m).
INTERMEDIATE 8 5-(3-Tetrapyranyloxypropyl)-5- [3, 4-dichlorophenyl] -piperidine (Alternative route)
Step A) 4-(3-Tetrahydropyranyloxypropyl)-4-cyano-4-[3,4- dichlorophenyn-butan-1-ol
The nitrile ester (Intermediate 2) (2.07g, 4.84mmol) was dissolved in tetrahydrofuran (10ml) and cooled on a ice-bath, lithium aluminium hydride (IM, THF, 14.5ml, 3eq) was added over 10 minutes. The solution was then stirred at 60°C on an oil bath for 2 hours after which it quenched carefully with sodium, hydroxide (2M, 2ml) and water (2ml). The solution was filtered through a Hyflo filter and the filtrate was dried (MgSO4) and evaporated to provide the title compound (1.71g, 91% yield).
Step B) 5-(3-Tetrapyranyloxypropyl)-5-[3,4-dichlorophenyl]- piperidine
The amino alcohol of Step (A) (1.70g, 436mmol) was dissolved in anhydrous dichloromethane and triphenyl phosphine (1.26g, l.leq) was added. After stirring for 5 minutes diethyl azodicarboxylate (0.73g, leq) was added and the mixture was stirred for 5 hours. The solution was diluted with water and extracted with dichloromethane (x2). The combined organic phase was washed with water (x2), brine (xl), dried (MgSO4) and the solvent was evaporated.
The residue was purified by flash chromatography using ethyl acetate/methanol/ammonia (gradient 100:0:0 to 90:10:0.2) as eluant to provide the title compound (1.123g, 69% yield).
INTERMEDIATE 9
5-(3-Tetrapyranyloxypropyl)-5-[3.4-dichlorophenyn-l-benzoylpiperidine The THP protected piperidine (Intermediate 7) (lO.Og,
0.027mol) was dissolved in dichloromethane (50ml) on an ice-bath. Triethylamine (3.00g, l.leq) was added. Benzoyl chloride (4.18g, l.leq) was dissolved in dichloromethane (50ml) and added dropwise. The reaction was allowed to warm to 23°C, stirred for 2 hours and then quenched with sodium bicarbonate and extracted with dichloromethane (x3). The combined organic phase was washed with water (xl), brine (xl) and dried (MgSO4). The solvent was removed in vacuo to provide the title compound as a brown solid. This material was used without further purification. 1H NMR at 353K (360MHz, DMSO): δ 7.53 (IH, d, J=8.58Hz) 7.50 (IH, m) 7.40 (3H, m) 7.31 (IH, m) 7.23 (2H, m) 4.41 (IH, m) 4.12 (IH, m) 3.66 (IH, m) 3.51-3.36 (5H, m) 3.22 (IH, m) 2.10 (IH, m) 1.84 (IH, m) 1.68 (2H, m) 1.56 (2H, m) 1.42 (6H, m) 1.18 (2H, m).
INTERMEDIATE 10 5-(3-Hydroxypropyl)-5-[3.4-dichlorophenyn-l-benzoylpiperidine
The THP protected amide (Intermediate 9) (12.8g, 0.027mol) was deprotected by stirring with 3M hydrochloric acid in methanol (150ml) for 2 hours. The solvent was removed in vacuo and the residue was redissolved in ethyl acetate and washed with sodium bicarbonate (xl), water (xl) and (MgSO4). The solvent was evaporated to provide the title compound. This material was used without further purification. 1H NMR at 353K (360MHz, DMSO): δ 7.53 (IH, d, J=8.47Hz) 7.49 (IH, s) 7.41 (3H, m) 7.30 (IH, m) 7.22 (2H, m) 4.18 (IH, m) 4.04 (IH, m) 3.43-3.22 (5H, m) 2.11 (IH, m) 1.81 (IH, m) 1.69-1.54 (3H, m) 1.36 (IH, m) 1.04 (2H, m).
INTERMEDIATE 11
5-(3-Methanesulfonylpropyl)-5-f3.4-dichlorophenvn-l-benzoylpiperidine The amido alcohol (Intermediate 10) (11.3g, 0.029mol) was dissolved in dichloromethane (100ml), triethylamine (4.36g, 1.5eq) and then methanesulfonyl chloride (3.63g, l.leq) were added and the mixture stirred for 1 hour. The reaction was quenched with sodium bicarbonate and extracted with dichloromethane (x3). The organic layer was washed with water (xl), brine (xl) and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography using ethyl acetate/petroleum ether (50:50 and 100:0) as eluant to provide the title compound as a gum (8.82g, 63% yield), m/z (ES+) 470. EXAMPLE 1
5-[3-{4,4-(iV-Sulfonamidomethyl-3,3-indolyl)piperidino}propyl]-5-[3,4- diphenyll-l-benzylpiperidin-2-one
The lactam mesylate (Intermediate 6) (0.433g, 0.923mmol) was dissolved in dimethylformamide (3ml). Potassium carbonate (0.262g, 2eq) and 4,4-[iV-sulfonamidomethyl-3,3-indolyl]-piperidine (0.268g, l.leq) was added and stirred at 60°C on an oil bath for 16 hours. The solution was diluted with water (xl5) and extracted with ethyl acetate (x2). The combined organic phase was washed with water (x2), brine (xl) and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography using dichloro- methane/methanol (gradient 100:0 to 95:5) as eluant to provide the title compound as a white amorphous solid (219mg, 37% yield). XH NMR (250MHz, CDCI3): δ 7.42-7.02 (11H, m) 6.80 (IH, dd, Ji=8.45Hz, J2=2.30Hz) 4.86 (IH, d, J=14.33Hz) 4.39 (IH, d, J=14.33Hz) 3.74 (2H, s) 3.56 (IH, d, J=12.76Hz) 3.26 (IH, d, J=12.76Hz) 2.88 (3H, s) 2.71 (2H, br.s) 2.50- 2.41 (IH, m) 2.25-1.46 (13H, m) 1.08 (2H, m). m/z (ES+) 640.
EXAMPLE 2
5-[3-{4-(2-Keto-l-benzimidazolinyl)-piperidino}propyl]-5-[3,4- dichlorophenyH-l-benzylpiperidin-2-one
The lactam mesylate (Intermediate 6) (0.336g, 0.716mmol) was dissolved in dimethylformamide (5ml). Potassium carbonate (0.198g, 2eq) and 4- [2-keto-l-benzimidazolinyl] -piperidine (0.175g, l.leq) was added and stirred at 60°C on an oil bath for 16 hours. The solution was diluted with water (xl5) and extracted with ethyl acetate (x2). The combined organic phase was washed with water (x2), brine (xl) and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography (three times) using dichloro- methane/methanol (gradient 100:0 to 96:4) as eluant to provide the title compound as a white amorphous solid (13mg, 3% yield). H NMR (250MHz, CDCI3): δ 7.42-7.20 (7H, m) 7.12-7.00 (4H, m) 6.81 (IH, dd, Jl=8.45Hz, J2=2.30Hz) 4.86 (IH, d, J=14.33Hz) 4.40 (IH, d, J=14.33Hz) 4.30 (IH, m) 3.56 (IH, d, J=12.76Hz) 3.26 (IH, d, J=12.76Hz) 2.86 (2H, br.s) 2.52- 2.01 (10H, m) 1.78-1.68 (4H, m) 1.60-1.47 (IH, m) 1.09 (2H, m). m z (ES+) 591
EXAMPLE 3
5- [3-{4-Acetyl-4-phenyl-piperidino}propyl] -5- [3 ,4-dichlorophenyl] - 1- benzylpiperidin-2-one
The lactam mesylate, (Intermediate 6) (0.437g, 0.932mmol) was dissolved in dimethylformamide (5ml). Potassium carbonate (0.385 g, 3 eq) and 4-acetyl-4-phenylpiperidine hydrochloride (0.248g, l.leq) was added and stirred at 60°C on an oil bath for 16 hours. The solution was diluted with water (xl5) and extracted with ethyl acetate (x2). The combined organic phase was washed with water (x2), brine (xl) and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography using dichloromethane/methanol (gradient 99:1 to 97:3) as eluant to provide the title compound as a white amorphous solid (220mg, 41% yield). 1H NMR (250MHz, CDCI3): δ 7.37- 7.24 (11H, m) 7.08 (IH, d, J=2.18Hz) 6.78 (IH, dd, Ji=8.45Hz, J2=2.18Hz) 4.86 (IH, d, J=14.31Hz) 4.36 (IH, d, J=14.31Hz) 3.53 (IH, d, J=12.70Hz) 3.23 (IH, d, J=12.70Hz) 2.49-2.38 (6H, m) 2.22-1.87 (11H, m) 1.69 (IH, td, Ji=12.78Hz, J2=5.51Hz) 1.48 (IH, td, Jι=12.78Hz, J2=5.51Hz) 1.03 (2H, m). m/z (ES+) 577
EXAMPLE 4
5- [3-{ 1-Phenyl- 1 ,3 ,8-triazaspiro [4.5] decan-4-one}propyl] -5- [3 ,4- dichlorophenvn-l-benzylpiperidin-2-one
The lactam mesylate (Intermediate 6) (0.420g, 0.896mmol) was dissolved in dimethylformamide (6ml). Potassium carbonate (0.493g, 4eq) and l-phenyl-l,3,8-triazaspiro[4.5]decan-4-one (0.231g, l.leq) was added and stirred at 60°C on an oil bath for 16 hours. The solution was diluted with water (xl5) and extracted with ethyl acetate (x2). The combined organic phase was washed with water (x2), brine (xl) and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography using dichloromethane/methanol (gradient 99:1 to 95:5) as eluant to provide the title compound as a white amorphous solid (186mg, 34% yield). 1H NMR (360MHz, CDCI3): δ 7.39- 7.23 (9H, m) 7.10 (IH, d, J=2.25Hz) 6.87 (3H, m) 6.81 (IH, dd, Jι=8.45Hz, J2=2.25Hz) 4.85 (IH, d, J=14.34Hz) 4.69 (2H, s) 4.39 (IH, d, J=14.34Hz) 3.55
(IH, d, J=12.70Hz) 3.26 (IH, d, J=12.70Hz) 2.65-2.42 (6H, m) 2.23-2.12 (4H, m) 2.06-1.97 (2H, m) 1.74 (IH, td, Ji=12.67Hz, J2=5.02Hz) 1.66 (2H, d,
J=13.15Hz) 1.52 (IH, td, Ji=12.67Hz, J2=5.02Hz) 1.06 (2H, m). m/z (ES+) 605
EXAMPLE 5 5-[3-{4,4-(A^-Sulfonamidomethyl-3,3-indolyl)piperidino}propyl]-5-[3,4- diphenyn-1-benzoylpiperidine
The amide mesylate (Intermediate 11) (0.70g, 1.49mmol) was dissolved in dimethylformamide (8ml). Potassium carbonate (0.44g, 2eq) and 4,4-(iV-sulfonamido-3,3-indolyl)-piperidine (0.48g, 1.2eq) were added and the mixture was stirred on an oil bath at 60°C for 16 hours. The reaction was diluted with water (xl5) and extracted with ethyl acetate (x2). The organic phase was washed with water (xl), brine (xl) and dried (MgSO4). The solvent was evaporated and the residue was purified twice by flash chromatography using dichloromethane/methanol (gradient 99:1 and 98:2) as eluant to provide the title compound as a white amorphous solid (178mg, 19% yield). H NMR at 353K (360MHz, DMSO): δ 7.54 (IH, d, J=8.47Hz) 7.52 (IH, s) 7.42 (3H, m) 7.33 (IH, m) 7.21 (5H, m) 7.02 (IH, t, J=7.34Hz) 4.11 (IH, br.s) 3.73 (2H, s) 3.53 (IH, d, J=13.32Hz) 3.36 (2H, br.s) 2.98 (3H, s) 2.62 (2H, m) 2.17 (3H, m) 1.95-1.75 (5H, m) 1.64-1.54 (5H, m) 1.39 (IH, br.s) 1.07 (2H, m). m/z (ES+) 640
EXAMPLE 6
5-[3-{4-(2-Keto-l-benzimidazolinyl)-piperidino}propyl]-5-[3,4- dichlorophenyll-l-benzoylpiperidine
The amide mesylate (Intermediate 11) (0.660g, 1.41mmol) was dissolved in dimethylformamide (5ml). Potassium carbonate (0.388g, 2eq) and 4-(2-keto-l-benzimidazolinyl)-piperidine (0.366g, 1.2eq) were added and the mixture was stirred on an oil bath at 60°C for 16 hours. The reaction was diluted with water (xl5) and extracted with ethyl acetate (x2). The organic phase was washed with water (xl), brine (xl) and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography using dichloromethane/ methanol (gradient 100:0 to 94:6) as eluant to provide the title compound as a white amorphous solid (174mg, 21% yield). 1H NMR at 353K (360MHz, DMSO): δ 10.52 (IH, s) 7.54 (IH, d, J=8.47Hz) 7.52 (IH, s) 7.42 (3H, m) 7.34 (IH, m) 7.24 (2H, m) 7.13 (IH, m) 6.94 (3H, m) 4.06 (2H, m) 3.53 (IH, d, J=13.46Hz) 3.37 (2H, br.s) 2.78 (2H, m) 2.29 (2H, m) 2.17 (3H, m) 1.97-1.87 (3H, m) 1.60 (5H, m) 1.38 (IH, br.s) 1.08 (2H, m). m z (ES+) 591 EXAMPLE 7
5-[3-{4-Acetyl-4-phenyl-piperidino}propyl]-5-[3,4-dichlorophenyl]-l- benzoylpiperidine
The amide mesylate (Intermediate 11) (0.567g, 1.21mmol) was dissolved in dimethylformamide (8ml). Potassium carbonate (0.333g, 2eq) and 4-acetyl-4-phenylpiperidine (0.270g, l.leq) were added and the mixture was stirred on an oil bath at 60°C for 16 hours. The reaction was diluted with water (xl5) and extracted with ethyl acetate (x2). The organic phase was washed with water (xl), brine (xl) and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography using dichloromethane/methanol (gradient 100:0 to 98:2) as eluant to provide the title compound as a white amorphous solid (123mg, 18% yield). 1H NMR at 353K (360MHz, DMSO): δ 7.54 (IH, d, J=8.47Hz) 7.52 (IH, s) 7.42-7.23 (11H, m) 4.08 (IH, m) 3.52 (IH, d, J=13.37Hz) 3.36 (2H, br.s) 2.37-2.30 (4H, m) 2.06 (5H, m) 1.95-1.85 (6H, m) 1.57 (3H, m) 1.37 (IH, br.s) 1.03 (2H, m). m/z (ES+) 577
EXAMPLE 8
5-[3-{l-Phenyl-l,3,8-triazaspiro[4.5]decan-4-one}propyl]-5-[3,4- dichlorophenyn-1-benzoylpiperidine
The amide mesylate (Intermediate 11) (0.760g, 1.62mmol) was dissolved in dimethylformamide (8ml). Potassium carbonate (0.847g, 3.8eq) and l-phenyl-l,3,8-triazaspiro[4.5]decan-4-one (0.270g, l.leq) were added and the mixture was stirred on an oil bath at 60°C for 16 hours. The reaction was diluted with water (xl5) and extracted with ethyl acetate (x2). The organic phase was washed with water (xl), brine (xl) and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography using dichloromethane/ methanol (gradient 100:0 to 98:2) as eluant to provide the title compound as a off- white amorphous solid (333mg, 34% yield). ^Η NMR at 353K (360MHz, DMSO): δ 8.29 (IH, s) 7.52 (2H, d, J=8.47Hz) 7.41 (3H, m) 7.33 (IH, br.s) 7.23 (4H, m) 6.88 (2H, d, J=8.11Hz) 6.78 (IH, t, J=7.28Hz) 4.56 (2H, s) 4.15 (IH, m) 3.52 (IH, d, J=13.40Hz) 3.38 (2H, br.s) 2.61-2.38 (6H, m) 2.19 (3H, m) 1.87 (IH, m) 1.72-1.51 (5H, m) 1.39 (IH, br.s) 1.10 (2H, m). m/z (ES+)
605
EXAMPLE 9
5- [3-{4,4-( 1 , l-Indanyl)piperidino}propyl] -5- [3 ,4-diphenyl] - 1- benzoylpiperidine
By employing essentially the procedures described above, the title compound was prepared from the amide mesylate (Intermediate 11) and 4,4-(l,l-indanyl)-piperidine. 1H NMR (DMSO-dβ): δ 7.54 (2H, m)
7.40 (3H, m) 7.32 (IH, br.m) 7.24 (2H, m) 7.10 (4H, m) 4.06 (IH, br.m) 3.53
(IH, d, J=13.4Hz) 3.36 (2H, br.s) 2.81 (2H, t, J=7.2Hz) 2.49 (2H, m) 2.18-
1.60 (14H, m) 1.37 (4H, m). m/z 561 (MH+, 100%).
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula I:
Figure imgf000061_0001
(I)
wherein: m is zero, 1 or 2; n is 1, 2 or 3, with the proviso that the sum of m + n is 1, 2, 3 or 4;
X is:
/ R /
R N or " c ; R2'
one of Y and Z is =O whereas the other represents two hydrogen atoms;
Ar is selected from the group consisting of: unsubstituted phenyl; phenyl which is substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, trifluoromethyl, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, C3_7cycloalkyl, C3-7cycloalkylCi-4alkyl, and Ci-6alkoxy; thienyl; benzothienyl; naphthyl; unsubstituted indolyl; and indolyl which is substituted on the nitrogen atom by a Cι_ 4alkyl group;
R is selected from the group consisting of: unsubstituted phenyl; and phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, trifluoromethyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3- 7cycloalkylCi-4alkyl, and Cl-6alkoxy;
d from the group consisting of: hydrogen; Ci-βalkyl; Ci-6alkyl substituted by 1 or 2 substituents selected from: hydroxy, -OR3, oxo, -NHCOR3, -NR3R4, cyano, halogen, trifluoromethyl, unsubstituted phenyl, and phenyl substituted by 1 or 2 substituents selected from: hydroxy, cyano, halogen and trifluoromethyl; unsubstituted phenyl; phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Cl-4alkyl, -S(O)pCi_4alkyl and -C(O)R3; unsubstituted aryl; aryl substituted by 1, 2 or 3 substituents selected from : hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(O)pCi-4alkyl and -C(O)R3; and a saturated heterocyclic ring of 4, 5 or 6 ring atoms which ring contains 1 or 2 nitrogen atoms, one of which may be at the point of attachment to the remainder of the molecule, and optionally containing in the ring an oxygen atom, which ring is substituted on any available nitrogen atom by
5 a group R and which ring may be further substituted by a group selected from: hydroxyCι_4alkyl, Cι_4alkoxyCi-
3 4alkoxy, oxo and COR , and which ring may have fuse< thereto a phenyl ring, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(O)pCl-4alkyl, and -C(O)R ,3" . R is selected from:
3 Ci-6alkyl hydroxyCi_6alkyl, hydroxy, OR , halogen, trifluoromethyl, nitro, cyano, -NR3R4, -NHCOR3, -NR3COR4, -NHCO2R3, -NR3CO2R4, -NHS(O)pR3,
-NR3S(O)pR4, -CONR3R4, -COR3, -CO2R3 and -S(O)pR3;
or R 1 and R 2 are joined together to form a 5- or 6-membered non- aromatic ring which may contain in the ring 1 or 2 groups 5 of the formula -NR -, which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, a phenyl group, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Cl_4alkyl, -S(O)pCl-4alkyl, and -C(O)R3;
A
R and R are each independently selected from: hydrogen; unsubstituted Cl-6alkyl; Cl-6alkyl substituted by 1 or 2 substituents selected from unsubstituted: phenyl, hydroxy, oxo, cyano, Cl- 4alkoxy and trifluoromethyl; Ci_6alkoxy; unsubstituted phenyl; and phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, Cl-4alkyl, cyano, halogen, and trifluoromethyl ; or the group -NR R is a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulfur atom or a
5 group selected from: -NR -, -S(O)- or -S(O)2- and which ring may be optionally substituted by one or two groups selected from: hydroxyCι_4alkyl, Ci-4alkoxyCi-4alkyl, oxo, -COR6 and -CO2R6;
5 R is selected from: hydrogen, Ci-4al yl, -S(O)2Ci_4alkyl, -C(O)R3, unsubstituted phenyl and benzyl;
R is selected from: hydrogen or Cl-4alkyl; and p is zero, 1 or 2; or a pharmaceutically acceptable salt thereof; with the exception of:
5-[3-{4,4-(iV-sulfonamidomethyl-3,3- indolyl)piperidino}propyl]-5-[3,4-diphenyl]-l-benzylpiperidin-2-one;
5-[3-{4-(2-keto-l-benzimidazolinyl)-piperidino}propyl]-5-[3,4- dichlorophenyl]-l-benzylpiperidin-2-one;
5-[3-{4-acetyl-4-phenyl-piperidino}propyl]-5-[3,4- dichlorophenyl]-l-benzylpiperidin-2-one;
5-[3-{l-phenyl-l,3,8-triazaspiro[4.5]decan-4-one}propyl]-5- [3,4-dichlorophenyl]-l-benzylpiperidin-2-one; 5-[3-{4,4-(Λ^-sulfonamidomethyl-3,3- indolyl)piperidino}propyl]-5-[3,4-diphenyl]-l-benzoylpiperidine;
5-[3-{4-(2-keto-l-benzimidazolinyl)-piperidino}propyl]-5-[3,4- dichlorophenyl]-l-benzoylpiperidine;
5- [3-{4-acetyl-4-phenyl-piperidino}propyl] -5- [3 ,4- dichlorophenyl]-l-benzoylpiperidine;
5-[3-{l-phenyl-l,3,8-triazaspiro[4.5]decan-4-one}propyl]-5- [3,4-dichlorophenyl]-l-benzoylpiperidine; and
5- [3-{4,4-( 1 , l-indanyl)piperidino}propyl] -5- [3 ,4-diphenyl] - 1- benzoylpiperidine.
2. The compound of Claim 1 wherein:
Ar is unsubstituted phenyl or phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, triflouromethyl, Cl-6alkyl, C2-6alkenyl, C2-6alkynyl, C3_7cycloalkyl, C3_7cycloalkylCl- 4alkyl, and Cl-6alkoxy; or a pharmaceutically acceptable salt thereof.
3. The compound of Claim 1 wherein:
R is unsubstituted phenyl or phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, trifluoromethyl, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, C3_7cycloalkyl, C3-7cycloalkylCl- 4alkyl, and Cl-6alkoxy; or a pharmaceutically acceptable salt thereof.
4. The compound of Claim 1 wherein:
X is
Figure imgf000065_0001
wherein: R is unsubstituted phenyl, or a saturated heterocyclic ring of 5 ring atoms which ring contains 1 or 2 nitrogen atoms, one of which is at the point of attachment to the remainder of the molecule, which
5 ring is substituted on any available nitrogen atom by a group R , where
5 R is hydrogen, and which ring is substituted by an oxo group, and which ring has fused thereto a phenyl ring, wherein the phenyl ring is unsubstituted or substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci_4alkyl, -S(O)pCι_4alkyl, and -C(O)R3;
R2 is hydrogen or -COR3, where R3 is Ci-3alkyl; or R 1 and R 2 are joined together to form a 5-membered non- aromatic ring which optionallly contains in the ring 1 or 2 groups of the formula NR , which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, a phenyl group, wherein the phenyl ring is unsubstituted or substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR R , -NR R , -NR3COR4, halogen, trifluoromethyl, Cl-4alkyl, -S(O)pCi_4alkyl, and
-C(O)R3; or a pharmaceutically acceptable salt thereof.
5. The compound of Claim 1 wherein: m is 2 and n is 1; or a pharmaceutically acceptable salt thereof.
6. The compound of Claim 1 which is of the formula (la):
Figure imgf000066_0001
da)
wherein:
R , R , R and R are selected from: hydrogen and halogen;
R is an unsubstituted phenyl group or a saturated heterocyclic ring of 5 ring atoms which ring contains 1 or 2 nitrogen atoms, one of which is at the point of attachment to the remainder of the molecule, which ring is substituted on any available nitrogen atom by a group R , and which ring may be substituted by an oxo group, and which ring has fused thereto a phenyl ring, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci_4alkyl, -S(O)pCι_
4alkyl, and -C(O)R3;
R15 is -COR3, where R3 is Ci-6alkyl; or R and R are joined together to form a 5-membered non-aromatic ring which may contain in the ring 1 or 2 groups of the formula NR , which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, a phenyl group, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR 3 R 4 , -
NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci_4alkyl, -S(O)pCi-4alkyl, and -C(O)R3; and
one of Y and Z is =O whereas the other represents two hydrogen atoms; or a pharmaceutically acceptable salt thereof.
The compound of Claim 6 wherein:
R and R each are chlorine;
R 12 and R 13 each are hydrogen;
R is unsubstituted phenyl;
R15 is -COCH3; or R and R are joined together to form a 5-membered non-aromatic ring which may contain in the ring 1 or
5 2 groups of the formula -NR -, which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, an
5 unsubstituted phenyl group, wherein R is selec from: hydrogen, -S(O)2CH3 and phenyl.
8. The compound of Claim 1 wherein: m is 2, n is 1 and X is:
C R2' X
to give a group which is selected from:
Figure imgf000069_0001
Figure imgf000069_0002
Figure imgf000069_0003
wherein each phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(O)pCi_4alkyl and -C(O)R3, where R , R and p are as previously defined above.
9. The compound of Claim 1 wherein: m is 2, n is 1 and X is:
R1
C
R 2' \
to give a group which is selected from:
Figure imgf000070_0001
10. A method for modulation of chemokine receptor activity in a mammal comprising the administration of an effective amount of a compound of formula I:
Figure imgf000071_0001
(I)
wherein: m is zero, 1 or 2; n is 1, 2 or 3, with the proviso that the sum of m + n is 1, 2, 3 or 4;
X is:
Figure imgf000071_0002
one of Y and Z is =O whereas the other represents two hydrogen atoms;
Ar is selected from the group consisting of: unsubstituted phenyl; phenyl which is substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, trifluoromethyl, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylCl-4alkyl, and Cl-6alkoxy; thienyl; benzothienyl; naphthyl; unsubstituted indolyl; and indolyl which is substituted on the nitrogen atom by a Ci-
4alkyl group;
R is selected from the group consisting of: unsubstituted phenyl; and phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, trifluoromethyl, Cl-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3- 7cycloalkylCi_4alkyl, and Ci-6alkoxy;
d from the group consisting of: hydrogen; d-βalkyl; Ci-6alkyl substituted by 1 or 2 substituents selected from: hydroxy, -OR3, oxo, -NHCOR3, -NR3R4, cyano, halogen, trifluoromethyl, unsubstituted phenyl, and phenyl substituted by 1 or 2 substituents selected from: hydroxy, cyano, halogen and trifluoromethyl; unsubstituted phenyl; phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Cι_4alkyl, -S(O) Cl_4alkyl and -C(O)R3; unsubstituted aryl; aryl substituted by 1, 2 or 3 substituents selected from : hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Cι_4alkyl, -S(O) Ci-4alkyl and -C(O)R3; and a saturated heterocyclic ring of 4, 5 or 6 ring atoms which ring contains 1 or 2 nitrogen atoms, one of which may be at the point of attachment to the remainder of the molecule, and optionally containing in the ring an oxygen atom, which ring is substituted on any available nitrogen atom by a group R and which ring may be further substituted by a group selected from: hydroxyCi-4alkyl, Ci-4alkoxyCi-
3 4alkoxy, oxo and COR , and which ring may have fusei thereto a phenyl ring, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci_4alkyl, -S(O)pCi_4alkyl, and -C(O)R ,3u . 2 R is selected from:
3 Ci_6alkyl hydroxyCι_6alkyl, hydroxy, OR , halogen, trifluoromethyl, nitro, cyano, -NR3R4, -NHCOR3, -NR3COR4, -NHCO2R3, -NR3CO2R4, -NHS(O)pR3,
-NR3S(O)pR4, -CONR3R4, -COR3, -CO2R3 and -S(O)pR3;
or R 1 and R 2 are joined together to form a 5- or 6-membered non- aromatic ring which may contain in the ring 1 or 2 groups 5 of the formula -NR -, which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, a phenyl group, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(0)pCi-4alkyl, and -C(O)R3;
R and R are each independently selected from: hydrogen; unsubstituted Ci-6alkyl; Ci-6alkyl substituted by 1 or 2 substituents selected from unsubstituted: phenyl, hydroxy, oxo, cyano, Cl- 4alkoxy and trifluoromethyl; Cl-6alkoxy; unsubstituted phenyl; and phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, Cl-4alkyl, cyano, halogen, and trifluoromethyl; or the group -NR R is a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulfur atom or a
5 group selected from: -NR -, -S(O)- or -S(O)2- and which ring may be optionally substituted by one or two groups selected from: hydroxyCι_4alkyl, Ci-4alkoxyCi-4alkyl, oxo, -COR6 and -CO2R6;
R is selected from: hydrogen, Cl-4alkyl, -S(0)2Ci-4alkyl, -C(O)R3, unsubstituted phenyl and benzyl;
R is selected from: hydrogen or Ci-4alkyl; and p is zero, 1 or 2; or a pharmaceutically acceptable salt thereof.
11. The method of Claim 10 wherein the compound of Formula I:
Ar is unsubstituted phenyl or phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, triflouromethyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylCi- 4alkyl, and Cl-6alkoxy; or a pharmaceutically acceptable salt thereof.
12. The method of Claim 10 wherein the compound of
Formula I:
R is unsubstituted phenyl or phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, trifluoromethyl,
Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylCi_ 4alkyl, and Ci-6alkoxy; or a pharmaceutically acceptable salt thereof.
13. The method of Claim 10 wherein the compound of Formula I: X is
Figure imgf000074_0001
wherein:
R is unsubstituted phenyl, or a saturated heterocyclic ring of 5 ring atoms which ring contains 1 or 2 nitrogen atoms, one of which is at the point of attachment to the remainder of the molecule, which ring is substituted on any available nitrogen atom by a group R 5 , where
R is hydrogen, and which ring is substituted by an oxo group, and which ring has fused thereto a phenyl ring, wherein the phenyl ring is unsubstituted or substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci_4alkyl, -S(O)pCι_4alkyl, and -C(O)R3;
R 2 is hydrogen or -COR 3 , where R 3 is Ci-3alkyl;
or R 1 and R 2 are joined together to form a 5-membered non- aromatic ring which optionallly contains in the ring 1 or 2 groups of the formula NR , which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, a phenyl group, wherein the phenyl ring is unsubstituted or substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR R , -NR R , -NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(O)pCi_4alkyl, and
-C(O)R3; or a pharmaceutically acceptable salt thereof.
14. The method of Claim 10 wherein the compound is of the formula (la):
Figure imgf000076_0001
da)
wherein: R , R , R and R are selected from: hydrogen and halogen;
R is an unsubstituted phenyl group or a saturated heterocyclic ring of 5 ring atoms which ring contains
1 or 2 nitrogen atoms, one of which is at the point of attachment to the remainder of the molecule, which ring is
5 substituted on any available nitrogen atom by a group R , and which ring may be substituted by an oxo group, and which ring has fused thereto a phenyl ring, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4,
-NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(0)pCi- 4alkyl, and -C(O)R3;
R15 is -COR3, where R3 is Ci-6alkyl; or R and R are joined together to form a 5-membered non-aromatic ring which may contain in the ring 1 or 2 groups of the formula NR , which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, a phenyl group, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR 3 R 4 , -
NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(O)pCi_4alkyl, and -C(O)R3; and
one of Y and Z is =O whereas the other represents two hydrogen atoms; or a pharmaceutically acceptable salt thereof.
15. The method of Claim 14 wherein the compound of formula (la):
R and R each are chlorine;
R 12 and R 13 each are hydrogen;
R is unsubstituted phenyl;
R15 is -COCH3; or R and R are joined together to form a 5-membered non-aromatic ring which may contain in the ring 1 or
5 2 groups of the formula -NR -, which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, an
5 unsubstituted phenyl group, wherein R is selected from: hydrogen, -S(O)2CH3 and phenyl.
16. The method of Claim 10 wherein the compound m is 2, n is 1 and X is:
Figure imgf000077_0001
to give a group which is selected from:
Figure imgf000078_0001
Figure imgf000078_0002
Figure imgf000078_0003
Figure imgf000078_0004
wherein each phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci_4alkyl, -S(0)pCl-4alkyl and -C(O)R3, where R , R and p are as previously defined above.
17. The method of Claim 10 wherein the compound m is 2, n is 1 and X is:
R1
C
R 2' \
to give a group which is selected from:
Figure imgf000079_0001
18. The method of Claim 10 wherein the compound is selected from the group consisting of:
5-[3-{4,4-CN-sulfonamidomethyl-3,3- indolyl)piperidino}propyl] -5- [3 ,4-diphenyl] - l-benzylpiperidin-2-one;
5- [3-{4-(2-keto- l-benzimidazolinyl)-piperidino}propyl] -5- [3 ,4- dichlorophenyl] - l-benzylpiperidin-2-one; 5- [3-{4-acetyl-4-phenyl-piperidino}propyl] -5- [3 ,4- dichlorophenyl]-l-benzylpiperidin-2-one;
5- [3-{ 1-phenyl- 1 ,3 ,8-triazaspiro [4.5] decan-4-one}propyl] -5- [3,4-dichlorophenyl]-l-benzylpiperidin-2-one; 5-[3-{4,4-(iV-sulfonamidomethyl-3,3- indolyl)piperidino}propyl]-5-[3,4-diphenyl]-l-benzoylpiperidine;
5- [3- {4-(2-keto- l-benzimidazolinyl)-piperidino}propyl] -5- [3 ,4- dichlorophenyl]-l-benzoylpiperidine;
5-[3-{4-acetyl-4-phenyl-piperidino}propyl]-5-[3,4- dichlorophenyl]-l-benzoylpiperidine;
5- [3-{ 1-phenyl- 1 ,3,8-triazaspiro [4.5] decan-4-one}propyl] -5- [3,4-dichlorophenyl]-l-benzoylpiperidine;
5- [3-{4,4-( 1, l-indanyl)piperidino}propyl] -5- [3 ,4-diphenyl] - 1- benzoylpiperidine ; or a pharmaceutically acceptable salt thereof.
19. A method for preventing infection by HIN, treating infection by HIN, delaying of the onset of AIDS, or treating AIDS comprising the administration to a patient of an effective amount of a compound of formula I:
Figure imgf000080_0001
(I)
wherein: m is zero, 1 or 2; n is 1, 2 or 3, with the proviso that the sum of m + n is 1 to 4;
X is:
Figure imgf000081_0001
one of Y and Z is =O whereas the other represents two hydrogen atoms;
Ar is selected from the group consisting of: unsubstituted phenyl; phenyl which is substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, trifluoromethyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylCi-4alkyl, and Ci-6alkoxy; thienyl; benzothienyl; naphthyl; unsubstituted indolyl; and indolyl which is substituted on the nitrogen atom by a Cχ_ 4alkyl group;
R is selected from the group consisting of: unsubstituted phenyl; and phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, trifluoromethyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3_7cycloalkyl, C3- 7cycloalkylCi-4alkyl, and Cl-6alkoxy;
R is selected from the group consisting of: hydrogen; Ci-6alkyl; Ci_6alkyl substituted by 1 or 2 substituents selected from: hydroxy, -OR3, oxo, -NHCOR3, -NR3R4, cyano, halogen, trifluoromethyl, unsubstituted phenyl, and phenyl substituted by 1 or 2 substituents selected from: hydroxy, cyano, halogen and trifluoromethyl; unsubstituted phenyl; phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(O) Cχ-4alkyl and -C(O)R3; unsubstituted aryl; aryl substituted by 1, 2 or 3 substituents selected from : hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Cι_4alkyl, -S(O)pCi-4alkyl and -C(O)R3; and a saturated heterocyclic ring of 4, 5 or 6 ring atoms which ring contains 1 or 2 nitrogen atoms, one of which may be at the point of attachment to the remainder of the molecule, and optionally containing in the ring an oxygen atom, which ring is substituted on any available nitrogen atom by a group R and which ring may be further substituted by a group selected from: hydroxyCi-4alkyl, Ci-4alkoxyCl-
3 4alkoxy, oxo and COR , and which ring may have fused thereto a phenyl ring, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(O)pCi_4alkyl, and -C(O)R3;
elected from: Ci-6alkyl hydroxyCi-βalkyl, hydroxy, OR , halogen, trifluoromethyl, nitro, cyano, -NR 3 R 4 , -NHCOR 3 , -
NR3COR4, -NHCO2R3, -NR3CO2R4, -NHS(O)pR3, - NR3S(O)pR4, -CONR3R4, -COR3, -CO2R3 and -S(O)pR3;
or R 1 and R 2 are joined together. to form a 5- or 6-membered non- aromatic ring which may contain in the ring 1 or 2 groups
5 of the formula -NR -, which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, a phenyl group, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Cl-4alkyl, -S(O)pCi-4alkyl, and -C(O)R3; R and R are each independently selected from: hydrogen; unsubstituted Cl-6alkyl;
Ci-6alkyl substituted by 1 or 2 substituents selected from unsubstituted: phenyl, hydroxy, oxo, cyano, Ci-
4alkoxy and trifluoromethyl; Ci_6alkoxy; unsubstituted phenyl; and phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, Ci-4alkyl, cyano, halogen, and trifluoromethyl; or the group -NR R is a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulfur atom or a group selected from: -NR -, -S(O)- or -S(O)2- and which ring may be optionally substituted by one or two groups selected from: hydroxyCi-4alkyl, Ci-4alkoxyCi_4alkyl, oxo,
-COR6 and -CO2R6;
R is selected from: hydrogen, Ci^alkyl, -S(0)2Ci-4alkyl, -C(O)R3, unsubstituted phenyl and benzyl; R is selected from: hydrogen or Ci-4alkyl; and p is zero, 1 or 2; or a pharmaceutically acceptable salt thereof.
20. The method of Claim 19 wherein the compound of Formula I:
Ar is unsubstituted phenyl or phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, triflouromethyl, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylCi- 4alkyl, and Ci_6alkoxy; or a pharmaceutically acceptable salt thereof.
21. The method of Claim 19 wherein the compound of Formula I:
R is unsubstituted phenyl or phenyl substituted by 1, 2 or 3 substituents selected from: hydroxy, cyano, halogen, trifluoromethyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylCl- 4alkyl, and Cl_6alkoxy; or a pharmaceutically acceptable salt thereof.
22. The method of Claim 19 wherein the compound of Formula I: X is
Figure imgf000084_0001
wherein:
R is unsubstituted phenyl, or a saturated heterocyclic ring of 5 ring atoms which ring contains 1 or 2 nitrogen atoms, one of which is at the point of attachment to the remainder of the molecule, which ring is substituted on any available nitrogen atom by a group R , where R is hydrogen, and which ring is substituted by an oxo group, and which ring has fused thereto a phenyl ring, wherein the phenyl ring is unsubstituted or substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(O)pCi_4alkyl, and -C(O)R3;
R2 is hydrogen or -COR3, where R3 is Ci-3alkyl;
or R 1 and R 2 are joined together to form a 5-membered non- aromatic ring which optionallly contains in the ring 1 or 2 groups of the formula NR , which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, a phenyl group, wherein the phenyl ring is unsubstituted or substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR R , -NR R , -NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(0)pCi-4alkyl, and
3 -C(O)R ; or a pharmaceutically acceptable salt thereof.
23. The method of Claim 19 wherein the compound is of the formula (la):
Figure imgf000085_0001
(la)
wherein:
R , R , R and R are selected from: hydrogen and halogen;
R is an unsubstituted phenyl group or a saturated heterocyclic ring of 5 ring atoms which ring contains 1 or 2 nitrogen atoms, one of which is at the point of attachment to the remainder of the molecule, which ring is substituted on any available nitrogen atom by a group R , and which ring may be substituted by an oxo group, and which ring has fused thereto a phenyl ring, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(0)pC _ 4alkyl, and -C(O)R3;
R15 is -COR3, where R3 is Ci-6alkyl; or R and R are joined together to form a 5-membered non-aromatic ring which may contain in the ring 1 or 2 groups of the formula NR , which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, a phenyl group, wherein the phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR R , - NR3R4, -NR3COR4, halogen, trifluoromethyl, Ci-4alkyl, -S(O)pCi-4alkyl, and -C(O)R3; and
one of Y and Z is =O whereas the other represents two hydrogen atoms; or a pharmaceutically acceptable salt thereof.
24. The method of Claim 23 wherein the compound of formula (la):
R and R each are chlorine;
R 12 and R 13 each are hydrogen;
R is unsubstituted phenyl;
R15 is -COCH3; or R and R are joined together to form a 5-membered non-aromatic ring which may contain in the ring 1 or
5 2 groups of the formula -NR -, which ring is optionally substituted by an oxo group and which ring may be substituted by, or have fused thereto, an unsubstituted phenyl group, wherein R is selected from: hydrogen, -S(O)2CH3 and phenyl.
25. The method of Claim 19 wherein the compound m is 2, n is 1 and X is:
R C R2' N to give a group which is selected from:
Figure imgf000087_0001
Figure imgf000087_0002
Figure imgf000087_0003
wherein each phenyl ring may be substituted by 1 or 2 substituents selected from: hydroxy, cyano, -C(O)NR3R4, -NR3R4, -NR3COR4, halogen, trifluoromethyl, C -4alkyl, -S(0)pCi-4alkyl and -C(O)R3, where R , R and p are as previously defined above.
26. The method of Claim 19 wherein the compound m is 2, n is 1 and X is:
R1
\ /
C
R 2 ' \
to give a group which is selected from:
Figure imgf000088_0001
Figure imgf000088_0003
Figure imgf000088_0002
27. The method of Claim 19 wherein the compound is selected from the group consisting of:
5-[3-{4,4-(ΛT-sulfonamidomethyl-3,3- indolyl)piperidino}propyl] -5- [3 ,4-diphenyl] - l-benzylpiperidin-2-one;
5- [3-{4-(2-keto- l-benzimidazolinyl)-piperidino}propyl] -5- [3 ,4- dichlorophenyl]-l-benzylpiperidin-2-one; 5- [3-{4-acetyl-4-phenyl-piperidino}propyl] -5- [3,4- dichlorophenyl]-l-benzylpiperidin-2-one;
5-[3-{l-phenyl-l,3,8-triazaspiro[4.5]decan-4-one}propyl]-5- [3,4-dichlorophenyl]-l-benzylpiperidin-2-one; 5-[3-{4,4-(iV-sulfonamidomethyl-3,3- indolyl)piperidino}propyl]-5-[3,4-diphenyl]-l-benzoylpiperidine;
5- [3-{4-(2-keto- l-benzimidazolinyl)-piperidino}propyl] -5- [3,4- dichlorophenyl]-l-benzoylpiperidine;
5- [3-{4-acetyl-4-phenyl-piperidino}propyl] -5- [3 ,4- dichlorophenyl] - 1 -benzoylpiperidine;
5-[3-{l-phenyl-l,3,8-triazaspiro[4.5]decan-4-one}propyl]-5- [3,4-dichlorophenyl]-l-benzoylpiperidine;
5-[3-{4,4-(l,l-indanyl)piperidino}propyl]-5-[3,4-diphenyl]-l- benzoylpiperidine; or a pharmaceutically acceptable salt thereof.
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