+

WO1998031364A1 - Piperidines 3,3-disubstituees utilisees comme modulateurs de l'activite de recepteurs de chemokines - Google Patents

Piperidines 3,3-disubstituees utilisees comme modulateurs de l'activite de recepteurs de chemokines Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
ring
phenyl
4alkyl
substituted
group
Prior art date
Application number
PCT/US1998/001101
Other languages
English (en)
Inventor
Malcolm Maccoss
Sander G. Mills
Timothy Harrison
Christopher John Swain
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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/fr
Priority to AU61330/98A priority patent/AU6133098A/en
Priority to JP53466298A priority patent/JP2001508798A/ja
Priority to CA002278309A priority patent/CA2278309A1/fr
Publication of WO1998031364A1 publication Critical patent/WO1998031364A1/fr

Links

Classifications

    • 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).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • AIDS & HIV (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention a trait à des pipéridines 3,3-disubstituées, représentées par la formule (I), (dans laquelle X, Y, Z, Ar, R, m et n sont définis dans la demande) qui sont utiles comme modulateurs de l'activité de récepteurs de chémokines. En particulier, ces composés sont utiles comme modulateurs des récepteurs CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, et/ou CXCR-4 de chémokines.
PCT/US1998/001101 1997-01-21 1998-01-20 Piperidines 3,3-disubstituees utilisees comme modulateurs de l'activite de recepteurs de chemokines WO1998031364A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP98905975A EP1003743A4 (fr) 1997-01-21 1998-01-20 Piperidines 3,3-disubstituees utilisees comme modulateurs de l'activite de recepteurs de chemokines
AU61330/98A AU6133098A (en) 1997-01-21 1998-01-20 3,3-disubstituted piperidines as modulators of chemokine receptor activity
JP53466298A JP2001508798A (ja) 1997-01-21 1998-01-20 ケモカインレセプター活性のモジュレーターとしての３，３−二置換ピペリジン類
CA002278309A CA2278309A1 (fr) 1997-01-21 1998-01-20 Piperidines 3,3-disubstituees utilisees comme modulateurs de l'activite de recepteurs de chemokines

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US3585497P 1997-01-21 1997-01-21
US60/035,854 1997-01-21
GBGB9707490.0A GB9707490D0 (en) 1997-04-14 1997-04-14 3,3-Disubstituted piperidines as modulators of chemokine receptor activity
GB9707490.0 1997-04-14

Publications (1)

Publication Number Publication Date
WO1998031364A1 true WO1998031364A1 (fr) 1998-07-23

Family

ID=26311372

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/001101 WO1998031364A1 (fr) 1997-01-21 1998-01-20 Piperidines 3,3-disubstituees utilisees comme modulateurs de l'activite de recepteurs de chemokines

Country Status (5)

Country Link
EP (1) EP1003743A4 (fr)
JP (1) JP2001508798A (fr)
AU (1) AU6133098A (fr)
CA (1) CA2278309A1 (fr)
WO (1) WO1998031364A1 (fr)

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000035877A1 (fr) * 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company Piperidines heterocycliques utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
WO2000044365A1 (fr) * 1999-01-29 2000-08-03 Millennium Pharmaceuticals, Inc. Methodes de prevention des rejets de greffes et des lesions par ischemie/reperfusion
WO2000069815A1 (fr) * 1999-05-13 2000-11-23 Teijin Limited Derives d'amines cycliques ureido-substituees et leur utilisation en tant que medicament
WO2000076972A1 (fr) * 1999-06-11 2000-12-21 Merck & Co., Inc. Modulateurs n-cyclopentyliques de l'activite du recepteur de la chimiokine
WO2001014333A1 (fr) * 1999-08-24 2001-03-01 Astrazeneca Uk Limited Composes de piperidine substitues utiles comme modulateurs de l'activite de recepteurs de chimiokine
US6331541B1 (en) 1998-12-18 2001-12-18 Soo S. Ko N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6358979B1 (en) 1999-06-11 2002-03-19 Merck & Co., Inc. N-cyclopentyl modulators of chemokine receptor activity
US6362177B1 (en) 2000-05-16 2002-03-26 Teijin Limited Cyclic amine derivatives and their use as drugs
US6432981B1 (en) 1999-06-11 2002-08-13 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6441001B1 (en) 1998-12-18 2002-08-27 Bristol-Myers Squibb Pharma Company 2-substituted-4-nitrogen heterocycles as modulators of chemokine receptor activity
US6444686B1 (en) 1998-12-18 2002-09-03 Brsitol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6451842B1 (en) 1997-11-18 2002-09-17 Dupont Pharmaceuticals Company Cyclic amine derivatives and their use as drugs
US6472410B1 (en) 1999-06-11 2002-10-29 Merck & Co., Inc. N-cyclopentyl modulators of chemokine receptor activity
US6486180B1 (en) 1998-12-18 2002-11-26 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6492400B1 (en) 1998-12-18 2002-12-10 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6500844B1 (en) 1999-06-11 2002-12-31 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6506777B1 (en) 1999-06-11 2003-01-14 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6511826B2 (en) 1995-06-06 2003-01-28 Human Genome Sciences, Inc. Polynucleotides encoding human G-protein chemokine receptor (CCR5) HDGNR10
US6525069B1 (en) 1998-12-18 2003-02-25 Bristol-Myers Squibb Pharma Co. N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6538002B1 (en) 1999-06-11 2003-03-25 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6586430B1 (en) 1998-12-23 2003-07-01 Pfizer Inc. CCR5 modulators
US6627629B2 (en) 2000-06-30 2003-09-30 Bristol-Myers Squibb Pharma N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
EP1378510A1 (fr) * 2001-03-19 2004-01-07 Ono Pharmaceutical Co., Ltd. Derives de triazaspiro 5.5]undecane et medicaments les contenant en tant que principe actif
WO2004005295A1 (fr) * 2002-07-08 2004-01-15 Astrazeneca Ab Nouvelles spiropiperidines ou spiropyrrolidines tricycliques
WO2004026873A1 (fr) * 2002-09-18 2004-04-01 Ono Pharmaceutical Co., Ltd. Derives triazaspiro[5.5]undecanes et medicaments les contenant en tant que principe actif
US6743594B1 (en) 1995-06-06 2004-06-01 Human Genome Sciences, Inc. Methods of screening using human G-protein chemokine receptor HDGNR10 (CCR5)
WO2005037814A1 (fr) * 2003-10-17 2005-04-28 Astrazeneca Ab Nouveaux spiroderives tricycliques en tant que modulateurs de l'activite de recepteur de chimiokine
US6897234B2 (en) 1999-12-17 2005-05-24 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
WO2005049620A1 (fr) * 2003-11-20 2005-06-02 Astrazeneca Ab Nouveaux composes
WO2005054249A1 (fr) * 2003-12-05 2005-06-16 Astrazeneca Ab Nouveaux composes
WO2005061499A1 (fr) * 2003-12-22 2005-07-07 Astrazeneca Ab Nouveaux spiroderives tricycliques en tant que modulateurs de l'activite des recepteurs de chimiokines
US6958350B2 (en) 2001-02-19 2005-10-25 Astrazeneca Ab Chemical compounds
US6960602B2 (en) 2001-03-22 2005-11-01 Astrazeneca Ab Piperidine derivatives as modulators of chemokine receptors
US7041667B1 (en) 1998-12-23 2006-05-09 Pfizer, Inc. CCR5 modulators
US7175988B2 (en) 2001-02-09 2007-02-13 Human Genome Sciences, Inc. Human G-protein Chemokine Receptor (CCR5) HDGNR10
US7192973B2 (en) 2001-11-15 2007-03-20 Astrazeneca Ab Piperidine derivatives and their use as modulators of chemokine receptor activity (especially CCR5)
US7217714B1 (en) 1998-12-23 2007-05-15 Agouron Pharmaceuticals, Inc. CCR5 modulators
US7294636B2 (en) 2003-05-09 2007-11-13 Astrazeneca Ab Chemical compounds
US7390830B1 (en) 1999-05-18 2008-06-24 Teijin Limited Remedies or prophylactics for diseases in association with chemokines
US7393934B2 (en) 2001-12-21 2008-07-01 Human Genome Sciences, Inc. Human G-protein chemokine receptor (CCR5) HDGNR10
US7501123B2 (en) 2004-03-12 2009-03-10 Human Genome Sciences, Inc. Human G-protein chemokine receptor (CCR5) HDGNR10
US7576117B1 (en) 1999-08-04 2009-08-18 Teijin Limited Cyclic amine CCR3 antagonist
EP3050574A1 (fr) 2015-01-28 2016-08-03 Universite De Bordeaux Nouvelles compositions et méthodes de traitement et/ou de prévention d'une maladie pulmonaire obstructive chronique
WO2018112264A1 (fr) 2016-12-14 2018-06-21 Progenity Inc. Traitement d'une maladie du tractus gastro-intestinal avec une chimoikine/un inhibiteur du récepteur de chimiokine
WO2020106704A2 (fr) 2018-11-19 2020-05-28 Progenity, Inc. Dispositif ingestible pour administrer un agent therapeutique dans le tractus digestif
WO2021119482A1 (fr) 2019-12-13 2021-06-17 Progenity, Inc. Dispositif ingérable pour administrer un agent thérapeutique dans le tractus gastro-intestinal
WO2021165960A1 (fr) 2020-02-19 2021-08-26 Ichilov Tech Ltd. Traitement par antidépresseur amélioré
EP4252629A2 (fr) 2016-12-07 2023-10-04 Biora Therapeutics, Inc. Procédés, dispositifs et systèmes de détection du tractus gastro-intestinal

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UY31162A1 (es) * 2007-06-20 2008-11-28 Glaxo Group Ltd Espiroindolinas como moduladores de receptores de quimioquinas

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5340822A (en) * 1991-05-03 1994-08-23 Elf Sanofi Polycyclic amine compounds and their enantiomers, their method of preparation and pharmaceutical compositions in which they are present
US5350852A (en) * 1990-09-05 1994-09-27 Sanofi Arylalkylamines, process for preparing them and pharmaceutical compositions containing them
US5434158A (en) * 1994-04-26 1995-07-18 Merck & Co., Inc. Spiro-substituted azacycles as neurokinin-3 antagonists
EP0673928A1 (fr) * 1994-03-18 1995-09-27 Sanofi Nouveaux dérivés de la N-(3,4-dichlorophényl-propyl)-pipéridine comme antagonistes sélectifs du récepteur NK3 humain
EP0714891A1 (fr) * 1994-11-22 1996-06-05 Eli Lilly And Company Antagonistes hétérocycliques de récepteurs de la tachykinine
US5559132A (en) * 1992-11-03 1996-09-24 Zeneca Limited Carboxamide derivatives for treating asthma
US5589489A (en) * 1993-12-15 1996-12-31 Zeneca Limited Cyclic amide derivatives for treating asthma
WO1997010211A1 (fr) * 1995-09-14 1997-03-20 Sanofi Nouveaux composes antagonistes selectifs du recepteur nk3 humain, procede pour leur obtention et compositions pharmaceutiques les contenant
US5635510A (en) * 1993-05-06 1997-06-03 Merrell Pharmaceuticals Inc. Substituted pyrrolidin-3-yl-alkyl-piperidines

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU4176997A (en) * 1996-09-16 1998-04-02 Warner-Lambert Company 3-alkyl-3-phenyl-piperidines

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5350852A (en) * 1990-09-05 1994-09-27 Sanofi Arylalkylamines, process for preparing them and pharmaceutical compositions containing them
US5340822A (en) * 1991-05-03 1994-08-23 Elf Sanofi Polycyclic amine compounds and their enantiomers, their method of preparation and pharmaceutical compositions in which they are present
US5559132A (en) * 1992-11-03 1996-09-24 Zeneca Limited Carboxamide derivatives for treating asthma
US5635510A (en) * 1993-05-06 1997-06-03 Merrell Pharmaceuticals Inc. Substituted pyrrolidin-3-yl-alkyl-piperidines
US5589489A (en) * 1993-12-15 1996-12-31 Zeneca Limited Cyclic amide derivatives for treating asthma
EP0673928A1 (fr) * 1994-03-18 1995-09-27 Sanofi Nouveaux dérivés de la N-(3,4-dichlorophényl-propyl)-pipéridine comme antagonistes sélectifs du récepteur NK3 humain
US5434158A (en) * 1994-04-26 1995-07-18 Merck & Co., Inc. Spiro-substituted azacycles as neurokinin-3 antagonists
EP0714891A1 (fr) * 1994-11-22 1996-06-05 Eli Lilly And Company Antagonistes hétérocycliques de récepteurs de la tachykinine
WO1997010211A1 (fr) * 1995-09-14 1997-03-20 Sanofi Nouveaux composes antagonistes selectifs du recepteur nk3 humain, procede pour leur obtention et compositions pharmaceutiques les contenant

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, 1 January 1900, Columbus, Ohio, US; abstract no. 124:53407, XP002911010 *
CHEMICAL ABSTRACTS, 1 January 1900, Columbus, Ohio, US; abstract no. 125:299098, XP002911009 *
See also references of EP1003743A4 *

Cited By (79)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7160546B2 (en) 1995-06-06 2007-01-09 Human Genome Sciences, Inc. Human G-protein chemokine receptor (CCR5) HDGNR10
US6800729B2 (en) 1995-06-06 2004-10-05 Human Genome Sciences, Inc. Human G-Protein chemokine receptor HDGNR10 (CCR5 receptor)
US6511826B2 (en) 1995-06-06 2003-01-28 Human Genome Sciences, Inc. Polynucleotides encoding human G-protein chemokine receptor (CCR5) HDGNR10
US6743594B1 (en) 1995-06-06 2004-06-01 Human Genome Sciences, Inc. Methods of screening using human G-protein chemokine receptor HDGNR10 (CCR5)
US6759519B2 (en) 1995-06-06 2004-07-06 Human Genome Sciences, Inc. Antibodies to human G-protein chemokine receptor HDGNR10 (CCR5receptor)
US6451842B1 (en) 1997-11-18 2002-09-17 Dupont Pharmaceuticals Company Cyclic amine derivatives and their use as drugs
US6492400B1 (en) 1998-12-18 2002-12-10 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6919368B2 (en) 1998-12-18 2005-07-19 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6331541B1 (en) 1998-12-18 2001-12-18 Soo S. Ko N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6525069B1 (en) 1998-12-18 2003-02-25 Bristol-Myers Squibb Pharma Co. N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6780857B2 (en) 1998-12-18 2004-08-24 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6441001B1 (en) 1998-12-18 2002-08-27 Bristol-Myers Squibb Pharma Company 2-substituted-4-nitrogen heterocycles as modulators of chemokine receptor activity
US6444686B1 (en) 1998-12-18 2002-09-03 Brsitol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US7312222B2 (en) 1998-12-18 2007-12-25 Bristol-Myers Squibb Pharma Company Heterocyclic piperidines as modulators of chemokine receptor activity
US6759411B2 (en) 1998-12-18 2004-07-06 Bristol-Myers Squibb Pharma Company Heterocyclic piperidines as modulators of chemokine receptor activity
US6486180B1 (en) 1998-12-18 2002-11-26 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6875776B2 (en) 1998-12-18 2005-04-05 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6521592B2 (en) 1998-12-18 2003-02-18 Bristol-Myers Squibb Pharma Co. N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6331545B1 (en) 1998-12-18 2001-12-18 Soo S. Ko Heterocycyclic piperidines as modulators of chemokine receptor activity
WO2000035877A1 (fr) * 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company Piperidines heterocycliques utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
US6706735B2 (en) 1998-12-18 2004-03-16 Bristol-Myers Squibb Pharma Company 2-substituted-4-nitrogen heterocycles as modulators of chemokine receptor activity
US7041667B1 (en) 1998-12-23 2006-05-09 Pfizer, Inc. CCR5 modulators
US7217714B1 (en) 1998-12-23 2007-05-15 Agouron Pharmaceuticals, Inc. CCR5 modulators
US6586430B1 (en) 1998-12-23 2003-07-01 Pfizer Inc. CCR5 modulators
WO2000044365A1 (fr) * 1999-01-29 2000-08-03 Millennium Pharmaceuticals, Inc. Methodes de prevention des rejets de greffes et des lesions par ischemie/reperfusion
WO2000069815A1 (fr) * 1999-05-13 2000-11-23 Teijin Limited Derives d'amines cycliques ureido-substituees et leur utilisation en tant que medicament
US7390830B1 (en) 1999-05-18 2008-06-24 Teijin Limited Remedies or prophylactics for diseases in association with chemokines
US6432981B1 (en) 1999-06-11 2002-08-13 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6538002B1 (en) 1999-06-11 2003-03-25 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6593346B2 (en) 1999-06-11 2003-07-15 Merck & Co. Inc. N-cyclopentyl modulators of chemokine receptor activity
US6472410B1 (en) 1999-06-11 2002-10-29 Merck & Co., Inc. N-cyclopentyl modulators of chemokine receptor activity
US6500844B1 (en) 1999-06-11 2002-12-31 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
JP2003502315A (ja) * 1999-06-11 2003-01-21 メルク エンド カムパニー インコーポレーテッド ケモカインレセプター活性のｎ−シクロペンチルモジュレーター
US6506777B1 (en) 1999-06-11 2003-01-14 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
JP4688381B2 (ja) * 1999-06-11 2011-05-25 メルク・シャープ・エンド・ドーム・コーポレイション ケモカインレセプター活性のｎ−シクロペンチルモジュレーター
US6358979B1 (en) 1999-06-11 2002-03-19 Merck & Co., Inc. N-cyclopentyl modulators of chemokine receptor activity
WO2000076972A1 (fr) * 1999-06-11 2000-12-21 Merck & Co., Inc. Modulateurs n-cyclopentyliques de l'activite du recepteur de la chimiokine
US7576117B1 (en) 1999-08-04 2009-08-18 Teijin Limited Cyclic amine CCR3 antagonist
US6903085B1 (en) 1999-08-24 2005-06-07 Astrazeneca, Ab Substituted piperidine compounds useful as modulators of chemokine receptor activity
WO2001014333A1 (fr) * 1999-08-24 2001-03-01 Astrazeneca Uk Limited Composes de piperidine substitues utiles comme modulateurs de l'activite de recepteurs de chimiokine
US6897234B2 (en) 1999-12-17 2005-05-24 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6362177B1 (en) 2000-05-16 2002-03-26 Teijin Limited Cyclic amine derivatives and their use as drugs
US6410566B1 (en) 2000-05-16 2002-06-25 Teijin Limited Cyclic amine derivatives and their use as drugs
US6627629B2 (en) 2000-06-30 2003-09-30 Bristol-Myers Squibb Pharma N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US6949546B2 (en) 2000-06-30 2005-09-27 Bristol-Myers Squibb Pharma Company N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US7175988B2 (en) 2001-02-09 2007-02-13 Human Genome Sciences, Inc. Human G-protein Chemokine Receptor (CCR5) HDGNR10
US6958350B2 (en) 2001-02-19 2005-10-25 Astrazeneca Ab Chemical compounds
US7053090B2 (en) 2001-03-19 2006-05-30 Ono Pharmaceutical Co., Ltd. Triazaspiro[5.5]undecane derivatives and drugs containing the same as the active ingredient
US7262193B2 (en) 2001-03-19 2007-08-28 Ono Pharmaceutical Co., Ltd. Triazaspiro[5.5]undecane derivative and pharmaceutical composition comprising the same as active ingredient
EP1378510A4 (fr) * 2001-03-19 2004-09-29 Ono Pharmaceutical Co Derives de triazaspiro (5.5) undecane et medicaments les contenant en tant que principe actif
EP1619194A2 (fr) * 2001-03-19 2006-01-25 Ono Pharmaceutical Co., Ltd. Dérivés de triazaspiro[5.5]undécane et le composition pharmaceutique qui les comprend comme ingrédient actif
EP1619194A3 (fr) * 2001-03-19 2006-06-07 Ono Pharmaceutical Co., Ltd. Dérivés de triazaspiro¬5.5|undécane et le composition pharmaceutique qui les comprend comme ingrédient actif
EP1378510A1 (fr) * 2001-03-19 2004-01-07 Ono Pharmaceutical Co., Ltd. Derives de triazaspiro 5.5]undecane et medicaments les contenant en tant que principe actif
US6960602B2 (en) 2001-03-22 2005-11-01 Astrazeneca Ab Piperidine derivatives as modulators of chemokine receptors
US7192973B2 (en) 2001-11-15 2007-03-20 Astrazeneca Ab Piperidine derivatives and their use as modulators of chemokine receptor activity (especially CCR5)
US7393934B2 (en) 2001-12-21 2008-07-01 Human Genome Sciences, Inc. Human G-protein chemokine receptor (CCR5) HDGNR10
WO2004005295A1 (fr) * 2002-07-08 2004-01-15 Astrazeneca Ab Nouvelles spiropiperidines ou spiropyrrolidines tricycliques
US7449475B2 (en) 2002-07-08 2008-11-11 Astrazeneca Ab Tricyclic spiropiperidines or spiropyrrolidines
WO2004026873A1 (fr) * 2002-09-18 2004-04-01 Ono Pharmaceutical Co., Ltd. Derives triazaspiro[5.5]undecanes et medicaments les contenant en tant que principe actif
US7294636B2 (en) 2003-05-09 2007-11-13 Astrazeneca Ab Chemical compounds
WO2005037814A1 (fr) * 2003-10-17 2005-04-28 Astrazeneca Ab Nouveaux spiroderives tricycliques en tant que modulateurs de l'activite de recepteur de chimiokine
US7498338B2 (en) 2003-11-20 2009-03-03 Astrazeneca Ab Compounds
WO2005049620A1 (fr) * 2003-11-20 2005-06-02 Astrazeneca Ab Nouveaux composes
WO2005054249A1 (fr) * 2003-12-05 2005-06-16 Astrazeneca Ab Nouveaux composes
US7524856B2 (en) 2003-12-22 2009-04-28 Astrazeneca Ab Tricyclic spiroderivatives as modulators of chemokine receptor activity
WO2005061499A1 (fr) * 2003-12-22 2005-07-07 Astrazeneca Ab Nouveaux spiroderives tricycliques en tant que modulateurs de l'activite des recepteurs de chimiokines
US7501123B2 (en) 2004-03-12 2009-03-10 Human Genome Sciences, Inc. Human G-protein chemokine receptor (CCR5) HDGNR10
EP3050574A1 (fr) 2015-01-28 2016-08-03 Universite De Bordeaux Nouvelles compositions et méthodes de traitement et/ou de prévention d'une maladie pulmonaire obstructive chronique
EP3613435A1 (fr) 2015-01-28 2020-02-26 Universite De Bordeaux Inhibiteurs du recepteur cxcr4 pour le traitement et/ou la prévention d'une maladie pulmonaire obstructive chronique
EP4252629A2 (fr) 2016-12-07 2023-10-04 Biora Therapeutics, Inc. Procédés, dispositifs et systèmes de détection du tractus gastro-intestinal
US10980739B2 (en) 2016-12-14 2021-04-20 Progenity, Inc. Treatment of a disease of the gastrointestinal tract with a chemokine/chemokine receptor inhibitor
WO2018112264A1 (fr) 2016-12-14 2018-06-21 Progenity Inc. Traitement d'une maladie du tractus gastro-intestinal avec une chimoikine/un inhibiteur du récepteur de chimiokine
WO2020106757A1 (fr) 2018-11-19 2020-05-28 Progenity, Inc. Dispositif ingérable pour administrer un agent thérapeutique au tube digestif
WO2020106750A1 (fr) 2018-11-19 2020-05-28 Progenity, Inc. Méthodes et dispositifs pour traiter une maladie au moyen d'une biothérapie
WO2020106754A1 (fr) 2018-11-19 2020-05-28 Progenity, Inc. Méthodes et dispositifs pour traiter une maladie à l'aide d'agents biothérapeutiques
WO2020106704A2 (fr) 2018-11-19 2020-05-28 Progenity, Inc. Dispositif ingestible pour administrer un agent therapeutique dans le tractus digestif
WO2021119482A1 (fr) 2019-12-13 2021-06-17 Progenity, Inc. Dispositif ingérable pour administrer un agent thérapeutique dans le tractus gastro-intestinal
EP4309722A2 (fr) 2019-12-13 2024-01-24 Biora Therapeutics, Inc. Dispositif ingérable pour l'administration d'un agent thérapeutique au tractus gastro-intestinal
WO2021165960A1 (fr) 2020-02-19 2021-08-26 Ichilov Tech Ltd. Traitement par antidépresseur amélioré

Also Published As

Publication number Publication date
JP2001508798A (ja) 2001-07-03
AU6133098A (en) 1998-08-07
CA2278309A1 (fr) 1998-07-23
EP1003743A4 (fr) 2001-04-11
EP1003743A1 (fr) 2000-05-31

Similar Documents

Publication Publication Date Title
US6124319A (en) 3,3-disubstituted piperidines as modulators of chemokine receptor activity
WO1998031364A1 (fr) Piperidines 3,3-disubstituees utilisees comme modulateurs de l'activite de recepteurs de chemokines
US6013644A (en) Spiro-substituted azacycles as modulators of chemokine receptor activity
US5919776A (en) Substituted aminoquinolines as modulators of chemokine receptor activity
US6399619B1 (en) Pyrrolidine modulators of chemokine receptor activity
US6303593B1 (en) 3-thienyl and 3-furanyl pyrrolidine modulators of chemokine receptor activity
US6362201B1 (en) 3-cyclopropyl and 3-cyclobutyl pyrrolidine modulators of chemokine receptor activity
US6140349A (en) Cyclic amine modulators of chemokine receptor activity
US6265434B1 (en) Pyrrolidine modulators of chemokine receptor activity
US6248755B1 (en) Pyrrolidine modulators of chemokine receptor activity
US5962462A (en) Spiro-substituted azacycles as modulators of chemokine receptor activity
WO1998025604A1 (fr) Azacycles a spiro-substitution utilises en tant que modulateurs de l'activite du recepteur de la chimiokine
US6489354B1 (en) 3-alkyl substituted pyrrolidine modulators of chemokine receptor activity
US6498161B1 (en) Pyrrolidine modulators of chemokine receptor activity
US6432981B1 (en) Cyclopentyl modulators of chemokine receptor activity
WO1998027815A1 (fr) Aminoquinoleines substituees utilisees comme modulateurs de l'activite des recepteurs de la chemokine
WO1998025617A1 (fr) Arylpiperazines substituees utilisees comme modulateurs de l'activite du recepteur de la chemokine
US6511994B2 (en) Modulators of CCR5 chemokine receptor activity
EP1052992A1 (fr) Amines cycliques utilisees en tant que modulateurs de l'activite du recepteur de chemokine
US6372764B1 (en) Pyrrolidine modulators of chemokine receptor activity
US6506777B1 (en) Cyclopentyl modulators of chemokine receptor activity
US6500844B1 (en) Cyclopentyl modulators of chemokine receptor activity
US20040087552A1 (en) Pyrrolidine modulators of ccr5 chemokine receptor activity
US6472410B1 (en) N-cyclopentyl modulators of chemokine receptor activity
US6538002B1 (en) Cyclopentyl modulators of chemokine receptor activity

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AU AZ BA BB BG BR BY CA CN CU CZ EE GE GW HU ID IL IS JP KG KR KZ LC LK LR LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK SL TJ TM TR TT UA US UZ VN YU

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref country code: JP

Ref document number: 1998 534662

Kind code of ref document: A

Format of ref document f/p: F

ENP Entry into the national phase

Ref document number: 2278309

Country of ref document: CA

Ref country code: CA

Ref document number: 2278309

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1998905975

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 61330/98

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 1998905975

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1998905975

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载