WO2001064213A1 - Composes et techniques - Google Patents

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Publication number
WO2001064213A1
WO2001064213A1 PCT/US2001/006837 US0106837W WO0164213A1 WO 2001064213 A1 WO2001064213 A1 WO 2001064213A1 US 0106837 W US0106837 W US 0106837W WO 0164213 A1 WO0164213 A1 WO 0164213A1
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Prior art keywords
spiro
benzofuran
piperidin
isopropyl
biphenyl
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PCT/US2001/006837
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English (en)
Inventor
William E. Bondinell
Thomas W. Ku
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Smithkline Beecham Corporation
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Priority to AU2001243394A priority Critical patent/AU2001243394A1/en
Publication of WO2001064213A1 publication Critical patent/WO2001064213A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed 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

Definitions

  • This invention relates to spiropiperidine-containing benzanilides which are modulators, agonists or antagonists, of the CC chemokine receptor CC-CKR5 now designated as CCR5 (Nature Medicine 1996, 2, 1174-8), methods for their preparation, pharmaceutical compositions containing them and their use in treating disease.
  • this invention relates to the treatment and prevention of disease states mediated by CCR5.
  • T cells are not only key regulators of the immune response to infectious agents but are believed critical for the initiation and maintenance of the inflammatory reaction in a variety of chronic diseases.
  • Increased numbers or enhanced activation state of T cells, especially CD4+ T cells have been demonstrated in the synovium of individuals with rheumatoid arthritis (M.J. Elliott and R. N. Maini, Int. Arch. Allergy Immunol. 104: 112-1125, 1994), in the bronchial mucosa of asthmatics (C.J. Corrigan and A.B. Kay, Immunol. Today 13: 501-506, 1992), in the lesions of multiple sclerosis (R. Martin and H. F. McFarland, Crit. Rev. Clin. Lab. Sci.
  • T cells as well as other inflammatory cells, will migrate into tissues in response to the production of a variety of chemotactic factors.
  • chemokines a superfamily of 8-12 kDa proteins known as the chemokines. These proteins share structural features such as the presence of 3-4 conserved cysteine residues.
  • RANTES which stands for Regulated upon Activation Normal T cell Expressed and Secreted, is a 8 kDa protein member of CC branch of the chemokine family. These proteins recruit and activate immune and inflammatory cells through an interaction with G-protein coupled receptors.
  • the CC branch is defined by the absence of an intervening amino acid residue between the first two cysteine residues and members of this family predominately elicit the migration of mononuclear cells, eosinophils and basophils (M. Baggiolini, B. Dewald, and B. Moser, Adv. Immunol. 55: 97-179, 1994; and J.J. Oppenheim, C.O.C. Zachariae, N. Mukaida, and K. Matsushima, Annu. Rev. Immunol. 9: 617-648, 1991).
  • RANTES potently produces chemotaxis of T cells, basophils, eosinophils, monocytes and mast cells.
  • RANTES was originally identified as gene product induced late after antigen activation of T-cells (T.J. Schall, J. Jongstra, B.J. Dyer, J. Jorgensen, et al., J. Immunol. 141:1018-1025, 1988), however, RANTES has been shown to be synthesized and secreted by a diverse group of cells that include epithelial and endothelial cells (C. Stellato, L.A. Beck, G.A. Gorgone, D. Proud, et al., J. Immunol. 155: 410-418, 1995; and A. Marfaing-Koka, O. Devergne, G. Gorgone, A.
  • RANTES mRNA is rapidly upregulated in response to IL-1 or TNF ⁇ .
  • RANTES mRNA is not usually detected in normal tissues (J.M. Pattison, P.J. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-8, 1995), increased mRNA or protein has been found in diseases characterized by a mononuclear infiltrate.
  • RANTES mRNA was visualized using in situ hybridization in renal allografts undergoing rejection (J.M. Pattison, P.J. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-8, 1995; and K.C. Nadeau, H. Azuma and N.I. Tilney, Proc. Natl. Acad. USA 92: 8729-8733, 1995) in the skin of atopic dermatitis patients after exposure to antigen (S. Ying, L. T presenteda-Barata, Q. Meng, M. Humbert, et al., J. Exp. Med.
  • CCR5 when expressed in either HEK 293 cells or CHO cells, binds RANTES. This receptor is expressed in T-cells and in monocytes and macrophages, immune/inflammatory cells which are important in the maintenance of a chronic inflammatory reaction. Pharmacological characterization of CCR5 indicates similarities to the RANTES binding site observed on isolated T cells. Therefore, antagonism of RANTES' action on CCR5, as well as antagonism of other natural modulators of CCR5, should inhibit the recruitment and activation of T cells and macrophages into inflammatory lesions and provide a novel therapeutic approach for the treatment of atopic and autoimmune disorders.
  • T cells express CCR5, selective receptor modulators of CCR5, particularly antagonists, are likely to provide beneficial effects in diseases including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, and inflammatory bowel disease, all in mammals, preferably humans.
  • atopic disorders for example, atopic dermatitis and allergies
  • rheumatoid arthritis for example, atopic dermatitis and allergies
  • rheumatoid arthritis for example, atopic dermatitis and allergies
  • sarcoidosis or idiopathic pulmonary fibrosis and other fibrotic diseases
  • psoriasis autoimmune diseases such as multiple sclerosis
  • CCR5 may play a role in their recruitment and therefore antagonists to CCR5 could provide potential therapeutic use in the treatment of COPD. Also, since CCR5 is a co-receptor for the entry of HIV into cells, selective receptor modulators may be useful in the treatment of HIV infection.
  • this class of non-peptide compounds in particular spiropiperidine-containing benzanilides of formula (I), function as CCR5 receptor modulators, and therefore, have utility in the treatment and prevention of disease states mediated by CCR5 receptor mechanisms.
  • the spiropiperidine-containing benzanilides compounds of formula (I) are dual antagonists, i.e., they antagonize both human and murine CCR5. Therefore, this invention also relates to a method for modulating human and murine CCR5 with spiro-substituted compounds in general, and the compounds of formula (I) in particular.
  • the present invention is to compounds of formula (I) and their use as CCR5 modulators for the treatment of certain disease states, including, but not limited to, COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, inflammatory bowel disease, and HIV infection, all in mammals, preferably humans.
  • the preferred compounds for use as CCR5 modulators herein are those compounds of formula (I) as noted.
  • the present invention further provides pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I), including pharmaceutically acceptable salts and hydrates thereof, in combination with a pharmaceutically acceptable carrier, which compositions are suitable for the treatment of the CCR5-mediated diseases.
  • spiropiperidine-containing benzanilides of formula (I) are potent CCR5 receptor modulators.
  • Selective inhibition of CCR5 receptor mechanisms by treatment with the receptor modulators of formula (I), or a pharmaceutically acceptable salt thereof represents an effective therapeutic and preventative approach to the treatment of a variety of disease states, including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, and inflammatory bowel disease, all in mammals, preferably humans.
  • atopic disorders for example, atopic dermatitis and allergies
  • rheumatoid arthritis for example, atopic dermatitis and allergies
  • rheumatoid arthritis for example, atopic dermatiti
  • CCR5 may play a role in their recruitment and therefore antagonists to CCR5 could provide potential therapeutic use in the treatment of COPD. Also, since CCR5 is a co-receptor for entry into cells, selective receptor modulators may be useful in the treatment of HIV infection. In addition, it has been discovered that the spiropiperidine-containing benzanilides of formula (I) are particularly useful in that they modulate both the human and murine CCR5 receptors.
  • Preferred compounds for use as CCR5 modulators are those compounds of formula (I) as noted herein.
  • a preferred group of compounds for use herein are those compounds of the formula (I) or a pharmaceutically acceptable salt thereof:
  • Ri and R 2 are independently one or more of hydrogen, C ⁇ .galkyl, C2- galkenyl, C2_6alkynyl, C3_7cycloalkyl, C3_gcycloalkenyl, aryl, (CH2) a R 7 R 8 , (CH 2 ) a NR 7 COR9, (CH2)aNR 7 CO 2 R 10 , (CH )aNR 7 SO2R n , (CH2) a CONR 12 Rl3 5 hydroxyCi.galkyl, C ⁇ alkoxyalkyl (optionally substituted by a C1 _ 4 alkoxy or hydroxy group), (CH2) a CO 2 C 1 .
  • R 3 and R 4 are independently one or more of hydrogen, Cj.galkyl, C3. cycloalkyl, C3_6cycloalkenyl, hydroxyC galkyl, Ci.galkylOCi.galkyl, CONR 29 R 3 0 ) CO2R 31 , cyano, aryl, trifluoromethyl, NR 29 R 0, n it ro , hydroxy, C _ galkoxy, acyloxy or halogen;
  • R ⁇ is one or more of hydrogen, C ⁇ .galkyl, Cj.galkoxy or halogen;
  • R6 is one or more of hydrogen, Cj.galkyl, C3_7cycloalkyl (optionally substituted by a hydroxy or an oxo group), hydroxyCj.galkyl, hydroxyC3_6alkenyl, hydroxyC 3 .
  • R 7 and R 8 are independently hydrogen or Cj.galkyl, or together with the nitrogen to which they are attached, R 7 and R 8 form a 5- to 6-membered heterocyclic ring, which ring may optionally be substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
  • R is hydrogen, C ⁇ .galkyl or C ⁇ _4a ⁇ koxyalkyl
  • R 10 is C ⁇ _6alkyl
  • R! 1 is Cj.galkyl or phenyl
  • R!2 and R ⁇ 3 are independently hydrogen or Ci .galkyl, or together with the nitrogen to which they are attached, R ⁇ 2 and R 13 form a 5- to 6-membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
  • R 14 is C ⁇ _4alkyl, optionally substituted by Cj.galkoxy; Rl5 and R 16 are independently hydrogen or Cj.galkyl;
  • R! is hydrogen or C ⁇ .galkyl
  • R! is hydrogen or C ⁇ .galkyl
  • Rl and R20 are independently hydrogen or C ⁇ .galkyl
  • R21 is hydrogen or C j .galkyl
  • R22 is hydrogen or C j .galkyl optionally substituted with one or two substituents selected from C ⁇ .galkyl, Cj.galkoxy, hydroxy, or NR R 8 ;
  • R 23 and R2 4 are independently hydrogen or C ⁇ .galkyl
  • R25 and R26 are independently hydrogen or Cj.galkyl, or together with the nitrogen to which they are attached, R 2 ⁇ and R 2 ⁇ form a 5- to 6-membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
  • R 27 is hydrogen or Cj.galkyl
  • R 28 is C ⁇ _6alkyl
  • R 2 9, R 0 and R ⁇ are independently hydrogen or C galkyl;
  • R 32 is Cj.galkyl, hydroxyC galkyl, or Ci _4alkanoyl;
  • R 33 is hydrogen or C ⁇ .galkyl
  • R 34 is hydrogen or Ci .galkyl
  • R ⁇ is hydrogen or C ⁇ .galkyl
  • R 3 ⁇ and R 37 are independently hydrogen or C ⁇ g lkyl or together with the nitrogen to which they are attached, R ° and R 37 form a 5- to 6-membered heterocyclic ring, which ring may be optionally substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain one oxygen or sulfur atom or an NH group or a group NR 43 , wherein R 43 is C ⁇ .galkyl, COR 44 or CO2R 4 - ⁇ wherein R 44 and R 4 ⁇ are independently hydrogen or C galkyl; R 38 is hydrogen or Cj.galkyl; R 3 is C ⁇ _6alkoxy, CO 2 H, CO 2 C ⁇ _6alkyl or CONR 3 6R 3 7 ;
  • R 40 is C ⁇ _ 6 alkyl
  • R 4 1 and R 42 are independently hydrogen or Ci .galkyl; P is a 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; a is 1, 2, 3 or 4; b is O, 1, 2 or 3; c is 1, 2 or 3; d is 0, 1, 2, 3, 4, 5, or 6; and e is 1, 2, 3, 4, 5 or 6; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR 46 , NHCO, or
  • R 47 , R 48 , R 49 , R50 ) R51 ; R52 ; R54 5 an d R 55 are independently hydrogen or Ci.galkyl;
  • R-5 3 is hydrogen, Cj.galkyl, or C3_7cycloalkyl
  • R 57 , R 58 , R 59 , R60 5 an d R61 are independently hydrogen or Chalky.
  • f is 1, 2 or 3
  • g is 1, 2 or 3
  • h is 2, 3, or 4
  • i is 0, 1, 2, or 3
  • j is 0, 1 or 2;
  • Ar is (i), (ii), or (iii).
  • Ar is (i) or (ii).
  • the terminal phenyl group in (i) and (ii) can be attached to the phenyl group bearing group A in any position.
  • the terminal phenyl ring is attached to the phenyl bearing group A in a position meta or para to group A, more preferably para to group A.
  • P is a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur.
  • Suitable heterocyclic rings include aromatic groups such as thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, and dioxanyl.
  • Saturated and partially saturated rings are also within the scope of the invention, in particular rings including an oxo or thioxo moiety such as lactams and thiolactams.
  • the heterocyclic ring can be linked to the remainder of the molecule via a carbon atom, or, when present, a nitrogen atom.
  • Suitable substituents for these rings include one or more of R 4 '.
  • a particularly preferred group of compounds for use herein are those compounds of the formula (I), or a pharmaceutically acceptable salt thereof, wherein, preferably, Ar is represented by sub-formula (i) a :
  • R ' are suitably hydrogen, CO2R 22 , wherein R 22 is Cj.galkyl, or halo.
  • Rl' is hydrogen, CO 2 R 22 , wherein R 22 is ethyl, or chloro.
  • Ar is represented by sub-formula (i) ⁇ : in which R 2 ' and R 3' are suitably halogen.
  • R 2 ' and R 3 ' are chloro.
  • Ar is represented by sub-formula (iii) a -
  • R 4 ' is suitably C3_6cycloalkyl, preferably cyclohexyl, or suitably halo, preferably iodo.
  • R* is suitably hydroxy
  • R ⁇ ' is suitably halogen.
  • R" is chloro.
  • Ar is represented by sub-formula (i) e : wherein R 7 ' and R 8 ' are suitably, independently, halogen. Preferably, R 7 and R 8 ' are chloro.
  • R ' and RlO' are suitably, independently, halogen.
  • R9 and RIO' are chloro.
  • Ar is (i) a , (i) ⁇ , (i) c , (i)d, (i) e , (i)f, or (iii) a , and E represents
  • A represents CONR 4 °, NHCO, or CH 2 NH where R 4 ⁇ is hydrogen or Cj.galkyl.
  • group A represents CONR 4 ", where R 4 ⁇ is hydrogen or Cj.galkyl. More preferably A is CONR 4 ⁇ and R 4 ⁇ is hydrogen.
  • the group A can be located at any open position on the phenyl ring. Preferably, the group A is located para to group B.
  • R 47 , R 48 , R 49 , R50 > R51 ; R52 ; R54 an d R 55 are preferably hydrogen, g is preferably 1, R ⁇ 3 is preferably Cj.galkyl, more preferably C3_6alkyl, most preferably isopropyl, f is preferably 2, and R ⁇ " is preferably hydrogen.
  • Ci.galkyl is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, and the like.
  • halo or halogen are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.
  • cycloalkyl and “cyclic alkyl” are used herein at all occurrences to mean cyclic radicals, preferably comprising 3 to 7 carbon atoms which may be mono- or bicyclo- fused ring systems which may additionally include unsaturation, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4- tetrahydronaphthyl, and the like.
  • alkenyl is used herein at all occurrences to mean a straight or branched chain radical of 2 to 6 carbon atoms, unless the length is limited thereto, wherein there is at least one double bond between two of the carbon atoms in the chain, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl, and the like.
  • cycloalkenyl is used herein to mean cyclic radicals, preferably of 5 to 8 carbons, which have at least one double bond between two of the carbon atoms in the ring, including but not limited to cyclopentenyl, cyclohexenyl, and the like.
  • alkynyl is used herein at all occurrences to mean a straight or branched chain radical of 2 to 8 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1- propylene, 2-propylene, and the like.
  • aryl is used herein at all occurrences to mean 5-14-membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems, including, but not limited to phenyl, naphthyl, and the like.
  • aralkyl is used herein at all occurrences to mean an aryl moiety as defined above, which is connected to an alkyl moiety as defined above, for example, benzyl or phenethyl, and the like.
  • alkoxy is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, and the like.
  • hydroxyC ⁇ _6alkyl and "hydroxyalkyl” are used herein interchangeably to mean an hydroxyl group bonded to a C ⁇ .galkyl group as defined above, including, but not limited to methanol, ethanol, n-propanol, isopropanol, n- butanol, sec-butanol, isobutanol, tert-butanol, and the like.
  • Ci ⁇ alkoxyalkyl is used herein at all occurrences to mean a C ⁇ _ 4alkoxy group as defined above bonded to an alkyl group as defined above, such as an ether, e.g., -CH 2 -CH 2 -O-CH -CH 2 -CH .
  • hydroxyC ⁇ _6alkoxy is used herein at all occurrences to mean an hydroxyl group bonded to an alkoxy group as defined above, e.g., -O-CH 2 -CH(OH)CH 3 .
  • Ci .galkoxyCj.galkoxy is used herein at all occurrences to mean an alkoxy group as defined above, substituted with an alkoxy group as defined above.
  • acyloxy is used herein at all occurrences to mean a moiety -O-C(O)-R, wherein R is hydrogen or C ⁇ .galkyl.
  • C ⁇ alkanoyl is used herein at all occurrences to mean a - C(O)Ci-4alkyl group wherein the alkyl portion is as defined above.
  • heteroatom is used herein at all occurrences to mean an oxygen atom, a sulfur atom or a nitrogen atom. It will be recognized that when the heteroatom is nitrogen, it may form an NR a R ⁇ moiety, wherein R a and R ⁇ , are, independently, hydrogen or C j to C alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6- or 7-membered ring, including, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, pyridine, and the like. It will be recognized that the saturated or unsaturated 5-, 6- or 7-membered ring may optionally have one or more additional heteroatoms in the ring.
  • oxo is used herein at all occurrences to mean a double bonded oxygen atom attached to a chemical moiety as a substituent.
  • CCR5 mediated disease state is used herein at all occurrences to mean any disease state which is mediated (or modulated) by the CCR5 receptor.
  • pharmaceutically acceptable salts of formula (I) include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate, or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p- toluenesulfonate, palmitate, salicylate, and stearate.
  • inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate
  • an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p- toluenesulfonate, palmitate, salicylate, and stearate.
  • the pharmaceutically effective compounds of this invention are administered in conventional dosage forms prepared by combining a compound of formula (I) ("active ingredient”) in an amount sufficient to treat COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, inflammatory bowel disease, and HIV infection, ("CCR5 -mediated disease states”) with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • atopic disorders for example, atopic dermatitis and allergies
  • rheumatoid arthritis for example, atopic dermatitis and allergies
  • sarcoidosis or idiopathic
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1000 mg.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • the active ingredient may also be administered topically to a mammal in need of treatment or prophylaxis of CCR5 mediated disease states.
  • the amount of active ingredient required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the disease state being treated and the mammal undergoing treatment, and is ultimately at the discretion of the physician.
  • a suitable dose of an active ingredient is 1.5 mg to 500 mg for topical administration, the most preferred dosage being 1 mg to 100 mg, for example 5 to 25 mg administered two or three times daily.
  • topical administration non-systemic administration and includes the application of the active ingredient externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream.
  • systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.
  • an active ingredient may be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the formulation.
  • the topical formulations of the present invention both for veterinary and for human medical use, comprise an active ingredient together with one or more acceptable carrier(s) therefor and optionally any other therapeutic ingredient(s).
  • the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous or alcoholic solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis.
  • the basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as esters or polyoxyethylene derivatives thereof.
  • suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as esters or polyoxyethylene derivatives thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • the active ingredient may also be administered by inhalation.
  • inhalation is meant intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the daily dosage amount of the active ingredient administered by inhalation is from about 0.1 mg to about 100 mg per day, preferably about 1 mg to about 10 mg per day.
  • this invention relates to a method of treating COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, inflammatory bowel disease, and HIV infection, all in mammals, preferably humans, which comprises administering to such mammal an effective amount of a CCR5 receptor modulator, in particular, a compound as depicted in formula (I).
  • atopic disorders for example, atopic dermatitis and allergies
  • sarcoidosis for example, atopic dermatitis and allergies
  • idiopathic pulmonary fibrosis and other fibrotic diseases for example, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis
  • autoimmune diseases such as multiple sclerosis
  • formula (I) compound can be administered to such mammal in a conventional dosage form prepared by combining the formula (I) compound with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
  • the formula (I) compound is administered to a mammal in need of treatment for COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, inflammatory bowel disease, and HIV infection, in an amount sufficient to decrease symptoms associated with these disease states.
  • the route of administration may be oral or parenteral.
  • parenteral as used herein includes intravenous, intramuscular, subcutaneous, intra-rectal, intravaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
  • the daily parenteral dosage regimen will preferably be from about 30 mg to about 300 mg per day of active ingredient.
  • the daily oral dosage regimen will preferably be from about 100 mg to about 2000 mg per day of active ingredient.
  • the optimal quantity and spacing of individual dosages of a formula (I) compound will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the formula (I) compound given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • the compounds of formula (I) can be prepared by art-recognized procedures from known or commercially available starting materials. If the starting materials are unavailable from a commercial source, their synthesis is described herein, or they can be prepared by procedures known in the art.
  • Example 12 Preparation of N-( 1 '-Ethyl-spirorbenzofuran-3(2H),4'-piperidin1-5-yl)- 1.1 '-biphenyl- 4-carboxamide Following the procedure of Procedure 2(d), except substituting the compound of Example 1(b) for the compound of Preparation 2(c) and substituting iodoethane for 2-iodopropane, afforded the title compound: MS (ES) m/e 412.9 [M+H]+.
  • CHO cell membranes (0.25 xlO 6 cell equivalents) derived from CHO cells stably transfected with CCR5 were incubated with 0.3 125 I-RANTES in a 96 well plate for 45 min. at room temperature (final reaction volume 200 ul). The reaction was terminated by filtration and the filters (GF/C) were washed twelve times with a solution of phosphate buffered saline containing 0.1 % bovine serum albumin and 0.05 % NaN3. The radioactivity bound to filters was measured by liquid scintillation spectrometry. Non-specific binding was determined in the presence of unlabelled RANTES (10 or 30 nM) and averages 30-50% of total binding.
  • the cellular functional assay used to assess antagonist activity of compounds was RANTES-induced Ca 2+ mobilization in RBL 2H3 cells stably expressing the hCCR5 or mCCR5 receptor (RBL 2H3 hCCR5).
  • Agonist activity is determined by Ca 2+ mobilization in the same cells which is inhibitable by a selective CCR5 antagonist.
  • Cells were grown to 80-100% confluency in T-150 flasks and washed with phosphate-buffered saline. Cells were lifted from the flasks by treating with 3 mL of 1 mM EDTA for 3 min.
  • the compounds of this invention show CCR5 receptor modulator activity having IC50 values in the range of 0.0001 to 100 ⁇ M.
  • the full structure/activity relationship has not yet been established for the compounds of this invention.
  • one of ordinary skill in the art can utilize the present assays in order to determine which compounds of formula (I) are modulators of the CCR5 receptor and which bind thereto with an IC50 value in the range of 0.0001 to 100 ⁇ M.

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Abstract

La présente invention concerne des benzanilides substituées qui sont des modulateurs, des agonistes ou des antagonistes, du récepteur CCR5. Cette invention concerne aussi le traitement et la prévention d'états pathologiques induits par CCR5, notamment l'asthme et les troubles atopiques (par exemple des dermatoses et des allergies atopiques), l'arthrite rhumatoïde, la sarcoïdose ou la fibrose pulmonaire idiopathique et d'autres maladies fibreuses, l'athérosclérose, le psoriasis, des maladies auto-immunes telles que la sclérose en plaques. Cette invention permet aussi le traitement et/ou la prévention du rejet d'organes transplantés, de maladies entériques inflammatoires, chez les mammifères, par utilisation de benzanilides substituées qui sont des antagonistes du récepteur CCR5. Par ailleurs, comme les lymphocytes T CD8 ont été impliqués dans la BPCO, CCR5 peut jouer un rôle dans leur recrutement et par conséquent des antagonistes de CCR5 pourraient fournir une utilisation thérapeutique potentielle dans le traitement de la BPCO. De plus, comme CCR5 est un co-récepteur pour l'entrée du VIH dans les cellules, des modulateurs de récepteur sélectifs peuvent être utiles dans le traitement de l'infection au VIH.
PCT/US2001/006837 2000-03-02 2001-03-02 Composes et techniques WO2001064213A1 (fr)

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WO2004005295A1 (fr) * 2002-07-08 2004-01-15 Astrazeneca Ab Nouvelles spiropiperidines ou spiropyrrolidines tricycliques
WO2005037814A1 (fr) * 2003-10-17 2005-04-28 Astrazeneca Ab Nouveaux spiroderives tricycliques en tant que modulateurs de l'activite de recepteur de chimiokine
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
WO2005075484A2 (fr) * 2004-02-10 2005-08-18 F. Hoffmann-La Roche Ag Modulateurs des recepteurs ccr5 de chimiokine
US7696201B2 (en) 2006-08-15 2010-04-13 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7786141B2 (en) 2004-08-19 2010-08-31 Vertex Pharmaceuticals Incorporated Dihydrospiroindene modulators of muscarinic receptors
US7786107B2 (en) 2006-08-18 2010-08-31 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7820817B2 (en) 2004-05-28 2010-10-26 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7858790B2 (en) 2006-06-29 2010-12-28 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7863449B2 (en) 2004-11-29 2011-01-04 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7879834B2 (en) 2004-08-19 2011-02-01 Vertex Pharmaceuticals Incorporated Spiroindoline modulators of muscarinic receptors
US7943130B2 (en) 2003-12-11 2011-05-17 Yale University Methods and compositions relating to CCR5 antagonist, IFN-γ and IL-13 induced inflammation
US8263605B2 (en) 2006-02-22 2012-09-11 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US8304423B2 (en) 2006-02-22 2012-11-06 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors

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US6166034A (en) * 1995-11-08 2000-12-26 Smithkline Beecham P. L. C Spiro piperidine derivatives as 5HT1D receptor antagonists
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Cited By (26)

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Publication number Priority date Publication date Assignee Title
JP2005537255A (ja) * 2002-07-08 2005-12-08 アストラゼネカ・アクチエボラーグ 新規三環式スピロピペリジンまたはスピロピロリジン
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
WO2005037814A1 (fr) * 2003-10-17 2005-04-28 Astrazeneca Ab Nouveaux spiroderives tricycliques en tant que modulateurs de l'activite de recepteur de chimiokine
WO2005049620A1 (fr) * 2003-11-20 2005-06-02 Astrazeneca Ab Nouveaux composes
US7498338B2 (en) 2003-11-20 2009-03-03 Astrazeneca Ab Compounds
WO2005054249A1 (fr) * 2003-12-05 2005-06-16 Astrazeneca Ab Nouveaux composes
US8221988B2 (en) 2003-12-11 2012-07-17 Yale University Methods and compositions relating to CCR5 antagonist, IFN-γ and IL-13 induced inflammation
US7943130B2 (en) 2003-12-11 2011-05-17 Yale University Methods and compositions relating to CCR5 antagonist, IFN-γ and IL-13 induced inflammation
WO2005061499A1 (fr) * 2003-12-22 2005-07-07 Astrazeneca Ab Nouveaux spiroderives tricycliques en tant que modulateurs de l'activite des recepteurs de chimiokines
US7524856B2 (en) 2003-12-22 2009-04-28 Astrazeneca Ab Tricyclic spiroderivatives as modulators of chemokine receptor activity
WO2005075484A3 (fr) * 2004-02-10 2005-10-20 Hoffmann La Roche Modulateurs des recepteurs ccr5 de chimiokine
KR100863854B1 (ko) * 2004-02-10 2008-10-15 에프. 호프만-라 로슈 아게 케모카인 ｃｃｒ5 수용체 조절제
WO2005075484A2 (fr) * 2004-02-10 2005-08-18 F. Hoffmann-La Roche Ag Modulateurs des recepteurs ccr5 de chimiokine
US7820817B2 (en) 2004-05-28 2010-10-26 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7879834B2 (en) 2004-08-19 2011-02-01 Vertex Pharmaceuticals Incorporated Spiroindoline modulators of muscarinic receptors
US7786141B2 (en) 2004-08-19 2010-08-31 Vertex Pharmaceuticals Incorporated Dihydrospiroindene modulators of muscarinic receptors
US8258148B2 (en) 2004-08-19 2012-09-04 Vertex Pharmaceutical Incorporated Spiroindoline modulators of muscarinic receptors
US8367691B2 (en) 2004-08-19 2013-02-05 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US8497295B2 (en) 2004-08-19 2013-07-30 Vertex Pharmaceuticals Incorporated Spiroindoline modulators of muscarinic receptors
US7863449B2 (en) 2004-11-29 2011-01-04 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US8263605B2 (en) 2006-02-22 2012-09-11 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US8304423B2 (en) 2006-02-22 2012-11-06 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US7858790B2 (en) 2006-06-29 2010-12-28 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7696201B2 (en) 2006-08-15 2010-04-13 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7786107B2 (en) 2006-08-18 2010-08-31 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors

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