WO2003097618A1 - Antagonistes du recepteur de morpholinylmethyluree ccr-3 - Google Patents

Antagonistes du recepteur de morpholinylmethyluree ccr-3 Download PDF

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Publication number
WO2003097618A1
WO2003097618A1 PCT/EP2003/005446 EP0305446W WO03097618A1 WO 2003097618 A1 WO2003097618 A1 WO 2003097618A1 EP 0305446 W EP0305446 W EP 0305446W WO 03097618 A1 WO03097618 A1 WO 03097618A1
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formula
compound
alkyl
hydrogen
unsubstituted
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PCT/EP2003/005446
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English (en)
Inventor
Michael Dennis Dowle
Paul Martin Gore
Simon Teanby Hodgson
Martin Redpath Johnson
Duncan Bruce Judd
Tracy Jane Redfern
John Edward Robinson
Stephen Swanson
Naimisha Trivedi
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Glaxo Group Limited
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Priority to AU2003240705A priority Critical patent/AU2003240705A1/en
Publication of WO2003097618A1 publication Critical patent/WO2003097618A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/10—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel compounds, processes for their preparation, pharmaceutical formulations containing them and their use in therapy.
  • Inflammation is a primary response to tissue injury or microbial invasion and is characterised by leukocyte adhesion to the endothelium, diapedesis and activation within the tissue.
  • Leukocyte activation can result in the generation of toxic oxygen species (such as superoxide anion), and the release of granule products (such as peroxidases and proteases).
  • Circulating leukocytes include neutrophils, eosinophils, basophils, monocytes and lymphocytes.
  • Different forms of inflammation involve different types of infiltrating leukocytes, the particular profile being regulated by the profile of adhesion molecule, cytokine and chemotactic factor expression within the tissue.
  • leukocytes The primary function of leukocytes is to defend the host from invading organisms, such as bacteria and parasites. Once a tissue is injured or infected, a series of events occurs which causes the local recruitment of leukocytes from the circulation into the affected tissue. Leukocyte recruitment is controlled to allow for the orderly destruction and phagocytosis of foreign or dead cells, followed by tissue repair and resolution of the inflammatory infiltrate. However in chronic inflammatory states, whereby recruitment is often inappropriate, resolution is not adequately controlled and the inflammatory reaction causes tissue destruction.
  • bronchial inflammation which is characteristic of asthma represents a specialised form of cell-mediated immunity, in which cytokine products, such as IL-4 and IL-5 released by T-helper 2 (Th2) lymphocytes, orchestrate the accumulation and activation of granulocytes, in particular eosinophils and to a lesser extent basophils.
  • Th2 T-helper 2
  • eosinophils have been implicated in other disease types such as rhinitis, eczema, irritable bowel syndrome and parasitic infections.
  • Chemokines are a large family of small proteins which are involved in trafficking and recruitment of leukocytes (for review see Luster, New Eng. J. Med., 338, 436-445 (1998)). They are released by a wide variety of cells and act to attract and activate various cell types, including eosinophils, basophils, neutrophils, macrophages, T and B lymphocytes.
  • chemokines There are two major families of chemokines, CXC- ( ⁇ ) and CC- ( ⁇ ) chemokines, classified according to the spacing of two conserved cysteine residues near to the amino terminus of the chemokine proteins. Chemokines bind to specific cell surface receptors belonging to the family of G-protein-coupled seven transmembrane-domain proteins (for review see Luster, 1998). Activation of chemokine receptors results 5 in, amongst other responses, an increase in intracellular calcium, changes in cell shape, increased expression of cellular adhesion molecules, degranulation and promotion of cell migration (chemotaxis).
  • CC chemokine receptor-3 To date a number of CC chemokine receptors have been identified and of particular importance to the current invention is the CC-chemokine receptor-3
  • CCR-3 CCR 10
  • RANTES RANTES
  • MCP-3 MCP-4
  • eotaxin and eotaxin-2 are known to recruit and activate eosinophils.
  • eotaxin and eotaxin-2 which specifically bind to CCR-3.
  • the localization and function of CCR-3 chemokines indicate that they play a
  • CCR- 3 is specifically expressed on all the major cell types involved in inflammatory allergic responses.
  • Chemokines that act at CCR-3 are generated in response to inflammatory stimuli and act to recruit these cell types to sites of inflammation, where they cause their activation (e.g. Griffiths et al., J. Exp. Med., 179, 881-887
  • anti-CCR-3 monoclonal antibodies completely inhibit eotaxin interaction with eosinophils (Heath, H. et al., J. Clin. Invest. 99 (2), 178-184 (1997)), while an antibody for the CCR-3 specific chemokine, eotaxin, reduced both bronchial hyperreactivity and lung eosinophilia in an animal model of asthma (Gonzalo et al., J. Exp. Med.,
  • chemokines and their receptors also play a role in infectious disease.
  • Mammalian cytomegaloviruses Mammalian cytomegaloviruses
  • chemokine receptor homologues which can be activated by human CC chemokines such as RANTES and MCP-3 receptors (for review see Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748, 1997).
  • human chemokine receptors such as CXCR-4, CCR-5 and CCR-3, can act as co-receptors for the infection of mammalian cells by microbes
  • chemokine receptor antagonists including CCR-3 antagonists, may be useful in blocking infection of CCR-3 expressing cells by HIV or in preventing the manipulation of immune cellular responses by viruses such as cytomegaloviruses.
  • WO 00/69830 discloses certain diazacyclic compounds, and libraries containing them, for biological screening.
  • WO 00/18767 discloses certain piperazine derivatives as dopamine D4 receptor antagonists.
  • United States Patent 6,031 ,097 and WO 99/21848 discloses certain aminoisoquinoline derivatives as dopamine receptor ligands.
  • WO 99/06384 discloses piperazine derivatives useful for the treatment of neuromuscular dysfunction of the lower urinary tract.
  • WO 98/56771 discloses certain piperazine derivatives as anti- inflammatory agents.
  • WO 97/47601 discloses certain fused heterocyclic compounds as dopamine D-receptor blocking agents.
  • WO 96/39386 discloses certain piperidine derivatives as neurokinin antagonists.
  • WO 96/02534 discloses certain piperazine thiopyridines useful for controlling helicobacter bacteria.
  • WO 95/32196 (Merck Sharp & Dohme Limited) discloses certain piperazine, piperidine, and tetrahydropyridine derivatives as 5-HT1D-alpha antagonists.
  • United States Patent 5,389,635 (E.I. Du Pont de Nemours and Company) discloses certain substituted imidazoles as angiotensin-ll antagonists.
  • European Patent Application publication number 0 306 440 (Schering Aktiengesellschaft) discloses certain imidazole derivatives as cardiovascular agents.
  • WO 02/26722 (Glaxo Group Limited) discloses certain morpholine amide derivatives as CCR3 antagonists.
  • WO 02/26723 (Glaxo Group Limited) discloses certain morpholine urea derivatives as CCR3 receptor antagonists.
  • CCR-3 receptor antagonists which are CCR-3 receptor antagonists. These compounds block the migration/chemotaxis of eosinophils and thus possess anti-inflammatory properties. These compounds are therefore of potential therapeutic benefit, especially in providing protection from eosinophil, basophil mast cell and Th2-cell-induced tissue damage in diseases where such cell types are implicated, particularly allergic diseases, including but not limited to bronchial asthma, allergic rhinitis and atopic dermatitis.
  • R 1 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
  • X represents -(CR ka R kb ) k -;
  • R ka and R kb are each independently hydrogen or C 1-6 alkyl; k is 0-5;
  • Y represents -NR 3 - or a bond
  • R 3 represents hydrogen or C 1-6 alkyl
  • Z represents a moiety of formula (ZA):
  • I and m are each independently 1 or 2 and l+m is at least 3; n is 1 or 2, and; R 4 is hydrogen or C 1-6 alkyl;
  • R 5 is hydrogen or C 1-6 alkyl; p is 1 or 2, and; q is O or 1; with the proviso that (ZB) does not represent a 2,4-morphinolyl moiety; or Z represents a moiety of formula (ZC):
  • r and s are each independently 1 or 2 and r+s is at least 3; t is 0, 1, or 2, and;
  • R 6 is hydrogen or C 1-6 alkyl
  • R 7 is hydrogen or C 1-6 alkyl
  • R 8 is hydrogen or C 1-6 alkyl; u is 1 or 2; visOor 1, and; wisO, 1, or 2;
  • x and y are each independently 1 or 2;
  • R 9 is hydrogen or C 1-6 alkyl; b is 1 or 2; c is 1 or 2;
  • Ar is a 5 or 6-membered aryl group
  • A represents -(CR ja Rjb)j-
  • R ja and R jb are each independently hydrogen or C 1-6 alkyl; j is 0, 1 or 2, and;
  • R 2 represents unsubstituted or substituted aryl; and salts and solvates thereof, with the proviso that the following compounds are excluded; 4-( ⁇ [( ⁇ [4-(3,4-dichlorobenzyl)-1 ,4-oxazepan-2-yl]methyl ⁇ amino)carbonyl]- -amino ⁇ methyl)benzamide.
  • R 1 is aryl
  • examples include phenyl.
  • R 1 is heteroaryl
  • examples include tetrazolyl.
  • R 1 When R 1 is substituted aryl, suitable substituents include C ⁇ _ 6 alkylsulphonylaminoC 1-6 alkyl; amino; C 3 . 8 cycloalkylaminocarbonyl; C ⁇ 6 aIkylcarbonyl; C-s-scycloalkylcarbonyl; C 1-6 alkylsulphonylamino; C ⁇
  • R 10 R 11 NC(O)- wherein R 10 and R 11 may each independently represent hydrogen or C 1-6 alkyl, or R 10 and R 11 may represent a -(CH 2 ) Z - group wherein z is 3 to 7 so that, together with the nitrogen atom to which they are attached, a 4 to 8-membered heterocyclyl ring is formed; C 1-6 alkoxycarbonyl; cyano; aminosulphonyl; aminocarbonyl; halo; carboxy; C 1-6 alkyl, hydroxy, nitro; C 1-6 alkoxy; mono-and di-(C 1-6 alkyl)amino; or mono- and di-(C 1-6 alky)laminocarbonyl.
  • R 1 is substituted heteroaryl
  • suitable substituents include Ci. 6 alkylsulphonylaminoC 1-6 alkyl; amino; C 3-8 cycloalkylaminocarbonyl; C-i. 6 alkylcarbonyl; C 3-8 cycloalkylcarbonyl; C 1-6 alkylsulphonylamino; Ci.
  • R 1 is unsubstituted or substituted phenyl.
  • R 1 is substituted tetrazolyl.
  • R 1 When R 1 is substituted phenyl, suitable substituents include C 3- scycloalkylaminocarbonyl, and R 8 R 9 NC(O)- wherein one of R 8 and R 9 is hydrogen and the other is C 1-6 alkyl.
  • R 1 When R 1 is substituted tetrazolyl, suitable substituents include C 1-6 alkyl.
  • R is phenyl, 4-(cyclopropylaminocarbonyI)phenyl, 3- (cyclopropylaminocarbonyl)phenyl, 3-aminocarbonylphenyl, 3- (methylaminocarbonyl)phenyl, or 2-methyltetrazol-5-yI.
  • R a and R kb are both hydrogen.
  • k is 0, 1, or 2.
  • R 3 is hydrogen
  • I and m are both 2.
  • R 4 is hydrogen or methyl.
  • R 5 is hydrogen.
  • q is 0.
  • r and s are both 2.
  • R 5 is hydrogen or methyl.
  • r is 2.
  • s is 2.
  • t is 1.
  • R 6 is hydrogen or methyl.
  • R 7 is hydrogen
  • u is 1.
  • v is 0.
  • R 8 is hydrogen.
  • x and y are both 1.
  • b is1.
  • c is 1.
  • R 9 is hydrogen.
  • Ar is unsubstituted benzo.
  • Rja and Rjb are both hydrogen.
  • j is 1.
  • Examples of the aryl group, R 2 include phenyl.
  • R 2 is substituted aryl
  • suitable substituents include halo, C 1-6 alkyl, C 1-6 alkoxycarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkoxy, nitro, C 1-6 alkylsulphonyl, hydroxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkylS-, (mono- and-di-C 1-6 alkyl)amino, and C ⁇ 6 alkylcarbonylamino.
  • R 2 is substituted phenyl.
  • R 2 is substituted phenyl suitable substituents include halo.
  • R 2 is phenyl substituted with chloro.
  • R 2 is 3,4-dichlorophenyl.
  • R A is unsubstituted aryl or unsubstituted arylC 1-6 alkyl
  • X A is a bond or -NH-; nA is 1 or 2
  • R A' is C -6 alkyl or hydrogen.
  • R A is aryl
  • examples include phenyl.
  • R A is arylC 1-6 alkyl
  • examples include benzyl and phenylethyl.
  • R is phenyl, benzyl, or phenylethyl.
  • R A' is hydrogen or methyl.
  • R B is unsubstituted aryl or unsubstituted arylC -6 alkyl
  • X B is -NH- or a bond, and; nB is 1 or 2.
  • R B is aryl
  • examples include phenyl.
  • R B is arylC 1-6 alkyl
  • examples include benzyl and phenylethyl.
  • R B is phenyl, benzyl, or phenylethyl.
  • R B' is unsubstituted aryl or unsubstituted arylC 1-6 alkyl, and; X B' is -NH- or a bond.
  • R B' is aryl
  • examples include phenyl.
  • R B' is arylC 1-6 alkyl
  • examples include benzyl and phenylethyl.
  • R B' is phenyl, benzyl, or phenylethyl.
  • X B" is a bond or-NH-, and
  • R B" is unsubstituted aryl or unsubstituted arylC 1-6 alkyl.
  • R B" is aryl
  • examples include phenyl
  • R B" is arylC 1-6 alkyl
  • examples include benzyl and phenylethyl.
  • R B" is phenyl, benzyl, or phenylethyl.
  • the stereochemistry at the position marked '*' is (RS), (R), or (S).
  • R c is unsubstituted or aryl or unsubstituted or substituted arylC 1-6 alkyl
  • X c is -NH- or a bond
  • R c' is hydrogen or methyl, and; nC is 0 or 1.
  • R c is aryl
  • examples include phenyl
  • R c is arylC -6 alkyl
  • examples include benzyl and phenylethyl.
  • R c is phenyl, benzyl, phenylethyl, or 4- (cyclopropylaminocarbonyl)benzyl.
  • the stereochemistry at the position marked '*' is (RS), (R), or (S).
  • R D is unsubstituted aryl, unsubstituted or substituted arylC 1-6 alkyl, or substituted heteroaryl;
  • X D is a bond or -NH-, and; nD is O, 1, or 2.
  • R D is aryl, examples include phenyl.
  • R D is arylC 1-6 alkyl
  • examples include benzyl and phenylethyl.
  • R D is heteroaryl
  • examples include tetrazolyl.
  • R D is benzyl, phenyl, phenylethyl, 4- (cyclopropylaminocarbonyl)benzyl, 3-(cyclopropylaminocarbonyl)benzyl, 3- (aminocarbonyl)benzyl, or 2-methyItetrazol-5-yl.
  • R E is unsubstituted aryl, or unsubstituted or substituted arylC 1-6 alkyl, and;
  • X E is a bond or -NH-.
  • R E is aryl
  • examples include phenyl.
  • R E is arylC ⁇ -6 alkyl
  • examples include benzyl and phenylethyl.
  • R E is benzyl, phenyl, phenylethyl, or 3- (methylaminocarbonyl)benzyl.
  • R F is unsubstituted or aryl or unsubstituted arylC 1-6 alkyl, and;
  • X F is a bond or -NH-.
  • R F is aryl
  • examples include phenyl.
  • R F is aryIC 1-6 alkyl
  • examples include benzyl and phenylethyl.
  • R F is benzyl, phenyl, or phenylethyl.
  • Suitable salts of the compounds of formula (I) include physiologically acceptable salts and salts which may not be physiologically acceptable but may be useful in the preparation of compounds of formula (I) and physiologically acceptable salts thereof.
  • acid addition salts may be derived from inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphates, phosphates, acetates, benzoates, citrates, succinates, lactates, tartrates, fumarates, maleates, 1-hydroxy-2-naphthoates, pamoates, methanesulphonates, formates or trifluoroacetates.
  • solvates include hydrates.
  • Certain of the compounds of formula (I) may contain chiral atoms and/or multiple bonds, and hence may exist in one or more stereoisomeric forms.
  • the present invention encompasses all of the stereoisomers of the compounds of formula (I), including geometric isomers and optical isomers, whether as individual stereoisomers or as mixtures thereof including racemic modifications.
  • a compound of formula (I) is in the form of a single enantiomer or diastereoisomer.
  • Certain of the compounds of formula (I) may exist in one of several tautomeric forms. It will be understood that the present invention encompasses all of the tautomers of the compounds of formula (I) whether as individual tautomers or as mixtures thereof.
  • references to 'aryl' refers to monocyclic and bicyclic carbocyclic aromatic rings, for example naphthyl and phenyl, especially phenyl.
  • 'aryl' refers to a monocyclic carbocyclic aromatic residue, for example benzo.
  • Suitable substituents for any aryl group include 1 to 5, suitably 1 to 3, substituents selected from the list consisting of cyano, perhaloalkyl, amido, halo, alkyl, alkoxycarbonyl, aminocarbonyl, mono- and di-(alkyl)aminocarbonyl, alkoxy, nitro, alkylsulphonyl, hydroxy, alkoxyalkyl, alkylthio, mono- and-di-(aIkyl)amino, and alkylcarbonylamino.
  • references to 'heteroaryl' refers to monocyclic heterocyclic aromatic rings containing 1-4 heteroatoms selected from nitrogen, oxygen and sulphur.
  • heterocyclic aromatic rings include tetrazolyl.
  • Suitable substituents for any heteroaryl group include 1 to 5, suitably 1 to 3, substituents selected from the list consisting of aminocarbonyl; mono-and di- (alkyl)aminocarbonyl; cycloalkylaminocarbonyl; amino; alkylsulphonylamino; alkylcarbonyl; alkyl; alkoxycarbonyl; unsubstituted heteroaryl; heteroaryl substituted with alkyl, halo, alkoxy, or hydroxy; halo; alkoxy; nitro; alkylsulphonyl; hydroxy; alkoxyalkyl; alkylthio; mono- and-di-(alkyl)amino; alkylcarbonylamino; cyano, perhaloalky
  • references to 'alkyl' include references to both straight chain and branched chain aliphatic isomers of the corresponding alkyl, suitably containing up to six carbon atoms.
  • references to 'cycloalkyl' include saturated alicyclic rings suitably containing 3-8 carbon atoms.
  • Suitable substituents for any cycloalkyl group include alkyl, halo, and hydroxy.
  • References to 'heterocyclyl' refer to monocyclic heterocyclic aliphatic rings containing 2 to 6, suitably 3 to 5, carbon atoms, and 1 to 3, heteroatoms selected from nitrogen, oxygen, and sulphur. Examples of heterocyclic rings include piperidinyl.
  • Suitable substituents for any heterocyclyl group include cycloalkylcarbonyl, aminocarbonyl, alkylsulphonylamino, alkylcarbonyl, cycloalkylaminocarbonyl, alkyl, alkoxycarbonyl, alkylaminocarbonyl, halo, alkoxy, nitro, alkylsulphonyl, hydroxy, alkoxyalkyl, alkylthio, mono- and di-(alkyl)amino, and alkylcarbonylamino.
  • references to 'halogen' or 'halo' include iodo, bromo, chloro or fluoro, especially fluoro and chloro.
  • Synthetic Method A may be performed as either of two alternatives; Alternative (i) and Alternative (ii).
  • R 1 , X, R 3 , R 2 , A, and Z are as hereinbefore defined, and U g is a urea- forming group, and thereafter, if required, carrying out one or more of the following optional steps:
  • a urea-forming group is a group which is derived from a reagent which introduces a carbonyl group and a leaving group to an amino compound.
  • urea-forming groups are imidazolylcarbonyl and chlorocarbonyl, and, when R 3 is hydrogen, 4-nitrophenoxycarbonyl may be used.
  • the reagents from which they are derived are 1,1'-carbonyldiimidazole, phosgene, and 4- nitrophenylchloroformate respectively.
  • a compound of formula (II) may be prepared by the reaction of a compound of formula (IV)
  • L g is a leaving group.
  • a suitable leaving group, L g is a halo group such as chloro, or an imidazolyl group.
  • a compound of formula (IV) is reacted with a compound of formula U g -L g followed by reaction with a compound of formula (III) in situ i.e. without isolation of a compound of formula (II).
  • a solution of a compound of formula (IV) and a suitable base, such as diisopropylethylamine, in a suitable solvent, such as acetonitrile is added dropwise to a stirred solution of a compound of formula U g -L g in the suitable solvent.
  • a suitable solvent such as acetonitrile
  • the solution is stirred for a suitable period of time, such as 1.5- 2 hours, then treated with a solution of a compound of formula (III) in the suitable solvent.
  • the reaction mixture is stirred for a suitable period of time, for example 4-6 hours, then left to stand for up to 18 hours.
  • the solvent is removed in vacuo and the crude compound of formula (I) isolated by conventional means. Purification may be undertaken by conventional means such as chromatography.
  • a compound of formula (V) may be prepared by reaction of a compound of formula (III) as hereinbefore defined with a compound of formula U g -L g as hereinbefore defined.
  • a solution of compound of formula U g -L g in a suitable anhydrous solvent such as anhydrous dichloromethane
  • a suitable reduced temperature such as minus 5 to 5°C
  • a suitable base such as triethylamine
  • Synthetic Method C comprises the reaction of a compound of formula (III) as hereinbefore defined, or a protected form thereof, with a compound of formula (VI);
  • R 1 and X are as hereinbefore defined, and thereafter, if required, carrying out one or more of the following optional steps:
  • a suitable anhydrous solvent such as dichloromethane
  • a suitable base such as triethylamine
  • the compound of formula (I) is then isolated typically by chromatography.
  • Synthetic Method B comprises the reaction of a compound of formula (VII)
  • a suitable activating agent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU).
  • a suitable activating agent such as HATU
  • a suitable solvent such as acetonitrile
  • a solution of a compound of formula (III) and a suitable base such as diisopropylethylamine
  • Synthetic Methods D and F the use of t-BOC protection/deprotection in Synthetic Methods B and C are denoted herein as Synthetic Methods D and F respectively, while the use of TFA protection/deprotection in Synthetic Methods B and C are denoted herein as Synthetic Methods E and G respectively.
  • Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected, for example those methods discussed in standard reference texts of synthetic methodology such as P J Kocienski, Protecting Groups, (1994), Thieme.
  • the absolute stereochemistry of compounds may be determined using conventional methods, such as X-ray crystallography.
  • the salts and solvates of the compounds of formula (I) or formula (III) may be prepared and isolated according to conventional procedures.
  • a CCR-3 competition binding SPA was used to assess the affinity of novel compounds for CCR-3.
  • Membranes prepared from K562 cells stably expressing CCR-3 (2.5 ⁇ g/well) were mixed with 0.25mg/well wheat-germ agglutinin SPA beads (Amersham) and incubated in binding buffer (HEPES 50 mM, CaCI 2 1 mM, MgCI 2 5 mM, 0.5% BSA) at 4°C for 1.5 hr.
  • diseases of the respiratory tract such as bronchitis (including chronic bronchitis), bronchiectasis, asthma (including allergen-induced asthmatic reactions), chronic obstructive pulmonary disease (COPD), cystic fibrosis, sinusitis and rhinitis.
  • Other relevant disease states include diseases of the gastrointestinal tract such as intestinal inflammatory diseases including inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis) and intestinal inflammatory diseases secondary to radiation exposure or allergen exposure.
  • the compound of the invention may be used to treat nephritis, skin diseases such as psoriasis, eczema, allergic dermatitis and hypersensitivity reactions and diseases of the central nervous system which have an inflammatory component (e.g. Alzheimer's disease, meningitis, multiple sclerosis) HIV and AIDS dementia.
  • skin diseases such as psoriasis, eczema, allergic dermatitis and hypersensitivity reactions
  • diseases of the central nervous system which have an inflammatory component (e.g. Alzheimer's disease, meningitis, multiple sclerosis) HIV and AIDS dementia.
  • Compounds of the present invention may also be of use in the treatment of nasal polyposis, conjunctivitis or pruritis.
  • Further examples of disease states in which the compound of the invention have potentially beneficial effects include cardiovascular conditions such as atherosclerosis, peripheral vascular disease and idiopathic hypereosinophilic syndrome.
  • cardiovascular conditions such as atherosclerosis, peripheral vascular disease and idiopathic hypereosinophilic syndrome.
  • Other diseases for which the compound of the present invention may be beneficial are other hypereosinophilic diseases such as Churg-strauss syndrome.
  • eosinophilia is commonly found in parasitic diseases, especially helminth infections, and thus the compound of the present invention may be useful in treating inflammation arising from hypereosinophilic states of diseases such as hydatid cyst (Echinococcus sp.), tapeworm infections (Taenia sp.), blood flukes (schistosomiasis), and nematode (round worms) infections such as:- Hookworm (Ancylostoma sp.), Ascaris, Strongyloides, Trichinella, and particularly lymphatic filariasis including Onchocerca, Brugia, Wucheria (Elephantiasis).
  • diseases such as hydatid cyst (Echinococcus sp.), tapeworm infections (Taenia sp.), blood flukes (schistosomiasis), and nematode (round worms) infections such as:- Hookworm (Ancylostoma sp.), Ascaris,
  • the compound of the invention may be useful as an immunosuppressive agent and so have use in the treatment of auto-immune diseases such as allograft tissue rejection after transplantation, rheumatoid arthritis and diabetes.
  • Compounds of the invention may also be useful in inhibiting metastasis.
  • Diseases of principal interest include asthma, COPD and inflammatory diseases of the upper respiratory tract involving seasonal and perennial rhinitis.
  • Preferred diseases of principal interest include asthma and inflammatory diseases of the upper respiratory tract involving seasonal and perennial rhinitis.
  • Further diseases also of principle interest include inflammatory diseases of the gastrointestinal tract such as inflammatory bowel disease.
  • a compound of formula (I'), or a physiologically acceptable salt or solvate thereof for use in the treatment of inflammatory conditions, eg. asthma or rhinitis.
  • a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of patients with inflammatory conditions, eg. asthma or rhinitis.
  • a method for the treatment of a human or animal subject with an inflammatory condition eg. asthma or rhinitis, which method comprises administering an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.
  • the compounds according to the invention may be formulated for administration in any convenient way.
  • a pharmaceutical composition comprising a compound of formula (I'), or a physiologically acceptable salt or solvate thereof, and optionally one or more physiologically acceptable diluents or carriers.
  • the compounds according to the invention may, for example, be formulated for oral, inhaled, intranasal, buccal, parenteral or rectal administration, preferably for oral administration.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, cellulose or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p_- hydroxybenzoates or sorbic acid.
  • the preparations may also contain buffer salts, flavouring, colouring and/or sweeten
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds according to the invention may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre-filled syringes, or in multidose containers with an added 5 preservative.
  • the compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or tonicity adjusting agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.
  • compositions according to the invention may also be used in combination with other therapeutic agents, for example
  • antihistaminic agents such as corticosteroids, e.g. fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide or budesonide; or non-steroidal anti-inflammatory drugs (NSAIDs) eg. sodium cromoglycate, nedocromil sodium, PDE-4 inhibitors, leukotriene antagonists, iNOS inhibitors,
  • corticosteroids e.g. fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide or budesonide
  • non-steroidal anti-inflammatory drugs eg. sodium cromoglycate, nedocromil sodium, PDE-4 inhibitors, leukotriene antagonists, iNOS inhibitors
  • beta adrenergic agents such as salmeterol, salbutamol, formoterol, fenoterol or terbutaline and salts thereof; or antiinfective agents e.g. antibiotic agents and antiviral agents.
  • the resultant pharmaceutical composition may be administered by the inhaled or intranasal route.
  • Compounds of the invention may conveniently be administered in amounts of, for example, 0.001 to 500mg/kg body weight, preferably 0.01 to
  • This system used a 250 x 4.6mm Chiralpak AD 10 ⁇ m column, eluting with absolute ethano heptane mixtures at a flow rate of 1ml per minute, with UV detection at 215nm.
  • Standard chiral preparative HPLC system This system used a Chiralpak AD column (2cm x 25cm), eluting with absolute ethanol:heptane mixtures (15ml/min over 25mins, UV detection at 215nm).
  • Intermediate 25 was prepared in a similar manner to Intermediate 17 using Intermediate 20 (0.303g) in ethanol (10ml), potassium carbonate (0.223g) and methyl iodide (0.051ml) to give the title compound (0.13g) as a diastereomeric mixture as a yellow oil.
  • Intermediate 55A was prepared by Synthetic Method B using Intermediate 54A(0.076g), in dry dimethylformamide(3ml), benzoic acid(0.025g), HATU(0.07 ⁇ g) and diisopropylethylamine(0.036ml).
  • the title compound (0.079g) was obtained from 1:1 cyclohexane/ethyl acetate as a colourless oil.
  • LC-MS (System A): Rt 3.64min. Mass Spectrum m/z 475[MH+].
  • Triphenylphosphine (0.77g) was added to a stirred solution of Intermediate 59 (1.07g) in tetrahydrofuran (15ml). The solution was cooled to 0° and treated with diisopropylazodicarboxylate (0.5 ⁇ ml). The reaction mixture was warmed to room temperature and stirred at room temperature for 4h. The solvent was removed in vacuo. Chromatographic purification of the residue on silica (90g Biotage), eluting with a (1 :1) mixture of cyclohexane and ethyl acetate, gave a solid.
  • Example 42 Synthetic Method A A solution of phenethylamine (0.012g) and diisopropylethylamine (0.020g) in acetonitrile (1ml) was added, dropwise, to a stirred solution of 4-nitrophenyl chloroformate (0.020g) in acetonitrile (1ml). The solution was stirred for 1.75h then treated with a solution of Intermediate 70 (0.023g) in acetonitrile (1ml). The reaction mixture was stirred for 5h then left to stand overnight. The solvent was removed in vacuo. The residue was partitioned between ethyl acetate (20ml) and 1M sodium carbonate (20ml).
  • Example 44 A solution of benzoic acid (0.012g) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (0.038g) in acetonitrile (3ml) was stirred for 5min then treated with a solution of Intermediate 70 (0.023g) and diisopropylethylamine (0.026g) in acetonitrile (2ml). The reaction mixture was stirred for 6h then left to stand overnight. The solvent was removed in vacuo. The residue was partitioned between ethyl acetate (30ml) and 0.5M sodium bicarbonate (25ml).
  • the starting material for Examples 42-45 may be prepared according to Intermediates 67-70 above.
  • Example 78 Synthetic Method B A solution of benzoic acid (0.01 Og) and O-(7-azabenzotriazol-1-yI)-N,N,N',N'- tetramethyluronium hexafluorophosphate (0.030g) in acetonitrile (3ml) was stirred for 5min then treated with a solution of Intermediate 61 (0.015g) and diisopropylethylamine (0.020g) in acetonitrile (1 ml). The reaction mixture was stirred for 2h then left to stand overnight. The solvent was removed in vacuo. The residue was partitioned between ethyl acetate (25ml) and 0.5M sodium bicarbonate (20ml).
  • the starting material for Examples 78-82 may be prepared according to Intermediates 59-61 above.
  • Example 81 Synthetic Method A A solution of phenethylamine (0.012g) and diisopropylethylamine (0.020g) in acetonitrile (1ml) was added, dropwise, to a stirred solution of 4-nitrophenyl chloroformate (0.020g) in acetonitrile (1ml). The solution was stirred for 1.25h then treated with a solution of Intermediate 61 (0.020g) in acetonitrile (1ml). The reaction mixture was stirred for 3h then left to stand overnight. The solvent was removed in vacuo. The residue was partitioned between ethyl acetate (25ml) and 0.5M sodium carbonate (20ml).

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Abstract

L'invention concerne des composés représentés par la formule (I') dans laquelle R1 représente un aryle substitué ou non substitué ou un hétéroaryle substitué ou non substitué; X représente -(CRkaRkb)k-; Rka et Rkb représentent chacun indépendamment hydrogène ou C1-6alkyle; k est compris entre 0 et 5;Y représente NR3 ou une liaison; R3 représente hydrogène ou C1-6alkyle; Z représente une fraction de la formule (ZA), (ZB), (ZC), (ZD), (ZE), ou (ZF):(ZA)(ZB)(ZC)(ZD)(ZE)(ZF); A représente -(CRjaRjb)j-; Rja et Rjb représentent chacun indépendamment hydrogène ou C1-6alkyle; j est égal à 0, 1 ou 2; et R2 représente aryle substitué ou non substitué. L'invention concerne également des sels et des solvates de ceux-ci qui sont des antagonistes du récepteur CCR3 et qui de ce fait, sont indiqués pour être utilisés à des fins thérapeutiques.
PCT/EP2003/005446 2002-05-22 2003-05-20 Antagonistes du recepteur de morpholinylmethyluree ccr-3 WO2003097618A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007106525A1 (fr) 2006-03-13 2007-09-20 The Regents Of The University Of California Inhibiteurs d'uree a conformation restreinte d'epoxyde hydrolase soluble
WO2008153182A1 (fr) * 2007-06-15 2008-12-18 Mitsubishi Tanabe Pharma Corporation Dérivé de morpholine
US7662910B2 (en) 2004-10-20 2010-02-16 The Regents Of The University Of California Inhibitors for the soluble epoxide hydrolase
US8455652B2 (en) 2003-04-03 2013-06-04 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Inhibitors for the soluble epoxide hydrolase
US8513302B2 (en) 2003-04-03 2013-08-20 The Regents Of The University Of California Reducing nephropathy with inhibitors of soluble epoxide hydrolase and epoxyeicosanoids
US9296693B2 (en) 2010-01-29 2016-03-29 The Regents Of The University Of California Acyl piperidine inhibitors of soluble epoxide hydrolase
WO2017050714A1 (fr) 2015-09-22 2017-03-30 Glaxosmithkline Intellectual Property (No.2) Limited Dicarboxamide de pyridinone à utiliser comme inhibiteur de bromodomaine
WO2017174621A1 (fr) 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property (No.2) Limited Dérivés de pyridyle à utiliser en tant qu'inhibiteurs de bromodomaine
CN109705052A (zh) * 2019-01-25 2019-05-03 苏州大学 一种制备1,4-二氢噁嗪的方法
CN114436983A (zh) * 2021-11-23 2022-05-06 辽宁中医药大学 马齿苋中Oleraze和Oleraoxazine acid及其提取分离方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0760362A1 (fr) * 1994-05-18 1997-03-05 Nisshin Flour Milling Co., Ltd. Nouveau derive de diaminomethylidene
WO2000071518A2 (fr) * 1999-05-25 2000-11-30 Sepracor, Inc. Composes heterocycliques analgesiques et procedes d'utilisation de ces derniers
WO2002026723A1 (fr) * 2000-09-29 2002-04-04 Glaxo Group Limited Composes utiles dans le traitement de maladies inflammatoires
WO2002026722A1 (fr) * 2000-09-29 2002-04-04 Glaxo Group Limited Derives de morpholine-acetamide permettant de traiter les maladies inflammatoires

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0760362A1 (fr) * 1994-05-18 1997-03-05 Nisshin Flour Milling Co., Ltd. Nouveau derive de diaminomethylidene
WO2000071518A2 (fr) * 1999-05-25 2000-11-30 Sepracor, Inc. Composes heterocycliques analgesiques et procedes d'utilisation de ces derniers
WO2002026723A1 (fr) * 2000-09-29 2002-04-04 Glaxo Group Limited Composes utiles dans le traitement de maladies inflammatoires
WO2002026722A1 (fr) * 2000-09-29 2002-04-04 Glaxo Group Limited Derives de morpholine-acetamide permettant de traiter les maladies inflammatoires

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8455652B2 (en) 2003-04-03 2013-06-04 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Inhibitors for the soluble epoxide hydrolase
US8513302B2 (en) 2003-04-03 2013-08-20 The Regents Of The University Of California Reducing nephropathy with inhibitors of soluble epoxide hydrolase and epoxyeicosanoids
US7662910B2 (en) 2004-10-20 2010-02-16 The Regents Of The University Of California Inhibitors for the soluble epoxide hydrolase
US8476043B2 (en) 2004-10-20 2013-07-02 The Regents Of The University Of California Inhibitors for the soluble epoxide hydrolase
AU2007225170B2 (en) * 2006-03-13 2012-11-01 The Regents Of The University Of California Piperidinyl, indolyl, pirinidyl, morpholinyl and benzimidazolyl urea derivatives as inhibitors of soluble epoxide hydrolase for the treatment of hypertension, inflammations and other diseases
WO2007106525A1 (fr) 2006-03-13 2007-09-20 The Regents Of The University Of California Inhibiteurs d'uree a conformation restreinte d'epoxyde hydrolase soluble
US8188289B2 (en) 2006-03-13 2012-05-29 The Regents Of The University Of California Conformationally restricted urea inhibitors of soluble epoxide hydrolase
US8501783B2 (en) 2006-03-13 2013-08-06 The Regents Of The University Of California Conformationally restricted urea inhibitors of soluble epoxide hydrolase
US9029550B2 (en) 2006-03-13 2015-05-12 The Regents Of The University Of California Conformationally restricted urea inhibitors of soluble epoxide hydrolase
US8975252B2 (en) 2007-06-15 2015-03-10 Shanghai Pharmaceuticals Holding Co., Ltd. Morpholine derivative
TWI452044B (zh) * 2007-06-15 2014-09-11 Mitsubishi Tanabe Pharma Corp 嗎啉衍生物
JP5368304B2 (ja) * 2007-06-15 2013-12-18 田辺三菱製薬株式会社 モルホリン誘導体
WO2008153182A1 (fr) * 2007-06-15 2008-12-18 Mitsubishi Tanabe Pharma Corporation Dérivé de morpholine
US9296693B2 (en) 2010-01-29 2016-03-29 The Regents Of The University Of California Acyl piperidine inhibitors of soluble epoxide hydrolase
WO2017050714A1 (fr) 2015-09-22 2017-03-30 Glaxosmithkline Intellectual Property (No.2) Limited Dicarboxamide de pyridinone à utiliser comme inhibiteur de bromodomaine
WO2017174621A1 (fr) 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property (No.2) Limited Dérivés de pyridyle à utiliser en tant qu'inhibiteurs de bromodomaine
CN109705052A (zh) * 2019-01-25 2019-05-03 苏州大学 一种制备1,4-二氢噁嗪的方法
CN114436983A (zh) * 2021-11-23 2022-05-06 辽宁中医药大学 马齿苋中Oleraze和Oleraoxazine acid及其提取分离方法

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