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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • 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
  • 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
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • 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
  • C07D417/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

• the present invention relates to novel compounds, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.
• the P2X ⁇ receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflamjmatory/ixnmune process, specifically, macrophages, mast cells and lymphocytes (T and B).
• P2X ⁇ receptors are also located on antigen-presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells) and hepatocytes.
• P2X receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases, in the aetiologies of which the P2X ⁇ receptor may play a role.
• X represents an oxygen or sulphur atom or a group NH, CH2, CH2CH2 or OCH2;
• R represents a pyridyl (especially 3-pyridyl or 4-pyridyl) orpyrimidinyl group;
• R represents a phenyl, pyridyl or pyrimidinyl group, each of which may be optionally substituted by one or more substituents independently selected from a halogen atom or an amino, cyano, hydroxyl, nitro, Ci-C ⁇ -alkyl, halo-Cj-Cg-alkyl, Cj-Cg-alkoxy,
• R 3 and R 4 each independently represent a hydrogen atom or a Q-Cg-alkyl group
• R and R each independently represent a hydrogen atom or a Q-Cg-alkyl group, or together with the nitrogen atom to which they are attached form apyrrolidinyl or piperidinyl group; or a pharmaceutically acceptable salt or solvate thereof.
• an alkyl substituent or alkyl moiety in a substituent group may be linear or branched and also the alkyl moieties in a dialkylamino substituent group may be the same or different.
• X represents a group OCH 2
• the oxygen atom is positioned adjacent the carbonyl group in the ring.
• the group R preferably represents a phenyl, pyridyl or pyrimidinyl group, each of which may be optionally substituted by one, two, three or four substituents independently selected from a halogen atom (e.g. fluorine, chlorine, bromine or iodine) or an amino, cyano, hydroxyl, nitro, Ci-Cg-alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl), halo-Ci-C ⁇ -alkyl (e.g. trifluoromethyl), -Cg-alkoxy (e.g.
• a halogen atom e.g. fluorine, chlorine, bromine or iodine
• an amino, cyano, hydroxyl, nitro Ci-Cg-alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl
• Ci-C ⁇ -alkylthio e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylthio
• Ci-C ⁇ -C6-alkylamino e.g. methylamino, dimethylamino, ethylamino or diethylamino
• Ci-Cg-alkylcarbonyl e.g. methyl-, ethyl-, propyl-, butyl-,pentyl- or hexylcarbonyl
• -C ⁇ -alkoxycarbonyl e.g.
• Ci-Cg-alkylsulphinyl e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylsulphinyl
• Ci-Cg-alkylsulphonyl e.g.
• -NR SO2R or -SO2NR R group or a group -Z-(CH2)p-Z-(CH2)q-H wherein each Z independently represents a nitrogen or oxygen atom, p is an integer from 2 to 5 and q is 0 or an integer from 1 to 5.
• R represents a phenyl, pyridyl or pyrimidinyl group, each of which may be optionally substituted by one, two or three substituents independently selected from a halogen atom or an amino, cyano, hydroxyl, nitro, C ⁇ -C 4 -alkyl, halo-C ⁇ -C 4 -alkyl,
• R represents a phenyl, pyridyl or pyrimidinyl group, each of which may be optionally substituted by one or two substituents independently selected from a halogen atom or an amino, cyano, nitro, C ⁇ -C4-alkyl, halo-C ⁇ -C4-alkyl,
• R represents a phenyl or pyridyl group optionally substituted by one or two substituents independently selected from a fluorine or chlorine atom or an amino, cyano, nitro, trifluoromethyl, methoxy or -SO2NR R group.
• R and R each independently represent a hydrogen atom or a
• C ⁇ -C4-alkyl group e.g. methyl or ethyl group.
• R and R each independently represent a hydrogen atom or a
• C ⁇ -C4-alkyl group e.g. methyl or ethyl group
• Preferred compounds of the invention include:
• (+/-)-N- [ 1 -(3 ' - ⁇ itrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-imidazolidine-2,4-dione, (+/-)-N-[l-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-piperidin-2-one, and (+/-)-N- [ 1 -(3 ' - ⁇ itrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2-one.
• the present invention further provides a process for the preparation of a compound of formula (I) as defined above which comprises: (a) reacting a compound of general formula
• L represents a leaving group (e.g. a hydroxyl group) and R 1 and R 2 are as
• X and Y are as hereinbefore defined except that when X is an oxygen atom or OCH 2 group, then Y is not a CH 2 group; or
• X represents an oxygen atom or OCH 2 group and Y and R 1 are as hereinbefore defined, with a compound of general formula (VI), R 2 -B(OH) 2 , wherein R 2 is as hereinbefore defined; or
• X represents an oxygen atom or OCH 2 group and Y and R 1 are as hereinbefore defined, with a compound of general formula (VHI), R ⁇ -Br, wherein R 2 is as hereinbefore defined; and optionally after (a), (b), (c), (d), (e), (f) or (g) converting the compound of formula (I) to a further compound of formula (I) and/or forming a pharmaceutically acceptable salt or solvate of the compound of formula (I).
• VHI general formula
• R ⁇ -Br wherein R 2 is as hereinbefore defined
• the processes (a), (b), (c), (d), (e), (f) and (g) may conveniently be carried out in a solvent (e.g. dichloromethane, chloroform, acetonitrile, dioxan or tetrahydrofuran), at a temperature in the range from 0 to 100 °C, preferably in the range from 10 to 80 °C, and especially at ambient temperature (20 °C).
• a solvent e.g. dichloromethane, chloroform, acetonitrile, dioxan or tetrahydrofuran
• the compounds of formula (II) are known from WO 97/20815 and WO 98/42670 or may be prepared by processes analogous to those described in WO 97/20815 and
• the compounds of formula (UI), (VI) and (VD3) are known or commercially available compounds, or may be prepared by processes known in the art.
• the compounds of formula (IV) may be prepared by methods known in the art starting from the compounds of formula (II).
• the compounds of formula (V) and (VII) may be prepared by processes analogous to (a), (b) or (c) above using the corresponding bromo- or boron-containing compound of formula (II) or (IN).
• nitrophenyl group can be converted to compounds of formula (I) where R is an aminophenyl group by reduction using iron powder and ammonium chloride in ethanol or an ethanol water mixture under reflux conditions.
• the compounds of formula (I) above may be converted to a pharmaceutically- acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orp-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.
• Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
• the compounds of the present invention are advantageous in that they possess pharmacological activity. They are therefore indicated as pharmaceuticals for use in the treatment or prevention of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myocardial ischaemia, cardiac reperfusion damage, cerebral ischaemia, stroke, myoblastic leukaemia, diabetes, Alzheimer's disease, osteoporosis, burn injury, stroke, varicose veins and meningitis.
• the present invention provides a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
• the invention provides the use of a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
• the invention further provides a method of effecting immunosuppression (e.g. in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis) which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined to a patient.
• a method of effecting immunosuppression e.g. in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis
• the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
• the compounds of formula (I) and pharmaceutically-acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically-acceptable adjuvant, diluent or carrier.
• the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.10 to 70 %w, of active ingredient, and, from 1 to 99.95 %w, more preferably from 30 to 99.90 %w, of a pharmaceutically-acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined in association with a pharmaceutically-acceptable adjuvant, diluent or carrier.
• the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined with a pharmaceutically-acceptable adjuvant, diluent or carrier.
• the pharmaceutical composition of the invention may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.
• topically e.g. to the lung and/or airways or to the skin
• solutions e.g. to the lung and/or airways or to the skin
• systemically e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.
• MS mass spectrometry
• nuclear magnetic resonance nuclear magnetic resonance
• dimethylsulphoxide
• Boiling point 140 °C (oil pump) MS (gems) 228/230 M +
• Example 6c Prepared according to the method of Example 6c) using l-(4-bromophenyloxy)-4- (4-pyridyl)-2-butanol (0.40 g) prepared as described in Example 6b) and 4-fluorophenylboronic acid (0.28 g), to deliver the sub-title compound as a colourless solid (0.23 g).
• (+/-)-N-[l-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-isoindole-l ,3-dione (3.41 g) was dissolved in a solution of 30 % methylamine in methanol (100 ml). The solution was heated to reflux temperature for 3 hours. The solvent was removed under reduced pressure, the residue dissolved in ethyl acetate, washed with water, dried over magnesium sulphate, filtered and concentrated. Purification by chromatography over neutral alumina, eluting with 10% methanol in dichloromethane gave the sub-title compound as a cream solid (1.08g).
• Example 40a Prepared according to the method of Example 1 with (2R)-l-(4-bromophenoxy)-4-(3- pyridyl)-2-butanol (0.214 g) as prepared in Example 40a) of WO 97/20815 and 3-chloro- 4-fluorophenylboronic acid (0.18 g), yielding the sub-title compound as a yellow gum (0.24 g).
• the reaction mixture was partitioned between diethyl ether and 2N hydrochloric acid and the layers separated.
• the aqueous phase was neutralised with 2N sodium hydroxide and extracted with ethyl acetate.
• the organic phase was separated, dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give a residue.
• the residue was dissolved in tetrahydrofuran (25ml) and tetrabutylammonium fluoride (0.163 g) was added. After stirring at room temperature overnight the mixture was concentrated under reduced pressure and partitioned between diethyl ether and 2N hydrochloric acid. The layers were separated.
• Example 6c Prepared according to the method of Example 6c) using l-(4-bromophenoxy)-4-(4- pyridyl)-2-butanol (0.20 g) prepared as described in Example 6b) and 3-trifluoromethylphenylboronic acid (0.13 g), to deliver the sub-title compound as a yellow oil (0.18 g).
• (+/-)-N-[l-(3'-(Trifluoromethyl)biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]- thiazo!idin-2,4-dione Prepared according to the method of Example 1 with (+/-)- 1 -(3' - trifluoromethylbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol (0.175g), from step a) and 2,4-thiazolinedione (0.106 g).
• Example 6c Prepared according to the method of Example 6c) using l-(4-bromophenoxy)-4-(4- pyridyl)-2-butanol (0.20 g) prepared as described in Example 6b) and
• Example 32a Prepared according to the method described in Example 6c) using (+/-)-N-[l-(4- bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (Example 32a), O.lOOg), phenylboronic acid (0.047 g), ethanol (3 ml), aqueous sodium bicarbonate solution (2M, 0.2 ml) and tetrakis-(triphenylphosphine)palladium(0) (0.010 g).
• Example 32a (+/-)-N-[l-(4- bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (Example 32a), O.lOOg), 4-chlorobenzeneboronic acid (0.060 g), ethanol (3 ml), aqueous sodium bicarbonate solution (2M, 0.2 ml) and tetrakis-(triphenylphosphine)palladium(0) (0.010 g).
• Example 32a Prepared according to the method described in Example 6c) using (+/-)-N-[l-(4- bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (Example 32a), O.lOOg), 4-methylbenzeneboronic acid (0.052 g), ethanol (3 ml), aqueous sodium bicarbonate solution (2M, 0.2 ml) and tetrakis-(triphenylphosphine)palladium(0) (0.010 g).
• Example 32a (+/-)-N-[l-(4- bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (Example 32a), O.lOOg), 4- methoxybenzeneboronic acid (0.059 g), ethanol (3 ml), aqueous sodium bicarbonate solution (2M, 0.2 ml) and tetrakis-(triphenylphosphine)palladium(0) (0.010 g). After work-up, the residue was purified by NPHPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.026 g).
• Example 32b ((+/-)-[4-(4- Pyridyl)-2-(oxazolidin-2-one-l-yl)butoxy]benzeneboronic acid (Example 32b), 0.050 g), 1- bromo-3,4-dichlorobenzene (0.048 g), ethanol (2 ml), aqueous sodium bicarbonate solution (2M, 0.1 ml) and tetrakis-(triphenylphosphine)palladium(0) (0.006 g).
• (+/-)-l-(4-Bromophenoxy)-4-(4-pyridyl)-2-(te/ -butyldimethylsilyloxy)butane tert-Butyldimethylsilyl chloride (20.53 g) andimidazole (9.25 g) were added to a solution of (+/-)- l-(4-bromophenyloxy)-4-(4-pyridyl)-2-butanol (Example 6b), 14.60g) in dry dichloromethane (500 ml). The solution was stirred overnight at room temperature.
• (+/-)-4-[4-(4-Pyridyl)-2-(fert-butyldimethylsayloxy)butoxy]benzeneboronic acid Prepared according to the method described in Example 18b) using (+/-)- 1 -(4- bromophenoxy)-4-(4-pyridyl)-2-(tert-butyldimethylsilyloxy)butane (lO.Og), from step a), tert-butyllithium (1.7 M solution in hexanes, 27 ml) and tri-wopropylborate (6 ml) in dry tetrahydrofuran (200 ml).
• (+/-)-l-[4-(6-Methoxypyridin-2-yl)phenoxy]-4-(4-pyridyl)-2-butanoI Prepared according to the method described in Example 6c) using (+/-)-4-[4-(4- pyridyl)-2-butoxy]benzeneboronic acid (0.20 g) from step c), 2-bromo-6-methoxypyridine (J. Org. Chem., 55, (1990), 69-73, 0.26 g), ethanol (3 ml), aqueous sodium bicarbonate solution (2M, 0.7 ml) and tetrakis-(triphenylphosphine)palladium(0) (0.020 g).
• Example 15a Prepared according to the method of Example 1 using (+/-)-N-l-(3'-nitrobiphenyl-4- yloxy)-4-(4-pyridyl)-2-butanol (Example 15a), 0.20 g), hydantoin (0.11 g), triphenylphosphine (0.29 g) and diethyl azodicarboxylate (0.17 ml) in dry tetrahydrofuran (10 ml) and dimethylformamide (2 ml).
• bbATP a P2X receptor agonist
• pyridoxal 5-phosphate a P2X ⁇ receptor antagonist

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