WO2004039762A1 - Phenethanolamine derivatives for the treatment of respiratory diseases - Google Patents

Phenethanolamine derivatives for the treatment of respiratory diseases Download PDF

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Publication number
WO2004039762A1
WO2004039762A1 PCT/EP2003/012194 EP0312194W WO2004039762A1 WO 2004039762 A1 WO2004039762 A1 WO 2004039762A1 EP 0312194 W EP0312194 W EP 0312194W WO 2004039762 A1 WO2004039762 A1 WO 2004039762A1
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formula
compound
alkyl
xnr
hydrogen
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PCT/EP2003/012194
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French (fr)
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Stephen Barry Guntrip
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Glaxo Group Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
    • C07C217/10—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention is concerned with phenethanolamine derivatives, processes for their preparation, compositions containing them and their use in medicine, particularly in the prophylaxis and treatment of respiratory diseases.
  • phenethanolamine compounds are known in the art as having selective stimulant action at ⁇ 2 -adrenoreceptors and therefore having utility in the treatment of bronchial asthma and related disorders.
  • GB 2 140 800 describes phenethanolamine compounds including 4-hydroxy- ⁇ 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1 ,3- benzenedimethanol 1-hydroxy-2-naphthalenecarboxylate (salmeterol xinafoate) which is now used clinically in the treatment of such medical conditions.
  • n is an integer of from 3 to 7; with the proviso that m + n is 5 to 12;
  • R 1 is selected from hydrogen, C ⁇ personally 6 alkyl, hydroxy, C ⁇ alkoxy, cyano, nitro, halo, Ci-ehaloalkyl, -XNR 8 C(O)R 9 , -XNR 8 C(O)NR 9 R 10 , -XNR 8 C(O)NC(O)IMR 9 R 10 , -XNR 8 SO 2 R 9 , -XSO 2 NR 9 R 10 , XSR 8 , XSOR 8 , XSO 2 R 8 , -XNR 9 R 10 , -XNR 8 C(O)OR 9 , XNR 8 SO 2 NR 9 R 10 , XCO 2 R 10 , or -XC(O)NR 9 R 10 ; or R 1 is selected from -X-aryl, -X-hetaryl, or -X-(aryloxy), each optionally substituted by 1 or 2 groups independently selected from hydroxy, C ⁇ . 6 alkoxy, halo, C
  • X is -(CH 2 ) r - or C 2 . 6 alkenylene
  • r is an integer from 0 to 6, preferably 0 to 4;
  • R 8 and R 9 are independently selected from hydrogen, C- ⁇ alkyl, C 3 . 7 cycloalkyl, aryl, hetaryl, hetaryl(C.
  • C 3 . 7 cycloalkyl, C,. 6 alkoxy, C-ehaloalkyl, -NHC(O)(C 1 . 6 alkyl), -SO 2 (C 1 . 6 alkyl), -SO 2 (aryl), -CO 2 H, and -CO 2 (C ⁇ alkyl), -NH 2 , -NH(C 1 . 6 alkyl), aryl(C
  • R 1 is -XNR 8 C(O)NR 9 R 10 , R 8 and R 9 may, together with the -NC(O)N- portion of the group R 1 to which they are bonded, form a saturated or unsaturated ring, preferably a 5-, 6-, or 7- membered ring, for example an imidazolidine ring, such as imidazolidine-2,4- dione;
  • R 1 is -XNR 8 C(O)OR 9
  • R 8 and R 9 may, together with the -NC(O)O- portion of the group R 1 to which they are bonded, form a saturated or unsaturated ring, preferably a 5-, 6-, or 7- membered ring, for example an oxazolidine ring, such as oxazolidine-2,4-dione;
  • R 10 is selected from hydrogen, C h alky! and C 3 . 7 cycloalkyl
  • R 1 contains a moiety -NR 9 R 10 or R 9 and R 10 may, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring;
  • R 2 , R 3 , R 6 , and R 7 are independently selected from hydrogen, C ⁇ alkyl, C-
  • . alkoxy, halo, and C haloalkyl; R 4 and R 5 are independently selected from hydrogen and C ⁇ alkyl with the proviso that the total number of carbon atoms in R 4 and R 5 is not more than 4.
  • Ar 1 is a group selected from
  • R 11 represents hydrogen, halogen, -(CH 2 ) q OR 15 , -NR 15 C(O)R 16 , -NR 15 SO 2 R 16 , -SO 2 NR 15 R 16 , -NR 15 R 16 , -OC(O)R 17 or OC(O)NR 15 R 16
  • R 12 represents hydrogen, halogen or C ⁇ alkyl
  • R 11 represents -NHR 18 and R 12 and -NHR 18 together form a 5- or 6- membered heterocyclic ring;
  • R' J represents hydrogen, halogen, -OR 1 1 5 0 or -NR 3 1 1 5 & D R1 ⁇ 6.
  • R 4 represents hydrogen, halogen, haloC ⁇ alkyl, -OR 15 , -NR 15 R 16 , -OC(O)R 17 or OC(O)NR 15 R 16 ;
  • R and R each independently represents hydrogen or C 1- alkyl, or in the groups -NR 15 R 16 , -SO 2 NR 15 R 16 and -OC(O)NR 15 R 16 , R 15 and R 16 independently represent hydrogen or d 4 alkyl or together with the nitrogen atom to which they are attached form a 5-, 6- or 7- membered nitrogen-containing ring,
  • R 17 represents an aryl (eg phenyl or naphthyl) group which may be unsubstituted or substituted by one or more substituents selected from halogen, C- M alkyl, hydroxy, C ⁇ alkoxy or halo C ⁇ 4 alkyl; and
  • q is zero or an integer from 1 to 4.
  • this invention provides a compound of formula (I) or a salt, solvate or physiologically functional derivative thereof wherein: R 1 is selected from hydrogen, C-
  • R 11 is as defined above except that R 11 is not hydrogen; and all other substituents are as defined for formula (I) above.
  • an aryl group or moiety may be for example phenyl or naphthyl.
  • a hetaryl group may be for example pyrrolyl, furyl, thienyl, pyridinyl, pyrazinyl, pyridazinyl, imidazolyl, tetrazolyl, tetrahydrofuranyl, oxazolyl, thiazolyl or thiadiazolyl.
  • the ring bearing the substituents R 1 , R 2 and R 3 ('outer' ring) is preferably attached at the meta- or para- position of the ring bearing the substituents R 6 and R 7 ('inner' ring) relative to the -O-(CH 2 ) n -, link.
  • the group R 1 is preferably attached to the ortho- or meta-position of the 'outer' phenyl ring, relative to the point of attachment to the 'inner' phenyl ring.
  • R 1 preferably represents hydroxy, -XR 8 (CO)NR 9 R 10 , -XSO 2 NR 9 R 10 , -XCO 2 R 10 , XC(O)NR 9 R 10 or X-hetaryl.
  • R 8 , R 9 and R 10 are preferably each independently selected from hydrogen, C ⁇ alkyl or C 3 . 7 cycloalkyl.
  • alkenylene includes both cis and trans structures.
  • X is preferably (CH 2 ) r where r is 0 to 2, or C 2 alkenylene.
  • R 2 and R 3 preferably each represent hydrogen.
  • R 4 and R 5 are preferably independently selected from hydrogen and methyl, more preferably R 4 and R 5 are both hydrogen.
  • n is suitably 3, 4, 5 or 6.
  • m is 5 and preferably n is 4 or 5, such that m + n is 9 or 10, preferably 9.
  • the group Ar 1 is preferably selected from groups (a) and (b) above.
  • R 11 represents halogen this is preferably chlorine or fluorine.
  • R 15 and R 16 preferably each independently represent hydrogen or methyl.
  • R 17 preferably represents substituted phenyl.
  • the integer q preferably represents zero or 1.
  • OR 15 preferably represents OH or -CH 2 OH
  • NR 15 C(O)R 16 preferably represents -NHC(O)H
  • -SO 2 NR 15 R 16 preferably represents -SO 2 NH 2 or SO 2 NHCH 3 ;
  • R 16 preferably represents NHSO 2 CH 3 ;
  • NR 15 R 16 preferably represents -NH 2 ;
  • -OC(O)R 17 preferably represents substituted benzoyloxy eg. OC(O)-C 6 H 4 -(p-CH 3 ); and -OC(O)N R 15 R 16 preferably represents OC(O)N(CH 3 ) 2 .
  • R 11 represents NHR 18 and together with R 12 forms a 5- or 6- membered heterocyclic ring -NHR 18 -R 12 - preferably represents a group: -NH-CO-R 19 - where R 19 is an alkyl, alkenyl or alkyloxy group; -NH-SO 2 R 20 - where R 20 is an alkyloxy group; -NH-R 21 - where R 21 is an alkyl or alkenyl group; optionally substituted by COOR 22 where R 22 is Ci. 4 alkyl; or -NH-CO-S-; wherein said alkyl, alkenyl and alkyloxy groups and moieties contain 1 or 2 carbon atoms.
  • Particularly preferred groups (a) and (b) may be selected from the following groups (i) to (xxi):
  • Ar 1 is a group (i):
  • Preferred compounds of the invention include: (2E)-3-[3'-(4- ⁇ [6-( ⁇ (2R)-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl ⁇ amino)hexyl]oxy ⁇ butyl ,1'-biphenyl-3-yl]prop-2-enoic acid; 3-[3'-(4- ⁇ [6-( ⁇ (2f?)-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl ⁇ amino)hexyl]oxy ⁇ butyl ,r-biphenyl-4-yl]propanoic acid; (2£)-3-[3'-(4- ⁇ [6-( ⁇ (2 )-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl ⁇ amino)hexyl]oxy ⁇ butyl ,1'-biphenyl-4-yl]
  • the compounds of formula (I) include an asymmetric centre, namely the carbon atom of the
  • the present invention includes both (S) and (R) enantiomers either in substantially pure form or admixed in any proportions.
  • the compounds of the invention are in the form of the (R) enantiomers.
  • R 4 and R 5 are different groups
  • the carbon atom to which they are attached is an asymmetric centre and the present invention includes both (S) and (R) enantiomers at this centre either in substantially pure form or admixed in any proportions.
  • the compounds of formula (I) include all enantiomers and diastereoisomers as well as mixtures thereof in any proportions.
  • Salts and solvates of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable.
  • salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives.
  • physiologically functional derivative a chemical derivative of a compound of formula (I) having the same physiological function as the free compound of formula (I) for example, by being convertible in the body thereto.
  • physiologically functional derivatives include esters.
  • Suitable salts according to the invention include those formed with both organic and inorganic acids or bases.
  • Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulphamic, sulphanilic, succinic, oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic, methanesulphonic, ethanesulphonic, arylsulphonic (for example p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl, methyl , methoxy or halo substituted
  • Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexyl amine and N-methyl-D-glucamine.
  • esters of the compounds of formula (I) may have a hydroxyl group converted to a C ⁇ _ 6 alkyl, aryl, aryl C ⁇ alkyl, or amino acid ester.
  • the compounds of formula (I) are selective ⁇ 2 -adrenoreceptor agonists as demonstrated using functional or reporter gene readout from cell lines transfected with human beta-adrenoreceptors as described below.
  • Compounds according to the present invention also have the potential to combine long duration of effect with rapid onset of action.
  • certain compounds have shown an improved therapeutic index in animal models relative to existing long-acting ⁇ 2 -agonist bronchodilators. As such, compounds of the invention may be suitable for once-daily administration.
  • compounds of formula (I) and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives have use in the prophylaxis and treatment of clinical conditions for which a selective ⁇ 2 -adrenoreceptor agonist is indicated.
  • Such conditions include diseases associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary diseases (COPD) (e.g. chronic and whez bronchitis, emphysema), respiratory tract infection and upper respiratory tract disease.
  • COPD chronic obstructive pulmonary diseases
  • the present invention provides a method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a selective ⁇ 2 -adrenoreceptor agonist is indicated, which comprises administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
  • the present invention provides such a method for the prophylaxis or treatment of a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease.
  • a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease.
  • COPD chronic obstructive pulmonary disease
  • the present invention provides such a method for the prophylaxis or treatment of a clinical condition selected from premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e.g. peptic and gastric ulceration) or muscle wasting disease.
  • skin diseases e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases
  • conditions where lowering peptic acidity is desirable e.g. peptic and gastric
  • a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for use in medical therapy, particularly, for use in the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a selective ⁇ 2 -adrenoreceptor agonist is indicated.
  • a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for the prophylaxis or treatment of a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease.
  • COPD chronic obstructive pulmonary disease
  • a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for the prophylaxis or treatment of a clinical condition selected from premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e.g. peptic and gastric ulceration) or muscle wasting disease.
  • a clinical condition selected from premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e.g. peptic and gastric ulceration) or muscle wasting disease.
  • the present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which a selective ⁇ 2 -adrenoreceptor agonist is indicated, for example a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease.
  • a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease.
  • COPD chronic obstructive pulmonary disease
  • a clinical condition selected from premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity 5 is desirable (e.g. peptic and gastric ulceration) and muscle wasting disease.
  • the amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the 0 subject under treatment, and the particular disorder or disease being treated.
  • the compounds of the invention may be administered by inhalation at a dose of from O.OOO ⁇ mg to 10mg, preferably O.OO ⁇ mg to 0.5mg, eg. 0.05mg to 0.5mg.
  • the dose range for adult humans is generally from 0.0005 mg to 10mg per day and preferably 0.01 mg to 1mg per day most preferably 0.05mg to 0.5mg per day. 5
  • the present invention further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.
  • active ingredient means a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), inhalation (including fine 0 particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulisers or insufflators), rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the ⁇ methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water- in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary 0 or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed ⁇ with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and ⁇ thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind 0 previously described.
  • Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine, or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator.
  • Powder blend formulations 5 generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier/diluent/excipient substance) such as mono-, di or poly- saccharides (eg. lactose or starch). Use of lactose is preferred.
  • Each capsule or cartridge may generally contain between 20 ⁇ g-10mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient.
  • the compound of the invention may be presented without excipients.
  • Packaging of the formulation may be suitable for unit dose or multi-dose delivery. In the case of multi-dose delivery, the formulation can be pre-metered (eg as in Diskus, see GB 2242134, US Patent Nos.
  • the Diskus inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing a compound of formula (I) preferably combined with lactose.
  • the strip is sufficiently flexible to be wound into a roll.
  • the lid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the said leading end portions is constructed to be attached to a winding means.
  • the hermetic seal between the base and lid sheets extends over their whole width.
  • the lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the said base sheet.
  • Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant.
  • Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the compound of formula (I) optionally in combination with another therapeutically active ingredient and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e.g.
  • the aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants eg oleic acid or lecithin and cosolvents eg ethanol. Pressurised formulations will generally be retained in a canister (eg an aluminium canister) closed with a valve (eg a metering valve) and fitted into an actuator provided with a mouthpiece.
  • a canister eg an aluminium canister
  • a valve eg a metering valve
  • Medicaments for administration by inhalation desirably have a controlled particle size.
  • the optimum particle size for inhalation into the bronchial system is usually 1-1 O ⁇ m, preferably 2-5 ⁇ m. Particles having a size above 20 ⁇ m are generally too large when inhaled to reach the small airways.
  • the particles of the active ingredient as produced may be size reduced by conventional means eg by micronisation.
  • the desired fraction may be separated out by air classification or sieving.
  • the particles will be crystalline.
  • an excipient such as lactose is employed, generally, the particle size of the excipient will be much greater than the inhaled medicament within the present invention.
  • the excipient is lactose it will typically be present as milled lactose, wherein not more than 85% of lactose particles will have a MMD of 60-90 ⁇ m and not less than 15% will have a MMD of less than 15 ⁇ m.
  • Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.
  • agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.
  • Solutions for inhalation by nebulation may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials. They may be sterilised by filtration or heating in an autoclave, or presented as a non-sterile product.
  • Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose an acacia.
  • Preferred unit dosage formulations are those containing an effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • the compounds and pharmaceutical formulations according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from anti-inflammatory agents, anticholinergic agents (particularly an M 1 ; M 2 , M- ⁇ /M 2 or M 3 receptor antagonist), other ⁇ 2 -adrenoreceptor agonists, antiinfective agents (e.g. antibiotics, antivirals), or antihistamines.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with one or more other therapeutically active agents, for example selected from an anti-inflammatory agent
  • a corticosteroid or an NSAID for example a corticosteroid or an NSAID
  • an anticholinergic agent for example a corticosteroid or an NSAID
  • another ⁇ 2 - adrenoreceptor agonist for example an antibiotic or an antiviral
  • an antiinfective agent e.g. an antibiotic or an antiviral
  • an antihistamine for example a corticosteroid or an NSAID
  • Preferred combinations are those comprising one or two other therapeutic agents.
  • the other therapeutic ingredient(s) may be used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts), or prodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates) to optimise the activity and/or stability and/or physical characteristics (e.g. solubility) of the therapeutic ingredient.
  • the therapeutic ingredients may be used in optically pure form.
  • Suitable anti-inflammatory agents include corticosteroids and NSAIDs.
  • Suitable corticosteroids which may be used in combination with the compounds of the invention are those oral and inhaled corticosteroids and their pro-drugs which have anti- inflammatory activity. Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ - hydroxy-16 ⁇ -methyl-3-oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 -methyl-3-oxo-17 ⁇ -propionyloxy- androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters (
  • the 17-propionate ester or the 17,21-dipropionate ester the 17-propionate ester or the 17,21-dipropionate ester
  • budesonide flunisolide
  • mometasone esters e.g. the furoate ester
  • triamcinolone acetonide e.g. the furoate ester
  • rofleponide triamcinolone acetonide
  • ciclesonide butixocort propionate
  • RPR-106541 the 17-propionate ester or the 17,21-dipropionate ester
  • ST-126 the 17-propionate ester or the 17,21-dipropionate ester
  • flunisolide e.g. the furoate ester
  • triamcinolone acetonide e.g. the furoate ester
  • rofleponide triamcinolone acetonide
  • ciclesonide butixocort propionate
  • Preferred corticosteroids include fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyl- 1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S- fluoromethyl ester and 6 ⁇ ,9 ⁇ -difluoro-17 -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ - methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, more preferably 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 -methyl-3-oxo- androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester.
  • Suitable NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g. chemokine antagonists) or inhibitors of cytokine synthesis.
  • PDE phosphodiesterase
  • Suitable other ⁇ 2 -adrenoreceptor agonists include salmeterol (e.g. as the xinafoate), salbutamol (e.g. as the sulphate or the free base), formoterol (e.g. as the fumarate), fenoterol or terbutaline and salts thereof.
  • the PDE4- specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family as well as PDE4.
  • a PDE4 inhibitor which has an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity.
  • the cAMP catalytic site which binds R and S rolipram with a low affinity is denominated the "low affinity” binding site (LPDE 4) and the other form of this catalytic site which binds rolipram with a high affinity is denominated the "high affinity” binding site (HPDE 4).
  • LPDE 4 low affinity binding site
  • HPDE 4 high affinity binding site
  • HPDE4 should not be confused with the term "hPDE4" which is used to denote human PDE4.
  • a method for determining IC50S ratios is set out in US patent 5,998,428 which is incorporated herein in full by reference as though set out herein. See also PCT application WO 00/51599 for an another description of said assay.
  • the preferred PDE4 inhibitors of use in this invention will be those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity.
  • the preferred compounds will have an IC 50 ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity.
  • a further refinement of this standard is that of one wherein the PDE4 inhibitor has an IC50 ratio of about 0.1 or greater; said ratio is the ratio of the IC50 value for competing with the binding of 1 nM of [3H]R-rolipram to a form of PDE4 which binds rolipram with a high affinity over the IC50 value for inhibiting the PDE4 catalytic activity of a form which binds rolipram with a low affinity using 1 ⁇ M[3H]-cAMP as the substrate.
  • PDE4 inhibitors which have an IC50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0.
  • Preferred compounds are cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1- carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan ⁇ 1-one and c/s-[4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-1-ol]; these are examples of compounds which bind preferentially to the low affinity binding site and which have an IC50 ratio of 0.1 or greater.
  • PDE-4 and mixed PDE3/PDE4 inhibitors include those listed in WO01/13953, the disclosure of which is hereby incorporated by reference.
  • Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptor, in particular those compounds which are antagonists of the Mi and M 2 receptors.
  • Exemplary compounds include the alkaloids of the belladonna plants as illustrated by the likes of atropine, scopolamine, homatropine, hyoscyamine; these compounds are normally administered as a salt, being tertiary amines.
  • These drugs, particularly the salt forms are readily available from a number of commercial sources or can be made or prepared from literature data via, to wit:
  • Atropine - CAS-51-55-8 or CAS-61-48-1 (anhydrous form), atropine sulfate - CAS-5908- 99-6; atropine oxide - CAS-4438-22-6 or its HCI salt - CAS-4574-60-1 and methylatropine nitrate - CAS-52-88-0.
  • Preferred anticholinergics include ipratropium (e.g. as the bromide), sold under the name Atrovent, oxitropium (e.g. as the bromide) and tiotropium (e.g. as the bromide) (CAS- 139404-48-1).
  • methantheline (CAS-53-46-3), propantheline bromide (CAS- 50-34-9), anisotropine methyl bromide or Valpin 50 (CAS- 80-50-2), clidinium bromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamide iodide (CAS-71- 81-8), mepenzolate bromide (U.S. patent 2,918,408), tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocyclium methylsulfate (Tral, CAS-115-63-9).
  • Suitable antihistamines include any one or more of the numerous antagonists known which inhibit Hrreceptors, and are safe for human use. All are reversible, competitive inhibitors of the interaction of histamine with H receptors. The majority of these inhibitors, mostly first generation antagonists, have a core structure, which can be represented by the following formula:
  • This generalized structure represents three types of antihistamines generally available: ethanolamines, ethylenediamines, and alkylamines.
  • first generation antihistamines include those which can be characterized as based on piperizine and phenothiazines.
  • Second generation antagonists which are non-sedating, have a similar structure-activity relationship in that they retain the core ethylene group (the alkylamines) or mimic the tertiary amine group with piperizine or piperidine.
  • Exemplary antagonists are as follows:
  • Ethanolamines carbinoxamine maleate, clemastine fumarate, diphenylhydramine hydrochloride, and dimenhydrinate.
  • Ethylenediamines pyrilamine amleate, tripelennamine HCI, and tripelennamine citrate.
  • Alkylamines chloropheniramine and its salts such as the maleate salt, and acrivastine.
  • Piperazines hydroxyzine HCI, hydroxyzine pamoate, cyclizine HCI, cyclizine lactate, meclizine HCI, and cetirizine HCI.
  • Piperidines Astemizole, levocabastine HCI, loratadine or its descarboethoxy analogue, and terfenadine and fexofenadine hydrochloride or another pharmaceutically acceptable salt.
  • Azelastine hydrochloride is yet another H-i receptor antagonist which may be used in combination with a PDE4 inhibitor.
  • Examples of preferred anti-histamines include methapyrilene and loratadine.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a corticosteroid.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an antihistamine.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor and a corticosteroid.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic and a PDE-4 inhibitor.
  • compositions comprising a combination as defined above together with a physiologically acceptable diluent or carrier represent a further aspect of the invention.
  • the individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
  • a process for preparing a compound of formula (1) or a salt, solvate, or physiologically functional derivative thereof which comprises a process as defined below, followed by the following steps in any order:
  • a compound of formula (I) may be obtained by deprotection of a protected intermediate, for example of formula (II):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, and n are as defined for the compound of formula (I)
  • Ar 1a represents an optionally protected form of Ar 1
  • P 1 and P 2 are each independently either hydrogen or a protecting group, provided that the compound of formula (II) contains at least one protecting group.
  • Protected forms of the preferred groups Ar 1 may be selected from:
  • P 3 and P 4 are each independently either hydrogen or a protecting group provided that at least one of P 3 and P 4 is a protecting group, and the dotted line in (xvia) and (xixa) denotes an optional double bond. It will be appreciated from the foregoing structures that where Ar 1 is a group (vii), (xi), (xii), (xiii) or (xiv) protection is not required.
  • Suitable protecting groups may be any conventional protecting group such as those described in "Protective Groups in Organic Synthesis” by Theodora W Greene and Peter G M Wuts, 3rd edition (John Wiley & Sons, 1999).
  • suitable hydroxyl protecting groups represented by P 3 and P 4 are esters such as acetate ester, aralkyl groups such as benzyl, diphenylmethyl, or triphenylmethyl, and tetrahydropyranyl.
  • Suitable amino protecting groups represented by P 2 include benzyl, ⁇ - methylbenzyl, diphenylmethyl, triphenylmethyl, benzyloxycarbonyl, tert-butoxycarbonyl, and acyl groups such as trichloroacetyl or trifluoroacetyl.
  • protecting groups may include orthogonal protection of groups in the compounds of formula (II) to facilitate the selective removal of one group in the presence of another, thus enabling selective functionalisation of a single amino or hydroxyl function.
  • the -CH(OH) group may be orthogonally protected as - CH(OP 1 ) using, for example, a trialkylsilyl group such as triethylsilyl.
  • a trialkylsilyl group such as triethylsilyl.
  • orthogonal protection strategies available by conventional means as described in Theodora W Greene and Peter G M Wuts (see above).
  • the deprotection to yield a compound of formula (I), may be effected using conventional techniques.
  • P 2 , P 3 , and/or P 4 is an aralkyl group, this may be cleaved by hydrogenolysis in the presence of a metal catalyst (e.g. palladium on charcoal).
  • a metal catalyst e.g. palladium on charcoal
  • P 3 and/or P 4 When P 3 and/or P 4 is tetrahydropyranyl this may be cleaved by hydrolysis under acidic conditions.
  • Acyl groups represented by P 2 may be removed by hydrolysis, for example with a base such as sodium hydroxide, or a group such as trichloroethoxycarbonyl may be removed by reduction with, for example, zinc and acetic acid.
  • Other deprotection methods may be found in Theodora W Greene and Peter G M Wuts (see above).
  • P 3 and P 4 may together represent a protecting group as in the compound of formula (III):
  • R 24 and R 25 are independently selected from hydrogen, C h alky!, or aryl or R 24 and R 25 together form a C 3 . 7 cycloalkyl ring. In a preferred aspect, both R 24 and R 25 are methyl.
  • the compound of formula (III) may be converted to a compound of formula (I), by hydrolysis with dilute aqueous acid, for example acetic acid or hydrochloric acid in a suitable solvent or by transketalisation in an alcohol, for example ethanol, in the presence of a catalyst such as an acid (for example, toluenesulphonic acid) or a salt (such as pyridinium tosylate) at normal or elevated temperature.
  • a catalyst such as an acid (for example, toluenesulphonic acid) or a salt (such as pyridinium tosylate) at normal or elevated temperature.
  • protecting groups P 1 , P 2 , P 3 and P 4 may be removed in a single step or sequentially.
  • the precise order in which protecting groups are removed will in part depend upon the nature of said groups and will be readily apparent to the skilled worker.
  • this protecting group is removed together with any protecting group on the CH(OH) moiety, followed by removal of P 2 .
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Ar 1a , m, and n are as defined for the compound of formula (II) or (III).
  • a compound of formula (IV) to a compound of formula (II) or (III) may be effected by treatment with a base, for example a non-aqueous base, such as potassium trimethylsilanolate, or an aqueous base such as aqueous sodium hydroxide, in a suitable solvent such as tetrahydrofuran.
  • a base for example a non-aqueous base, such as potassium trimethylsilanolate, or an aqueous base such as aqueous sodium hydroxide, in a suitable solvent such as tetrahydrofuran.
  • a leaving group group such as halo, eg. bromo or iodo, preferably iodo; or a haloalkylsulphonate such as trifluoromethane sulfonate; or (ii) a reactive group selected from boronic acid, or a boronic acid ester or an organo-zinc or organo-tin moiety;
  • a 1 is either:
  • a leaving group group such as halo, eg. bromo or iodo, preferably iodo; or a haloalkylsulphonate such as trifluoromethane sulfonate; or (ii) a reactive group selected from boronic acid, or a boronic acid ester or an organo-zinc or organo-tin moiety; provided that when A is selected from a leaving group (i) then A 1 is selected from a reactive group (ii) and vice versa.
  • a leaving group group such as halo, eg. bromo or iodo, preferably iodo; or a haloalkylsulphonate such as trifluoromethane sulfonate
  • a reactive group selected from boronic acid, or a boronic acid ester or an organo-zinc or organo-tin moiety provided that when A is selected from a leaving group (i) then A 1 is selected from
  • a or A 1 represents a boronic acid ester
  • the coupling of a compound of formula (V) with a compound of formula (VI) is conveniently effected in the presence of a catalyst system such as palladium, for example, tetrakis(triphenylphosphine) palladium (0) or bis(diphenylphosphino)ferrocene palladium dichloride with a base such as sodium carbonate or caesium carbonate, in a suitable solvent for example 1 ,2- dimethoxyethane, or N,N-dimethylformamide.
  • a catalyst system such as palladium, for example, tetrakis(triphenylphosphine) palladium (0) or bis(diphenylphosphino)ferrocene palladium dichloride with a base such as sodium carbonate or caesium carbonate, in a suitable solvent for example 1 ,2- dimethoxyethane, or N,N-dimethylformamide.
  • R 4 , R 5 , R 6 , R 7 , A, m and n are as defined for the compound of formula (V) and L 1 is a leaving group for example a halo group, (typically bromo or iodo) or a sulfonate such as an alkyl sulfonate (typically methanesulfonate) an aryl sulfonate (typically toluenesulfonate) or a haloalkylsulfonate (typically trifluoromethane sulfonate).
  • a halo group typically bromo or iodo
  • a sulfonate such as an alkyl sulfonate (typically methanesulfonate) an aryl sulfonate (typically toluenesulfonate) or a haloalkylsulfonate (typically trifluoromethane sulf
  • the coupling of a compound of formula (VII) with a compound of formula (VIII) may be effected in the presence of a base, such as a metal hydride, for example sodium hydride, or an inorganic base such as cesium carbonate, in an aprotic solvent, for example N,N- dimethylformamide or tetrahydrofuran.
  • a base such as a metal hydride, for example sodium hydride, or an inorganic base such as cesium carbonate
  • an aprotic solvent for example N,N- dimethylformamide or tetrahydrofuran.
  • the group A in the compound of formula (V) represents a leaving group
  • this may if desired be converted into a boronic acid derivative, by reaction with bis(pinacolato)diboron and 1 ,1'-bis(diphenylphosphino)ferrocene palladium dichloride in the presence of potassium acetate and in a solvent such as a mixture of dichloromethane and N,N-dimethylformamide.
  • compounds of formula (V) may be prepared from a corresponding alkyne of formula (IX):
  • R 6 , R 7 and A are as defined hereinabove for compounds of formula (V) and L 2 is a leaving group for example a halo group, (typically bromo or iodo) or a haloalkylsulfonate (typically trifluoromethane sulfonate), followed by reduction.
  • L 2 is a leaving group for example a halo group, (typically bromo or iodo) or a haloalkylsulfonate (typically trifluoromethane sulfonate), followed by reduction.
  • the coupling of a compound of formula (IX) with a compound of formula (X) or a precursor thereof is conveniently effected in the presence of a catalyst system such as bis(triphenylphosphino) palladium dichloride and a copper catalyst such as cuprous iodide, with an organic base such as a trialkylamine, for example triethylamine, in a suitable solvent for example acetonitrile or dimethylformamide.
  • a catalyst system such as bis(triphenylphosphino) palladium dichloride and a copper catalyst such as cuprous iodide
  • an organic base such as a trialkylamine, for example triethylamine
  • a suitable solvent for example acetonitrile or dimethylformamide.
  • the resulting alkyne may then be reduced, either with or without being isolated to form the compound of formula (V).
  • the reduction may be effected by any suitable method such as hydrogenation in the presence of a catalyst, for example palla
  • a compound of formula (VIII) may be prepared from a corresponding compound of formula (XI):
  • R , R , A and n are as defined for compounds of formula (VIII).
  • the coupling of compounds (XI) and (XII) may be effected in the presence of an inorganic base, such as aqueous sodium hydroxide, under phase transfer conditions in the presence of an ammonium salt such as a tetraalkylammonium bromide, e.g.tetrabutylammonium bromide.
  • an inorganic base such as aqueous sodium hydroxide
  • an ammonium salt such as a tetraalkylammonium bromide, e.g.tetrabutylammonium bromide.
  • a compound of formula (IV) may also be preapred by reacting a compound of formula (XIII):
  • L 2 is a leaving group as defined for compounds of formula (X) above;
  • a compound of formula (XIII) may be prepared by coupling a compound of formula (X) as defined hereinabove with a compound of formula (VI) as defined hereinabove, in an analogous manner to the coupling of a compound of formula (V) with a compound of formula (VI), as described hereinabove.
  • a compound of formula (IV) may also be prepared by coupling a compound of formula (VII) with a compound of formula (XIV):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m and n are as defined for formula (II) and L 1 is as defined for formula (VIII); in an analogous manner to process (b) below.
  • a compound of formula (I) may be obtained by alkylation of an amine of formula (XV):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 m and n are as defined for formula (II) and L 1 is as defined for formula (VIII); followed by removal of any protecting groups present by conventional methods as described above for the deprotection of compounds of formula (II).
  • reaction of compounds of formulae (XIII) and (XIV) is optionally effected in the presence of an organic base such as a trialkylamine, for example, diisopropylethylamine, and in a suitable solvent for example N,N-dimethylformamide.
  • organic base such as a trialkylamine, for example, diisopropylethylamine
  • suitable solvent for example N,N-dimethylformamide.
  • a compound of formula (XIV) may be prepared from a compound of formula (VIII) by reaction with a compound (VI) in an analogous manner to the reaction of a compound of formula (V) with a compound of formula (VI). It will be appreciated that the precise order of the synthetic steps by which the various groups and moieties are introduced into the molecule may be varied. It will be within the skill of the practitioner in the art to ensure that groups or moieties introduced at one stage of the process will not be affected by subsequent transformations and reactions, and to select the order of synthetic steps accordingly.
  • the enantiomeric compounds of the invention may be obtained (i) by separation of the components of the corresponding racemic mixture, for example, by means of a chiral chromatography column, enzymic resolution methods, or preparing and separating suitable diastereoisomers, or (ii) by direct synthesis from the appropriate chiral intermediates by the methods described above.
  • Optional conversions of a compound of formula (I) to a corresponding salt may conveniently be effected by reaction with the appropriate acid or base.
  • Optional conversion of a compound of formula (I) to a corresponding solvate or physiologically functional derivative may be effected by methods known to those skilled in the art.
  • the present invention provides novel intermediates for the preparation of compounds of formula (I) for example, compounds of formula (II), (III) and (IV) as defined above, or an optical isomer, a salt, or a protected derivative thereof.
  • thermospray mass spectrum positive mode HPLC high pressure liquid chromatography
  • Silica gel refers to Merck silica gel 60 Art number 7734.
  • Flash silica gel refers to Merck silica gel 60 Art number 9385.
  • Biotage refers to prepacked silica gel cartridges containing KP-Sil run on flash 12i chromatography module.
  • Bond Elut are prepacked cartridges used in parallel purifications, normally under vacuum. These are commercially available from Varian.
  • LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1% HCO 2 H and 0.01 M ammonium acetate in water (solvent A), and 0.05% HCO 2 H 5% water in acetonitrile (solvent B), using the following elution gradient 0-0.7 min 0%B, 0.7-4.2 min 100%B, 4.2-5.3 min 100%B, 5.3-5.5 min 0%B at a flow rate of 3 ml/min.
  • the mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).
  • HPLC HPLC was conducted on a LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1% formic acid and 0.01 M ammonium acetate in water (solvent A), and 0.05% formic acid 5% water in acetonitrile (solvent B) using the following elution gradient 0-1 min 0%B, 1-10 min100%B, 10-13 min 100%B, 13-15 min 0%B at a flow rate of 1 ml/min
  • the potencies of the aforementioned compounds were determined using frog melanophores transfected with the human beta 2 adrenoreceptor.
  • the cells were incubated with melatonin to induce pigment aggregation.
  • Pigment dispersal was induced by compounds acting on the human beta 2 adrenoreceptor.
  • the beta 2 agonist activity of test compounds was assessed by their ability to induce a change in light transmittance across a melanophore monolayer (a consequence of pigment dispersal).
  • compounds of examples 1-26 had IC 50 values below 1 ⁇ M.
  • Potency at other beta adrenoreceptor subtypes was determined using Chinese hamster ovary cells transfected with either the human beta 1 adrenoreceptor or the human beta 3 adrenoreceptor. Agonist activity was assessed by measuring changes in intracellular cyclic AMP.

Abstract

The present invention relates to novel compounds of formula (I), to a process for their manufacture, to pharmaceutical compositions containing them, and to their use in therapy, in particular their use in the prophylaxis and treatment of respiratory diseases.

Description

PHENETHANOLAMINE DERIVATIVES FOR THE TREATMENT OF RESPIRATORY DISEASES
The present invention is concerned with phenethanolamine derivatives, processes for their preparation, compositions containing them and their use in medicine, particularly in the prophylaxis and treatment of respiratory diseases.
Certain phenethanolamine compounds are known in the art as having selective stimulant action at β2-adrenoreceptors and therefore having utility in the treatment of bronchial asthma and related disorders. Thus GB 2 140 800 describes phenethanolamine compounds including 4-hydroxy-α1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1 ,3- benzenedimethanol 1-hydroxy-2-naphthalenecarboxylate (salmeterol xinafoate) which is now used clinically in the treatment of such medical conditions.
Although salmeterol and the other commercially available β2-adrenoreceptor agonists are effective bronchodilators, the duration of action is approximately 12 hours, hence twice daily dosing is often required. There is therefore a clinical need for compounds having potent and selective stimulant action at β2.adrenoreceptors and having an advantageous profile of action.
According to the present invention, there is provided a compound of formula (I)
Ar1
Figure imgf000002_0001
or a salt, solvate, or physiologically functional derivative thereof, wherein:
m is an integer of from 2 to 8; n is an integer of from 3 to 7; with the proviso that m + n is 5 to 12;
R1 is selected from hydrogen, Cι„6alkyl, hydroxy, C^ alkoxy, cyano, nitro, halo, Ci-ehaloalkyl, -XNR8C(O)R9, -XNR8C(O)NR9R10, -XNR8C(O)NC(O)IMR9R10, -XNR8SO2R9, -XSO2NR9R10, XSR8, XSOR8, XSO2R8, -XNR9R10, -XNR8C(O)OR9, XNR8SO2NR9R10, XCO2R10, or -XC(O)NR9R10; or R1 is selected from -X-aryl, -X-hetaryl, or -X-(aryloxy), each optionally substituted by 1 or 2 groups independently selected from hydroxy, Cι.6alkoxy, halo, Chalky!, C-ehaloalkyl, cyano, nitro, CONR9R10,
-NR8C(O)R9, SR8, SOR8, -SO2R8, -SO2NR9R10, -CO2R10, -NR9R10, or hetaryl optionally substituted by 1 or 2 groups independently selected from hydroxy, Cι_6alkoxy, halo, Cι.6alkyl, or C-ehaloalkyl;
X is -(CH2)r- or C2.6 alkenylene;
r is an integer from 0 to 6, preferably 0 to 4;
R8 and R9 are independently selected from hydrogen, C-^alkyl, C3.7cycloalkyl, aryl, hetaryl, hetaryl(C.|..6alkyl)- and aryl(C|..6alkyl)- and R8 and R9 are each independently optionally substituted by 1 or 2 groups independently selected from halo, Cι„6alkyl,
C3.7 cycloalkyl, C,.6 alkoxy, C-ehaloalkyl, -NHC(O)(C1.6alkyl), -SO2(C1.6alkyl), -SO2(aryl), -CO2H, and -CO2(Cι^alkyl), -NH2, -NH(C1.6alkyl), aryl(C|.6alkyl)-, aryl(C2.6alkenyl)-, aryl(C2.6alkynyl)-, hetaryl(Cι.6alkyl)-, -NHSO2aryl, -NH(hetarylC1.6alkyl), -NHSO2hetaryl, -NHSO2(C.,.6alkyl), -NHC(O)aryl, or -NHC(O)hetaryl:
or where R1 is -XNR8C(O)NR9R10 , R8 and R9 may, together with the -NC(O)N- portion of the group R1 to which they are bonded, form a saturated or unsaturated ring, preferably a 5-, 6-, or 7- membered ring, for example an imidazolidine ring, such as imidazolidine-2,4- dione;
or where R1 is -XNR8C(O)OR9, R8 and R9 may, together with the -NC(O)O- portion of the group R1 to which they are bonded, form a saturated or unsaturated ring, preferably a 5-, 6-, or 7- membered ring, for example an oxazolidine ring, such as oxazolidine-2,4-dione;
R10 is selected from hydrogen, Chalky! and C3.7 cycloalkyl;
or where R1 contains a moiety -NR9R10 or R9 and R10 may, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring;
R2, R3, R6, and R7are independently selected from hydrogen, C^alkyl, C-|. alkoxy, halo, and C haloalkyl; R4 and R5 are independently selected from hydrogen and C^ alkyl with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4.
Ar1 is a group selected from
Figure imgf000004_0001
(a) (b) (C)
and
Figure imgf000004_0002
(d) wherein R11 represents hydrogen, halogen, -(CH2)qOR15, -NR15C(O)R16, -NR15SO2R16, -SO2NR15R16, -NR15R16, -OC(O)R17 or OC(O)NR15R16, and R12 represents hydrogen, halogen or C^ alkyl;
or R11 represents -NHR18 and R12 and -NHR18 together form a 5- or 6- membered heterocyclic ring;
R'J represents hydrogen, halogen, -OR 1150 or -NR 3115& DR1π6.
R 4 represents hydrogen, halogen, haloC^ alkyl, -OR15, -NR15 R16, -OC(O)R17 or OC(O)NR15R16;
R and R each independently represents hydrogen or C1- alkyl, or in the groups -NR15R16, -SO2NR15R16 and -OC(O)NR15R16, R15 and R16 independently represent hydrogen or d4 alkyl or together with the nitrogen atom to which they are attached form a 5-, 6- or 7- membered nitrogen-containing ring,
R17 represents an aryl (eg phenyl or naphthyl) group which may be unsubstituted or substituted by one or more substituents selected from halogen, C-M alkyl, hydroxy, C^ alkoxy or halo C^4 alkyl; and
q is zero or an integer from 1 to 4.
In a particular embodiment, this invention provides a compound of formula (I) or a salt, solvate or physiologically functional derivative thereof wherein: R1 is selected from hydrogen, C-|.6alkyl, hydroxy, Cι.e alkoxy, cyano, nitro, halo, C^haloalkyl, -XNR8C(O)R9, -XNR8C(O)NR9R10, -XNR8C(O)NC(O)NR9R10, -XNR8SO2R9, -XSO2NR9R10, XSR8, XSOR8, XSO2R8, -XNR9R10, -XNR8C(O)OR9, XNR8SO2NR9R10, XCO2R10, or -XC(O)NR9R10;
R11 is as defined above except that R11 is not hydrogen; and all other substituents are as defined for formula (I) above.
In the compounds of formula (I) an aryl group or moiety may be for example phenyl or naphthyl.
In the compounds of formula (I) a hetaryl group may be for example pyrrolyl, furyl, thienyl, pyridinyl, pyrazinyl, pyridazinyl, imidazolyl, tetrazolyl, tetrahydrofuranyl, oxazolyl, thiazolyl or thiadiazolyl.
In the compounds of formula (I), the ring bearing the substituents R1, R2 and R3 ('outer' ring) is preferably attached at the meta- or para- position of the ring bearing the substituents R6 and R7 ('inner' ring) relative to the -O-(CH2)n-, link. The group R1 is preferably attached to the ortho- or meta-position of the 'outer' phenyl ring, relative to the point of attachment to the 'inner' phenyl ring.
In the compounds of formula (I) R1 preferably represents hydroxy, -XR8(CO)NR9R10, -XSO2NR9R10, -XCO2R10, XC(O)NR9R10 or X-hetaryl. R8, R9 and R10 are preferably each independently selected from hydrogen, C^alkyl or C3.7cycloalkyl.
In the definition of X, the term alkenylene includes both cis and trans structures. Examples of suitable alkenylene groups include -CH=CH-.
X is preferably (CH2)r where r is 0 to 2, or C2alkenylene.
In the compounds of formula (I) R2 and R3 preferably each represent hydrogen.
R4 and R5 are preferably independently selected from hydrogen and methyl, more preferably R4 and R5 are both hydrogen.
In the compounds of formula (I), m is suitably 3, 4, 5 or 6 and n is suitably 3, 4, 5 or 6. Preferably m is 5 and preferably n is 4 or 5, such that m + n is 9 or 10, preferably 9.
In the compounds of formula (I) the group Ar1 is preferably selected from groups (a) and (b) above.
In said groups (a) and (b), when R11 represents halogen this is preferably chlorine or fluorine.
R15and R16 preferably each independently represent hydrogen or methyl.
R17 preferably represents substituted phenyl.
The integer q preferably represents zero or 1.
Thus for example -(CH2)qOR15 preferably represents OH or -CH2OH; NR15C(O)R16 preferably represents -NHC(O)H;
-SO2NR15R16 preferably represents -SO2NH2 or SO2NHCH3;
-NR15SO2R16 preferably represents NHSO2CH3;
NR15R16 preferably represents -NH2;
-OC(O)R17 preferably represents substituted benzoyloxy eg. OC(O)-C6H4-(p-CH3); and -OC(O)N R15 R16 preferably represents OC(O)N(CH3)2. When R11 represents NHR18 and together with R12 forms a 5- or 6- membered heterocyclic ring -NHR18-R12- preferably represents a group: -NH-CO-R19- where R19 is an alkyl, alkenyl or alkyloxy group; -NH-SO2R20- where R20 is an alkyloxy group; -NH-R21- where R21 is an alkyl or alkenyl group; optionally substituted by COOR22 where R22 is Ci.4 alkyl; or -NH-CO-S-; wherein said alkyl, alkenyl and alkyloxy groups and moieties contain 1 or 2 carbon atoms.
Particularly preferred groups (a) and (b) may be selected from the following groups (i) to (xxi):
Figure imgf000007_0001
Figure imgf000007_0002
(V) (vi) (vϋ) (viii)
Figure imgf000007_0003
(ix) (x) (xi) (xϋ)
Figure imgf000008_0001
(xiϋ) (xiv) (xv)
o
Figure imgf000008_0002
(xvi) (xvii) (xviii)
Figure imgf000008_0003
(xix) (xx) (xxi) wherein the dotted line in (xvi) and (xix) represents an optional double bond.
Most preferably Ar1 is a group (i):
Figure imgf000009_0001
0)
It is to be understood that the present invention covers all combinations of particular and preferred groups described hereinabove.
Preferred compounds of the invention include: (2E)-3-[3'-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl ,1'-biphenyl-3-yl]prop-2-enoic acid; 3-[3'-(4-{[6-({(2f?)-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl ,r-biphenyl-4-yl]propanoic acid; (2£)-3-[3'-(4-{[6-({(2 )-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl ,1'-biphenyl-4-yl]prop-2-enoic acid; 3'-(4-{[6-({(2f?)-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl ,1'-biphenyl-3-carboxylic acid; [3'-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl ,1'-biphenyl-4-yl]acetic acid; 3'-(4-{[6-({(2r?)-2-Hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl -biphenyl^-carboxylic acid; [3'-(4-{[6-({(2 )-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl ,1'-biphenyl-2-yl]acetic acid; [3'-(4-{[6-({(2r?)-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl ,1'-biphenyl-3-yl]acetic acid; 3'-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl ,1'-biphenyl-4-carboxylic acid; 4'-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl ■N-isopropyl[1 , 1 '-biphenyl]-2- sulfonamide; Λ/-Cyclopropyl-4,-(4-{[6-({(2 ?)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)[1 , 1 '-biphenyl]-2-sulfonamide;
2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[2'-(morpholin-4-ylsulfonyl)[1 ,1'-biphenyl]-4- yl]butoxy}hexyl)amino]ethyl}phenol; Λ/-Ethyl-4,-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-A/-methyl[1 , 1 '-biphenyl]-2- sulfonamide;
4'-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)[1 ,1'-biphenyl]-2-sulfonamide; 4'-(4-{[6-({(2 ?)-2-Hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)[1 ,1'-biphenyl]-4-sulfonamide;
Λ/-Cyclopropyl-3'-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)[1 , 1 '-biphenyl]-2-sulfonamide;
3"-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)[1 , 1 '-biphenyl]-2-sulfonamide;
3'-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)[1 , 1 '-biphenyl]-4-sulfonamide;
3'-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-1 , 1 '-biphenyl-3-sulfonamide; Λ/-[3'-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-1 ,1'-biphenyl-3-yl]urea;
Λ/-cyclopropyl-4'-(4-{[6-({(2f?)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-1 , 1 '-biphenyl-2-carboxamide;
3'-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-1 ,1 '-biphenyl-3-ol;
3'-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-1 ,1'-biphenyl-2-ol;
3'-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-1 , 1 '-biphenyl-4-ol; 2-(hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[2,-(1H-tetraazol-5-yl)-1 ,1'-biphenyl-4- yl]butoxy}hexyl)amino]ethyl}phenol;
2-Hydroxy-5-[(1R)-1-hydroxy-2-({6-[4-(3'-hydroxy-1 ,1'-biphenyl-3- yl)butoxy]hexyl}amino)ethyl]phenylformamide with (2£)-but-2-enedioic acid (1 :1);
and salts, solvates and physiologically functional derivatives thereof. The compounds of formula (I) include an asymmetric centre, namely the carbon atom of the
-CH- I OH
group. The present invention includes both (S) and (R) enantiomers either in substantially pure form or admixed in any proportions. Preferably, the compounds of the invention are in the form of the (R) enantiomers.
Similarly, where R4 and R5 are different groups, the carbon atom to which they are attached is an asymmetric centre and the present invention includes both (S) and (R) enantiomers at this centre either in substantially pure form or admixed in any proportions.
Thus the compounds of formula (I) include all enantiomers and diastereoisomers as well as mixtures thereof in any proportions.
Salts and solvates of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable.
However, salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives.
By the term "physiologically functional derivative" is meant a chemical derivative of a compound of formula (I) having the same physiological function as the free compound of formula (I) for example, by being convertible in the body thereto. According to the present invention, examples of physiologically functional derivatives include esters.
Suitable salts according to the invention include those formed with both organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulphamic, sulphanilic, succinic, oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic, methanesulphonic, ethanesulphonic, arylsulphonic (for example p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl, methyl , methoxy or halo substituted cinnamic, including 4-methyl and 4-methoxycinnamic acid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), naphthaleneacrylic (for example naphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (for example 1 ,4- benzenediacrylic) and isethionic acids. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexyl amine and N-methyl-D-glucamine.
Pharmaceutically acceptable esters of the compounds of formula (I) may have a hydroxyl group converted to a Cι_6alkyl, aryl, aryl C^ alkyl, or amino acid ester.
As mentioned above, the compounds of formula (I) are selective β2-adrenoreceptor agonists as demonstrated using functional or reporter gene readout from cell lines transfected with human beta-adrenoreceptors as described below. Compounds according to the present invention also have the potential to combine long duration of effect with rapid onset of action. Furthermore, certain compounds have shown an improved therapeutic index in animal models relative to existing long-acting β2-agonist bronchodilators. As such, compounds of the invention may be suitable for once-daily administration.
Therefore, compounds of formula (I) and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives have use in the prophylaxis and treatment of clinical conditions for which a selective β2-adrenoreceptor agonist is indicated. Such conditions include diseases associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary diseases (COPD) (e.g. chronic and wheezy bronchitis, emphysema), respiratory tract infection and upper respiratory tract disease.
Other conditions which may be treated include premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e.g. peptic and gastric ulceration) and muscle wasting disease. Accordingly, the present invention provides a method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a selective β2-adrenoreceptor agonist is indicated, which comprises administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. In particular, the present invention provides such a method for the prophylaxis or treatment of a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease. In a further aspect the present invention provides such a method for the prophylaxis or treatment of a clinical condition selected from premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e.g. peptic and gastric ulceration) or muscle wasting disease.
In the alternative, there is also provided a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for use in medical therapy, particularly, for use in the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a selective β2-adrenoreceptor agonist is indicated. In particular, there is provided a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for the prophylaxis or treatment of a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease. In a further aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for the prophylaxis or treatment of a clinical condition selected from premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e.g. peptic and gastric ulceration) or muscle wasting disease.
The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which a selective β2-adrenoreceptor agonist is indicated, for example a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease.
In a further aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition selected from premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity 5 is desirable (e.g. peptic and gastric ulceration) and muscle wasting disease.
The amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the 0 subject under treatment, and the particular disorder or disease being treated. The compounds of the invention may be administered by inhalation at a dose of from O.OOOδmg to 10mg, preferably O.OOδmg to 0.5mg, eg. 0.05mg to 0.5mg. The dose range for adult humans is generally from 0.0005 mg to 10mg per day and preferably 0.01 mg to 1mg per day most preferably 0.05mg to 0.5mg per day. 5
While it is possible for a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof to be administered alone, it is preferable to present it as a pharmaceutical formulation.
0 Accordingly, the present invention further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.
5 Hereinafter, the term "active ingredient" means a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), inhalation (including fine 0 particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulisers or insufflators), rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the δ methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
5 Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water- in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary 0 or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed δ with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. 0
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and δ thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind 0 previously described.
Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine, or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator. Powder blend formulations 5 generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier/diluent/excipient substance) such as mono-, di or poly- saccharides (eg. lactose or starch). Use of lactose is preferred.
Each capsule or cartridge may generally contain between 20μg-10mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient. Alternatively, the compound of the invention may be presented without excipients. Packaging of the formulation may be suitable for unit dose or multi-dose delivery. In the case of multi-dose delivery, the formulation can be pre-metered (eg as in Diskus, see GB 2242134, US Patent Nos. 6,632,666, 5,860,419, 5,873,360 and 5,590,646 or Diskhaler, see GB 2178966, 2129691 and 2169266, US Patent No.s 4,778,054, 4,811 ,731 , 5,036,237, the disclosures of which are hereby incorporated by reference) or metered in use (eg as in Turbuhaler, see EP 69715 or in the devices described in US Patents No. 6,321 ,747 the disclosures of which are hereby incorporated by reference). An example of a unit-dose device is Rotahaler (see GB 2064336 and US Patent No. 4,353,666, the disclosures of which are hereby incorporated by reference). The Diskus inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing a compound of formula (I) preferably combined with lactose. Preferably, the strip is sufficiently flexible to be wound into a roll. The lid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the said leading end portions is constructed to be attached to a winding means. Also, preferably the hermetic seal between the base and lid sheets extends over their whole width. The lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the said base sheet.
Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant. Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the compound of formula (I) optionally in combination with another therapeutically active ingredient and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra- fluoroethane, especially 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane or a mixture thereof. Carbon dioxide or other suitable gas may also be used as propellant. The aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants eg oleic acid or lecithin and cosolvents eg ethanol. Pressurised formulations will generally be retained in a canister (eg an aluminium canister) closed with a valve (eg a metering valve) and fitted into an actuator provided with a mouthpiece.
Medicaments for administration by inhalation desirably have a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually 1-1 Oμm, preferably 2-5μm. Particles having a size above 20μm are generally too large when inhaled to reach the small airways. To achieve these particle sizes the particles of the active ingredient as produced may be size reduced by conventional means eg by micronisation. The desired fraction may be separated out by air classification or sieving. Preferably, the particles will be crystalline. When an excipient such as lactose is employed, generally, the particle size of the excipient will be much greater than the inhaled medicament within the present invention. When the excipient is lactose it will typically be present as milled lactose, wherein not more than 85% of lactose particles will have a MMD of 60-90μm and not less than 15% will have a MMD of less than 15μm.
Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.
Solutions for inhalation by nebulation may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials. They may be sterilised by filtration or heating in an autoclave, or presented as a non-sterile product.
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose an acacia. Preferred unit dosage formulations are those containing an effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
The compounds and pharmaceutical formulations according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from anti-inflammatory agents, anticholinergic agents (particularly an M1 ; M2, M-ι/M2 or M3 receptor antagonist), other β2-adrenoreceptor agonists, antiinfective agents (e.g. antibiotics, antivirals), or antihistamines. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with one or more other therapeutically active agents, for example selected from an anti-inflammatory agent
(for example a corticosteroid or an NSAID), an anticholinergic agent, another β2- adrenoreceptor agonist, an antiinfective agent (e.g. an antibiotic or an antiviral), or an antihistamine. Preferred are combinations comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a corticosteroid, and/or an anticholinergic, and/or a PDE-4 inhibitor.
Preferred combinations are those comprising one or two other therapeutic agents.
It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredient(s) may be used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts), or prodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates) to optimise the activity and/or stability and/or physical characteristics (e.g. solubility) of the therapeutic ingredient. It will be clear also that where appropriate, the therapeutic ingredients may be used in optically pure form.
Suitable anti-inflammatory agents include corticosteroids and NSAIDs. Suitable corticosteroids which may be used in combination with the compounds of the invention are those oral and inhaled corticosteroids and their pro-drugs which have anti- inflammatory activity. Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11 β- hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α,9α-difluoro-11 β-hydroxy-16 -methyl-3-oxo-17α-propionyloxy- androsta-1 ,4-diene-17β- carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters (e.g. the 17-propionate ester or the 17,21-dipropionate ester), budesonide, flunisolide, mometasone esters (e.g. the furoate ester), triamcinolone acetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541 , and ST-126. Preferred corticosteroids include fluticasone propionate, 6α,9α-difluoro-11 β-hydroxy-16α-methyl-17α-[(4-methyl- 1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethyl ester and 6α,9α-difluoro-17 -[(2-furanylcarbonyl)oxy]-11 β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester, more preferably 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy-16 -methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester.
Suitable NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g. chemokine antagonists) or inhibitors of cytokine synthesis. Suitable other β2-adrenoreceptor agonists include salmeterol (e.g. as the xinafoate), salbutamol (e.g. as the sulphate or the free base), formoterol (e.g. as the fumarate), fenoterol or terbutaline and salts thereof.
Of particular interest is use of the compound of formula (I) in combination with a phosphodiesterase 4 (PDE4) inhibitor or a mixed PDE3/PDE4 inhibitor. The PDE4- specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family as well as PDE4. Generally it is preferred to use a PDE4 inhibitor which has an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity. For the purposes of this disclosure, the cAMP catalytic site which binds R and S rolipram with a low affinity is denominated the "low affinity" binding site (LPDE 4) and the other form of this catalytic site which binds rolipram with a high affinity is denominated the "high affinity" binding site (HPDE 4). This term "HPDE4" should not be confused with the term "hPDE4" which is used to denote human PDE4. A method for determining IC50S ratios is set out in US patent 5,998,428 which is incorporated herein in full by reference as though set out herein. See also PCT application WO 00/51599 for an another description of said assay.
The preferred PDE4 inhibitors of use in this invention will be those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity. Another way to state this is that the preferred compounds will have an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity.
A further refinement of this standard is that of one wherein the PDE4 inhibitor has an IC50 ratio of about 0.1 or greater; said ratio is the ratio of the IC50 value for competing with the binding of 1 nM of [3H]R-rolipram to a form of PDE4 which binds rolipram with a high affinity over the IC50 value for inhibiting the PDE4 catalytic activity of a form which binds rolipram with a low affinity using 1 μM[3H]-cAMP as the substrate.
Most preferred are those PDE4 inhibitors which have an IC50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0. Preferred compounds are cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1- carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan~1-one and c/s-[4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-1-ol]; these are examples of compounds which bind preferentially to the low affinity binding site and which have an IC50 ratio of 0.1 or greater.
Other compounds of interest include: Compounds set out in U.S. patent 5,652,438 issued 03 September, 1996; this patent and the compounds it discloses are incorporated herein in full by reference. The compound of particular interest, which is disclosed in U.S. patent 5,652,438, is c/s-4-cyano-4-[3- (cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1 -carboxylic acid (also known as cilomalast) and its salts, esters, pro-drugs or physical forms; AWD-12-281 from elbion (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98; CAS reference No. 247684020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering- Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, L.J. et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a pthalazinone (WO99/47506, the disclosure of which is hereby incorporated by reference) from Byk-Gulden; Pumafentrine, (-)-p-[(4aR*.10ibS*)-9-ethoxy-1 ,2,3,4,4a, 10b-hexahydro-8-methoxy-2- methylbenzo[c][1 ,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide which is a mixed PDE3/PDE4 inhibitor which has been prepared and published on by Byk-Gulden, now Altana; arofylline under development by Almirall-Prodesfarma; VM5δ4/UM56δ from Vernalis; or T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther,1998, 284(1): 162), and T2586.
Other possible PDE-4 and mixed PDE3/PDE4 inhibitors include those listed in WO01/13953, the disclosure of which is hereby incorporated by reference.
Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptor, in particular those compounds which are antagonists of the Mi and M2 receptors. Exemplary compounds include the alkaloids of the belladonna plants as illustrated by the likes of atropine, scopolamine, homatropine, hyoscyamine; these compounds are normally administered as a salt, being tertiary amines. These drugs, particularly the salt forms, are readily available from a number of commercial sources or can be made or prepared from literature data via, to wit:
Atropine - CAS-51-55-8 or CAS-61-48-1 (anhydrous form), atropine sulfate - CAS-5908- 99-6; atropine oxide - CAS-4438-22-6 or its HCI salt - CAS-4574-60-1 and methylatropine nitrate - CAS-52-88-0. Homatropine - CAS-87-00-3, hydrobromide salt - CAS-51-56-9, methylbromide salt - CAS-80-49-9.
Hyoscyamine (d, I) - CAS-101-31-5, hydrobromide salt - CAS-306-03-6 and sulfate salt - CAS-6835-16-1. Scopolamine - CAS-51-34-3, hydrobromide salt - CAS-6533-68-2, methylbromide salt- CAS-155-41-9. Preferred anticholinergics include ipratropium (e.g. as the bromide), sold under the name Atrovent, oxitropium (e.g. as the bromide) and tiotropium (e.g. as the bromide) (CAS- 139404-48-1). Also of interest are: methantheline (CAS-53-46-3), propantheline bromide (CAS- 50-34-9), anisotropine methyl bromide or Valpin 50 (CAS- 80-50-2), clidinium bromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamide iodide (CAS-71- 81-8), mepenzolate bromide (U.S. patent 2,918,408), tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocyclium methylsulfate (Tral, CAS-115-63-9). See also cyclopentolate hydrochloride (CAS-5870-29-1 ), tropicamide (CAS-1508-75-4), trihexyphenidyl hydrochloride (CAS-144-11-6), pirenzepine (CAS-29868-97-1), telenzepine (CAS-80880-90-9), AF-DX 116, or methoctramine, and the compounds disclosed in WO01/04118, the disclosure of which is hereby incorporated by reference.
Suitable antihistamines (also referred to as H^receptor antagonists) include any one or more of the numerous antagonists known which inhibit Hrreceptors, and are safe for human use. All are reversible, competitive inhibitors of the interaction of histamine with H receptors. The majority of these inhibitors, mostly first generation antagonists, have a core structure, which can be represented by the following formula:
Figure imgf000022_0001
This generalized structure represents three types of antihistamines generally available: ethanolamines, ethylenediamines, and alkylamines. In addition, other first generation antihistamines include those which can be characterized as based on piperizine and phenothiazines. Second generation antagonists, which are non-sedating, have a similar structure-activity relationship in that they retain the core ethylene group (the alkylamines) or mimic the tertiary amine group with piperizine or piperidine. Exemplary antagonists are as follows:
Ethanolamines: carbinoxamine maleate, clemastine fumarate, diphenylhydramine hydrochloride, and dimenhydrinate. Ethylenediamines: pyrilamine amleate, tripelennamine HCI, and tripelennamine citrate.
Alkylamines: chloropheniramine and its salts such as the maleate salt, and acrivastine.
Piperazines: hydroxyzine HCI, hydroxyzine pamoate, cyclizine HCI, cyclizine lactate, meclizine HCI, and cetirizine HCI. Piperidines: Astemizole, levocabastine HCI, loratadine or its descarboethoxy analogue, and terfenadine and fexofenadine hydrochloride or another pharmaceutically acceptable salt.
Azelastine hydrochloride is yet another H-i receptor antagonist which may be used in combination with a PDE4 inhibitor.
Examples of preferred anti-histamines include methapyrilene and loratadine.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a corticosteroid.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an antihistamine.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor and a corticosteroid.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic and a PDE-4 inhibitor.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a physiologically acceptable diluent or carrier represent a further aspect of the invention. The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
According to a further aspect of the invention, there is provided a process for preparing a compound of formula (1) or a salt, solvate, or physiologically functional derivative thereof which comprises a process as defined below, followed by the following steps in any order:
(i) optional removal of any protecting groups; (ii) optional separation of an enantiomer from a mixture of enantiomers;
(iii) optional conversion of the product to a corresponding salt, solvate, or physiologically functional derivative thereof.
In one general process (a), a compound of formula (I), may be obtained by deprotection of a protected intermediate, for example of formula (II):
Arπa—
Figure imgf000024_0001
or a salt or solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7, m, and n are as defined for the compound of formula (I), Ar1a represents an optionally protected form of Ar1; and P1 and P2 are each independently either hydrogen or a protecting group, provided that the compound of formula (II) contains at least one protecting group.
Protected forms of the preferred groups Ar1 may be selected from:
Figure imgf000024_0002
(ia) (iia) (iiia) (iva)
Figure imgf000025_0001
(va) (via) (viia) (viiia)
Figure imgf000025_0002
(ixa) (xa) (xia) (xiia)
Figure imgf000025_0003
(xiiia) (xiva) (xva)
Figure imgf000025_0004
(xvia) (xvϋa) (xviiia)
Figure imgf000026_0001
(xixa) (xxa) (xxia)
wherein P3 and P4 are each independently either hydrogen or a protecting group provided that at least one of P3 and P4 is a protecting group, and the dotted line in (xvia) and (xixa) denotes an optional double bond. It will be appreciated from the foregoing structures that where Ar1 is a group (vii), (xi), (xii), (xiii) or (xiv) protection is not required.
Suitable protecting groups may be any conventional protecting group such as those described in "Protective Groups in Organic Synthesis" by Theodora W Greene and Peter G M Wuts, 3rd edition (John Wiley & Sons, 1999). Examples of suitable hydroxyl protecting groups represented by P3 and P4 are esters such as acetate ester, aralkyl groups such as benzyl, diphenylmethyl, or triphenylmethyl, and tetrahydropyranyl. Examples of suitable amino protecting groups represented by P2 include benzyl, α- methylbenzyl, diphenylmethyl, triphenylmethyl, benzyloxycarbonyl, tert-butoxycarbonyl, and acyl groups such as trichloroacetyl or trifluoroacetyl.
As will be appreciated by the person skilled in the art, use of such protecting groups may include orthogonal protection of groups in the compounds of formula (II) to facilitate the selective removal of one group in the presence of another, thus enabling selective functionalisation of a single amino or hydroxyl function. For example, the -CH(OH) group may be orthogonally protected as - CH(OP1) using, for example, a trialkylsilyl group such as triethylsilyl. A person skilled in the art will also appreciate other orthogonal protection strategies, available by conventional means as described in Theodora W Greene and Peter G M Wuts (see above).
The deprotection to yield a compound of formula (I), may be effected using conventional techniques. Thus, for example, when P2, P3, and/or P4 is an aralkyl group, this may be cleaved by hydrogenolysis in the presence of a metal catalyst (e.g. palladium on charcoal).
When P3 and/or P4 is tetrahydropyranyl this may be cleaved by hydrolysis under acidic conditions. Acyl groups represented by P2 may be removed by hydrolysis, for example with a base such as sodium hydroxide, or a group such as trichloroethoxycarbonyl may be removed by reduction with, for example, zinc and acetic acid. Other deprotection methods may be found in Theodora W Greene and Peter G M Wuts (see above). In a particular embodiment of process (a), P3 and P4 may together represent a protecting group as in the compound of formula (III):
Figure imgf000027_0001
(III)
or a salt or solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7, P1, P2, m, and n are as defined for the compound of formula (I), R24 and R25 are independently selected from hydrogen, Chalky!, or aryl or R24 and R25 together form a C3.7cycloalkyl ring. In a preferred aspect, both R24 and R25 are methyl.
The compound of formula (III) may be converted to a compound of formula (I), by hydrolysis with dilute aqueous acid, for example acetic acid or hydrochloric acid in a suitable solvent or by transketalisation in an alcohol, for example ethanol, in the presence of a catalyst such as an acid (for example, toluenesulphonic acid) or a salt (such as pyridinium tosylate) at normal or elevated temperature.
It will be appreciated that the protecting groups P1, P2, P3 and P4 (including the cyclised protecting group formed by P3 and P4 as depicted in formula (III) may be removed in a single step or sequentially. The precise order in which protecting groups are removed will in part depend upon the nature of said groups and will be readily apparent to the skilled worker. Preferably, when P3 and P4 together form a protecting group as in formula (III) this protecting group is removed together with any protecting group on the CH(OH) moiety, followed by removal of P2.
Compounds of formulae (II) and (III) wherein P1 and P2 represent hydrogen may be prepared from the corresponding compound of formula (IV):
Figure imgf000028_0001
(IV)
or a salt or solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7, Ar1a, m, and n are as defined for the compound of formula (II) or (III).
The conversion of a compound of formula (IV) to a compound of formula (II) or (III) may be effected by treatment with a base, for example a non-aqueous base, such as potassium trimethylsilanolate, or an aqueous base such as aqueous sodium hydroxide, in a suitable solvent such as tetrahydrofuran.
Compounds of formula (IV) may be prepared from the corresponding compound of formula (V):
Figure imgf000028_0002
(V)
or a salt or solvate thereof, wherein R4, R5, R6, R7, Ar1a, m and n are as defined for the compound of formula (II) and A is either
(i) a leaving group group such as halo, eg. bromo or iodo, preferably iodo; or a haloalkylsulphonate such as trifluoromethane sulfonate; or (ii) a reactive group selected from boronic acid, or a boronic acid ester or an organo-zinc or organo-tin moiety;
by coupling with a compound of formula (VI):
Figure imgf000029_0001
wherein R , R and R are as defined for formula (I)
and A1 is either:
(i) a leaving group group such as halo, eg. bromo or iodo, preferably iodo; or a haloalkylsulphonate such as trifluoromethane sulfonate; or (ii) a reactive group selected from boronic acid, or a boronic acid ester or an organo-zinc or organo-tin moiety; provided that when A is selected from a leaving group (i) then A1 is selected from a reactive group (ii) and vice versa.
When either A or A1 represents a boronic acid ester, this should be an ester which is hydrolysed in situ to the boronic acid.
The coupling of a compound of formula (V) with a compound of formula (VI) is conveniently effected in the presence of a catalyst system such as palladium, for example, tetrakis(triphenylphosphine) palladium (0) or bis(diphenylphosphino)ferrocene palladium dichloride with a base such as sodium carbonate or caesium carbonate, in a suitable solvent for example 1 ,2- dimethoxyethane, or N,N-dimethylformamide.
Compounds of formula (V) may be prepared by coupling a compound of formula (VII):
Figure imgf000029_0002
or a salt or solvate thereof, wherein Ar1a is defined for the compound of formula (V) with a compound of formula (VIII):
RD
Figure imgf000030_0001
wherein, R4, R5, R6, R7, A, m and n are as defined for the compound of formula (V) and L1 is a leaving group for example a halo group, (typically bromo or iodo) or a sulfonate such as an alkyl sulfonate (typically methanesulfonate) an aryl sulfonate (typically toluenesulfonate) or a haloalkylsulfonate (typically trifluoromethane sulfonate).
The coupling of a compound of formula (VII) with a compound of formula (VIII) may be effected in the presence of a base, such as a metal hydride, for example sodium hydride, or an inorganic base such as cesium carbonate, in an aprotic solvent, for example N,N- dimethylformamide or tetrahydrofuran.
When the group A in the compound of formula (V) represents a leaving group, this may if desired be converted into a boronic acid derivative, by reaction with bis(pinacolato)diboron and 1 ,1'-bis(diphenylphosphino)ferrocene palladium dichloride in the presence of potassium acetate and in a solvent such as a mixture of dichloromethane and N,N-dimethylformamide.
Compounds of formula (VII) may be prepared as described for example in WO02/066422.
Alternatively, compounds of formula (V) may be prepared from a corresponding alkyne of formula (IX):
Figure imgf000030_0002
— (CH2)m — o— (CH2)n— C ≡ CH (|χ) wherein Ar1a, R4, R5, m and n are as defined for formula (II);
by coupling with a compound of formula (X):
Figure imgf000031_0001
wherein R6, R7 and A are as defined hereinabove for compounds of formula (V) and L2 is a leaving group for example a halo group, (typically bromo or iodo) or a haloalkylsulfonate (typically trifluoromethane sulfonate), followed by reduction.
The coupling of a compound of formula (IX) with a compound of formula (X) or a precursor thereof is conveniently effected in the presence of a catalyst system such as bis(triphenylphosphino) palladium dichloride and a copper catalyst such as cuprous iodide, with an organic base such as a trialkylamine, for example triethylamine, in a suitable solvent for example acetonitrile or dimethylformamide. The resulting alkyne may then be reduced, either with or without being isolated to form the compound of formula (V). The reduction may be effected by any suitable method such as hydrogenation in the presence of a catalyst, for example palladium/charcoal or platinum oxide.
Compounds of formula (IX) may be prepared for example as described in WO 02/070490.
Compounds of formula (X) may be prepared by standard methods well known to those skilled in the art.
A compound of formula (VIII) may be prepared from a corresponding compound of formula (XI):
L1CR4R5(CH2)mL1 (XI) wherein R4, R5 and m are as defined for compounds of formula (I) and each L1, which may be the same or different, represents a leaving group eg. as defined above for compounds of formula (VIII);
by reaction with an alcohol of formula (XII):
RD
Figure imgf000032_0001
wherein R , R , A and n are as defined for compounds of formula (VIII).
The coupling of compounds (XI) and (XII) may be effected in the presence of an inorganic base, such as aqueous sodium hydroxide, under phase transfer conditions in the presence of an ammonium salt such as a tetraalkylammonium bromide, e.g.tetrabutylammonium bromide.
It will be appreciated that when the group A in compounds of formula (VIII) initially obtained represents bromo, this may, if desired, be exchanged for an iodo substituent by reaction with iodine in the presence of an alkyl lithium, such as n-butyl lithium, in a solvent such as tetrahydrofuran.
Compounds of formula (XII) are known in the art, for example EP 995752A, or may be prepared by standard methods.
A compound of formula (IV) may also be preapred by reacting a compound of formula (XIII):
Figure imgf000033_0001
wherein L2 is a leaving group as defined for compounds of formula (X) above;
with a compound of formula (IX) as hereinbefore defined, in an analogous manner to the coupling of a compound of formula (IX) with a compound of formula (X) as described hereinabove.
A compound of formula (XIII) may be prepared by coupling a compound of formula (X) as defined hereinabove with a compound of formula (VI) as defined hereinabove, in an analogous manner to the coupling of a compound of formula (V) with a compound of formula (VI), as described hereinabove.
A compound of formula (IV) may also be prepared by coupling a compound of formula (VII) with a compound of formula (XIV):
Figure imgf000033_0002
wherein R1, R2, R3, R4, R5, R6, R7, m and n are as defined for formula (II) and L1 is as defined for formula (VIII); in an analogous manner to process (b) below.
Thus in a further process (b) a compound of formula (I) may be obtained by alkylation of an amine of formula (XV):
Figure imgf000034_0001
wherein Ar1a, P1 and P2 are as defined for formula (II); with a compound of formula (XIV):
Figure imgf000034_0002
wherein R1, R2, R3, R4, R5, R6, R7 m and n are as defined for formula (II) and L1 is as defined for formula (VIII); followed by removal of any protecting groups present by conventional methods as described above for the deprotection of compounds of formula (II).
The reaction of compounds of formulae (XIII) and (XIV) is optionally effected in the presence of an organic base such as a trialkylamine, for example, diisopropylethylamine, and in a suitable solvent for example N,N-dimethylformamide.
Compounds of formula (XV) are known in the art (for example EP-A 0947498 or WO 02/070490) or may be readily prepared by a person skilled in the art. Further details concerning preparation of compounds (XV) wherein Ar1 is a group (v) can be found in DE3524990; concerning the preparation of compounds (XV) wherein Ar1 is a group (ii), (viii), and (xvi) in EP-A-162576; concerning the preparation of compounds (XV) wherein Ar1 is a group (iv) in EP-A-220054; concerning the preparation of compounds (XV) wherein Ar1 is a group (xi) in GB2165542 and concerning the preparation of compounds (XV) wherein Ar1 is a group (c) in GB2230523.
A compound of formula (XIV) may be prepared from a compound of formula (VIII) by reaction with a compound (VI) in an analogous manner to the reaction of a compound of formula (V) with a compound of formula (VI). It will be appreciated that the precise order of the synthetic steps by which the various groups and moieties are introduced into the molecule may be varied. It will be within the skill of the practitioner in the art to ensure that groups or moieties introduced at one stage of the process will not be affected by subsequent transformations and reactions, and to select the order of synthetic steps accordingly.
The enantiomeric compounds of the invention may be obtained (i) by separation of the components of the corresponding racemic mixture, for example, by means of a chiral chromatography column, enzymic resolution methods, or preparing and separating suitable diastereoisomers, or (ii) by direct synthesis from the appropriate chiral intermediates by the methods described above.
Optional conversions of a compound of formula (I) to a corresponding salt may conveniently be effected by reaction with the appropriate acid or base. Optional conversion of a compound of formula (I) to a corresponding solvate or physiologically functional derivative may be effected by methods known to those skilled in the art.
According to a further aspect, the present invention provides novel intermediates for the preparation of compounds of formula (I) for example, compounds of formula (II), (III) and (IV) as defined above, or an optical isomer, a salt, or a protected derivative thereof.
For a better understanding of the invention, the following Examples are given by way of illustration.
SYNTHETIC EXAMPLES
Throughout the examples, the following abbreviations are used:
LCMS: Liquid Chromatography Mass Spectrometry
MS : mass spectrum
TSP+ve : thermospray mass spectrum positive mode HPLC: high pressure liquid chromatography
RT : retention time
THF : tetrahydofuran
DCM : dichloromethane
DMF : N,N-dimethylformamide EtOAc : ethyl acetate
Et2O : diethyl ether EtOH : ethanol MeOH : methanol bp : boiling point ca : circa h : hour(s) min : minute(s)
All temperatures are given in degrees centigrade. Silica gel refers to Merck silica gel 60 Art number 7734. Flash silica gel refers to Merck silica gel 60 Art number 9385. Biotage refers to prepacked silica gel cartridges containing KP-Sil run on flash 12i chromatography module.
Bond Elut are prepacked cartridges used in parallel purifications, normally under vacuum. These are commercially available from Varian.
LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1% HCO2H and 0.01 M ammonium acetate in water (solvent A), and 0.05% HCO2H 5% water in acetonitrile (solvent B), using the following elution gradient 0-0.7 min 0%B, 0.7-4.2 min 100%B, 4.2-5.3 min 100%B, 5.3-5.5 min 0%B at a flow rate of 3 ml/min. The mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).
HPLC was conducted on a LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1% formic acid and 0.01 M ammonium acetate in water (solvent A), and 0.05% formic acid 5% water in acetonitrile (solvent B) using the following elution gradient 0-1 min 0%B, 1-10 min100%B, 10-13 min 100%B, 13-15 min 0%B at a flow rate of 1 ml/min
Example 1
(2a-3-f3,-(4-(r6-({(2 )-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenvnethyl)amino)hexyπoxy)butyl)-1 ,1 '-biphenyl-3-vnprop-2-enoic acid acetate
i) 6-Bromohexyl 4-(3-bromophenyl)butyl ether
A stirred mixture of 4-(3-bromophenyl) butan-1-ol (18 g) ( EP 0 995 752A1), 1 ,6 dibromohexane (48 ml), tetrabutylammonium bromide (1.5 g) and 50% aqueous sodium hydroxide solution (500 ml) was stirred for 2 days at ambient temperature. The mixture was poured into water (1000 ml) and extracted into ethyl acetate. The combined extracts were washed with water, dried (Na2SO4) and evaporated. The residual oil was purified on a biotage cartridge (90 g) eluting with light petroleum (40-60 °C), and then light petroleum (40-60 °C) - ether (9:1). The appropriate fractions were evaporated to give the title compound (18 g). LCMS RT= 4.34 min.
ij) 6-Bromohexyl 4-(3-iodophenyl)butyl ether
A solution of n-butyl lithium in hexane (1.6 M; 50 ml ) was added to a stirred solution of 6- bromohexyl 4-(3-bromophenyl)butyl ether (21 g) in dry THF (150 ml) at -85 °C under nitrogen. After 15 min a solution of iodine (19.8 g) in THF (100 ml) was added dropwise over 20 min. The solution was then allowed to warm up to 0 °C and aqueous sodium bisulphite was added. The mixture was poured into water and extracted into ether. The combined extracts were dried (Na2SO ) and evaporated. The residue was purified by flash silica gel column chromatography (1 kg) eluting with cyclohexane - ether (9:1). The appropriate fractions were evaporated to give the title compound (17 g). LCMS RT = 4.41 min.
jii) (5R -5-(2,2-Dimethyl-4H-1.3-benzodioxin-6-vn-3-(6-r4-(3-iodophenyl)butoxylhexyl>- 1 ,3-oxazolidin-2-one Sodium hydride (60% oil dispersion, 1.26 g) was added to a stirred, cooled (ice-bath) solution of (5R)-5-(4 - -1,3-benzodioxin-6-yl)-2-oxazolidinone (5.47 g) in dry DMF (50 ml) under nitrogen and the mixture was stirred for 15 min at 5 °C. A solution of 6-bromohexyl 4-(3-iodophenyl)butyl ether (10.7 g) in DMF (30 ml) was then added dropwise over 10 min. The mixture was stirred for 2 h at ambient temperature, then poured into aqueous solution of ammonium chloride and extracted into ethyl acetate. The combined extracts were washed with water, dried (Na2SO4) and evaporated. The residue was purified on a biotage cartridge (90 g) eluting with ether - hexane (3:2) to give the title compound (9.8 g). LCMS RT= 4.20 min.
jy) Methyl (2a-3-(3'-r4-«6-r(5ffl-5-(2.2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3- oxazolidin-3-vnhexyl)oxy)butyll-1.1'-biphenyl-3-yl)prop-2-enoate To a solution of (5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-{6-[4-(3- iodophenyl)butoxy]hexyl}-1 ,3-oxazolidin-2-one (220mg) in 1 ,2-dimethoxyethane (3 ml) and aqueous sodium carbonate solution (2M, 2 ml) were added (3-methoxy-3-oxo-1- propen-1-yl)phenyl boronic acid (94.9 mg), and tetrakis(triphenylphosphine) palladium (0) (10 mg). The mixture was heated to 80 °C under nitrogen for 1h. Water was then added and the mixture was extracted into ethyl acetate, dried (Na2SO ) and concentrated in vacuo to give the title compound (150 mg). LCMS RT = 4.35 min.
γl (2a-3-(3'-(4-f(6-(r(2r?)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2- hvdroxyethvnamino)hexyl)oxylbutyl)-1.1'-biphenyl-3-yl)prop-2-enoic acid To a solution of methyl (2a-3-{3'-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2- oxo-1 ,3-oxazolidin-3-yl]hexyl}oxy)butyl]-1 ,1 '-biphenyl-3-yl}prop-2-enoate (143mg) in tetrahydrofuran (3 ml) was added potassium trimethylsilanolate (84 mg). The mixture was stirred and heated at 80 °C for 1 h. Water was added to the reaction mixture and the product was extracted into ethyl acetate. The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound (100 mg). LCMS RT = 3.26 min.
yj) (2E)-3-f3'-(4-(r6-({(2f?)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenvnethyl)amino)hexyl1oxy)butyl)-1 , 1 '-biphenyl-3-yllprop-2-enoic acid acetate
A mixture of (2£)-3-(3'-{4-[(6-{[(2 ?)-2-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}-1 ,1'-biphenyl-3-yl)prop-2-enoic acid (100 mg) in acetic acid (3 ml) and water (1ml) was heated to 80°C for 1 h. The mixture was concentrated in vacuo to give the title compound (90 mg). LCMS RT= 3.09 min; ES+ve 562 (MH+).
Example 2
3-f3'-(4-(f6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyllethyl}amino)hexylloxylbutyl)-1.1 '-biphenyl-4-yllpropanoic acid acetate
i] Methyl 3-(3'-r4-((6-r(5R)-5-(2.2-dimethyl-4H-1 ,3-benzodioxin-6-vn-2-oxo-1 ,3-oxazolidin- 3-yllhexyl)oxy)butyll-1 ,r-biphenyl-4-yl)propanoate Prepared using methods similar to those described in Example 1 iv) LCMS RT = 4.29 min.
ii] 3-(3'-{4-r(6- r(2ffl-2-(2,2-Dimethyl-4H-1.3-benzodioxin-6-vn-2- hvdroxyethyl1amino|hexyl)oxy1butyl)-1 ,1 '-biphenyl-4-yl)propanoic acid Prepared using methods similar to those described in Example 1 v) LCMS RT = 3.25 min.
HO 3-r3'-(4-{r6-(((2ffl-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyllethyl)amino)hexynoxylbutyl)-1 ,1 '-biphenyl-4-vnpropanoic acid acetate
Prepared using methods similar to those described in Example 1 vi) LCMS RT = 3.28 min, ES+ve 564 (MH+).
Example 3
(2E)-3-r3'-(4-(r6-({(2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenvnethyl>amino)hexylloxy)butyl)-1 , -biphenyl-4-yllprop-2-enoic acid acetate
i] Methyl (2a-3-(3'-r4-((6-r(5r?)-5-(2.2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1.3- oxazolidin-3-yllhexyl)oxy)butvn-1.r-biphenyl-4-yl)prop-2-enoate Prepared using methods similar to those described in Example 1 iv) LCMS RT = 4.41 min
ii] (2a-3-(3'-(4-r(6-(r(2ffl-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethvπamino)hexy0oxylbutyl)-1 ,1 '-biphenyl-4-yl)prop-2-enoic acid
Prepared using methods similar to those described in Example 1 v) LCMS RT = 3.25 min
ijj] (2a-3-r3'-(4-{r6-({(2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyllethyl)amino)hexyl1oxy)butyl)-1.1 '-biphenyl-4-vnprop-2-enoic acid acetate
Prepared using methods similar to those described in Example 1 vi) LCMS RT 3.08 min, ES+ve 562 (MH+).
Example 4 3'-(4-(r6-({(2r?)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenvnethyl>amino)hexyl1oxy)butyl)-1.r-biphenyl-3-carboxylic acid acetate
j) Methyl 3'-r4-({6-r(5f?)-5-(2,2-dimethyl-4r/-1.3-benzodioxin-6-vn-2-oxo-1 ,3-oxazolidin-3- vnhexyl}oxy)butyll-1.r-biphenyl-3-carboxylate Prepared using methods similar to those described in Example 1 iv) LCMS RT = 4.32 min
ji] 3'-(4-r(6-(r(2R)-2-(2,2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethvnamino)hexyl)oxylbutyl)-1 ,1 '-biphenyl-3-carboxylic acid Prepared using methods similar to those described in Example 1 v) LCMS RT = 3.29 min
iii] 3'-(4-(r6-(((2ft)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenvπethyl)amino)hexyπoxylbutyl)-1 , 1 '-biphenyl-3-carboxylic acid acetate Prepared using methods similar to those described in Example 1 vi) LCMS RT = 2.95 min, ES+ve 536 (MH+).
Example 5 r3'-(4-(r6-(((2 )-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl1ethyl)amino)hexynoxy)butyl)-1 ,1 '-biphenyl-4-yllacetic acid acetate
i] Methyl (3'-r4-({6-r(5R)-5-(2.2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yllhexyl}oxy)butyll-1.1 '-biphenyl-4-yl)acetate
Prepared using methods similar to those described in Example 1 iv) LCMS RT = 4.17 min
π] (3'-(4-r(6-{r(2ffl-2-(2.2-Dimethyl-4H-1 ,3-benzodioxin-6-yl)-2- hvdroxyethyl1amino>hexyl)oxylbutyl)-1 , 1 '-biphenyl-4-yl)acetic acid
Prepared using methods similar to those described in Example 1 v) LCMS RT = 3.24 min.
in] f3'-(4-(r6-({(2 ?)-2-Hvdroxy-2-f4-hvdroxy-3-
(hvdroxymethyl)phenyllethyl)amino)hexylloxy)butyl)-1 ,1'-biphenyl-4-vnacetic acid acetate Prepared using methods similar to those described in Example 1 vi) LCMS RT = 3.00 min, ES+ve 550 (MH+).
Example 6
3'-(4-{f6-({(2r?)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenvnethyl>amino)hexylloxy)butyl)-1 , 1 '-biphenyl-2-carboxylic acid acetate i) (5r?)-5-(2,2-Dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-(6-(4-r3-(4.4.5.5-tetramethyl-1.3.2- dioxaborolan-2-yl)phenvπbutoχy)hexyl)-1 ,3-oxazolidin-2-one
A stirred mixture of (5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-{6-[4-(3- iodophenyl)butoxy]hexyl}-1 ,3-oxazolidin-2-one (1.0 g), bis(pinacolato)diboron (0.628g), potassium acetate (485 mg) and 1 ,1' -bis(diphenylphosphino) ferrocene palladium dichloride complex with dichloromethane (60 mg) in dimethylformamide (25ml) was heated at 80° under nitrogen for 20 h. The mixture was cooled and poured into water and extracted into ethyl acetate. The organic extracts were washed with water, dried (Na2SO4) and evaporated. The residual oil was purified by chromatography on a biotage cartridge (90 g) eluting with ether-petroleum ether (40-60°) to give the title compound (700 mg). LCMS RT = 4.35 min.
π] Methyl 3'-r4-({6-r(5fl)-5-(2,2-dimethyl-4r7-1.3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- vnhexyl)θxy)butvn-1.1 '-biphenyl-2-carboxylate A mixture of (5f?)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-(6-{4-[3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl]butoxy}hexyl)-1 ,3-oxazolidin-2-one (100 mg), methyl 2- iodobenzoate (65 mg) and potassium carbonate (114 mg) in 1 ,2-dimethoxyethane (4 ml) was heated to 95°C under nitrogen. 1 ,1-Bis(diphenylphosphino)ferrocene palladium dichloride (50 mg) was added and the mixturewas heated for 4 h. The reaction mixture was poured into water and extracted into ethyl acetate. The organic layer was dried and evaporated to dryness. The residue was purified on a Bond Elut cartridge (10 g) eluting with DCM and then ether to give the title compound (90 mg). LCMS RT 4.14 min
Hi] 3'-{4-r(6-ir(2/:?)-2-(2,2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethvnamino|hexyl)oxylbutyl)-1 , 1 '-biphenyl-2-carboxylic acid
Prepared using methods similar to those described in Example 1 v) LCMS RT = 3.09 min
i ] 3'-(4-(r6-({(2f?)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyl1ethyl}amino)hexylloxy)butyl)-1 ,1 '-biphenyl-2-carboxylic acid acetate
Prepared using methods similar to those described in Example 1 vi) LCMS RT = 2.82 min, ES+ve 536 (MH+).
Example 7 r3'-(4-fr6-(((2 )-2-Hvdroxy-2-f4-hvdroxy-3- (hvdroxymethvπphenyllethyl}amino)hexylloxy)butvπ-1 ,1'-biphenyl-2-vnacetic acid acetate
i] Methyl (3'-l -«6-r(5ffl-5-(2.2-dimethyl-4f7-1.3-benzodioxin-6-vn-2-oxo-1.3-oxazolidin-3- vnhexylloxy)butvn-1 ,1 '-biphenyl-2-yl}acetate
Prepared using methods similar to those described in Example 6 ii) LCMS RT = 4.15 min
ii] (3'-{4-r(6-(f(2 )-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethyl1amino)hexyl)oxylbutyl)-1 ,1 '-biphenyl-2-yl)acetic acid Prepared using methods similar to those described in Example 1 v) LCMS RT = 3.05 min
in] r3'-(4-(r6-(((2 )-2-Hvdroxy-2-r4-hvdroχy-3-
(hvdroxymethyl)phenvnethyl>amino)hexynoxy)butyl)-1 ,1'-biphenyl-2-vπacetic acid acetate Prepared using methods similar to those described in Example 1 vi) LCMS RT = 2.81 min, ES+ve 550 (MH+).
Example 8 r3'-(4-(r6-(((2 )-2-Hvdroxy-2-f4-hvdroxy-3-
(hydroxymethyl)phenvnethyl>amino)hexylloxy>butyl)-1 ,1 '-biphenyl-3-yllacetic acid acetate
i] Methyl {3'-r4- 6-r(5RV5-(2.2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- vπhexyl)oxy)butvπ-1.1 '-biphenyl-3-yl)acetate
Prepared using methods similar to those described in Example 6 ii) LCMS RT = 4.12 min
ii] (3'-{4-r(6-{r(2ffl-2-(2.2-Dimethyl-4ry-1.3-benzodioxin-6-yl)-2- hvdroxyethyllamino|hexyl)oxy1butyl}-1.1 '-biphenyl-3-v0acetic acid Prepared using methods similar to those described in Example 1 v) LCMS RT = 3.05 min
in] r3'-(4-(r6-({(2f?)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenynethyl)amino)hexylloxy|butyl)-1 ,1 '-biphenyl-3-ynacetic acid acetate Prepared using methods similar to those described in Example 1 vi) LCMS RT = 2.90 min, ES+ve 550 (MH+).
Example 9 3'-(4-{f6-(((2R)-2-Hvdroχy-2-f4-hvdroxy-3-
(hvdroxymethyl)phenyl1ethyl)amino)hexyl1oxy)butyl)-1 , 1 '-biphenyl-4-carboxylic acid acetate
i] (5RV3-r6-(But-3-vnyloxy)hexyn-5-(2.2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-1.3- oxazolidin-2-one A solution of (5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (4 g) in DMF (25 ml) was added to a suspension of sodium hydride (60% oil dispersion, 1.32 g) in DMF (10 ml) at 0 °C and the mixture was stirred for 10 min. A solution of 6-bromohexyl but-3-ynyl ether (5 g) in DMF (15 ml) was added and the cooling bath was removed. The mixture was stirred for 18 h and then concentrated under reduced pressure. The residue was purified by column chromatography on flash silica gel eluting with heptane-ether (2:1) and then with neat ether to give the title compound (5.8 g). LCMS RT = 3.26 min.
ii] 2-(3-lodophenvD-4,6-diphenyl-1 ,3,2-dioxaborinane
A mixture of 3-iodophenylboronic acid (15 g) and 1,3-diphenyl-1 ,3-propanediol (15 g) in tetrahydrofuran (150 ml) was heated to reflux for 15 min in the presence of molecular sieves. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was crystallised from heptane - ethyl acetate (5:1) to give the title compound (25.3 g) LCMS RT = 3.03 min.
in] (5R)-5-(2.2-Dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-r6-((4-r3-(4.6-diphenyl-1.3,2- dioxaborinan-2-vπphenvnbut-3-vnyl>oxy)hexyn-1 ,3-oxazolidin-2-one A solution of (5R)-3-[6-(but-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4rV-1 ,3-benzodioxin-6-yl)-1 ,3- oxazolidin-2-one (500 mg) and 2-(3-iodophenyl)-4,6-diphenyl-1 ,3,2-dioxaborinane (603 mg) in acetonitrile (5 ml) and triethylamine (3 ml) was treated with bis(triphenylphosphine)palladium dichloride (84 mg) and copper (I) iodide (23 mg) and the mixture was stirred under nitrogen for 4.5 h. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on a Bond Elut cartridge (10 g) eluting with DCM, followed by ether to give the title compound (572mg). LCMS RT = 3.50min.
iy] Methyl 3'-r4-((6-f(5R)-5-(2.2-dimethyl-4fV-1 ,3-benzodioxin-6-vn-2-oxo-1 ,3-oxazolidin-3- yl1hexyl)oxy)butvn-1.1 '-biphenyl-4-carboxylate
A solution of (5R)-5-(2,2-dimethyl-4ry-1 ,3-benzodioxin-6-yl)-3-[6-({4-[3-(4,6-diphenyl-1 ,3,2- dioxaborinan-2-yl)phenyl]but-3-ynyl}oxy)hexyl]-1 ,3-oxazolidin-2-one (570 mg) in ethanol (3 ml) and ethyl acetate (1 ml) was hydrogenated over 10% palladium on carbon (57 mg) over 2 days. The catalyst was removed by filtration and the filtrated was concentrated under reduced pressure to give the saturated boronic ester (470 mg). A portion of this (200 mg) was dissolved in DMF (3 ml) and treated with methyl 4-iodobenzoate (110 mg), caesium carbonate (137 mg), and tetrakis(triphenylphosphine) palladium (0) (35 mg) and the mixture was heated to 100 °C for 1 h. The mixture was cooled and then partitioned between ether and water. The organic layer was washed with water, brine dried and chromatographed on a biotage cartridge (40 g) eluting with heptane-ether (1 :2) to give the title compound (126 mg) LCMS RT = 4.21 min.
y] 3'-(4-r(6-{r(2R)-2-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2- hydroxyethyllaminolhexyDoxy'lbutylV-l .1 '-biphenyl-4-carboxylic acid
Prepared using methods similar to those described in Example 1 v) LCMS RT = 2.97 min
yi] 3'-(4-{[6-({(2RV2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenvnethyl)amino)heχylloxy)butyl)-1 , 1 '-biphenyl-4-carboxylic acid acetate
Prepared using methods similar to those described in Example 1 vi) LCMS RT = 2.61 min, ES-ve 534(M-HV.
Example 10 4'-(4-{r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hydroxymethyl)phenyllethyl)amino)hexylloxy)butvπ-N-isopropyll"1 , -biphenvn-2- sulfonamide acetate
i] 4-(4-lodophenvQbutan-1 -ol A solution of borane-tetrahydrofuran (200ml) was added dropwise to a stirred solution of 4-(4-iodophenyl)butanoic acid (25g) at 0°C under nitrogen. After 2h methanol (200ml) was added dropwise. And then the solvent was removed in vacuo. The residue was partitioned between ether and water and the organic phase was separated. The combined organic layers were dried (Na2SO4 ) and evaporated to give the title compound (23 g). LCMS RT = 3.34 min.
π] 1-{4-r(6-Bromohexyl)oxy1butyl>-4-iodobenzene
4-(4-lodophenyl)butan-1-ol (22g) was stirred with 1 ,6-dibromohexane (61ml) and tetrabutylammonium hydrogen sulphate(1.0g) in 50% sodium hydroxide solution (300ml) for 18h. The reaction was poured into water and extracted into ether. The organic extracts were washed with water, dried (Na2SO4) and evaporated. The residual oil was purified by chromatography on flash silica (800g) eluting with n-heptane and then heptane-ether (3:1) to give the title compound (12 g). LCMS RT = 4.23 min.
in] (5R 5-(2.2-Dimethyl-4ry-1.3-benzodioxin-6-vn-3-{6-r4-(4-iodophenvnbutoxylhexyl>- 1 ,3-oxazolidin-2-one
Sodium hydride (60% oil dispersion, 1.4g) was added to a stirred solution of (5R)-(2,2- dimethyl-4 -/-1 ,3-benzodioxin-6yl)-1 ,3oxazolidin-2-one (6.0g) in dry dimethylformamide (80ml) at 0° under nitrogen. After 20 min a solution of 1-{4-[(6-bromohexyl)oxy]butyl}-4- iodobenzene (12.6g) in dry dimethylformamide (30ml) was added dropwise. The mixture was stirred for 15h at ambient temperature. The mixture was poured into an aqueous ammonium chloride solution (700ml) and extracted into ethyl acetate. The organic extracts were washed with water, dried (Na2SO4) and evaporated. Purification by chromatography on a biotage cartridge (90g) using ether- petroleum ether (40-60°) (4:1) gave the title compound as a clear oil (10g). LCMS RT = 4.19 min.
iy] (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-3-(6-(4-r4-(4.4.5.5-tetramethyl-1.3.2- dioxaborolan-2-yl)phenyllbutoxy)hexyl)-1.3-oxazolidin-2-one
A stirred mixture of (5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-{6-[4-(4- iodophenyl)butoxy]hexyl}-1 ,3-oxazolidin-2-one (3.6 g), bis(pinacolato)diboron (3.6g), potassium acetate(2.2g) and 1 ,1 -bis(diphenylphosphino)ferrocene palladium dichloride complex with dichloromethane (200mg) in dimethylformamide (80ml) was heated at 80° under nitrogen for 18h. The mixture was cooled and poured into water and extracted into ethyl acetate. The organic extracts were washed with water, dried (Na2SO4) and evaporated. The residual oil was purified by chromatography on a biotage cartridge (90g) eluting with ether-petroleum ether (40-60°) to give the title compound (3.4g) LCMS RT = 4.19 min.
y] fer/--Butyl (2-bromophenyl)sulfonyl(isopropyl)carbamate
A stirred solution of 2-bromo-benzenesulphonyl chloride (2.0g) in tetrahydrofuran (50ml) was treated with isopropylamine (5ml) at 0° for 10 min. The solvent was evaporated and the residual solid triturated under water. A portion of the compound (1.0g) in acetonitrile (20ml) was treated with di-tert-butyl dicarbonate (1.0g), 4-(dimethylamino)pyridine (44mg) and triethylamine (0.7ml) at 0° under nitrogen for 15 min. The solvent was evaporated and the residue was partitioned between ethyl acetate and 2M hydrochloric acid. The organic extract was washed with water, dried (Na2SO ) and evaporated to give the title compound as a pale yellow solid (1.2g).
TLC (silica, petroleum ether-ether 4:1 ) Rf = 0.44
i] .erf-Butyl {4'-r4-({6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-viy-2-oxo-1.3- oxazolidin-3-yl]hexyl}oxy)butyl][1 ,1'-biphenyl]-2-yl}sulfonyl(isopropyl)carbamate A stirred mixture of (5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-(6-{4-[4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]butoxy}hexyl)-1 ,3-oxazolidin-2-one) (216 mg), fert-butyl (2-bromophenyl)sulfonyl(isopropyl)carbamate (160mg), potassium carbonate (20mg) and 1 ,1' bis(diphenylphosphino) ferrocene palladium dichloride complex with dichloromethane (50mg) in 1 ,2-dimethoxyethane (4ml) was heated at 85° for 4h. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic extract was washed with water, dried (Na2SO4) and evaporated. Purification of the residual oil by chromatography on a biotage cartridge (8g) using ether-hexane (4:1) as the eluent gave the title compound as a clear oil (130mg). LCMS RT = 4.36 min
yji] 4'-(4-r(6-(r(2R)-2-(2.2-Dimethyl-4ry-1.3-benzodioxin-6-yl)-2- hvdroxyethyllamino|hexyl)oxylbutyl)-Λ/-isopropyiπ .1'-biphenvn-2-sulfonamide Prepared using methods similar to those described in Example 1 v). TLC (SiO2) dichloromethane-ethanol-ammonia (100:8:1) Rf = 0.2
yjii] 4'-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenvnethyl)amino)hexylloxylbutyl)-A/-isopropyiπ , 1 '-biphenyl1-2- sulfonamide acetate Prepared using methods similar to those described in Example 1 vi). LCMS RT = 2.81 min, ES+ve 613 (MH)+
Example 11
/V-Cvclopropyl-4'-(4-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenvnethyl)amino)hexynoxy)butyl)π ,1 '-biphenyll-2-sulfonamide acetate
i] ferf-Butyl (2-bromophenyl)sulfonyl(cvclopropyl)carbamate
Was prepared using methods similar to those described in example 10 v) LCMS RT= 3.37min
ii] tett-Butyl cvclopropyl((3'-r4-((6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-vn-2-oxo- 1 ,3-oxazolidin-3-yllhexyl)oxy)butvnf1 ,1'-biphenvn-2-yl}sulfonyl)carbamate
Was prepared using methods similar to those described in Example 10vi) LCMS RT= 4.19min.
m] /V-Cvclopropyl-4'-(4-r(6-(r(2R)-2-(2.2-dimethyl-4H-1.3-benzodioxin-6-vn-2- hydroxyethyllaminolhexyDoxylbutyllf 1 , 1 '-biphenyll-2-sulfonamide
Was prepared using methods similar to those described in Example 1 v) LCMS RT = 3.12 min.
iy] A/-Cvclopropyl-4'-(4-{r6-({(2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenvπethyl}amino)hexynoxy)butyl)[1.1'-biphenvn-2-sulfonamide acetate Was prepared using methods similar to those described in Example 1 vi) LCMS RT= 2.87min, ES+ve 612(MH+).
Example 12 2-(Hvdroxymethyl)-4-((1R)-1-hvdroxy-2-f(6-(4-r2'-(morpholin-4-ylsulfonyl)ri .1'-biphenyll-4- yllbutoxy}hexyl)amino1ethyl)phenol acetate
i] 4-r(2-Bromophenyl)sulfonvnmorpholine
Morpholine (2ml) was added to a stirred solution of 2- bromo benzenesulphonyl chloride(I .Og) in dichloromethane (20ml) at 5° under nitrogen. The solvent was evaporated and the residual solid was triturated with water to give the title compound (1.3g). TLC (SiO2, ether-hexane 1 :1 ) Rf 0.35. π] (5RV5-(2.2-Pimethyl-4r7-1 ■3-benzodioxin-6-vn-3-(6-(4-r2'-(morpholin-4-ylsulfonvnri .1 '- bi phenyll-4-yll butoxy)hexyl)- 1.3-oxazol idin-2-one
Was prepared using methods similar to those described in Example 10 vi) LCMS RT= 3.96 min.
in] (1 ffl-1 -(2.2-Dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-r(6-(4-r2'-(morpholin-4-ylsulfonvnri .1 '- biphenyll-4-yllbutoxy)hexyl)aminolethanol
Was prepared using methods similar to those described in Example 1 v) LCMS RT = 3.08 min.
iy] 2-(Hvdroxymethvn-4-((1 R)-1-hvdroxy-2-f(6-(4-r2'-(morpholin-4-ylsulfonyl)π .1 '- biphenyll-4-yllbutoxy)hexyl)aminolethyl)phenol acetate
Was prepared using methods similar to those described in Example 1 vi) LCMS RT = 2.95 min, ES+ve 641 (MH)+.
Example 13
Λ/-Ethyl-4'-(4-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenvnethyl|amino)hexylloxy)butyl)-Λ/-methylf1.1'-biphenyll-2- sulfonamide acetate
i] 2-Bromo-Λ/-ethyl-/V-methylbenzenesulfonamide
Was prepared using methods similar to those described in Example 12 i) LCMS RT= 3.04 min
ii] 4'-r4-({6-r(5RV5-(2.2-Dimethyl-4ry-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yllhexyl)oxy)butvn-A/-ethyl-Λ/-methylf 1 , 1 '-biphenvπ-2-sulfonamide
Was prepared using methods similar to those described in Example 10 vi) LCMS RT= 4.08 min.
in] 4'-{4-r(6-(r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2- hvdroxyethyllamino)hexyl)oxylbutyl>-A/-ethyl-/\/-methviri . -biphenvn-2-sulfonamide
Was prepared using methods similar to those described in Example 1 v) LCMS RT = 3.29 min. iy] A/-Ethyl-4'-(4-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyllethyl)amino)hexylloxy)butvπ-Λ/-methylf 1.1 '-biphenyl1-2- sulfonamide acetate
Was prepared using methods similar to those described in Example 1 vi) LCMS RT = 2.93 min, ES+ve (MH)+.
Example 14
4l-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyllethyl|amino)hexylloxy)butyl)ri .1 '-biphenvn-2-sulfonamide acetate
i) ferf-Butyl (2-bromophenyl)sulfonylcarbamate
Ammonia (50ml) was added to a stirred solution of 2-bromo benzenesulphonyl chloride (5.0g) in tetrahydrofuran (100ml) at 5°C. The mixture was stirred for 20 min and then evaporated to dryness and then the residual solid was triturated with water. The solid was collected by filtration and suspended in dichloromethane (100ml). 4-
(Dimethylamino)pyridine (0.25 g) and triethylamine (3.2ml) were added, followed by di- tetf-butyl dicarbonate (5.8 g) and the solution was stirred at ambient temperature for 1h. The solution was washed with 1 M hydrochloric acid, water and dried (Na2SO4). The solvent was evaporated to give the title compound (5.8g). LCMS RT = 3.08 min.
ii) fetf-Butyl (2-bromophenyl)sulfonyl(r2-(trimethylsilyl)ethoxylmethyl)carbamate Sodium hydride (60% dispersion in oil, 252 mg) was added to a stirred solution of tert- butyl (2-bromophenyl)sulfonylcarbamate (2.0 g ) in dry dimethylformamide (20ml) at 5° under nitrogen. After 15min 2-(trimethylsilyl)ethoxymethyl chloride (2 ml) was added and the mixture was stirred for 30 min at 5°. The mixture was poured into an aqueous ammonium chloride solution and extracted into ether. The organic extract was washed with water, dried (Na2SO4) and evaporated to give the title compound as a clear oil (2.4 g). LCMS RT = 3.99 min.
iii) fert-Butyl f4'-r4-((6-r(5R)-5-(2.2-dimethyl-4r/-1.3-benzodioxin-6-yl)-2-oxo-1.3- oxazolidin-3-yl1hexyl)oxy)butvnf1. -biphenvn-2-yl)sulfonyl{r2-
(trimethylsilyl)ethoxylmethyl}carbamate
Was prepared using methods similar to those described in ExamplelO vi) LCMS RT =
4.46 min i] 4'-(4-r(6-{r(2R 2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethyl1amino|hexyl)oxylbutylM1. -biphenvn-2-sulfonamide
Was prepared using methods similar to those described in Example 1 v) LCMS = 2.80 min.
ii] 4'-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyllethyl)amino)hexynoxy)butyl)π ,1 '-biphenvn-2-sulfonamide acetate Was prepared using methods similar to those described in Example 1 vi) LCMS = 2.57 min, ES+ve 571 (MH)+.
Example 15
4'-(4-{[6-({(2R)-2-Hvdroxy-2-f4-hvdroxy-3-
(hvdroxymethyl)phenyllethyl)amino)hexynoxy>butyl)n ,1 '-biphenylH-sulfonamide acetate
i] 4-(Tributylstannyl)benzenesulfonamide
A stirred mixture of 4-iodobenzenesulfonamide (8.33 g), hexabutylditin (20.5g) and tetrakis(triphenylphosphine) palladium (0) (200mg) in dioxan (80ml) and toluene (70ml) was heated at reflux for 18 h. The mixture was absorbed onto silica gel (merck 9385) and purified by flash chromatography (200g) eluting with cyclohexane-ethyl acetate (3:1 ). The appropriate fractions were evaporated to give the title compound as a clear oil (6.95g). LCMS RT = 4.34 min.
ii) 4'-r4-({6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2-oxo-1.3-oxazolidin-3- yllhexyl)oxy)butyliπ ,1 '-biphenylH-sulfonamide A stirred mixture of (5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-{6-[4-(4- iodophenyl)butoxy]hexyl}-1 ,3-oxazolidin-2-one( 225mg), 4-(tributylstannyl) benzenesulfonamide (250mg) and silver oxide (86mg) with [1 ,4- bis(diphenylphosphino)butane]palladium dichloride in dioxan (5ml) was heated at 85° for 18h. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was evaporated to dryness and the residual oil was purified by chromatography on a biotage cartridge (8g) eluting with ether. The appropriate fractions were evaporated to give the title compound as a clear oil (60mg). LCMS RT = 4.01 min.
iii) 4'-(4-r(6-(r(2R)-2-(2.2-dimethyl-4H-1,3-benzodioxin-6-vn-2- hvdroxyethyl1amino)hexyl)oxy1butyl)ri ,1 '-biphenylH-sulfonamide Was prepared using methods similar to those described in Example 1 v) LCMS RT = 2.96 min.
iv) 4'-(4-fr6-({(2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethvθphenvπethyl)amino)hexyl1oxy}butyl)l'1.1 '-biphenvn-4-sulfonamide acetate Was prepared using methods similar to those described in Examplel vi) LCMS RT=2.72 min, ES+ve 571 (MHf
Example 16 -Cvclopropyl-3'-(4-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyllethyl)amino)hexyl1oxy)butyl)π .1'-biphenvπ-2-sulfonamide
i] terf-Butyl cvclopropy|({3'-r4-({6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-vn-2-oxo- 1 ,3-oxazolidin-3-yllhexyl)oxy)butyliπ ,1'-biphenyl1-2-yl)sulfonyl)carbamate Prepared using methods similar to those described in Example 10 vi) LCMS RT = 4.12 min.
ii] A/-Cvclopropyl-3'-(4-r(6-(f(2R -2-(2,2-dimethyl-4H-1.3-benzodioxin-6-vn-2- hvdroxyethyllamino>hexyπoxy1butyl)f1.1'-biphenyll-2-sulfonamide Prepared using methods similar to those described in Example 1 v) TLC [SiO2, dichloromethane - ethanol -0.88 ammonia (100:8:1)], Rf0.27
iii] Λ/-Cvclopropyl-3'-(4-{r6-({(2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenvnethyl)amino)hexynoxy>butyl)π ,1'-biphenvn-2-sulfonamide Was prepared using methods similar to those described in Examplel vi) LCMS RT = 2.75 min, ES+ve 611 (MHf.
Example 17
3'-(4-(r6-({(2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyllethyl)amino)hexyπoxy)butvθri ,1 '-biphenyll-2-sulfonamide acetate
i] ferf-Butyl (3'-f4-({6-f(5RV5-(2.2-dimethyl-4H-1 ,3-benzodioxin-6-vD-2-oxo-1 ,3-oxazolidin- 3-yl1hexyl)oxy)butvnπ ,1'-biphenvn-2-yl)sulfonyl{f2-(trimethylsilyl)ethoxy1methyl}carbamate Was prepared using methods similar to those described in Example 10 vi) LCMS RT = 4.47 min. π] 3' 4-r(6-(r(2R)-2-(2.2-Dimethyl-4 y-1.3-benzodioxin-6-yl)-2- hvdroxyethvnamino}hexyπoxylbutyl)-1.1'-biphenyl-2-sulfonamide
Was prepared using methods similar to those described in Example 1 v) LCMS RT = 2.80 min.
I] 3'-(4-(r6-({(2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hydroxymethyl)phenvHethyl}amino)hexyrioxy}butvDri ,1 '-biphenvπ-2-sulfonamide acetate Was prepared using methods similar to those described in Example 1 vi) LCMS RT = 2.56 min, ES+ve 571 (MH)+.
Example 18
3'-(4-{r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethvπphenvnethyl>amino)hexynoxy>butvππ .1'-biphenyl1-4-sulfonamide
i] 3'-r4-({6-f(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2-oxo-1.3-oxazolidin-3- vπhexyDoχy)butvπf1.1 '-biphenylH-sulfonamide
Was prepared using methods similar to those described in Example 10 vi) LCMS RT = 3.89 min.
ii] 3'-{4-r(6-{r(2R)-2-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroχvethvflamino)hexy0oxy1butylH1 , 1 '-biphenylH-sulfonamide
Was prepared using methods similar to those described in Example 1 v) LCMS RT = 3.05 min.
in] 3'-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenvπethyl)amino)hexyπoxy|butvOH ,r-biphenvn-4-sulfonamide acetate Was prepared using methods similar to those described in Example 1 vi) LCMS RT = 2.76 min, ES+ve 571 (MH+)
Example 19
3'-(4-(f6-(((2R)-2-Hvdroχy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyllethyl>amino)hexynoxy>butyl)-1 ,1 '-biphenyl-3-sulfonamide acetate
i] ferf-Butyl (3'-r4-(f6-r(5RV5-(2.2-dimethyl-4ry-1.3-benzodioxin-6-vn-2-oxo-1 ,3-oxazolidin- 3-vnhexyl}oxy)butvn-1 ,1'-biphenyl-3-yl>sulfonyl{r2-(trimethylsilyl)ethoxylmethyl)carbamate Was prepared using methods similar to those described in Example 17 i) LCMS RT = 4.76 min
M] 3'-{4-f(6-{f(2R)-2-(2.2-Dimethyl-4ry-1.3-benzodioxin-6-yl)-2- hvdroxyethvnamino)hexyπoxy1butyl>-1.1 '-biphenyl-3-sulfonamide
Was prepared using methods similar to those described in Example 1 v) LCMS RT = 3.29 min
Mi] 3'-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenvπethyl)amino)hexyπoxy)butvD-1.1 '-biphenyl-3-sulfonamide acetate Was prepared using methods similar to those described in Example 1 vi) LCMS RT = 2.50 min, ES+ve 571 (MHf.
Example 20 A/-r3'-(4-(r6-({(2R)-2-hvdroxy-2-r4-hvdroxy-3-
(hydroxymethvQphenvπethyl)amino)hexyrioxy)butv0-1.1 '-biphenyl-3-vπurea acetate
i] (5R)-5-(2,2-Dimethyl-4H-1 ,3-benzodioxin-6-v0-3-(6-r4-(3'-nitro-1.1 '-biphenyl-3- yl)butoxy1hexylV1.3-oxazolidin-2-one Prepared using methods similar to those described in Example 10 vi) LCMS RT = 4.25 min.
π] (5R)-3-{6-r4-(3'-Amino-1,1'-biphenyl-3-yl)butoxylhexyl>-5-(2.2-dimethyl-4ry-1.3- benzodioxin-6-yl)-1 ,3-oxazolidin-2-one A solution of (5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-{6-[4-(3'-nitro-1,1'-biphenyl- 3-yl)butoxy]hexyl}-1 ,3-oxazolidin-2-one (0.38 g) in ethanol (20ml) and ethyl acetate (20ml) was hydrogenated at room temperature and pressure in the presence of platinum oxide (50 mg) for 1 h. The catalyst was removed by filtration through celite and the filtrate evaporated to dryness to give the title compound as a clear oil (0.29 g). LCMS RT = 4.08 min.
ni] /V-(3'-r4-({6-r(5R)-5-(2.2-Dimethyl-4ry-1.3-benzodioxin-6-vπ-2-oxo-1.3-oxazolidin-3- yllhexyl}oxy)butyll-1 ,1 '-biphenyl-3-yl)urea
Sodium cyanate (39 mg) was added to a stirred solution of (5R)-3-{6-[4-(3'-amino-1,1'- biphenyl-3-yl)butoxy]hexyl}-5-(2,2-dimethyl-4/-/-1 ,3-benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (0.38g) in glacial acetic acid (2 ml) and water (2 ml) at room temperature. After 20 min the solution was poured into a phosphate buffer solution (pH 5, 25 ml) and extracted into dichloromethane. The extracts were dried and evaporated to give the title compound (160 mg). LCMS RT = 3.98 min.
iy] / -(3'-(4-r(6-(f(2RV2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2- hvdroxyethvnamino)hexyl)oxy1butyl)-1 ,1 '-biphenyl-3-yl)urea Prepared using methods similar to those described in Example 1 v) LCMS RT = 3.25 min.
y] A/-r3'-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethvπphenyllethyllamino)hexynoxy>butyl)-1.1'-biphenyl-3-vnurea acetate
Prepared using methods similar to those described in Example 1 vi) LCMS RT = 2.51 min, ES+ve 550 (MH+).
Example 21 Λ/-cvclopropyl-4'-(4-{f6-({(2R)-2-hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyl]ethyl)amino)hexyrioxy)butyl)-1 , 1 '-biphenyl-2-carboxamide
i] Methyl 4'-f4-({6-r(5RV5-(2.2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yllhexyl)oxy)butyll-1 ,1'-biphenyl-2-carboxylate Prepared using methods similar to those described in Example 10 vi TLC [SiO2, diethylether-Heptane (4:1)], Rf0.33.
ii] 4'-r4- 6-f(5RV5-(2,2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- yllhexyl)oxy)butyl1-1 ,1'-biphenyl-2-carboxylic acid A stirred mixture of methyl 4'-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-
1 ,3-oxazolidin-3-yl]hexyl}oxy)butyl]-1,1'-biphenyl-2-carboxylate (93 mg) in methanol (1ml) and 2M sodium hydroxide solution (1 ml) was heated at 80°C for 45 min. The mixture was cooled, poured into a phosphate buffer solution (pH 5) and extracted into ethyl acetate.
The extracts were washed with water, dried (Na2SO4) and evaporated. The residual oil was purified by chromatography on a biotage cartridge (4g) eluting with ether. The appropriate fractions were evaporated to give the title compound as a clear oil (62 mg)
TLC (SiO2, diethylether) Rf0.28.
iii] Λ/-cvclopropyl-4'-f4-({6-r(5RV5-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3- oxazolidin-3-vnhexyl}oxy)butvn-1 ,1 '-biphenyl-2-carboxamide A stirred mixture of 4'-[4-({6-[(5R)-5-(2,2-dimethyl-4ry-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3- oxazolidin-3-yl]hexyl}oxy)butyl]-1 ,1'-biphenyl-2-carboxylic acid (126 mg), 1-[ 3- (dimethylamino)propyl]-3~-ethyl carbodii ide hydrochloride (0.048g), 1- hydroxybenzotriazole (0.028g), triethylamine (0.67ml) and cyclopropylamine (0.067g) in dichloromethane (3ml) was left for 18 h. The mixture was then partitioned between dichloromethane and water. The organic extracts were dried (Na2SO4) and evaporated. The residual oil was purified by chromatography on a biotage cartridge (4g) eluting with ether-hexane (4:1). The fractions were evaporated to give the title compound as a clear oil (O.OTg) LCMS RT = 3.79 min.
iy] A/-cvclopropyl-4'-{4-r(6-{r(2R)-2-(2.2-dimethyl-4ry-1.3-benzodioxin-6-vn-2- hvdroxyethvnamino)hexyl)oxy1butyl)-1.1'-biphenyl-2-carboxamide
Prepared using similar methods to those described in Example 1 v) TLC [SiO2, dichloromethane - ethanol -0.88 ammonia (100:8:1)] Rf0.42.
y] Λ/-cvclopropyl-4'-(4-(f6-({(2R]-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenvπethyl)amino)hexyHoxy)butyl)-1 , 1 '-biphenyl-2-carboxamide Prepared using methods similar to those described in Example 1 vi LCMS RT = 2.68 min, ES+ve 575 (MH+).
Example 22
3'-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenvπethyl)amino)hexyπoxy)butyQ-1 ,1'-biphenyl-3-ol acetate
i] (5RV3-(6-(4-r3'-(Benzyloxy)-1.1 '-biphenyl-3-vnbutoxy hexyl)-5-(2,2-dimethyl-4H-1.3- benzodioxin-6-vπ-1.3-oxazolidin-2-one
Prepared using methods similar to those described in Example 10 vi LCMS RT = 4.41 min.
ii] (1 R)-2-r(6-(4-r3'-(Benzyloxy)-1.1 '-biphenyl-3-yllbutoxy}hexyl)amino1-1 -(2.2-dimethyl- 4H-1 ,3-benzodioxin-6-yl)ethanol Prepared using methods similar to those described in Example 1 v) LCMS RT = 3.65 min.
Hi] 4-1(1 R)-2-f(6-{4-f3'-(Benzyloxy)-1,1'-biphenyl-3-vnbutoxy)hexyl)amino1-1- hvdroxyethyl)-2-(hvdroxymethyl)phenol acetate Prepared using methods similar to those described in Example 1 vi) LCMS RT = 3.41 min.
]y] 3'-(4-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyl1ethyl}amino)hexyπoxy}butvD-1.1 '-biphenyl-3-ol acetate A solution of 4-{(1R)-2-[(6-{4-[3'-(benzyloxy)-1 ,1'-biphenyl-3-yl]butoxy}hexyl)amino]-1- hydroxyethyl}-2-(hydroxymethyl)phenol acetate (41 mg) in ethanol (5ml) was hydrogenated over 10% palladium on carbon (15 mg) for 1 h at room temperature. The catalyst was removed by filtration through celite and the filtrate evaporated to dryness to give the title compound as a clear oil (31 mg). LCMS RT = 2.95 min, ES+ve 508 (MH+).
Example 23
3'-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenvnethyl)amino)hexynoxy)butyl)-1 , 1 '-biphenyl-2-ol acetate
i] (5R)-3-(6-(4-r2'-(Benzyloxy)-1.1 '-biphenyl-3-yllbutoxy)hexyn-5-(2.2-dimethyl-4H-1.3- benzodioxin-6-yl)-1.3-oxazolidin-2-one
Prepared using methods similar to those described in Example 10 vi) LCMS RT = 4.30 min.
ii] 4-1(1 R 2-r(6-(4-r4'-(Benzyloxy)-1 ,1'-biphenyl-3-vnbutoχy>hexynamino1-1-hvdroxyethyl>- 2-(hydroxymethyl)phenol Prepared using methods similar to those described in Example 1 v) LCMS RT = 3.26 min.
in] 4-1(1 RV2-r(6-{4-r2'-(Benzyloxy)-1 , 1 '-biphenyl-3-vπbutoxy)hexyl)amino1-1 - hvdroxyethyl)-2-(hvdroxymethyl)phenol acetate
Prepared using methods similar to those described in Example 1 vi) LCMS RT = 3.07 min.
]y] 3'-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyl1ethyl|amino)hexyl1oxy)butyl)-1 ,1'-biphenyl-2-ol acetate Prepared using methods similar to those described in Example 22 iv) LCMS RT = 2.78 min, ES+ve 508 (MH+).
Example 24
3'-(4-{f6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl1ethyl}amino)hexylloxy}butyl)-1 ,1 '-biphenyl-4-ol acetate i] (5R 3-(6-(4-r4'-(Benzyloxy)-1.1'-biphenyl-3-vnbutoxy>hexyl)-5-(2.2-dimethyl-4H-1.3- benzodioxin-6-yl)-1 ,3-oxazolidin-2-one
Prepared using methods similar to those described in Example 10 vi) LCMS RT = 4.35 min.
ii] (1R)-2-r(6-f4-r4'-(Benzyloxy)-1.1'-biphenyl-3-yllbutoxy)hexyl)amino1-1-(2.2-dimethyl- 4H-1 ,3-benzodioxin-6-yl)ethanol
Prepared using methods similar to those described in Example 1 v) LCMS RT = 3.61 min.
Hi] 4-1(1 R -2-r(6-(4-r4'-(Benzyloxy)-1.1 '-biphenyl-3-yl1butoχy|hexyl)amino1-1 - hvdroxyethyl)-2-(hvdroxymethyl)phenol
Prepared using methods similar to those described in Example 1 vi) LCMS RT = 3.15 min.
iv] 3'-(4-(r6-({(2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenvπethyl)amino)hexyl1oxy}butyl)-1.1 '-biphenyl-4-ol acetate Prepared using methods similar to those described in Example 22 iv LCMS RT = 2.78, ES+ve 508 (MH+).
Example 25
2-(hvdroxymethyl)-4-((1 R)-1 -hvdroxy-2-r(6-{4-r2'-(1 H-tetraazol-5-yl)-1.1 '-biphenyl-4- vπbutoxy}hexyl)aminolethyl)phenol acetate
i] (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-3-(6-{4-r2'-(1-trityl-1rV-tetraazol-5-vn- 1 ,1'-biphenyl-4-vnbutoxy|hexyl)-1 ,3-oxazolidin-2-one
Prepared using methods similar to those described in Example 10 vi) LCMS RT = 4.56 min.
n] (1R)-1-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2-r(6-{4-r2'-(1-trityl-1H-tetraazol-5-yl)- 1 ,1 '-biphenyl-4-vπbutoxy)hexyl)amino1ethanol
Prepared using methods similar to those described in Example 1 v) TLC (SiO2) Rf 0.26 dichloromethane-ethanol- 0.88 ammonia (100:8:1). in] 2-(Hvdroxymethyl)-4-f (1 ffl-1 -hvdroxy-2-r(6-(4-r2'-(1 H-tetraazol-5-vn-1.1 '-biphenyl-4- yllbutoxylhexyDaminolethvDphenol acetate
Prepared using methods similar to those described in Example 1 vi) LCMS RT = 2.70 min, ES+ve 560 (MH+).
Example 26
2-Hvdroxy-5-r(1R)-1-hvdroxy-2-((6-r4-(3'-hvdroxy-1.1'-biphenyl-3- yl)butoxy1hexyl)amino)ethyl1phenylformamide with (2£)-but-2-enedioic acid (1 :1)
i] 2-(Benzyloxy)-5-{(1RV1-(benzyloxy)-2-r(6-(r4-(3'-bromo-1.1'-biphenyl-3-yl)but-3- vnvnoxy)hexyl)amino1ethyl)phenylformamide
A stirred solution of 5-((1R)-2-{benzyl[6-(but-3-ynyloxy)hexyl]amino}-1-hydroxyethyl)-2- (benzyloxy)phenylformamide (WO02/076933, 562 mg) 3-bromo-1-iodobenzene (435 mg), cuprous iodide (0.1g) and 1 ,1 bis(triphenylphosphine) palladium dichloride (0.1g) in DMF (10ml) and triethylamine (10ml) was left for 2 days at room temperature. The mixture was poured into water and extracted into ethyl acetate. The combined organic extracts were dried (Na2SO4) and evaporated. The residual oil was purified by chromatography on a biotage cartridge (40g) eluting with ether-ethyl acetate (9:1). The appropriate fractions were evaporated to give the title compound (21 mg). LCMS RT = 3.43 min.
π] 2-(BenzyloxyV5-((1R)-1-(benzyloxy)-2-{r6-({4-r3'-(benzyloxy)-1.1'-biphenyl-3-yllbut-3- vnyl)oxy)hexyπamino)ethyl)phenylformamide
A stirred solution of 2-(benzyloxy)-5-{(1R)-1-(benzyloxy)-2-[(6-{[4-(3'-bromo-1 ,1'-biphenyl-
3-yl)but-3-ynyl]oxy}hexyl)amino]ethyl}phenylformamide (0.27g), 3- (benzyloxy)phenylboronic acid (130 mg) and tetrakis(triphenylphosphine) palladium (0) (50 mg) in 1 ,2-dimethoxymethane (10 ml) and 1 M sodium carbonate solution (5 ml) was heated at 90 °C for 4 h. The mixture was poured into water and extracted into ethyl acetate. The combined extracts were washed with water, dried (Na2SO4) and evaporated. The residual oil was purified by chromatography on a biotage cartridge (40g) eluting with dichloromethane-ethanol-0.88 ammonia (100:8:1). The appropriate fractions were evaporated to give the title compound (0.15g). LCMS RT = 3.70 min.
in] 2-Hvdroxy-5-f(1 R)-1 -hvdroxy-2-α6-r4-(3'-hvdroxy-1 , 1 '-biphenyl-3- yl)butoxy1hexyl)amino)ethvnphenylformamide with (2E)-but-2-enedioic acid (1 :1 ) A stirred solution of 2-(benzyloxy)-5-((1R)-1-(benzyloxy)-2-{[6-({4-[3'-(benzyloxy)-1 ,1'- biphenyl-3-yl]but-3-ynyl}oxy)hexyl]amino}ethyl)phenylformamide (0.15g) in ethanol (10ml) and ethyl acetate (5ml) was hydrogenated over 10% palladium on carbon (0.03g) and palladium hydroxide on carbon (0.06g) for 18 h at 100 p.s.i. The catalysts were removed by filtration through celite and the filtrate was evaporated to dryness. The residual oil was purified by chromatography on a biotage cartridge (4g) eluting with dichloromethane- ethanol-0.88 ammonia (50:8:1). The appropriate fractions were evaporated and the residual oil was dissolved in methanol (10ml) and treated with fumaric acid (0.5 equivalents) and evaporated to dryness to give the title compound (0.027g). LCMS RT = 2.92 min, ES+ve 521 (MH+).
BIOLOGICAL ACTIVITY
The potencies of the aforementioned compounds were determined using frog melanophores transfected with the human beta 2 adrenoreceptor. The cells were incubated with melatonin to induce pigment aggregation. Pigment dispersal was induced by compounds acting on the human beta 2 adrenoreceptor. The beta 2 agonist activity of test compounds was assessed by their ability to induce a change in light transmittance across a melanophore monolayer (a consequence of pigment dispersal). At the human beta 2 adrenoreceptor, compounds of examples 1-26 had IC50 values below 1 μM.
Potency at other beta adrenoreceptor subtypes was determined using Chinese hamster ovary cells transfected with either the human beta 1 adrenoreceptor or the human beta 3 adrenoreceptor. Agonist activity was assessed by measuring changes in intracellular cyclic AMP.
The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims:

Claims

1. A compound of formula (I):
Ar1
Figure imgf000060_0001
or a salt, solvate, or physiologically functional derivative thereof, wherein:
m is an integer of from 2 to 8; n is an integer of from 3 to 7; with the proviso that m + n is 5 to 12;
R1 is selected from hydrogen, d-ealkyl, hydroxy, d_6 alkoxy, cyano, nitro, halo, d-ehaloalkyl, -XNR8C(O)R9, -XNR8C(O)NR9R10, -XNR8C(O)NC(O)NR9R10, -XNR8SO2R9, -XSO2NR9R10, XSR8, XSOR8, XSO2R8, -XNR9R10, -XNR8C(O)OR9, XNR8SO2NR9R10, XCO2R10, or -XC(O)NR9R10;
or R1 is selected from -X-aryl, -X-hetaryl, or -X-(aryloxy), each optionally substituted by 1 or 2 groups independently selected from hydroxy, d.6alkoxy, halo, d-ealkyl, d-ehaloalkyl, cyano, nitro, CONR9R10,
-NR8C(O)R9, SR8, SOR8, -SO2R8, -SO2NR9R10, -CO2R10, -NR9R10, or hetaryl optionally substituted by 1 or 2 groups independently selected from hydroxy, d.6alkoxy, halo, d-ealkyl, or d-ehaloalkyl;
X is -(CH2)r- or C2.6 alkenylene;
r is an integer from 0 to 6;
R8 and R9 are independently selected from hydrogen, d„6alkyl, C3.7cycloalkyl, aryl, hetaryl, hetaryl(Cι.6alkyl)- and aryl(d-ealkyl)- and R8 and R9 are each independently optionally substituted by 1 or 2 groups independently selected from halo, Chalky!, C3.7 cycloalkyl, Cι.6 alkoxy, C,.6haloalkyl, -NHC(O)(C1.6alkyl), -SO2(C1.6alkyl), -SO2(aryl), -CO2H, and -CO2(C^alkyl), -NH2, -NH(C1.6alkyl), aryl(C,.6alkyl)-, aryl(C2-6alkenyl)-, aryl(C2.6alkynyl)-, hetaryl(d.6alkyl)-, -NHSO2aryl, -NH(hetarylC1.6alkyl), -NHSO2hetaryl, -NHSO2(d.6alkyl), -NHC(O)aryl, or -NHC(O)hetaryl:
or where R1 is -XNR8C(O)NR9R10 , R8 and R9 may, together with the -NC(O)N- portion of the group R1 to which they are bonded, form a saturated or unsaturated ring;
or where R1 is -XNR8C(O)OR9, R8 and R9 may, together with the -NC(O)O- portion of the group R1 to which they are bonded, form a saturated or unsaturated ring;
R10 is selected from hydrogen, d_6alkyl and C3.7 cycloalkyl;
or where R contains a moiety -NR9R10 or R9 and R10 may, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring;
R2, R3, R6, and R7are independently selected from hydrogen, d^alkyl, d_4alkoxy, halo, and C-M haloalkyl;
R4 and R5 are independently selected from hydrogen and d.4 alkyl with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4.
Ar1 is a group selected from
Figure imgf000062_0001
and
Figure imgf000062_0002
(d) wherein R11 represents hydrogen, halogen, -(CH2)qOR15, -NR15C(O)R16, -NR15SO2R16, -SO2NR15R16, -NR15R16, -OC(O)R17 or OC(O)NR15R16, and R12 represents hydrogen, halogen or C1-4 alkyl;
or R11 represents -NHR18 and R12 and -NHR18 together form a 5- or 6- membered heterocyclic ring;
R1d represents hydrogen, halogen, -ORπo or-NR10R1 ;
R14 represents hydrogen, halogen, halod.4 alkyl, -OR15, -NR15 R16, -OC(O)R17 or OC(O)NR15R16;
R s1'6° and R16 each independently represents hydrogen or C1-4 alkyl, or in the groups -NR15R16, -SO2NR15R16 and -OC(O)NR15R16, R15 and R16 independently represent hydrogen or -4 alkyl or together with the nitrogen atom to which they are attached form a 5-, 6- or 7- membered nitrogen-containing ring,
R represents an aryl (eg phenyl or naphthyl) group which may be unsubstituted or substituted by one or more substituents selected from halogen, d-4 alkyl, hydroxy, C1-4 alkoxy or halo C-M alkyl; and
q is zero or an integer from 1 to 4.
2. A compound of formula (I) as defined in claim 1 , or a salt, solvate or physiologically functional derivative thereof, wherein R1 is selected from hydrogen, d-ealkyl, hydroxy, C,.6 alkoxy, cyano, nitro, halo, Cι„6haloalkyl, -XNR8C(O)R9, -XNR8C(O)NR9R10, -XNR8C(O)NC(O)NR9R10, -XNR8SO2R9, -XSO2NR9R10, XSR8, XSOR8, XSO2R8, -XNR9R10, -XNR8C(O)OR9, XNR8SO2NR9R10, XCO2R10, or -XC(O)NR9R10;
R11 is as defined above except that R11 is not hydrogen; and all other substituents are as defined for formula (I) above.
3. A compound according to claim 1 or claim 2 wherein R1 represents hydroxy, -XR8(CO)NR9R10, -XSO2NR9R10, -XCO2R10, XC(O)NR9R10 or X-hetaryl.
4. A compound according to any of claims 1 to 3 wherein R2 and R3 each represent hydrogen.
5. A compound according to any of claims 1 to 4 wherein R4 and R5 are independently selected from hydrogen and methyl.
6. A compound according to any of claims 1 to 5 wherein R6 and R7 are independently selected from hydrogen and methyl.
7. A compound according to any of claims 1 to 6 wherein m is suitably 3, 4, 5 or 6 and n is suitable 3, 4, 5 or 6.
8. A compound of formula (I) wherein Ar1 is a group of structure (a) or (b) as defined in claim 1.
9. A method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a selective β2-adrenoreceptor agonist is indicated, which comprises administration of a therapeutically effective amount of a compound of formula (I) according to any of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
10. A compound of formula (I) according to any of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for use in medical therapy.
11. A pharmaceutical formulation comprising a compound of formula (I) according to any of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.
12. The use of a compound of formula (I) according to any of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which a selective β2-adrenoreceptor agonist is indicated.
13. A process for the preparation of a compound of formula (I), according to any of claims 1 to 8, or a salt, solvate, or physiologically functional derivative thereof, which comprises:
(a) deprotection of a protected intermediate, for example of formula (II).
Figure imgf000064_0001
or a salt or solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7, m, and n are as defined for the compound of formula (I), Ar1a represents an optionally protected form of Ar1; and P1 and P2 are each independently either hydrogen or a protecting group, provided that the compound of formula (II) contains at least one protecting group;
(b) alkylation of an amine of formula (XV):
Figure imgf000065_0001
wherein Ar1a, P1 and P2 are as defined for formula (II); with a compound of formula (XIV):
L 1 C,Rn44nRS°(CH2)m (XIV)
Figure imgf000065_0002
wherein R1, R2, R3, R4, R5, R6, R7 m and n are as defined for formula (II) and L1 is as defined for formula (VIII);
followed by the following steps in any order:
(i) optional removal of any protecting groups; (ii) optional separation of an enantiomer from a mixture of enantiomers;
(iii) optional conversion of the product to a corresponding salt, solvate, or physiologically functional derivative thereof.
14. A compound of formula (II), (III) or (IV) as defined hereinabove.
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