WO2003024439A1 - Phenethanolamine derivatives for treatment of respiratory diseases - Google Patents

Phenethanolamine derivatives for treatment of respiratory diseases Download PDF

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Publication number
WO2003024439A1
WO2003024439A1 PCT/GB2002/004140 GB0204140W WO03024439A1 WO 2003024439 A1 WO2003024439 A1 WO 2003024439A1 GB 0204140 W GB0204140 W GB 0204140W WO 03024439 A1 WO03024439 A1 WO 03024439A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
ethoxy
amino
aryl
hydroxy
Prior art date
Application number
PCT/GB2002/004140
Other languages
French (fr)
Inventor
Philip Charles Box
Diane Mary Coe
Brian Edgar Looker
Panayiotis Alexandrou Procopiou
Inderjit Singh Mann
Original Assignee
Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0122201A external-priority patent/GB0122201D0/en
Priority claimed from GB0126997A external-priority patent/GB0126997D0/en
Priority to US10/489,569 priority Critical patent/US7361787B2/en
Priority to HU0401619A priority patent/HU228508B1/en
Priority to KR1020047003795A priority patent/KR100912324B1/en
Priority to CN02822325XA priority patent/CN1585633B/en
Priority to IL16059502A priority patent/IL160595A0/en
Priority to BRPI0212455A priority patent/BRPI0212455B8/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to BRPI0216127A priority patent/BRPI0216127B8/en
Priority to DE60230425T priority patent/DE60230425D1/en
Priority to DK02760407T priority patent/DK1425001T3/en
Priority to US13/719,797 priority patent/USRE44874E1/en
Priority to JP2003528536A priority patent/JP4191034B2/en
Priority to SI200230795T priority patent/SI1425001T1/en
Priority to MXPA04002405A priority patent/MXPA04002405A/en
Priority to CA2458534A priority patent/CA2458534C/en
Priority to NZ531651A priority patent/NZ531651A/en
Priority to EP02760407A priority patent/EP1425001B1/en
Priority to AU2002326026A priority patent/AU2002326026B2/en
Publication of WO2003024439A1 publication Critical patent/WO2003024439A1/en
Priority to IL160595A priority patent/IL160595A/en
Priority to NO20041041A priority patent/NO333813B1/en
Priority to HK04109440.3A priority patent/HK1066479A1/en
Priority to US11/566,346 priority patent/US7439393B2/en
Priority to US12/211,322 priority patent/US7776895B2/en
Priority to US12/836,025 priority patent/US7982067B2/en
Priority to US13/165,037 priority patent/US8198483B2/en
Priority to FR14C0028C priority patent/FR14C0028I2/en
Priority to NO2014007C priority patent/NO2014007I1/en
Priority to HUS1400025C priority patent/HUS1400025I1/en
Priority to BE2014C026C priority patent/BE2014C026I2/fr
Priority to CY2014019C priority patent/CY2014019I1/en
Priority to LU92439C priority patent/LU92439I2/en

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
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    • 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
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    • C07C217/76—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and etherified hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/32—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C271/38—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
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    • 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
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    • 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
    • C07C275/40—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 nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen 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
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
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    • C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

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.
  • R 1 is selected from hydrogen, C 1-6 aikyl, hydroxy, halo, C 1-6 haloalkyl, -XC(O)NR 9 R 10 , -XNR 8 C(O)R 9 , -XNR 8 C(O)NR 9 R 10 , -XNR 8 SO 2 R 9 , -XSO 2 NR 11 R 12 , XNR 8 SO 2 R 9 R 10 , -XNR 9 R 10 , XN + R 8 R 9 R 10 , -XNR 8 C(0)OR 9 , -XCO 2 R 9 , -XNR 8 C(O)NR 8 C(O)NR 9 R 10 , -XSR 9 , XSOR 9 , and -XSO 2 R 9 ; or R 1 is selected from -X-aryl, -X-hetaryl,
  • 1 or 2 groups independently selected from hydroxy, C 1-6 alkoxy, halo, C 1-6 alkyl, Cmhaloalkyl, -NHC(O)(C 1-6 alkyl), -SO 2 (C 1-6 alkyl), -SO 2 (aryl), -SO 2 NH 2 , -SO 2 NH(d. 6 alkyl), -SO 2 NH(C 3-7 cycloalkyl), -CO 2 H, -CO 2 (d. 6 alkyl), -SO 2 NH(C 3-7 cycloalkyld.6alkyl), -NH 2 , -NH(d. 6 alkyl), or hetaryl optionally substituted by 1 or 2 groups independently selected from hydroxy, C 1-6 alkoxy, halo, C 1-6 alkyl, or d. 6 haloalkyl;
  • X is -(CH 2 ) p - or C 2 . 6 alkenylene
  • p is an integer from 0 to 6, preferably 0 to 4;
  • R 8 and R 9 are independently selected from hydrogen, d. 6 alkyl, C 3-7 cycloalkyl, aryl, hetaryl, hetaryl(C 1-6 alkyl)- and aryl(C 1-6 alkyl)- and R 8 and R 9 are each independently optionally substituted by 1 or 2 groups independently selected from halo, C 1-6 alkyl, d. 6 haloalkyl, -NHC(O)(C 1-6 alkyl), -SO 2 (d -6 alkyl), -SO 2 (aryl), -CO 2 H, -CO 2 (C ⁇ alkyl),
  • -NH 2 -NH(C ⁇ _ 6 alkyl), aryl(C 1-6 alkyl)-, aryl(C 2-6 alkenyl)-, aryl(C 2-6 alkynyl)-, hetaryl(C 1-6 alkyl)-, -NHSO 2 aryl, -NH(hetarylC 1-6 alkyl), -NHSO 2 hetaryl, -NHSO 2 (C 1-6 alkyl), -NHC(O)aryl, or -NHC(O)hetaryl:
  • R 10 is selected from hydrogen, d. 6 alkyl and C 3 . 7 cycloalkyl
  • R 11 and R 2 are independently selected from hydrogen, C 1-6 alkyl, C 3 . 7 cycloalkyl, aryl, hetaryl, hetaryl(C ⁇ - ⁇ alkyl)- and ary d-ealkyl)-, or R 11 and R 12 , together with the nitrogen to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring; and R 1 and R 12 are each optionally substituted by one or two groups independently selected from halo, C h alky!, and d. 6 haloalkyl;
  • 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 or pyrimidine ring, such as imidazolidine-2,4-dione or pyrimidine -2, 4-dione;
  • R 1 is -XNR 8 C(0)OR 9
  • R 8 and R 9 may, together with the -NC(O)O- portion of the group R to which they are bonded, form a saturated or unsaturated ring, preferably a 5-
  • oxazolidine ring such as oxazolidine-2,4- dione
  • 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 is selected from hydrogen, hydroxy, C 1-6 alkyl, d -6 alkoxy, halo, aryl, aryl(C 1-6 alkyl)-, C ⁇ -6 haloalkoxy, and C 1-6 haloalkyl;
  • R 3 is selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halo, aryl, ary C ⁇ alkyl)-, C 1 . 6 haloalkoxy, and d. 6 haloalkyl;
  • R 4 and R 5 are independently selected from hydrogen and C 1-4 alkyl with the proviso that the total number of carbon atoms in R 4 and R 5 is not more than 4;
  • R 6 and R 7 are independently selected from hydrogen and C 1-4 alkyl with the proviso that the total number of carbon atoms in R 4 and R 5 is not more than 4.
  • R 6 and R 7 are preferably independently selected from hydrogen and methyl, more preferably R 6 and R 7 are both hydrogen.
  • n is suitably 2 or 3 and preferably n is 2.
  • R 1 , R 2 , R 3 , R 6 and R 7 are as defined above for formula (I) and m is 4 or 5.
  • the group R 1 is preferably attached to the para- or meta-position, and more preferably to the meta-position relative to the -OCR 6 R 7 - link.
  • the groups R 2 and R 3 are each independently preferably attached to the ortho- or meta- position, more preferably to the ortho position relative to the -OCR 6 R 7 - link.
  • R 1 represents a substituent as defined above, other than hydrogen, most preferably attached to the meta-position relative to the -OCR 6 R 7 -link, and R 2 and R 3 each represent hydrogen.
  • R 1 represents hydrogen and R 2 and R 3 each represent a substituent as defined above, at least one of which is other than hydrogen, and R 2 and R 3 are each independently attached to the ortho- or meta- positions relative to the -OCR 6 R 7 -link.
  • R 2 and R 3 each represent halogen they are preferably attached at the ortho positions and when R 2 and R 3 each represent methyl they are preferably attached at the meta positions.
  • R 1 is suitably selected from hydrogen
  • R 8 and R 10 suitably represent hydrogen.
  • R 9 suitably represents hydrogen, d. 6 alkyl, C 3-7 cycloalkyl, aryl, hetaryl or hetary d-ealkyl)-, any of which may be optionally substituted by C 1-6 alkyl, C 1-6 haloalkyl, -SO 2 (C ⁇ alkyl,), NH 2 , aryl (C ⁇ alkyl), aryl(C 2 . 6 alkynyl), NHSO 2 aryl, -NH(hetaryl(d. 6 alkyl), NHC(O)aryl or NHC(O)hetaryl.
  • R 11 and R 12 are suitably each independently selected from hydrogen, C 1-6 alkyl and
  • the term "5-, 6-, or 7- membered nitrogen containing ring” means a 5-, 6-, or 7- membered saturated or unsaturated ring which includes a nitrogen atom and optionally 1 or 2 other heteroatoms independently selected from nitrogen, sulphur, and oxygen. Suitable examples of such a ring include piperidinyl, morpholinyl, pyridyl, 2,4-dihydroxypyrimidinyl, and piperazinyl.
  • heteroaryl means a 5- to 10- membered heteroaromatic ring or bicyclic ring system which includes 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, such as thienyl, pyridyl, 2,4- dihydroxypyrimidinyl, 2,3-dihydroimidazo[2,1-b][1 ,3]thiazol-6-yl, or bipyridyl, preferably a 5- or 6-membered heteroaromatic ring.
  • aryl either alone or in the term “aryloxy” means a monocyclic or bicyclic aromatic ring system, such as phenyl, naphthyl, or biphenyl.
  • aryl means phenyl.
  • the group R is preferably selected from hydrogen, C 1-4 alkyl, hydroxy, halo, -NR 8 C(0)NR 9 R 10 , and -NR 8 SO 2 R 9 wherein R 8 and
  • R 9 are as defined above or more suitably wherein R 8 is hydrogen and R 9 is selected from hydrogen, d ⁇ alkyl, C 3-6 cycloalkyl, and aryl and is optionally substituted as described above.
  • R 8 and/or R 10 are suitably hydrogen.
  • R 2 and R 3 are preferably independently selected from hydrogen, halogen (eg. fluorine or more preferably chlorine), halo C 1-6 alkyl (eg. CF 3 ), d- 6 alkyl (eg. methyl) and phenyl or substituted phenyl (eg. p-methoxyphenyl).
  • halogen eg. fluorine or more preferably chlorine
  • halo C 1-6 alkyl eg. CF 3
  • d- 6 alkyl eg. methyl
  • phenyl or substituted phenyl eg. p-methoxyphenyl
  • R 4 and R 5 are preferably independently selected from hydrogen and methyl, more preferably R 4 and R 5 are both hydrogen.
  • Preferred compounds of the invention include:
  • Particularly preferred compounds of the invention include:
  • Particularly preferred compounds of the invention further include: 4- ⁇ (1 ?)-2-[(6- ⁇ 2-[(2,6-dichlorobenzyl)oxy]ethoxy ⁇ hexyl)amino]-1-hydroxyethyl ⁇ -2- (hydroxymethyl)phenol;
  • the compounds of formulae (I) and (la) 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.
  • R 4 and R 5 are different groups or where R 6 and R 7 are different groups
  • the carbon atom to which they are attached is an asymmetric centre and the present invention includes both (S) and (R) isomers at these centres either in substantially pure form or admixed in any proportions.
  • Salts and solvates of compounds of formulae (I) and (la) 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 formulae (I) and (la) and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives.
  • physiologically functional derivative is meant a chemical derivative of a compound of formula (I) or (la) having the same physiological function as the free compound of formula (I) or (la), for example, by being convertible in the body thereto.
  • physiologically functional derivatives include esters.
  • esters of the compounds of formula (I) and (la) may have a hydroxyl group converted to a C 1-6 alkyl, aryl, aryl C 1-6 alkyl, or amino acid ester.
  • 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, phenylacetic, substituted phenyl acetic eg.
  • 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.
  • preferred compounds of the invention such as 4- ⁇ (1f?)-2-[(6- ⁇ 2-[(2,6- dichlorobenzyl)oxy]ethoxy ⁇ hexyl)amino]-1-hydroxyethyl ⁇ -2-(hydroxymethyl)phenol are provided in the form of a crystalline salt, for example selected from those exemplified in the experimental section below.
  • Said crystalline salts have favourable physical properties such as low hygroscopicity and/or improved stability.
  • the compounds of formulae (I) and (la) 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. Furthermore, certain compounds have shown an improved therapeutic index in animal models relative to existing long-acting ⁇ 2 -agonist bronchodilators. In addition, compounds of the invention demonstrate pharmacokinetic properties that will reduce systemic exposure relative to existing long- acting beta2 agonist bronchodilators. As such, compounds of the invention may be suitable for once-daily administration. Therefore, compounds of formulae (I) and (la) 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 (eg. rhinitis, including seasonal and allergic rhinitis).
  • COPD chronic obstructive pulmonary diseases
  • rhinitis respiratory tract infection
  • upper respiratory tract disease eg. rhinitis, including seasonal and allergic rhinitis
  • 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.
  • skin diseases e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases
  • conditions where lowering peptic acidity is desirable e.g. peptic and gastric ulceration
  • muscle wasting disease e.g. peptic and gastric ulceration
  • 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 (la), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
  • a mammal such as a human
  • a selective ⁇ 2 - adrenoreceptor agonist is indicated
  • 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.
  • 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.
  • 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 compound of formula (I) or (la) 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 (la) 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 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 (la), 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 is desirable (e.g. peptic and gastric ulceration) and muscle wasting disease.
  • the amount of a compound of formula (I) or (la), 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 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 10 mg, preferably 0.005mg to 0.5mg.
  • the dose range for adult humans is generally from 0.0005 mg to 100mg per day and preferably 0.01 mg to 1 mg per day.
  • the present invention further provides a pharmaceutical formulation comprising a compound of formula (I) or (la) 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.
  • 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 anti-inflammatory agents, anticholinergic agents (particularly an M L M 2 , M I /M 2 or M 3 receptor antagonist), other ⁇ 2 -adrenoreceptor agonists, antiinfective agents (e.g. antibiotics, antivirals), or antihistamines.
  • anti-inflammatory agents for example anti-inflammatory agents, anticholinergic agents (particularly an M L M 2 , M I /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, an anti-inflammatory agent (for example a corticosteroid or an NSAID), an anticholinergic agent, another ⁇ 2 - adrenoreceptor agonist, an antiinfective agent (e.g. an antibiotic or an antiviral), or an antihistamine.
  • an anti-inflammatory agent for example a corticosteroid or an NSAID
  • an anticholinergic agent for example a corticosteroid or an NSAID
  • an antiinfective agent e.g. an antibiotic or an antiviral
  • Preferred 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.
  • 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, 6 ⁇ ,9oc
  • 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, and 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy- 16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester and 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, 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 PDE
  • leukotriene antagonists e.g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors
  • leukotriene antagonists inhibitors of leukot ene synthesis
  • iNOS inhibitors tryptase and elastase inhibitors
  • beta-2 integrin antagonists e.g. adenosine receptor agonists or antagonists
  • cytokine antagonists e.g. chemokine antagonists
  • 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
  • the preferred PDE4 inhibitors for 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 [ ⁇ HjR-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.
  • 2-pyrrolidone cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1 -carboxylic acid]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]; (R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; and
  • 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.
  • AWD-12-281 from Asta Medica (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); 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.
  • PDE-4 and mixed PDE3/PDE4 inhibitors include those listed in WO01/13953, the disclosure of which is hereby incorporated by reference.
  • Isolated human monocyte PDE4 and hrPDE human recombinant PDE4 was determined to exist primarily in the low affinity form.
  • the activity of test compounds against the low affinity form of PDE4 can be assessed using standard assays for PDE4 catalytic activity employing 1 ⁇ M [ 3 H]cAMP as a substrate (Torphy et a]., J. of Biol. Chem., Vol. 267, No. 3 pp1798-1804, 1992).
  • Rat brain high speed supernatants were used as a source of protein and both enantiomers of [ H]-rolipram were prepared to a specific activity of 25.6 Ci/mmol.
  • Standard assay conditions were modified from the published procedure to be identical to the PDE assay conditions, except for the last of the cAMP: 50mM Tris HCI (pH 7.5), 5 mM MgCl2, 50 ⁇ M 5'-AMP and 1 nM of [ 3 H]-rolipram (Torphy et_aj., J. of Biol. Chem., Vol. 267, No. 3 pp1798-1804, 1992).
  • the assay was run for 1 hour at 30° C. The reaction was terminated and bound ligand was separated from free ligand using a
  • PDE activity was assayed using a [ 3 H]cAMP SPA or [ 3 H]cGMP SPA enzyme assay as described by the supplier (Amersham Life Sciences).
  • the reactions were conducted in 96-well plates at room temperature, in 0.1 ml of reaction buffer containing (final concentrations): 50 mM Tris-HCI, pH 7.5, 8.3 mM MgCI 2 , 1.7 mM EGTA, [ 3 H]cAMP or
  • [ 3 H] cGMP (approximately 2000 dpm/pmol), enzyme and various concentrations of the inhibitors.
  • the assay was allowed to proceed for 1 hr and was terminated by adding 50 ⁇ l of SPA yttrium silicate beads in the presence of zinc sulfate. The plates were shaken and allowed to stand at room temperature for 20 min. Radiolabeled product formation was assessed by scintillation spectrometry.
  • the assay was performed at 30°C for 1 hr in 0.5 ⁇ l buffer containing (final concentrations): 50 mM Tris-HCI, pH 7.5, 5 mM MgCI 2 , 0.05% bovine serum albumin, 2 nM [ 3 H]R- rolipram (5.7 x 104 dpm/pmol) and various concentrations of non-radiolabeled inhibitors.
  • the reaction was stopped by the addition of 2.5 ml of ice-cold reaction buffer (without
  • Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptor, in particular those compounds which are antagonists of the M ⁇ 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-51-48-1 (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 Robotul
  • isopropamide iodide CAS-71-81-8
  • mepenzolate bromide U.S. patent 2,918,408
  • tridihexethyl chloride Pathilone, CAS-4310-35-4
  • hexocycliu methylsulfate Tral, CAS-115-
  • 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 chlropheniramine 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 Hi 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.
  • 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.
  • active ingredient means a compound of formula (I) or (la), 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 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 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, bacte ostats 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 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.
  • Formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier substance) such as lactose or starch. Use of lactose is preferred.
  • Carrier substance such as lactose or starch.
  • lactose lactose or starch.
  • 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.
  • the formulation can be pre-metered (eg as in Diskus, see GB 2242134 or Diskhaler, see GB 2178965, 2129691 and 2169265) or metered in use (eg as in Turbuhaler, see EP 69715).
  • An example of a unit-dose device is Rotahaler (see GB 2064336).
  • 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. 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.
  • 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
  • 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
  • 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 nebulisation 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.
  • a process for preparing a compound of formula (I) or (la) or a salt, solvate, or physiologically functional derivative thereof which comprises a process as described below followed where necessary or desired by one or more of the following steps in any order:
  • a compound of formula (I) or (la) may be obtained by deprotection of a protected intermediate, for example of formula (II):
  • R 4 , R 5 , R 6 , R 7 , m, and n are as defined for the compound of formula (I) or (la)
  • R 1a , R 2a , and R 3a are each independently either the same as R 1 , R 2 , and R 3 respectively as defined for the compound of formulae (I) or (la) or a precursor for said group
  • R 1 , R 2 , or R 3 , and R 13 , R 14 , and R 15 are each independently either hydrogen or a protecting group provided that at least one of R 3 , R 14 , and R 15 is a protecting group, and R 19 is hydrogen or a protecting group.
  • Suitable protecting groups may be any conventional protecting group such as those described in “Protective Groups in Organic Synthesis” by Theodora W Greene and
  • Examples of suitable hydroxyl protecting groups represented by R 13 and R 4 are esters such as acetate ester, aralkyl groups such as benzyl, diphenylmethyl, or triphenylmethyl, and tetrahydropyranyl.
  • Examples of suitable amino protecting groups represented by R 15 include benzyl, ⁇ - methylbenzyl, diphenylmethyl, triphenylmethyl, benzyloxycarbonyl, tert-butoxycarbonyl, and acyl groups such as t chloroacetyl 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 CHOR 19 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
  • deprotection to yield a compound of formula (I) or (la) may be effected using conventional techniques. It will be apparent to persons skilled in the art that the deprotection method employed should not effect cleavage of the -OCR 6 R 7 moiety.
  • R 13 and/or R 14 When R 13 and/or R 14 is tetrahydropyranyl this may be cleaved by hydrolysis under acidic conditions, for example using aqueous acetic acid.
  • Acyl groups represented by R 15 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 (see above).
  • R 13 and R 14 may together represent a protecting group as in the compound of formula (III):
  • R 4 , R 5 , R 6 , R 7 , m, and n are as defined for the compound of formula (I) or (la)
  • R 1a , R 2a , and R 3a are each independently either the same as R 1 , R 2 , and R 3 respectively as defined for the compound of formulae (I) or (la) or a precursor for said group
  • R 1 , R 2 , or R 3 , R 16 and R 17 are independently selected from hydrogen, d. 6 alkyl, or aryl. In a preferred aspect, both R 16 and R 17 are methyl.
  • a suitable precursor group R 1a , R 2a , and/or R 3a in the compounds of formulae (II) and (III) would be a group which is convertible to the desired group R 1 , R 2 , and/or R 3 , before, after or simultaneously with the removal of the protecting groups R 13 , R 14 , and/or R 15 .
  • R 1a , R 2a , and/or R 3a may suitably be a protected version of a group R 1 , R 2 , and R 3 respectively, such that removal of the protecting group gives the desired group R 1 , R 2 , or R 3 .
  • Preferred protecting groups in R 1a , R 2a , and/or R 3a are those which may be removed under the conditions used for the removal of the protecting groups R 13 , R 14 , and/or R 15
  • the compound of formula (III) may be converted to a compound of formula (I) or (la) 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.
  • R 4 , R 5 , R 6 , R 7 , R 3 , R 14 , m, and n are as defined for the compound of formula (II) or (III) and R 1a , R 2a , and R 3a are each independently either the same as R 1 , R 2 , and R 3 respectively as defined for the compound of formula (II) or (III) or a precursor for said group R 1 , R 2 , or R 3 .
  • a suitable precursor group R 1a , R 2a , and/or R 3a in the compound of formula (IV) would be a group which is convertible to the desired group R 1 , R 2 , and/or R 3 .
  • conversions are carried out using conventional methods which are known in the art.
  • R 1 is to be -NR 8 SO 2 R 9
  • a suitable precursor group R a in the compound of formula (IV) would have the amine -NHR 8 in place of the substituent R 1 , such that the desired substituent R 1 may be formed by reaction with the appropriate sulphonyl chloride (i.e. R 9 SO 2 CI) before deprotection to form the compound of formula (I).
  • R 1 is to be -NR 8 C(O)NHR 9
  • a suitable precursor group R 1a in the compound of formula (IV) would have the amine -NHR 8 in place of the substituent R 1 , such that the desired substituent R 1 may be formed by reaction with the appropriate isocyanate (i.e. R 9 NCO) before deprotection to form the compound of formula (I).
  • a suitable precursor group R 1a in the compound of formula (IV) has -NO 2 in place of the substituent R 1 which may be reduced to form the corresponding primary amine before reaction with the isocyanate R 9 NCO as described above to form the desired urea substituent R 1 .
  • the reduction of the -NO 2 group may be effected by any suitable method such as hydrogenation in the presence of a catalyst, for example, palladium/charcoal or platinum oxide, or by reaction with aluminium amalgam in tetrahydrofuran, or with zinc in ammonium chloride solution.
  • R 1 is to be -NR 8 C(O)R 9
  • a suitable precursor group R 1a in the compound of formula (IV) would have the amine -NHR 8 in place of the substituent
  • R 1 such that the desired substituent R 1 may be formed by reaction with the appropriate acyl chloride (i.e. R 9 C(O)CI) before deprotection to form the compound of formula (I).
  • R 9 C(O)CI acyl chloride
  • R 1 is to be -NR 8 C(O)OR 9
  • a suitable precursor group R 1a in the compound of formula (IV) would have the amine -NHR 8 in place of the substituent
  • R 1 such that the desired substituent R 1 may be formed by reaction with the appropriate chloroformate (i.e. R 9 OC(O)CI) before deprotection to form the compound of formula (I).
  • R 9 OC(O)CI
  • R 1 is to be an optionally substituted aryl group
  • a suitable precursor group R 1a in the compound of formula (IV) would have a halo substituent, for example iodo, in place of the substituent R 1 , such that the desired substituent R 1 may be formed by reaction with bis(pinacolato)diboron followed by reaction with the appropriate optionally substituted haloaryl group, before deprotection to form the compound of formula (I).
  • R is to be an optionally substituted aryl group
  • a suitable precursor group R 1a in the compound of formula (IV) would have a halo substituent, for example iodo, in place of the substituent R 1 , such that the desired substituent R 1 may be formed by reaction with the appropriate optionally substituted arylboronic acid, for example an optionally substituted phenylboronic acid, before deprotection to form the compound of formula (I).
  • R 1a , R 2a , and/or R 3a may suitably be a protected version of a group R 1 , R 2 , and R 3 respectively, such that removal of the protecting group gives the desired group R 1 , R 2 , or R 3 .
  • Preferred protecting groups in R 1a , R 2a , and/or R 3a are those which may be removed under the conditions used for the removal of the protecting groups R 13 and R 14 , or the conditions used for the conversion of the compound of formula (IV) to the compound of formulae (II) or (III).
  • an -NH- group in the desired group R 1 , R 2 , or R 3 may be protected by a 2-(trimethylsilyl)ethoxymethyl group or a tert- butoxycarbonyl group.
  • 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.
  • R 1a , R 2a ,R 3a ,R 4 , R 5 , R 6 , R 7 , m, and n are as defined for the compound of formula (IV) and L 1 is a leaving group, for example a halo group (typically bromo or iodo) or a sulphonate such as an alkyl sulphonate (typically, methanesulphonate), an arylsulphonate (typically, toluenesulphonate), or a haloalkyl sulphonate (typically, trifluoromethanesulphonate).
  • a halo group typically bromo or iodo
  • a sulphonate such as an alkyl sulphonate (typically, methanesulphonate), an arylsulphonate (typically, toluenesulphonate), or a haloalkyl sulphonate (typically, trifluorome
  • the coupling of a compound of formula (V) with a compound of formula (VI) may be effected in the presence of a base, such as a metal hydride, for example sodium hydride, anathoride such as potassium t-butoxide or an inorganic base such as caesium carbonate, in an aprotic solvent, for example dimethylformamide.
  • a base such as a metal hydride, for example sodium hydride, anathoride such as potassium t-butoxide or an inorganic base such as caesium carbonate
  • R 13 and R 14 are as defined for the compound of formula (V) and R 18 is C 1-6 alkyl, for example tert-butyl, or aryl, for example phenyl.
  • the ring closure may be effected by treatment with a base, such as a metal hydride, for example sodium hydride, in the presence of an aprotic solvent, for example, dimethylformamide.
  • R 13 , R 14 and R 18 are as defined for the compound of formula (VII), by reduction by any suitable method, for example by treatment with borane, in the presence of a chiral catalyst, such as CBS-oxazaborolidine, in a suitable solvent such as tetrahydrofuran.
  • a chiral catalyst such as CBS-oxazaborolidine
  • the compound of formula (VIII) may be prepared from the corresponding halide of formula (IX):
  • R 13 and R 14 are as defined for the compound of formula (VIII) and Y is a halo group, suitably bromo.
  • the conversion of a compound of formula (IX) to a compound of formula (VIII) may be effected by reaction with the protected amine HN(COOR 18 ) 2 wherein R 18 is as defined for the compound of formula (VIII) in the presence of an inorganic base such as caesium carbonate, followed by selective removal of one of the COOR 8 groups, for example by treatment with an acid such as trifluoroacetic acid.
  • an inorganic base such as caesium carbonate
  • Compounds of formula (IX) may be prepared from the corresponding compound having free hydroxymethyl and hydroxy substituents by forming the protected groups R 13 OCH 2 - and R 14 O- wherein R 13 and R 14 are as defined for the compound of formula (IX). Such methods are described in DE 3513885 (Glaxo).
  • R a , R 2a ,R 3a ,R 6 , R 7 , and n are as defined for the compound of formula (VI), with a compound of formula (XI):
  • R 4 , R 5 , and m are as defined for the compound of formula (VI), and L 2 is a leaving group such as halo (typically bromo).
  • the coupling of compounds (X) and (XI) may be effected in the presence of a base, such as a metal hydride, for example sodium hydride, or an inorganic base such as caesium carbonate, in an aprotic solvent, for example dimethylformamide.
  • a base such as a metal hydride, for example sodium hydride, or an inorganic base such as caesium carbonate
  • an aprotic solvent for example dimethylformamide.
  • the coupling of compounds (X) and (XI) may be effected under phase transfer conditions, suitably in excess aqueous alkali such as 50% aqueous sodium hydroxide, optionally in the presence of a phase transfer catalyst such as a tetrabutylammonium salt, for example tetrabutylammonium bromide.
  • R 1a , R 2a , R 3a , R 6 , and R 7 are as defined for the desired compound of formula
  • (X), and L 3 is a leaving group such as halo (typically bromo);
  • a compound of formula (IV) as defined above may be prepared by coupling the corresponding compound of formula (XIII):
  • R 4 , R 5 , R 13 , R 14 , m, and n are as defined for the desired compound of formula (IV), with the corresponding compound of formula (XII) as defined above in which R 1a , R 2a , R 3a , R 6 , and R 7 are as defined for the desired compound of formula (IV) and L 3 is a leaving group such as halo (typically bromo).
  • This coupling may be effected by methods analogous to those described for the coupling of compounds (X) and (XI).
  • compounds of formula (XIII) may be prepared by coupling the corresponding compound of formula (XV):
  • R 13 , R 14 , R 4 , R 5 , and m are as defined for the desired compound of formula (XIII) and L 2 is a leaving group such as halo (typically bromo), followed by coupling the compound of formula (XV) with the dihydroxy compound of formula HO(CH 2 ) n OH, wherein n is as defined for the desired compound of formula (XIII), by methods analogous to those described for the coupling of compounds of formula (X) and (XI).
  • the compound of formula (XV) may be prepared by coupling the corresponding compound of formula (V) as previously defined wherein R 13 and R 14 are as defined for the desired compound of formula (XIII), with the corresponding compound of formula (XI) as previously defined wherein R 4 , R 5 , and m are as defined for the desired compound of formula (XIII) and L 2 is a leaving group such as halo (typically bromo).
  • R 13 , R 14 , R 4 , R 5 , m and n are as defined for the compound of formula (IV) and L 5 is a leaving group, for example a sulphonate such as an alkyl sulphonate (typically, methanesulphonate), an arylsulphonate (typically, toluenesulphonate), or a haloalkyl sulphonate (typically, trifluoromethanesulphonate), with a compound of formula (XVII):
  • a sulphonate such as an alkyl sulphonate (typically, methanesulphonate), an arylsulphonate (typically, toluenesulphonate), or a haloalkyl sulphonate (typically, trifluoromethanesulphonate):
  • R a , R 2a , R 3a , R 6 , and R 7 are as defined for the compound of formula (IV).
  • the compound of formula (XVI) may be prepared by converting the hydroxyl group in a compound of formula (XIII) into a leaving group L 4 such as a methansulphonate group using methods known in the art, for example by reaction with methanesulphonyl chloride in the presence of a suitable base, for example NEt('Pr) 2 , in a suitable solvent such as dichloromethane.
  • a suitable base for example NEt('Pr) 2
  • a suitable solvent such as dichloromethane.
  • R 13 , R 14 , R 4 , R 5 , and m are as defined for formula (IV) and L 2 is defined as for formula (XI), with a compound of formula (X) as defined above.
  • the reaction of compounds (XVIII) and (X) may be effected in a similar manner to the coupling of compounds (XI) and (X).
  • Compounds of formula (XVIII) may be prepared by reacting a compound of formula (V) with a compound of formula (XI) in a similar manner to the reaction of compounds (V) and (XIV).
  • reaction of compounds of formulae (XIX) and (VI) may be optionally effected in the presence of an organic base, such as a trialkylamine, for example diisopropyl ethylamine, and in a suitable solvent, for example dimethyformamide.
  • organic base such as a trialkylamine, for example diisopropyl ethylamine
  • suitable solvent for example dimethyformamide
  • a compound of formula (I) or (la) may be prepared by reacting an amine of formula (XIX) as defined hereinabove, with a compound of formula (XX):
  • R 4 , R 6 , R 7 , R 1a , R 2a , R 3a , m and n are as hereinbefore defined; under conditions suitable to effect reductive amination, for example in the presence of a reducing agent such as borohydride, typically tetramethylammonium (triacetoxy) borohydride.
  • a reducing agent such as borohydride, typically tetramethylammonium (triacetoxy) borohydride.
  • a compound of formula (XX) may be prepared by methods known in the art, for example from a compound of formula (VI) as defined hereinabove via Kornblum oxidation.
  • the enantiome c 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 herein.
  • Optional conversion of a compound of formula (I) or (la) to a corresponding salt may conveniently be effected by reaction with the appropriate acid or base.
  • Optional conversion of a compound of formula (I) or (la) 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) or (la), for example: compounds of formula (II) and (III) as defined above, or an optical isomer, a salt, or a protected derivative thereof; particularly, a compound selected from:
  • LCMS Liquid Chromatography Mass Spectrometry
  • MIBK methyl-isobutylketone
  • PE petroleum ether 40 °-60°
  • Ammonia refers to 0.880 (aqueous) ammonia.
  • 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.
  • SCX refers to prepacked SPE cartridges containing benzenesulphonic acid ion exchange resin.
  • LC was conducted on a Luna 3 ⁇ m C18(2) column (50mm x 2mm id) eluting with 0.05% v/v trifiuoroacetic acid in water (solvent A) and 0.05% v/v trifiuoroacetic acid in acetonitrile (solvent B) using the elution gradient 0-8.0 min 0%B-95%B, 8.0-8.01 min 95%B-0%B, with a flow rate of 1ml_/min with a column temperature of 40°C.
  • the XRPD analysis shown in the Figures were performed on a Phillips X pert Prop powder diffractometer, Model PW3040/60, serial number DY1379. The method runs from 2 to 45 degrees 2Theta with 0.02 degree 2Theta step size and a 2 second collection time at each step.
  • Potassium trimethylsilanolate (0.056g) was added to a solution of N-(3- ⁇ [2-( ⁇ 6-[(5R)-5- (2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3-yl]hexyl ⁇ oxy)- ethoxy]methyl ⁇ phenyl)-N'-phenylurea (0.061g) in degassed anhydrous THF (4ml) whilst stirring under nitrogen. The reaction mixture was heated to 65°C for 4 h, adding additional potassium trimethylsilanolate (0.057g) and heating for a further 2.5h, at which point the reaction mixture was cooled to room temperature.
  • Potassium trimethylsilanolate (0.177g) was added to a solution of ⁇ /-cyclohexyl-/V-(3- ⁇ [2-( ⁇ 6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- yl]hexyl ⁇ oxy)ethoxy]methyl ⁇ phenyl)urea (0.207g) in deoxygenated anhydrous THF (6ml) whilst stirring under nitrogen. The reaction mixture was heated to 65°C for 4.5h, at which point the reaction mixture was cooled to room temperature.
  • Example 17 4-1(1 R)-1-Hvdroxy-2-f(6-(2-r(3-hvdroxybenzvnoxylethoxy hexyl)aminolethyll-2-
  • the title compound was prepared by a procedure similar to that described in example 21 vii). It was purified using Prep. TLC (silica, 1 mm thick, 20x20cm) eluting with DCM-
  • the title compound was prepared by a procedure similar to that described in example 70 i) purified using Biotage eluting with EtOAc-PE (3:1 ).
  • Example 78 Salts of 4-((R)-2-(6-r2-(2.6-Dichlorobenzyloxy)-ethoxyl-hexylamino -1 -hvdroxyethyl)-2- hvdroxymethyl-phenol
  • Triphenylacetic acid (1.81g, 1eq) was added to a solution of 4-((R)-2- ⁇ 6-[2-(2,6- dichlorobenzyloxy)-ethoxy]-hexylamino ⁇ -1-hydroxyethyl)-2-hydroxymethyl-phenol
  • 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 and 4 to 82 had IC 50 values below 1 ⁇ M.
  • Potency at human betal and beta3 adrenoceptors was determined in functional studies using Chinese hamster ovary cells transfected with either the human betal adrenoceptor or the human beta3 adrenoceptor. Agonist activity was assessed by measuring changes in intracellular cyclic AMP. For particularly preferred compounds of the invention, selectivity for beta2 adrenoceptors over betal adrenoceptors was typically 10 fold or greater. Selectivity for beta2 adrenoceptors over beta3 adrenoceptors was typically 5 fold or greater.
  • onset was typically less than
  • Particularly preferred compounds of the invention are potent and long-acting inhibitors of histamine-induced bronchospasm in conscious guinea pigs. They also demonstrate an improved therapeutic index in conscious guinea pigs (bronchoprotective effects vs blood pressure lowering effects) relative to established long-acting beta2 agonist bronchodilators.
  • the particularly preferred compounds of the invention show low oral bioavailability in rat and dog. In human hepatocyte cultures they are metabolised to products that are significantly less potent at the beta2 adrenoceptor than the parent compound.

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

PHENETHANO AMINE DERIVATIVES FOR 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 maximum duration of action is 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)
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 2 to 5; with the proviso that m + n is 4 to 10; R1 is selected from hydrogen, C1-6aikyl, hydroxy, halo, C1-6haloalkyl, -XC(O)NR9R10, -XNR8C(O)R9, -XNR8C(O)NR9R10, -XNR8SO2R9, -XSO2NR11R12, XNR8SO2R9R10, -XNR9R10, XN+R8R9R10, -XNR8C(0)OR9, -XCO2R9, -XNR8C(O)NR8C(O)NR9R10, -XSR9, XSOR9, and -XSO2R9; or R1 is selected from -X-aryl, -X-hetaryl, and -X-(aryloxy), each optionally substituted by
1 or 2 groups independently selected from hydroxy, C1-6alkoxy, halo, C1-6alkyl, Cmhaloalkyl, -NHC(O)(C1-6alkyl), -SO2(C1-6alkyl), -SO2(aryl), -SO2NH2, -SO2NH(d.6alkyl), -SO2NH(C3-7cycloalkyl), -CO2H, -CO2(d.6alkyl), -SO2NH(C3-7cycloalkyld.6alkyl), -NH2, -NH(d.6alkyl), or hetaryl optionally substituted by 1 or 2 groups independently selected from hydroxy, C1-6alkoxy, halo, C1-6alkyl, or d.6haloalkyl;
X is -(CH2)p- or C2.6 alkenylene;
p is an integer from 0 to 6, preferably 0 to 4;
R8and R9 are independently selected from hydrogen, d.6alkyl, C3-7cycloalkyl, aryl, hetaryl, hetaryl(C1-6alkyl)- and aryl(C1-6alkyl)- and R8 and R9 are each independently optionally substituted by 1 or 2 groups independently selected from halo, C1-6alkyl, d.6haloalkyl, -NHC(O)(C1-6alkyl), -SO2(d-6alkyl), -SO2(aryl), -CO2H, -CO2(C^alkyl),
-NH2, -NH(Cι_6alkyl), aryl(C1-6alkyl)-, aryl(C2-6alkenyl)-, aryl(C2-6alkynyl)-, hetaryl(C1-6alkyl)-, -NHSO2aryl, -NH(hetarylC1-6alkyl), -NHSO2hetaryl, -NHSO2(C1-6alkyl), -NHC(O)aryl, or -NHC(O)hetaryl:
R10 is selected from hydrogen, d.6alkyl and C3.7 cycloalkyl;
R11 and R 2are independently selected from hydrogen, C1-6alkyl, C3.7cycloalkyl, aryl, hetaryl, hetaryl(Cι-δalkyl)- and ary d-ealkyl)-, or R11 and R12 , together with the nitrogen to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring; and R1 and R12are each optionally substituted by one or two groups independently selected from halo, Chalky!, and d.6haloalkyl;
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 or pyrimidine ring, such as imidazolidine-2,4-dione or pyrimidine -2, 4-dione;
where R1 is -XNR8C(0)OR9, R8 and R9 may, together with the -NC(O)O- portion of the group R 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;
where R is -XC(O)NR9R10 or -XNR8C(O)NR9R10 , R9 and R10 may, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring;
R2 is selected from hydrogen, hydroxy, C1-6alkyl, d-6alkoxy, halo, aryl, aryl(C1-6alkyl)-, Cι-6haloalkoxy, and C1-6 haloalkyl;
R3 is selected from hydrogen, hydroxy, C1-6alkyl, C1-6alkoxy, halo, aryl, ary C^alkyl)-, C1.6haloalkoxy, and d.6haloalkyl;
R4 and R5 are independently selected from hydrogen and C1-4 alkyl with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4; and,
R6 and R7 are independently selected from hydrogen and C1-4alkyl with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4.
In the compounds of formula (I) and (la), R6 and R7 are preferably independently selected from hydrogen and methyl, more preferably R6 and R7 are both hydrogen.
In the compounds of formula (I), is suitably 4, 5 or 6, more suitably 4 or 5 and preferably ,5 and n is suitably 2 or 3 and preferably n is 2.
According to a preferred aspect of the invention, there is provided a compound of formula (la)
Figure imgf000005_0001
or a salt, solvate, or physiologically functional derivative thereof, wherein R1, R2, R3, R6 and R7 are as defined above for formula (I) and m is 4 or 5.
In the compounds of formulae (I) and (la), the group R1 is preferably attached to the para- or meta-position, and more preferably to the meta-position relative to the -OCR6R7- link. The groups R2 and R3 are each independently preferably attached to the ortho- or meta- position, more preferably to the ortho position relative to the -OCR6R7- link.
In one preferred embodiment R1 represents a substituent as defined above, other than hydrogen, most preferably attached to the meta-position relative to the -OCR6R7-link, and R2 and R3 each represent hydrogen.
In another preferred embodiment R1 represents hydrogen and R2 and R3 each represent a substituent as defined above, at least one of which is other than hydrogen, and R2 and R3 are each independently attached to the ortho- or meta- positions relative to the -OCR6R7-link. In a particular embodiment, when R2 and R3 each represent halogen they are preferably attached at the ortho positions and when R2 and R3 each represent methyl they are preferably attached at the meta positions.
In the compounds of formulae (I) and (la) R1 is suitably selected from hydrogen,
Cι-6alkyl, hydroxy, halo, d.6haloalkyl, -XNR8(C)OR9, -XNR8C(O)NR9R10, -XNR8SO2R9, -XSO2NR11R12, -XNR9R10, -XNR8C(O)OR9, XSR9, XSOR9, XSO2R9, or from X-aryl, X- hetaryl or X-aryloxy, optionally substituted as defined above. X is suitably (CH2)P wherein p is preferably zero.
R8and R10 suitably represent hydrogen.
R9 suitably represents hydrogen, d.6alkyl, C3-7cycloalkyl, aryl, hetaryl or hetary d-ealkyl)-, any of which may be optionally substituted by C1-6alkyl, C1-6haloalkyl, -SO2(C^alkyl,), NH2, aryl (C^alkyl), aryl(C2.6alkynyl), NHSO2aryl, -NH(hetaryl(d.6alkyl), NHC(O)aryl or NHC(O)hetaryl.
R11 and R12 are suitably each independently selected from hydrogen, C1-6alkyl and
C3-7cycloalkyl.
In the definition of R1, the term "5-, 6-, or 7- membered nitrogen containing ring" means a 5-, 6-, or 7- membered saturated or unsaturated ring which includes a nitrogen atom and optionally 1 or 2 other heteroatoms independently selected from nitrogen, sulphur, and oxygen. Suitable examples of such a ring include piperidinyl, morpholinyl, pyridyl, 2,4-dihydroxypyrimidinyl, and piperazinyl.
In the definition of R1, the term "hetaryl" means a 5- to 10- membered heteroaromatic ring or bicyclic ring system which includes 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, such as thienyl, pyridyl, 2,4- dihydroxypyrimidinyl, 2,3-dihydroimidazo[2,1-b][1 ,3]thiazol-6-yl, or bipyridyl, preferably a 5- or 6-membered heteroaromatic ring.
As used herein, the term "aryl" either alone or in the term "aryloxy" means a monocyclic or bicyclic aromatic ring system, such as phenyl, naphthyl, or biphenyl. Preferably the term "aryl" means phenyl.
In the compounds of formulae (I) and (la), the group R is preferably selected from hydrogen, C1-4alkyl, hydroxy, halo, -NR8C(0)NR9R10, and -NR8SO2R9 wherein R8and
R9are as defined above or more suitably wherein R8 is hydrogen and R9 is selected from hydrogen, d^alkyl, C3-6cycloalkyl, and aryl and is optionally substituted as described above. In the compounds of formulae (I) and (la) wherein the group R1 is substituted by R8 and/or R10, R8 and/or R10 are suitably hydrogen.
In the compounds of formula (I) and (la) R2 and R3 are preferably independently selected from hydrogen, halogen (eg. fluorine or more preferably chlorine), halo C1-6alkyl (eg. CF3), d-6alkyl (eg. methyl) and phenyl or substituted phenyl (eg. p-methoxyphenyl).
In the compounds of formula (I), R4 and R5 are preferably independently selected from hydrogen and methyl, more preferably R4 and R5 are both hydrogen.
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:
N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}-N'-phenylurea;
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-
(hydroxymethyl)phenol; N-(1,r-biphenyl-4-yl)-N'-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethoxy)methyl]phenyl}urea;
N-cyclohexyl-N"-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethoxy)methyl]phenyl}urea;
4-[(1 R)-2-({6-[2-(benzyloxy)ethoxy]hexyl}amino)-1-hydroxyethyl]-2- (hydroxymethyl)phenol;
4-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)- hexyl]oxy}ethoxy)methyl]benzenesulfonamide;
4-{(1 R)-1-hydroxy-2-[(6-{2-[(4-iodobenzyl)oxy]ethoxy}hexyl)amino]ethyl}-2-
(hydroxymethyl)phenol; 3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)- hexyl]oxy}ethoxy)methyl]benzenesulfonamide;
2-(hyd roxymethyl )-4-(( 1 R)- 1 -hyd roxy-2-{[6-(2-{[( 1 R)- 1 -phenylethyl]oxy}ethoxy )- hexyl]amino}ethyl)phenol;
2-(hydroxymethyl)-4-((1 R)-1-hydroxy-2-{[6-(2-{[(1 S)-1-phenylethyl]oxy}ethoxy)- hexyl]amino}ethyl)phenol; 4-{(1 R)-2-[(6-{2-[(4-chlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-
(hydroxymethyl)phenol;
2-(hyd roxymethyl )-4-{( 1 R)- 1 -hyd roxy-2-[(6-{2-[(4-methylbenzy l)oxy]- ethoxy}hexyl)amino]ethyl}phenol; 4-{(1 R)-2-[(6-{2-[(2,4-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-
(hydroxymethyl)phenol;
2-(hydroxymethyl)-4-((1R)-1-hydroxy-2-{[6-(2-{[4-(trifluoromethyl)benzyl]- oxy}ethoxy)hexyl]amino}ethyl)phenol;
4-{(1 R)-1-hydroxy-2-[(6-{2-[(3-hydroxybenzyl)oxy]ethoxy}hexyl)amino]ethyl}-2- (hydroxymethyl)phenol;
N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}urea;
N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethoxy)methyl]phenyl}-4- (methylsulfonyl)benzenesulfonamide;
N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}methanesulfonamide;
N-(3-{[({3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}amino)carbonyl]amino}phenyl)pyridine-3- carboxamide;
N-(3-ethylphenyl)-N'-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)- phenyl]ethyl}amino)hexyl]oxy}ethoxy)methyl]phenyl}urea;
N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]- ethyl}amino)hexyl]oxy}ethoxy)methyl]phenyl}-N'-(3-methylphenyl)urea; N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}-N'-[3-(trifluoromethyl)phenyl]urea;
N-(3,5-dichlorophenyl)-N"-{2-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethoxy)methyl]phenyl}urea;
N-(3-chlorophenyl)-N'-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethoxy)methyl]phenyl}urea;
N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]- ethyl}amino)hexyl]oxy}ethoxy)methyl]phenyl}-N'-(3-iodophenyl)urea;
4-{(1 R)-2-[(6-{2-[(3-aminobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-
(hydroxymethyl)phenol; N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]pheny|}pyridine-3-carboxamide;
N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]pheny|}thiophene-2-carboxamide; N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}benzamide;
3-(benzoylamino)-N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)- phenyl]ethyl}amino)hexyl]oxy}ethoxy)methyl]phenyl}benzamide;
N-{3-[({3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}amino)carbonyl]phenyl}thiophene-2- carboxamide;
N-{3-[({3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}amino)carbonyl]phenyl}nicotinamide;
N-(3-{[({3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}amino)carbonyl]amino}phenyl)- benzenesulfonamide;
4-[(1R)-2-({6-[2-(1 ,1'-biphenyl-2-ylmethoxy)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-
(hydroxymethyl)phenol;
4-{(1 R)-1-hydroxy-2-[(6-{2-[(4,-methoxy-1 ,1'-biphenyl-2-yl)methoxy]ethoxy}- hexyl)amino]ethyl}-2-(hydroxymethyl)phenol;
4-{(1 R)-2-[(6-{2-[(3-bromobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-
(hydroxymethyl)phenol;
2-(hydroxymethyl)-4-{(1 R)-1-hydroxy-2-[(6-{2-[(3-phenoxybenzyl)oxy]ethoxy}- hexyl)amino]ethyl}phenol; 4-{(1R)-1-hydroxy-2-[(6-{2-[(4-hydroxybenzyl)oxy]ethoxy}hexyl)amino]ethyl}-2-
(hydroxymethyl)phenol;
5-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}pyrimidine-2,4-diol;
4-{(1 R)-2-[(6-{2-[(2,5-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2- (hydroxymethyl)phenol;
4-{(1 R)-2-[(6-{2-[(3,5-dimethylbenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-
(hydroxymethyl)phenol;
4-((1 R)-2-{[6-(2-{[2-fluoro-6-(trifluoromethyl)benzyl]oxy}ethoxy)hexyl]amino}-1- hydroxyethyl)-2-(hydroxymethyl)phenol; 2-(hydroxymethyl)-4-((1 R)-1-hydroxy-2-{[6-(2-{[3-(trifluoromethoxy)benzyl]- oxy}ethoxy)hexyl]amino}ethyl)phenol;
2-(hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{2-[(2-methyl-1 ,r-biphenyl-3- yl)methoxy]ethoxy}hexyl)amino]ethyl}phenol; 3-[(2,3-dihydroimidazo[2,1-b][1 ,3]thiazol-6-ylmethyl)amino]-N-{3-[(2-{[6-({(2R)-2- hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethoxy)- methyl]phenyl}benzamide;
N-(3-{[({3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethoxy)methyl]phenyl}amino)carbonyl]ami no}phenyl)benzamide;
N-(3-{[({3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}amino)carbonyl]amino}phenyl)thiophene-2- carboxamide;
N-(1 ,r-biphenyl-3-yl)-N'-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethoxy)methyl]phenyl}urea;
N-(3-aminophenyl)-N'-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethoxy)methyl]phenyl}urea;
3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)- hexyl]oxy}ethoxy)methyl]-N-methylbenzenesulfonamide; N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}-3-[(thien-2-ylsulfonyl)amino]benzamide;
N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)- phenyl]ethyl}amino)hexyl]oxy}ethoxy)methyl]phenyl}-N'-[3-(2-phenylethyl)-phenyl]urea; cyclopentyl 3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]- ethyl}amino)hexyl]oxy}ethoxy)methyl]phenylcarbamate;
5-{3'-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)- phenyl]ethyl}amino)hexyl]oxy}ethoxy)methyl]-1 ,1'-biphenyl-3-yl}pyrimidine-2,4(1 H,3H)- dione;
4-{(1 R)-1-hydroxy-2-[(6-{2-[(3-iodobenzyl)oxy]ethoxy}hexyl)amino]-ethyl}-2- (hydroxymethyl)phenol;
3'-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]- ethyl}amino)hexyl]oxy}ethoxy)methyl]-1 ,1'-biphenyl-3-ol;
N-cyclohexyl-3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]- ethyl}amino)hexyl]oxy}ethoxy)methyl]benzenesulfonamide; N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}-3-[(phenylsulfonyl)amino]benzamide;
4-[(1 R)-2-({6-[2-({3-[(2,3-dihydroimidazo[2,1-b][1 ,3]thiazol-6-ylmethyl)amino]- benzyl}oxy)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol; N-cyclopropyl-3'-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxy-methyl)- phenyl]ethyl}amino)hexyl]oxy}ethoxy)methyl]-1 ,1'-biphenyl-2-sulfonamide;
N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}-N'-[3-(phenylethynyl)phenyl]urea; Λ/-{3-[(2-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl} amino)pentyl]oxy}ethoxy)methyl]phenyl}-Λ/'-phenylurea;
Λ/-{3-[(3-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl} amino)pentyl]oxy}propoxy)methyl]phenyl}-Λ/'-phenylurea;
Λ/-{3-[(2-{[7-({(2f?)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl} amino)heptyl]oxy}ethoxy)methyl]phenyl}-/V-phenylurea; Λ/-(3-{[({3-[(2-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl] ethyl}amino)pentyl]oxy}ethoxy)methyl]phenyl}amino)carbonyl]amino}phenyl) nicotinamide;
Λ/-(3-{[({3-[(3-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl] ethyl}amino)pentyl]oxy}propoxy)methyl]phenyl}amino)carbonyl]amino}phenyl) nicotinamide;
Λ/-(3-{[({3-[(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl] ethyl}amino)heptyl]oxy}propoxy)methyl]phenyl}amino)carbonyl]amino}phenyl) nicotinamide;
Λ/-{3-[(2-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl} amino)pentyl]oxy}ethoxy)methyl]phenyl}methanesulfonamide;
Λ/-{3-[(3-{[5-({(2f?)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl} amino)pentyl]oxy}prop)methyl]phenyl}methanesulfonamide;
Λ/-{3-[(2-{[7-({(2f?)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl} amino)heptyl]oxy}ethoxy)methyl]phenyl}methanesulfonamide; Λ/-{3-[(2-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl} amino)hexyl]oxy}ethoxy)methyl]phenyl}benzenesulfonamide;
4-((1 R)-2-{[6-(2-{[3-(Dimethylamino)benzyl]oxy}ethoxy)hexyl]amino}-1-hydroxyethyl)-2-
(hydroxymethyl)phenol; 3-[(2-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethoxy)methyl]-N,N,N- trimethylbenzenaminium;
N-{4-[(2-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethoxy)methyl]phenyl}-N'-phenylurea;
4-{(1R)-2-[(5-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}pentyl)amino]-1-hydroxyethyl}-2-
(hydroxymethyl)phenol;
and salts, solvates, and physiologically functional derivatives thereof.
Particularly preferred compounds of the invention include:
N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}-N'-phenylurea;
4-{(1f?)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2- (hydroxymethyl)phenol;
N-(3-{[({3-[(2-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}amino)carbonyl]amino}phenyl)pyridine-3- carboxamide;
4-{(1 R)-1-Hydroxy-2-[(6-{2-[(3-hydroxybenzyl)oxy]ethoxy}hexyl)amino]ethyl}-2- (hydroxymethyl)phenol;
4-{(1 R)-2-[(6-{2-[(3,5-Dimethylbenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-
(hydroxymethyl)phenol;
Λ/-{3-[(2-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl} amino)pentyl]oxy}ethoxy)methyl]phenyl}-Λ/'-phenylurea;
and salts, solvates, and physiologically functional derivatives thereof.
Particularly preferred compounds of the invention further include: 4-{(1 ?)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2- (hydroxymethyl)phenol;
and salts and solvates thereof. The compounds of formulae (I) and (la) 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.
Similarly, where R4 and R5 are different groups or where R6 and R7 are different groups, the carbon atom to which they are attached is an asymmetric centre and the present invention includes both (S) and (R) isomers at these centres either in substantially pure form or admixed in any proportions.
Thus the compounds of formulae (I) and (la) include all enantiomers and diastereoisomers as well as mixtures thereof in any proportions.
Salts and solvates of compounds of formulae (I) and (la) 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 formulae (I) and (la) 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) or (la) having the same physiological function as the free compound of formula (I) or (la), for example, by being convertible in the body thereto. According to the present invention, examples of physiologically functional derivatives include esters.
Pharmaceutically acceptable esters of the compounds of formula (I) and (la) may have a hydroxyl group converted to a C1-6alkyl, aryl, aryl C1-6 alkyl, or amino acid ester.
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, phenylacetic, substituted phenyl acetic eg. ethoxyphenyl acetic, sulphamic, sulphanilic, succinic, oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic, methanesulphonic, ethanesulphonic, arylsulponic (for example p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic, mandelic, cinnamic, substituted cinnamic (for example, methyl, methoxy, halo or phenyl substituted cinnamic, including 4-methyl and 4-methoxycinnamic acid and α-phenyl cinnamic 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, bezeneacrylic (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.
Advantageously, preferred compounds of the invention such as 4-{(1f?)-2-[(6-{2-[(2,6- dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol are provided in the form of a crystalline salt, for example selected from those exemplified in the experimental section below. Said crystalline salts have favourable physical properties such as low hygroscopicity and/or improved stability.
As mentioned above, the compounds of formulae (I) and (la) 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. In addition, compounds of the invention demonstrate pharmacokinetic properties that will reduce systemic exposure relative to existing long- acting beta2 agonist bronchodilators. As such, compounds of the invention may be suitable for once-daily administration. Therefore, compounds of formulae (I) and (la) 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 (eg. rhinitis, including seasonal and allergic rhinitis).
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 (la), 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 (la) 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 (la) 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 (la) 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 (la), 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 (la), 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 is desirable (e.g. peptic and gastric ulceration) and muscle wasting disease.
The amount of a compound of formula (I) or (la), 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 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 10 mg, preferably 0.005mg to 0.5mg. The dose range for adult humans is generally from 0.0005 mg to 100mg per day and preferably 0.01 mg to 1 mg per day.
While it is possible for the compound of formula (I) or (la), 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. Accordingly, the present invention further provides a pharmaceutical formulation comprising a compound of formula (I) or (la) 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.
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 anti-inflammatory agents, anticholinergic agents (particularly an ML M2, MI/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, 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-16α-methyl-3-oxo-17α-propionyloxy- androsta-1 ,4- diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester, 6α,9oc-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, 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, and 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy- 16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester and 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, more preferably 6α,9 -difluoro-17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy-16α-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 leukot ene 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. Initial experiments were conducted to establish and validate a [3H]-rolipram binding assay. Details of this work are given in the Binding Assays described in detail below.
The preferred PDE4 inhibitors for 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 [^HjR-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.
Examples of useful PDE4 inhibitors are:
(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone;
3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N2-cyano-S-methyl-isothioureido]benzyl)-
2-pyrrolidone; cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1 -carboxylic acid]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]; (R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; and
(S)-(-)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate. 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 5,552,438 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 5,552,438, 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 Asta Medica (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); 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 (WO99/47505, the disclosure of which is hereby incorporated by reference) from Byk- Gulden; Pumafentrine, (-)-p-[(4aR*,10bS*)-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; VM554/UM565 from Vemalis; or T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther,1998, 284(1): 162), and T2585.
Other possible PDE-4 and mixed PDE3/PDE4 inhibitors include those listed in WO01/13953, the disclosure of which is hereby incorporated by reference. Phosphodiesterase and Rolipram Binding Assays Assay method 1 A
Isolated human monocyte PDE4 and hrPDE (human recombinant PDE4) was determined to exist primarily in the low affinity form. Hence, the activity of test compounds against the low affinity form of PDE4 can be assessed using standard assays for PDE4 catalytic activity employing 1 μM [3H]cAMP as a substrate (Torphy et a]., J. of Biol. Chem., Vol. 267, No. 3 pp1798-1804, 1992). Rat brain high speed supernatants were used as a source of protein and both enantiomers of [ H]-rolipram were prepared to a specific activity of 25.6 Ci/mmol.
Standard assay conditions were modified from the published procedure to be identical to the PDE assay conditions, except for the last of the cAMP: 50mM Tris HCI (pH 7.5), 5 mM MgCl2, 50 μM 5'-AMP and 1 nM of [3H]-rolipram (Torphy et_aj., J. of Biol. Chem., Vol. 267, No. 3 pp1798-1804, 1992). The assay was run for 1 hour at 30° C. The reaction was terminated and bound ligand was separated from free ligand using a
Brandel cell harvester. Competition for the high affinity binding site was assessed under conditions that were identical to those used for measuring low affinity PDE activity, expect that [ H]-cAMP was not present.
Assay method 1 B
Measurement of Phosphodiesterase Activity
PDE activity was assayed using a [3H]cAMP SPA or [3H]cGMP SPA enzyme assay as described by the supplier (Amersham Life Sciences). The reactions were conducted in 96-well plates at room temperature, in 0.1 ml of reaction buffer containing (final concentrations): 50 mM Tris-HCI, pH 7.5, 8.3 mM MgCI2, 1.7 mM EGTA, [3H]cAMP or
[3H] cGMP (approximately 2000 dpm/pmol), enzyme and various concentrations of the inhibitors. The assay was allowed to proceed for 1 hr and was terminated by adding 50 μl of SPA yttrium silicate beads in the presence of zinc sulfate. The plates were shaken and allowed to stand at room temperature for 20 min. Radiolabeled product formation was assessed by scintillation spectrometry.
f3HlR-rolipram binding assay The [3H]R-rolipram binding assay was performed by modification of the method of Schneider and co-workers, see Nicholson, et al.. Trends Pharmacol. Sci., Vol. 12, pp.19-27 (1991) and McHale et al.. Mol. Pharmacol., Vol. 39, 109-113 (1991). R- Rolipram binds to the catalytic site of PDE4 see Torphy et al.. Mol. Pharmacol., Vol. 39, pp. 376-384 (1991). Consequently, competition for [3H]R-rolipram binding provides an independent confirmation of the PDE4 inhibitor potencies of unlabeled competitors. The assay was performed at 30°C for 1 hr in 0.5 μl buffer containing (final concentrations): 50 mM Tris-HCI, pH 7.5, 5 mM MgCI2, 0.05% bovine serum albumin, 2 nM [3H]R- rolipram (5.7 x 104 dpm/pmol) and various concentrations of non-radiolabeled inhibitors. The reaction was stopped by the addition of 2.5 ml of ice-cold reaction buffer (without
[3H]-R-rolipram) and rapid vacuum filtration (Brandel Cell Harvester) through Whatman GF/B filters that had been soaked in 0.3% polyethylenimine. The filters were washed with an additional 7.5 ml of cold buffer, dried, and counted via liquid scintillation spectrometry.
Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptor, in particular those compounds which are antagonists of the M^ 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-51-48-1 (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 hexocycliu 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 ^-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 imgf000023_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: chlropheniramine 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 Hi 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.
Hereinafter, the term "active ingredient" means a compound of formula (I) or (la), 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 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 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, bacte ostats 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 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. Formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier substance) such as 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 or Diskhaler, see GB 2178965, 2129691 and 2169265) or metered in use (eg as in Turbuhaler, see EP 69715). An example of a unit-dose device is Rotahaler (see GB 2064336). 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 nebulisation 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.
According to a further aspect of the invention, there is provided a process for preparing a compound of formula (I) or (la) or a salt, solvate, or physiologically functional derivative thereof which comprises a process as described below followed where necessary or desired by one or more of the following steps in any order:
(i) optional removal of any protecting groups;
(ii) optional separation of an enantiomer or diastereoisomer from a mixture of enantiomers or diastereoisomers;
(iii) optional conversion of the product to a corresponding salt, solvate, or physiologically functional derivative thereof.
(iv) optional conversion of a group R1a, R2a and/or R3a to a group R1, R2 and/or
R3 respectively.
In one general process (A), a compound of formula (I) or (la) may be obtained by deprotection of a protected intermediate, for example of formula (II):
Figure imgf000029_0001
or a salt or solvate thereof, wherein R4, R5, R6, R7, m, and n are as defined for the compound of formula (I) or (la), and R1a, R2a, and R3a are each independently either the same as R1, R2, and R3 respectively as defined for the compound of formulae (I) or (la) or a precursor for said group R1, R2, or R3, and R13, R14, and R15 are each independently either hydrogen or a protecting group provided that at least one of R 3, R14, and R15 is a protecting group, and R19 is hydrogen or a protecting group.
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 R13 and R 4 are esters such as acetate ester, aralkyl groups such as benzyl, diphenylmethyl, or triphenylmethyl, and tetrahydropyranyl. Examples of suitable amino protecting groups represented by R15 include benzyl, α- methylbenzyl, diphenylmethyl, triphenylmethyl, benzyloxycarbonyl, tert-butoxycarbonyl, and acyl groups such as t chloroacetyl 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 CHOR19 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 (see above).
The deprotection to yield a compound of formula (I) or (la) may be effected using conventional techniques. It will be apparent to persons skilled in the art that the deprotection method employed should not effect cleavage of the -OCR6R7 moiety.
When R13 and/or R14 is tetrahydropyranyl this may be cleaved by hydrolysis under acidic conditions, for example using aqueous acetic acid. Acyl groups represented by R15 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 (see above). In a particular embodiment of the above process, R13 and R14 may together represent a protecting group as in the compound of formula (III):
Figure imgf000030_0001
or a salt or solvate thereof, wherein R4, R5, R6, R7, m, and n are as defined for the compound of formula (I) or (la), and R1a, R2a, and R3a are each independently either the same as R1, R2, and R3 respectively as defined for the compound of formulae (I) or (la) or a precursor for said group R1, R2, or R3, R16 and R17 are independently selected from hydrogen, d.6alkyl, or aryl. In a preferred aspect, both R16 and R17 are methyl.
A suitable precursor group R1a, R2a, and/or R3a in the compounds of formulae (II) and (III) would be a group which is convertible to the desired group R1, R2, and/or R3, before, after or simultaneously with the removal of the protecting groups R13, R14, and/or R15. For example, R1a, R2a, and/or R3a may suitably be a protected version of a group R1, R2, and R3 respectively, such that removal of the protecting group gives the desired group R1, R2, or R3. Preferred protecting groups in R1a, R2a, and/or R3a are those which may be removed under the conditions used for the removal of the protecting groups R13, R14, and/or R 15
The compound of formula (III) may be converted to a compound of formula (I) or (la) 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.
Compounds of formulae (II) and (III) wherein R15 is hydrogen may be prepared from the corresponding compound of formula (IV):
Figure imgf000031_0001
or a salt or solvate thereof, wherein R4, R5, R6, R7, R 3, R14 , m, and n are as defined for the compound of formula (II) or (III) and R1a, R2a, and R3a are each independently either the same as R1, R2, and R3 respectively as defined for the compound of formula (II) or (III) or a precursor for said group R1, R2, or R3.
A suitable precursor group R1a, R2a, and/or R3a in the compound of formula (IV) would be a group which is convertible to the desired group R1, R2, and/or R3. Suitably, such conversions are carried out using conventional methods which are known in the art. For example, where R1 is to be -NR8SO2R9, a suitable precursor group R a in the compound of formula (IV) would have the amine -NHR8 in place of the substituent R1, such that the desired substituent R1 may be formed by reaction with the appropriate sulphonyl chloride (i.e. R9SO2CI) before deprotection to form the compound of formula (I).
As a second example, where R1 is to be -NR8C(O)NHR9, a suitable precursor group R1a in the compound of formula (IV) would have the amine -NHR8 in place of the substituent R1, such that the desired substituent R1 may be formed by reaction with the appropriate isocyanate (i.e. R9NCO) before deprotection to form the compound of formula (I).
Alternatively, where R1 is to be -NHC(O)NHR9, a suitable precursor group R1a in the compound of formula (IV) has -NO2 in place of the substituent R1 which may be reduced to form the corresponding primary amine before reaction with the isocyanate R9NCO as described above to form the desired urea substituent R1. The reduction of the -NO2 group may be effected by any suitable method such as hydrogenation in the presence of a catalyst, for example, palladium/charcoal or platinum oxide, or by reaction with aluminium amalgam in tetrahydrofuran, or with zinc in ammonium chloride solution.
As a further example, where R1 is to be -NR8C(O)R9, a suitable precursor group R1a in the compound of formula (IV) would have the amine -NHR8 in place of the substituent
R1, such that the desired substituent R1 may be formed by reaction with the appropriate acyl chloride (i.e. R9C(O)CI) before deprotection to form the compound of formula (I).
As a further example, where R1 is to be -NR8C(O)OR9, a suitable precursor group R1a in the compound of formula (IV) would have the amine -NHR8 in place of the substituent
R1, such that the desired substituent R1 may be formed by reaction with the appropriate chloroformate (i.e. R9OC(O)CI) before deprotection to form the compound of formula (I).
Alternatively, where R1 is to be an optionally substituted aryl group, a suitable precursor group R1a in the compound of formula (IV) would have a halo substituent, for example iodo, in place of the substituent R1, such that the desired substituent R1 may be formed by reaction with bis(pinacolato)diboron followed by reaction with the appropriate optionally substituted haloaryl group, before deprotection to form the compound of formula (I). Alternatively, where R is to be an optionally substituted aryl group, a suitable precursor group R1a in the compound of formula (IV) would have a halo substituent, for example iodo, in place of the substituent R1, such that the desired substituent R1 may be formed by reaction with the appropriate optionally substituted arylboronic acid, for example an optionally substituted phenylboronic acid, before deprotection to form the compound of formula (I).
Alternatively, R1a, R2a, and/or R3a may suitably be a protected version of a group R1, R2, and R3 respectively, such that removal of the protecting group gives the desired group R1, R2, or R3. Preferred protecting groups in R1a, R2a, and/or R3a are those which may be removed under the conditions used for the removal of the protecting groups R13and R14, or the conditions used for the conversion of the compound of formula (IV) to the compound of formulae (II) or (III). For example, an -NH- group in the desired group R1, R2, or R3 may be protected by a 2-(trimethylsilyl)ethoxymethyl group or a tert- butoxycarbonyl group.
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 according to a first method (a) by coupling the corresponding compound of formula (V):
Figure imgf000033_0001
or a salt or solvate thereof, wherein R13 and R14 are as defined for the compound of formula (IV) with a compound of formula (VI):
Figure imgf000033_0002
wherein R1a, R2a ,R3a ,R4, R5, R6, R7 , m, and n are as defined for the compound of formula (IV) and L1 is a leaving group, for example a halo group (typically bromo or iodo) or a sulphonate such as an alkyl sulphonate (typically, methanesulphonate), an arylsulphonate (typically, toluenesulphonate), or a haloalkyl sulphonate (typically, trifluoromethanesulphonate).
The coupling of a compound of formula (V) with a compound of formula (VI) may be effected in the presence of a base, such as a metal hydride, for example sodium hydride, anathoride such as potassium t-butoxide or an inorganic base such as caesium carbonate, in an aprotic solvent, for example dimethylformamide.
Compounds of formula (V) may be prepared by ring closure of a compound of formula (VII):
Figure imgf000034_0001
wherein R13 and R14 are as defined for the compound of formula (V) and R18 is C1-6alkyl, for example tert-butyl, or aryl, for example phenyl. The ring closure may be effected by treatment with a base, such as a metal hydride, for example sodium hydride, in the presence of an aprotic solvent, for example, dimethylformamide.
Compounds of formula (VII) may be prepared from the corresponding ketone of formula (VIII):
Figure imgf000034_0002
wherein R13 , R14 and R18 are as defined for the compound of formula (VII), by reduction by any suitable method, for example by treatment with borane, in the presence of a chiral catalyst, such as CBS-oxazaborolidine, in a suitable solvent such as tetrahydrofuran.
The compound of formula (VIII) may be prepared from the corresponding halide of formula (IX):
Figure imgf000035_0001
wherein R13 and R14are as defined for the compound of formula (VIII) and Y is a halo group, suitably bromo.
The conversion of a compound of formula (IX) to a compound of formula (VIII) may be effected by reaction with the protected amine HN(COOR18)2 wherein R18 is as defined for the compound of formula (VIII) in the presence of an inorganic base such as caesium carbonate, followed by selective removal of one of the COOR 8 groups, for example by treatment with an acid such as trifluoroacetic acid.
Compounds of formula (IX) may be prepared from the corresponding compound having free hydroxymethyl and hydroxy substituents by forming the protected groups R13OCH2- and R14O- wherein R13 and R14 are as defined for the compound of formula (IX). Such methods are described in DE 3513885 (Glaxo).
Compounds of formula (VI) may be prepared by coupling a compound of formula (X):
Figure imgf000035_0002
wherein R a, R2a ,R3a ,R6, R7, and n are as defined for the compound of formula (VI), with a compound of formula (XI):
L2 — CR4R5(CH2)m - L2 (χ|)
wherein R4, R5, and m are as defined for the compound of formula (VI), and L2 is a leaving group such as halo (typically bromo).
The coupling of compounds (X) and (XI) may be effected in the presence of a base, such as a metal hydride, for example sodium hydride, or an inorganic base such as caesium carbonate, in an aprotic solvent, for example dimethylformamide. Alternatively, the coupling of compounds (X) and (XI) may be effected under phase transfer conditions, suitably in excess aqueous alkali such as 50% aqueous sodium hydroxide, optionally in the presence of a phase transfer catalyst such as a tetrabutylammonium salt, for example tetrabutylammonium bromide.
Compounds of formula (XI) are commercially available or may be prepared by methods well known to the person skilled in the art.
Compounds of formula (X) may be prepared by coupling the corresponding compound of formula (XII):
Figure imgf000036_0001
wherein R1a, R2a, R3a, R6, and R7 are as defined for the desired compound of formula
(X), and L3 is a leaving group such as halo (typically bromo);
with the dihydroxy compound of formula HO(CH2)nOH wherein n is as defined for the compound of formula (X). The coupling of a compound of formula (XII) with the dihydroxy compound may be effected by methods analogous to those described for the coupling of compounds (X) and (XI).
Compounds of formula (XII) are commercially available or may be prepared by methods well known to the person skilled in the art.
According to an alternative process (b), a compound of formula (IV) as defined above may be prepared by coupling the corresponding compound of formula (XIII):
(CH2)n OH
Figure imgf000037_0001
wherein R4, R5, R13, R14, m, and n are as defined for the desired compound of formula (IV), with the corresponding compound of formula (XII) as defined above in which R1a, R2a, R3a, R6, and R7 are as defined for the desired compound of formula (IV) and L3 is a leaving group such as halo (typically bromo). This coupling may be effected by methods analogous to those described for the coupling of compounds (X) and (XI).
Compounds of formula (XIII) may be prepared by coupling the corresponding compound of formula (V) as defined above wherein R13 and R14 are as defined for the desired compound of formula (XIII) with the corresponding compound of formula (XIV):
L4 — CR4R5 (CH2)m— O— (CH2) — OH (XIV)
or a protected derivative thereof, wherein R4, R5, m and n are as defined for the desired compound of formula (XIII) and L4 is a leaving group such as halo (typically bromo). The coupling of compounds of formulae (V) and (XIV) may be effected by methods analogous to those described for the coupling of compounds of formulae (X) and (XI).
Compounds of formula (XIV) may be prepared from the corresponding compounds of formula (XI) as defined above with the dihydroxy compound of formula HO(CH2)nOH wherein n is as defined for the desired compound of formula (XIV), by methods analogous to those described for the coupling of compounds of formula (X) and (XI).
Alternatively, compounds of formula (XIII) may be prepared by coupling the corresponding compound of formula (XV):
Figure imgf000038_0001
wherein R13, R14, R4, R5, and m are as defined for the desired compound of formula (XIII) and L2 is a leaving group such as halo (typically bromo), followed by coupling the compound of formula (XV) with the dihydroxy compound of formula HO(CH2)nOH, wherein n is as defined for the desired compound of formula (XIII), by methods analogous to those described for the coupling of compounds of formula (X) and (XI).
The compound of formula (XV) may be prepared by coupling the corresponding compound of formula (V) as previously defined wherein R13 and R14 are as defined for the desired compound of formula (XIII), with the corresponding compound of formula (XI) as previously defined wherein R4, R5, and m are as defined for the desired compound of formula (XIII) and L2 is a leaving group such as halo (typically bromo).
The coupling of compounds of formulae (V) and (XI) may be effected by methods analogous to those described for the coupling of compounds of formulae (V) and (VI).
In a further alternative process (c) compounds of formula (IV) as defined above may be prepared by coupling the corresponding compound of formula (XVI): (CH2)n— L5
Figure imgf000039_0001
wherein R13, R14, R4, R5, m and n are as defined for the compound of formula (IV) and L5is a leaving group, for example a sulphonate such as an alkyl sulphonate (typically, methanesulphonate), an arylsulphonate (typically, toluenesulphonate), or a haloalkyl sulphonate (typically, trifluoromethanesulphonate), with a compound of formula (XVII):
Figure imgf000039_0002
wherein R a, R2a, R3a, R6, and R7 are as defined for the compound of formula (IV).
The coupling of compounds of formulae (XVI) and (XVII) may be effected by methods analogous to those described for the coupling of compounds of formulae (V) and (VI).
The compound of formula (XVI) may be prepared by converting the hydroxyl group in a compound of formula (XIII) into a leaving group L4 such as a methansulphonate group using methods known in the art, for example by reaction with methanesulphonyl chloride in the presence of a suitable base, for example NEt('Pr)2, in a suitable solvent such as dichloromethane.
The compounds of formula (XVII) are commercially available or may be prepared using methods known in the art.
During the synthesis of the compound of formula (XIII), appropriate protecting chemistry may be used, for example, the compounds of formula (XIV) and the dihydroxy compound of formula HO(CH2)nOH may be protected so as to improve the yield of the desired intermediates. Suitable protecting strategies will be appreciated by the person skilled in the art and may also be found in Theodora W. Greene (see above). Thus, for example, a primary hydroxyl group may be protected with a trialkylsilyl group such as tert-butyldimethylsilyl or with a benzyl group.
In a further process (d) compounds of formula (IV) as defined above may be prepared by coupling a compound of formula (XVIII):
Figure imgf000040_0001
(XVIII)
wherein R13, R14, R4, R5, and m are as defined for formula (IV) and L2 is defined as for formula (XI), with a compound of formula (X) as defined above. The reaction of compounds (XVIII) and (X) may be effected in a similar manner to the coupling of compounds (XI) and (X).
Compounds of formula (XVIII) may be prepared by reacting a compound of formula (V) with a compound of formula (XI) in a similar manner to the reaction of compounds (V) and (XIV).
In a further general process (B) a compound of formula (I) and (la) may be obtained by alkylation of an amine of formula (XIX):
Figure imgf000040_0002
(XIX) wherein R13, R14, R15 and R19 are as hereinbefore defined, with a compound of formula (VI) wherein L1 represents a leaving group such as halo (typically bromo), 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 (XIX) and (VI) may be optionally effected in the presence of an organic base, such as a trialkylamine, for example diisopropyl ethylamine, and in a suitable solvent, for example dimethyformamide.
Compounds of formula (XIX) are known in the art, for example EP-A-0947498, or may readily be prepared by a person skilled in the art.
In a yet further general process (C), a compound of formula (I) or (la) may be prepared by reacting an amine of formula (XIX) as defined hereinabove, with a compound of formula (XX):
Figure imgf000041_0001
(XX)
wherein R4, R6, R7, R1a, R2a, R3a, m and n are as hereinbefore defined; under conditions suitable to effect reductive amination, for example in the presence of a reducing agent such as borohydride, typically tetramethylammonium (triacetoxy) borohydride.
A compound of formula (XX) may be prepared by methods known in the art, for example from a compound of formula (VI) as defined hereinabove via Kornblum oxidation.
It will be appreciated that in any of the general processes (A), (B) or (C) as well as the processes for (a) to (d) for preparing compounds (IV) described above, 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. It will also be appreciated that in general processes (B) and (C) appropriate protecting groups may be employed if necessary and/or desired and removed at any suitable stage of the synthesis, eg. in the last stage, as described in general process (A).
The enantiome c 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 herein.
Optional conversion of a compound of formula (I) or (la) to a corresponding salt may conveniently be effected by reaction with the appropriate acid or base. Optional conversion of a compound of formula (I) or (la) 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) or (la), for example: compounds of formula (II) and (III) as defined above, or an optical isomer, a salt, or a protected derivative thereof; particularly, a compound selected from:
N-[3-({2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]ethoxy}methyl)phenyl]-N'-phenylurea; and
(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-(2,2-dimethyl-4H-1 ,3- benzodioxin-6-yl)ethanol; Λ/-cyclohexyl-ΛT-[3-({2-[(6-{[(2R)-2-(2,2-dimethyl-4rV-1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]ethoxy}methyl)phenyl]urea;
N-(1 , 1 '-biphenyl-4-yl)-N'-[3-({2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]ethoxy}methyl)phenyl]urea;
N-cyclopropyl-3'-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]ethoxy)methyl]-1 ,1'-biphenyl-2-sulfonamide; (1 R)-2-{[6-(2-[{3-(2,3-dihydroimidazo[2,1-b][1,3]thiazol-6-ylmethyl)amino]- phenyl}methoxy]ethoxy)hexyl]amino}-1-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)ethanol;
N-{3-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-hydroxyethyl]- amino}hexyl)oxy]ethoxy)methyl]phenyl}-3-[(phenylsulfonyl)amino]benzamide; N-(3-{[({3-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxy- ethyl]amino}hexyl)oxy]ethoxy)methyl]phenyl}amino)carbonyl]amino}phenyl)-pyridine-3- carboxamide;
N-cyclohexyl-3-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]ethoxy)methyl]-N-({[2-(trimethylsilyl)ethyl]- oxy}methyl)benzenesulfonamide;
3'-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]- amino}hexyl)oxy]ethoxy)methyl]-1 , 1 '-biphenyl-3-ol;
(1 R)-1 -(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-[(6-{2-[(3-iodobenzyl)oxy]- ethoxy}hexyl)amino]ethanol; N-{3-[(2-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}-N'-[3-(phenylethynyl)phenyl]urea;
(1 R)-2-{[6-(2-{[3'-{2,4-bis[(1 ,1-dimethylethyl)oxy]pyrimidin-5-yl}-1 ,r-biphenyl-3- yl]methoxy}ethoxy)hexyl]amino}-1 -(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)ethanol; and cyclopentyl 3-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-hydroxy- ethyl]amino}hexyl)oxy]ethoxy)methyl]phenylcarbamate; and other similar intermediates exemplified hereinafter;
compounds of formula (IV) as defined above, or an optical isomer, a salt, or a protected derivative thereof; particularly, a compound selected from: (5f?)-3-(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-
6-yl)-1 ,3-oxazolidin-2-one;
(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-(6-{2-[(3-nitrobenzyl)oxy]- ethoxy}hexyl)-1 ,3-oxazolidin-2-one;
N-(3-{[2-({6-[(5R)-5-(2,2-Dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- yl]hexyl}oxy)ethoxy]methyl}phenyl)-N'-phenylurea;
Λ/-cyclohexyl-Λ/'-(3-{[2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3- oxazolidin-3-yl]hexyl}oxy)ethoxy]methyl}phenyl)urea;
N-(1 ,r-biphenyl-4-yl)-N'-(3-{[2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-
1 ,3-oxazolidin-3-yl]hexyl}oxy)ethoxy]methyl}phenyl)urea; (5R)-3-(6-{2-[(3-aminobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6- yl)-1 ,3-oxazolidin-2-one;
(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-{6-[2-{[(3-nitrophenyl)- methyl]oxy}ethoxy]hexyl}-1 ,3-oxazolidin-2-one; N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- yl]hexyl}oxy)ethoxy}methyl)phenyl]-3-[(phenylsulfonyl)amino]-benzamide;
3-amino-N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3- oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]benzamide;
N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- yl]hexyl}oxy)ethoxy}methyl)phenyl]-3-nitrobenzamide;
N-(3-aminophenyl)-N'-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-
1 ,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]urea;
N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- yl]hexyl}oxy)ethoxy}methyl)phenyl]-N'-(3-nitrophenyl)urea; N-cyclohexyl-3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3- oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)-N-({[2-(trimethylsilyl)ethyl]oxy}- methyl)benzenesulfonamide;
N-{3-[({[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- yl]hexyl}oxy)ethoxy}methyl)phenyl]amino}carbonyl)amino]-phenyl}pyridine-3- carboxamide; cyclopentyl 3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3- oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenylcarbamate;
N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- yl]hexyl}oxy)ethoxy}methyl)phenyl]-N'-[3-(phenylethynyl)phenyl]urea; 1 ,1-dimethylethyl cyclopropyl{[3'-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-
2-0X0-1 , 3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)-1 ,r-biphenyl-2- yl]sulfonyl}carbamate;
(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-(6-{2-([3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methoxy)ethoxy}hexyl)-1 ,3-oxazolidin-2-one; (5R)-3-[6-(2-[{3-[(2,3-dihydroimidazo[2,1-b][1 ,3]thiazol-6-ylmethyl)amino]- phenyl}methoxy]ethoxy)hexyl]-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-1 ,3-oxazolidin-
2-one;
(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-{6-[2-{(3- iodophenyl)methoxy}ethoxy]hexyl}-1 ,3-oxazolidin-2-one; (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[2-{(3'-hydroxy-1 ,r-biphenyl-3- yl)methoxy}ethoxy]hexyl}-1 ,3-oxazolidin-2-onel; and
(5R)-3-{6-[2-{(3'-{2,4-bis[(1 ,1-dimethylethyl)oxy]pyrimidin-5-yl}-1 ,1 '-biphenyl-3- yl)methoxy}ethoxy]hexyl}-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-1 ,3-oxazolidin-2- one; and other similar intermediates exemplified hereinafter;
compounds of formula (XIII) as defined above, or an optical isomer, a salt, or a protected derivative thereof; particularly, the compound: (5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-[6-(2-hydroxyethoxy)hexyl]-1 ,3- oxazolidin-2-one, and other similar intermediates exemplified hereinafter.
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
SPE: solid phase extraction
XRPD -x-ray powder diffraction RT: retention time
THF : tetrahydofuran
DMF : N,N-dimethylformamide
EtOAc: ethyl acetate
EtOH: ethanol MeOH: methanol
MIBK: methyl-isobutylketone
PE: petroleum ether 40 °-60°
HPLC: high performance liquid chromatography
TLC: thin layer chromatography Sat: saturated bp: boiling point ca : circa h: hour(s) min: minute(s) d: doublet dd: double doublet s: singlet brs: broad singlet
All temperatures are given in degrees centigrade.
Ammonia refers to 0.880 (aqueous) ammonia.
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.
SCX refers to prepacked SPE cartridges containing benzenesulphonic acid ion exchange resin.
Preparative thin layer chromatography was carried out on silica gel, 20x20cm, Whatman
PK6F, 60A, 1 mm thick.
LC was conducted on a Luna 3 μm C18(2) column (50mm x 2mm id) eluting with 0.05% v/v trifiuoroacetic acid in water (solvent A) and 0.05% v/v trifiuoroacetic acid in acetonitrile (solvent B) using the elution gradient 0-8.0 min 0%B-95%B, 8.0-8.01 min 95%B-0%B, with a flow rate of 1ml_/min with a column temperature of 40°C.
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 0%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 using the same chromatographic system as for the LCMS.
The XRPD analysis shown in the Figures were performed on a Phillips X pert Prop powder diffractometer, Model PW3040/60, serial number DY1379. The method runs from 2 to 45 degrees 2Theta with 0.02 degree 2Theta step size and a 2 second collection time at each step.
Example 1 Synthesis of N-(3-r(2 r6-({(2R)-2-hvdroxy-2-r4-hvdroxy-3-(hvdroxymethvn- phenvnethyl)amino)hexylloxy>ethoxy)methvnphenyl)-N'-phenylurea acetate
i) Di(tert-butyl) 2-(2,2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate Caesium carbonate (70.4g) was added to a stirred suspension of 2-bromo-1-(2,2- dimethyl-4H-1 ,3-benzodioxin-6-yl)ethanone, (Glaxo, DE 3513885, 1985) (61.8g) and di- t-butyl iminodicarboxylate (47.15g) in acetonitrile (600ml) under nitrogen. After vigorous stirring at 21° for 24 h the mixture was diluted with water (caδOOml) and the product was extracted with diethyl ether (1 litre, then 200ml). The combined organic layers were washed with brine, dried (MgSO4) and concentrated to ca400ml. The white crystals were collected by filtration, washed with diethyl ether and dried to give the title compound (24.4g) δ (CDCI3) 7.78(1 H, dd, J 8, 2Hz), 7.65 (1 H, brs), 6.87(1 H, d, J 8Hz), 4.97(2H, s), 4.88(2H, s), 1.56(6H, s) and 1.48 (18H, s). Further concentration of the mother liquors gave additional product (13.8g). A third crop (7.1g) was obtained by chromatographing the mother liquors on silica gel, evaporating the appropriate eluate and triturating with diethyl ether.
ii) tert-Butyl 2-(2,2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxoethylcarbamate Trifiuoroacetic acid (92ml) was added to a stirred solution of di(tert-butyl) 2-(2,2- dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate, (352.55g) in dichloromethane (3.6litres) at 21° and the reaction was stirred for 1.5 h. Aqueous
NaOH solution (1.75litres) was added and after 10 min the phases were separated. The organic layer was washed with water, dried (MgSO4) and evaporated to an oil. This was stored under high vacuum overnight and then triturated with hexane:ether (3:1 ) to give the crude product (226.61g). This was purified by recrystallisation from diethyl ether to give the title compound (122.78g). Further product (61.5g) was obtained from the mother liquors by evaporation and chromatography on a Biotage using 15% EtOAc in hexane. LCMS RT = 3.37min.
iii) tert-Butyl (2R)-2-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-hvdroxyethylcarbamate A 2M solution of borane - dimethyl sulphide in THF (28ml) was added slowly to a 1M solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-1 H,3H-pyrrolo[1 ,2-c][1 ,3,2]oxazaborole in toluene (56ml) at 0° under nitrogen. A solution of tert-butyl 2-(2,2-dimethyl-4H-1 ,3- benzodioxin-6-yl)-2-oxoethylcarbamate, (108.2g) in THF (1.3litres) was added slowly keeping the temperature below 5° followed by 2M solution of borane - dimethyl sulphide in THF (252ml) over 50 min. After 1 h, 2M HCI (170ml) was added with cooling and the mixture was partitioned between EtOAc and water . The organic layer was washed with saturated NaHCO3 solution and brine and dried (MgSO4). The solution was concentrated and the product purified by chromatography on flash silica gel (800g), eluting successively with hexane:EtOAc (4:1 then 3:1 ) to give the title compound (93.3g), LCMS RT = 3.31 min.
iv) (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-1.3-oxazolidin-2-one tert-Butyl (2R)-2-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate,
(86.37g) in DMF (600ml) was added dropwise to a stirred suspension of sodium hydride (60% oil dispersion, 11.9g) in DMF (160ml) with cooling such that the internal temperature remained at 0° under nitrogen. The mixture was stirred at 21 ° for 2 h. The mixture was recooled to 0° and 2M HCI (134ml) was added. The mixture was diluted with water and the product was extracted with EtOAc twice. The solution was washed with brine twice, dried (MgSO4) and evaporated to give the title compound (63.55g). LCMS RT = 2.66min.
v) 2- ftert-Butyl(dimethyl)silylloxy)ethanol Ethylene glycol (2.00g) in anhydrous THF (60ml) under nitrogen was treated portionwise with sodium hydride (60% dispersion in mineral oil, 1.29g) and the mixture stirred at 20°C for 45min. Tert-butyl dimethylsilyl chloride (4.86g) was added and the mixture stirred at 20°C for 45min. Phosphate buffer (60ml, pH6.5) was added and the mixture stirred for 20 min before extracting with ether (60ml). The organic layer was then washed with water (60ml) and brine (60ml), before drying over Na2SO4, filtering, and removing the solvent in vacuo. This was purified by flash chromatography on silica. Elution with 1 :4 EtOAc/cyclohexane followed by solvent evaporation in vacuo gave the title compound (3.82g). TSP+ve 194 MNH4 + .
vi) (2-r(6-Bromohexyl)oxylethoxy)(tert-butyl)dimethylsilane 2-{[tert-Butyl(dimethyl)silyl]oxy}ethanol (1.82g), 1 ,6-dibromohexane (7.56g) and tetrabutylammonium bromide (0.067g) were stirred under nitrogen and treated with 50%w/v sodium hydroxide (2g in 4ml). The mixture was stirred vigorously at 20°C for 5 days. Water (100ml) was added, and the product extracted with dichloromethane
(3x50ml). The combined organic layer was separated and dried over Na2SO4 before filtering. The solvent was evaporated in vacuo to give a residue which was purified by flash chromatography on silica. Elution with 5% ether/cyclohexane followed by solvent evaporation in vacuo gave the title compound (2.35g). LCMS RT = 4.32min, ES +ve 339 (MH)+.
vii) (5R)-3-r6-(2-(rtert-Butyl(dimethvnsilylloxy ethoxy)hexyll-5-(2.2-dimethyl-4H-1.3- benzodioxin-6-vP-1 ,3-oxazolidin-2-one
A solution of (5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (0.83g) in DMF (20ml) was treated with sodium hydride (60% dispersion in mineral oil,
0.20g) and the mixture stirred under nitrogen at 20°C for 30 min. A solution of {2-[(6- bromohexyl)oxy]ethoxy}(tert-butyl)dimethylsilane (1.47g) in DMF (4ml) was added and the mixture stirred at 20°C for 90min. Phosphate buffer (20ml, pH6.5) was added, before partitioning between EtOAc (50ml) and water (50ml). The layers were separated and the aqueous layer re-extracted with EtOAc (3x30ml). The combined organic layer was washed with water (3x50ml) and dried over Na2SO4 before filtering. Solvent evaporation in vacuo gave a residue which was purified by flash chromatography on silica. Elution with EtOAc-cyclohexane (1 :1) followed by solvent evaporation in vacuo gave the title compound (0.84g). LCMS RT = 4.11 min, ES+ve 507 (MH) +.
viii) (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-3-r6-(2-hvdroxyethoxy)hexyll-1.3- oxazolidin-2-one A solution of (5R)-3-[6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)hexyl]-5-(2,2-dimethyl-4H- 1 ,3-benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (0.79g) in THF (30ml) was treated with tetrabutylammonium fluoride on silica gel (3.08g) and the mixture stirred under nitrogen at 20°C for 2.75h. The reaction mixture was filtered and the filtrate evaporated in vacuo to give a residue which was purified by SPE on silica. Elution with dichloromethane, then EtOAc followed by solvent evaporation in vacuo gave the title compound (0.56g). LCMS RT = 3.05min, ES+ve 394 (MH) +.
ix) (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vπ-3-(6- 2-f(3-nitrobenzyl)oxyl- ethoxy)hexyQ-1 ,3-oxazolidin-2-one
A solution of (5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-[6-(2- hydroxyethoxy)hexyl]-1 ,3-oxazolidin-2-one (0.20g) in DMF (5ml) was treated with sodium hydride (60% dispersion in mineral oil, 0.030g) and the mixture stirred under nitrogen at 20°C for 15 min. 3-nitrobenzylbromide (0.11g) was added, and the mixture stirred at 20°C for a further 3 h. Phosphate buffer (20ml, pH6.5) was added and the mixture was stirred for 5 min before extracting with EtOAc (3x20ml). The organic layer was washed with water (3x20ml), dried over Na2SO4 and filtered. Solvent evaporation gave the crude product which was purified by flash chromatography on silica. Elution with EtOAc-cyclohexane (7:3) followed by solvent evaporation in vacuo gave the title compound (0.1 Og). LCMS RT = 3.61 min, ES+ve 529 (MH) +.
x) (5R)-3-(6-(2-r(3-Aminobenzyl)oxylethoxy hexyl)-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)-3-(6-{2-[(3- nitrobenzyl)oxy]ethoxy}hexyl)-1 ,3-oxazolidin-2-one (0.1 Og) in EtOH (3ml) and EtOAc
(3ml) was hydrogenated for 19.5h over platinum oxide (0.020g). The mixture was filtered through celite, and the solvent evaporated in vacuo to give a residue which was purified by flash chromatography on silica. Elution with EtOAc-cyclohexane (8:2) followed by solvent evaporation in vacuo gave the title compound (0.057g). LCMS RT = 3.43min, ES+ve 499 (MH) +.
xi) N-(3-fr2-«6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yllhexyl)oxy)ethoxylmethyl)phenyl)-N'-phenylurea
A solution of (5R)-3-(6-{2-[(3-aminobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1 ,3- benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (0.057g) in dichloromethane (2ml) was treated with phenyl isocyanate (0.020g) and the mixture stirred under nitrogen at 20°C for 2h. Isopropanol (5ml) was added to quench excess isocyanate, and the mixture stirred for 30min before leaving to stand for 15 h. The solvents were removed in vacuo to give a residue which was purified by SPE. Elution with a stepped gradient of eluants from cyclohexane to cyclohexane-EtOAc (9:1) and onwards to EtOAc followed by solvent evaporation in vacuo gave the title compound (0.062g). LCMS RT = 3.70min, ES+ve 618 (MH) +.
xii) N-r3-((2-r(6-fr(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethyllamino)hexyl)oxylethoxy)methyl)phenvπ-N'-phenylurea
Potassium trimethylsilanolate (0.056g) was added to a solution of N-(3-{[2-({6-[(5R)-5- (2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3-yl]hexyl}oxy)- ethoxy]methyl}phenyl)-N'-phenylurea (0.061g) in degassed anhydrous THF (4ml) whilst stirring under nitrogen. The reaction mixture was heated to 65°C for 4 h, adding additional potassium trimethylsilanolate (0.057g) and heating for a further 2.5h, at which point the reaction mixture was cooled to room temperature. Phosphate buffer (20ml, pH6.5) was added and the mixture extracted with EtOAc (3x20ml). The combined organic layers were separated and dried over Na2S04 before filtering. Solvent evaporation in vacuo gave the title compound (0.027g). LCMS RT = 2.80min, ES+ve 592 (MH) +.
xiii) N-(3-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyl)- amino)hexyl1oxy)ethoxy)methyllphenyl)-N'-phenylurea acetate
A solution of N-[3-({2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]ethoxy}methyl)phenyl]-N'-phenylurea (0.025g) in acetic acid (1 ml) and water (0.5ml) were stirred under nitrogen at 70°C for 75min. The reaction mixture was cooled to room temperature before concentrating under vacuum and azeotroping with MeOH (2x10ml) to give the title compound (0.028g). LCMS RT =
2.50min, ES+ve 552 (MH) +.
Example 2
Alternative synthesis of (5R)-5-(2.2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-(6-r2- hvdroxyethoxy1hexyl)-1.3-oxazolidin-2-one
i) r(2-r(6-Bromohexyl)oxylethoxylmethyllbenzene A solution of 2-(benzyloxy)ethanol (2.00g) and tetrabutylammonium bromide (84mg) in 1 ,6-dibromohexane (6.06ml) was treated with 50% w/v sodium hydroxide solution (5.0ml) and the mixture was vigorously stirred for 18h at 20°. Water (50ml) was added and the mixture was extracted with dichloromethane (40ml). The organic extract was dried (Na2SO4) and the solvent evaporated in vacuo to give a residue which was purified by flash chromatography on silica gel. Elution with EtOAc-PE (1 :9) gave the title compound (2.87g). LCMS RT = 3.94min, ES +ve 337 (MNa)+, 339 (MNa)+
ii) 2-r(6-Bromohexyl)oxylethanol A solution of [(2-[(6-bromohexyl)oxy]ethoxy)methyl]benzene (1.5g) in EtOAc (20ml) and
EtOH (20ml) was hydrogenated over 10% palladium on carbon (200mg). After 2h the mixture was filtered through celite and the filtrate evaporated in vacuo to give the title compound (1.05g). TSP +ve 242 (MNH4)+, 244 (MNH4)+
iii) (5R)-5-(2,2-Dimethyl-4H-1.3-benzodioxin-6-yl)-3-(6-r2-hvdroxyethoxyl-hexyl)-1.3- oxazolidin-2-one
A solution of (5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (1.067g) in DMF (10ml) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 222mg) and the mixture was stirred at 20° for 15min. A solution of 2-[(6-bromohexyl)oxy]ethanol (1.157g) in DMF (1 ml) was added and the mixture was stirred at 20° for 3.5h. Phosphate buffer solution (pH 6.5, 20ml) and water (30ml) were added. The mixture was extracted with EtOAc (2x20ml) and the combined extracts were washed with water (30ml) and dried (Na2S04). Solvent evaporation in vacuo gave a residue which was purified by flash chromatography on silica gel. Elution with MeOH-EtOAc (1 :9) gave the title compound (1.42g). LCMS RT = 2.90min, ES +ve
394 (MH)+.
Example 3
Alternative synthesis of (5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-3-(6-r2- hvdroxyethoxylhexyl)-1.3-oxazolidin-2-one
) (5Rl-3-(6-Bromohexyπ-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 (5.00g) and 1 ,6-dibromohexane (9.26ml) in DMF (50ml) at 0° under nitrogen was treated in three equal portions with sodium hydride (60% dispersion in mineral oil, 963mg). The mixture was stirred at 0° for 30min and then at 20° for a further 2.5h. Phosphate buffer solution (pH 6.5, 50ml) and water (150ml) were added and the mixture was extracted with diethyl ether (2x150ml). The combined extracts were washed with water (2x150ml) and were dried (Na2S04). The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel. Elution with MeOH-dichloromethane
(1 :4) gave the title compound (7.10g). LCMS RT = 3.52min, ES +ve 412 (MH)+, 414 (MH)+.
ii) (5R)-5-(2.2-Dimethyl-4H-1 ■3-benzodioxin-6-yl)-3- 6-r2-hvdroxyethoxylhexyl)-1.3- oxazolidin-2-one
A solution of ethylene glycol (5.00ml) in DMF (40ml) under nitrogen at 0° was treated portionwise with sodium hydride (60% dispersion in mineral oil, 1.292g) and the mixture was stirred at 0° for 15min. A solution of (5R)-3-(6-bromohexyl)-5-(2,2-dimethyl-4H- ,3- benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (7.40g) in DMF (10ml) was added. The mixture was stirred at 0° for 0.5h then at 20° for 3h. Phosphate buffer solution (pH 6.5, 40ml) and water (160ml) were added and the mixture was extracted with EtOAc (2x100ml). The combined extracts were washed with water (2x150ml), brine (50ml) and were dried (Na2S04). The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel. Elution with MeOH-EtOAc (1 :9) gave the title compound (4.10g). LCMS RT = 2.90min, ES +ve 394 (MH)+.
Example 4
Synthesis of 4-((1 f?)-2-r(6-(2-[(2,6-dichlorobenzyl)oxylethoxy)hexyl)aminol-1- hvdroxyethyl)-2-(hydroxymethyl)phenol acetate
i) (5R)-3-(6-(2-r(2.6-Dichlorobenzyl)oxylethoxy hexyl)-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)-3-[6-(2- hydroxyethoxy)hexyl]-1 ,3-oxazolidin-2-one (200mg) in DMF (4ml) under nitrogen was treated with sodium hydride (26mg, 60% in oil) and the mixture was stirred at 20° for
10min. 2,6-Dichlorobenzyl bromide (122mg) was added and the mixture was stirred at 20° for 3h. Phosphate buffer solution (20ml, pH6.5) was added and the mixture was extracted with EtOAc (30ml). The extract was washed with water (2x20ml), dried (NaS0 ) and the solvent evaporated in vacuo to give a residue. The residue was purified by chromatography on flash silica gel 20mm diameter column. Elution with EtOAc-cyclohexane (1 :1) gave the title compound (155mg). LCMS RT = 3.97 min.
ii) (1 )-2-r(6-{2-r(2.6-Dichlorobenzvnoxylethoxy hexyl)aminol-1 -(2.2-dimethyl-4H-1.3- benzodioxin-6-yl)ethanol
A solution of (5f?)-3-(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1 ,3- benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (140mg) in THF (7ml) under nitrogen was treated with potassium trimethylsilanolate (130mg) and the mixture was heated (oil bath temperature 80°) with stirring for 3 h. The mixture was cooled to 20° and was partitioned between phosphate buffer solution (20ml, pH6.5) and EtOAc (20ml). The organic phase was separated, dried (NaS04) and the solvent evaporated in vacuo to give the title compound (130mg). LCMS RT = 3.00 min.
iii) 4-((1 R)-2-F(6-(2-r(2.6-Dichlorobenzyl)oxylethoxy)hexyl)aminol-1 -hvdroxyethyl)-2- (hvdroxymethyl)phenol acetate
A solution of (1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-(2,2-dimethyl- 4H-1 ,3-benzodioxin-6-yl)ethanol (130mg) in acetic acid (2ml) and water (1ml) was heated (oil bath temperature 80°) with stirring for 30 min. The mixture was cooled to 20° and the solvent was evaporated in vacuo. The residue was azeotroped in vacuo with MeOH (2x1 ml) to give the title compound (135mg) . LCMS RT = 2.57 min, ES +ve 486
(MH)+, 488 (MH)+, 490 (MH)+.
Example 5
Synthesis of N-(1 ,1'-biphenyl-4-yl)-N'-(3-r(2-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyllethyl>amino)hexylloxy)ethoxy)methyllphenyl)urea
i) N-(1.1'-Biphenyl-4-yl)-N,-(3-(r2-((6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-vn-2- oxo-1 ,3-oxazolidin-3-vnhexyl)oxy)ethoxylmethyl>phenyl)urea A solution of (5R)-3-(6-{2-[(3-aminobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1 ,3- benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (0.202g) in dichloromethane (4ml) was treated with 4-biphenylyl isocyanate (0.126g) and the mixture stirred under nitrogen at 20°C for 19 h. Isopropanol (15ml) was added to quench excess isocyanate, and the mixture stirred for 2 h. The solvents were removed in vacuo to give a residue which was purified by Biotage. Elution with 6:4 EtOAc/cyclohexane followed by solvent evaporation in vacuo gave the title compound (0.119g). LCMS RT = 4.09min, ES+ve 694 (MH) +.
ii) N-(1.1'-Biphenyl-4-vn-N'-r3-((2-r(6-(r(2R)-2-(2.2-dimethyl-4H-1.3-benzodioxin-6-vn-2- hvdroxyethvHamino)hexyl)oxylethoxy}methyl)phenvπurea
Potassium trimethylsilanolate (0.090g) was added to a solution of N-(1 ,1'-biphenyl-4-yl)- N'-(3-{[2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- yl]hexyl}oxy)ethoxy]methyl}phenyl)urea (0.119g) in deoxygenated anhydrous THF (4ml) whilst stirring under nitrogen. The reaction mixture was heated to 65°C for 3h, at which point the reaction mixture was cooled to room temperature. Phosphate buffer (25ml, pH6.5) was added and the mixture extracted with EtOAc (3x25ml). The combined organic layers were separated and dried over Na2S04 before filtering. Solvent evaporation in vacuo gave a residue which was purified by Biotage. Elution with 150:8:1 dichloromethane:EtOH:ammonia followed by solvent evaporation in vacuo gave the title compound (0.092g). LCMS RT = 3.16min, ES+ve 668 (MH) \
iii) N-(1 ,1,-Biphenyl-4-yl)-N'-(3-r(2- r6-( 2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl1ethyl)amino)hexylloxy)ethoxy)methyllphenyl|urea acetate A solution of N-(1 ,1'-biphenyl-4-yl)-N'-[3-({2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1 ,3- benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]ethoxy}methyl)phenyl]urea (0.089g) in acetic acid (4ml) and water (2ml) were stirred under nitrogen at 70°C for 30min. The reaction mixture was cooled to room temperature before concentrating under vacuum and azeotroping with MeOH (2x10ml) to give the title compound (0.097g). LCMS RT = 3.08min, ES+ve 628 (MH) +.
Example 6
Synthesis of N-cvclohexyl-N'-(3-r(2-(r6-( (2R)-2-hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyllethyl)amino)hexylloxy)ethoxy)methyl1phenyl)urea
i) Λ/-Cvclohexyl-/V-(3- r2-((6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-vn-2-oxo-1.3- oxazolidin-3-yllhexyl)oxy)ethoxy1methyl)phenyl)urea
A solution of (5R)-3-(6-{2-[(3-aminobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1 ,3- benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (0.209g) in dichloromethane (4ml) was treated with cyclohexyl isocyanate (0.075g) and the mixture stirred under nitrogen at 20°C for 3h. At this point further cyclohexyl isocyanate (0.150g) was added, and the reaction mixture stirred for a further 65h. Isopropanol (15ml) was added to quench excess isocyanate, and the mixture stirred for 3 h. The solvents were removed in vacuo to give a residue which was purified by Biotage. Elution with 6:4 EtOAc/cyclohexane followed by solvent evaporation in vacuo gave the title compound (0.212g). LCMS RT = 3.77min, ES+ve 624 (MH)+.
ii) Λ/-Cvclohexyl-Λ/'-r3- 2-r(6-(r(2R)-2-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethvHamino)hexyl)oxylethoxy)methyl)phenyllurea
Potassium trimethylsilanolate (0.177g) was added to a solution of Λ/-cyclohexyl-/V-(3- {[2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- yl]hexyl}oxy)ethoxy]methyl}phenyl)urea (0.207g) in deoxygenated anhydrous THF (6ml) whilst stirring under nitrogen. The reaction mixture was heated to 65°C for 4.5h, at which point the reaction mixture was cooled to room temperature. Phosphate buffer (25ml, pH6.5) was added and the mixture left to stir for 10min before extracting with EtOAc (3x25ml). The combined organic layers were separated and dried over Na2SO4 before filtering. Solvent evaporation in vacuo gave a residue which was purified by Biotage. Elution with 150:8:1 dichloromethane:EtOH:ammonia followed by solvent evaporation in vacuo gave the title compound (0.138g). LCMS RT = 2.87min, ES+ve 598 (MHf.
iii) N-Cvclohexyl-N'-(3-r(2- r6-( 2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyllethyl)amino)hexylloxy ethoxy)methvnphenyl)urea triacetate A solution of Λ/-cyclohexyl-/V-[3-({2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)- 2-hydroxyethyl]amino}hexyl)oxy]ethoxy}methyl)phenyl]urea (0.138g) in acetic acid (4ml) and water (1ml) were stirred under nitrogen at 70°C for
45min. The reaction mixture was cooled to room temperature before concentrating under vacuum and azeotroping with MeOH (3x10ml) to give a residue which was purified by Biotage. Elution with 50:8:1 dichloromethane:EtOH:ammonia followed by solvent evaporation in vacuo gave the title compound (0.126g). LCMS RT = 2.65min, ES+ve 558 (MH) +.
The following examples 7 to 9 and 11 to 20 were prepared similarly: Example 7
4-r(1 R)-2-((6-r2-(Benzyloxy)ethoxy1hexyl)aminoV1-hvdroxyethvn-2-
(hvdroxymethvPphenol acetate.
LCMS RT = 2.47 min, ES+ve 418 (MH)+.
Example 8
4-r(2- r6-(((2R)-2-Hvdroxy-2-f4-hvdroxy-3-(hvdroxymethyl)phenyllethyl)aminol- hexynoxy)ethoxy)methyllbenzenesulfonamide.
LCMS RT = 2.18 min, ES+ve 497 (MH)+.
Example 9
4-((1 R)-1-Hvdroxy-2-r(6-(2-r(4-iodobenzvnoxylethoxy)hexyl)aminolethyl)-2-
(hvdroxymethyl)phenol acetate.
LCMS RT = 2.64 min, ES+ve 544 (MH)\
Example 10
3-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethvπphenyllethyl)amino)hexyl1oxylethoxy)methyl1 benzenesulfonamide acetate
i) 3-(Hvdroxymethyl)-N.N-bis(r2-(trimethylsilyl)ethoxylmethyl benzenesulfonamide A solution of 3-(hydroxymethyl)benzenesulfonamide (670mg) in DMF (20ml) under nitrogen was treated with sodium hydride (315mg, 60% in oil) and the mixture was stirred at 20° for 15 min. The mixture was then treated with 2- (trimethylsilyl)ethoxymethyl chloride (1.27ml) and the mixture was stirred at 20° for 1 h.
Phosphate buffer solution (50ml, pH6.5) was added and the mixture was extracted with EtOAc. The extract was washed with water, dried (Na2S04) and the solvent evaporated in vacuo to give a residue. The residue was purified by chromatography on flash silica gel (40mm diameter column). Elution with EtOAc-cyclohexane (3:7) gave the title compound (985mg). LCMS RT = 3.84 min.
ii) 3- r2-((6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2-oxo-1.3-oxazolidin-3- yllhexyl)oxy)ethoxylmethyl)-N.N-bis{r2-
(trimethylsilvDethoxylmethvDbenzenesulfonamide A solution of 3-(hydroxymethyl)-N,N-bis{[2-
(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (512mg) in DMF (4ml) under nitrogen was treated with sodium hydride (1.295g, 60% in oil) and the mixture was stirred at 20° for 30 min. A solution of 2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3- oxazolidin-3-yl]hexyl}oxy)ethyl methanesulfonate (359mg) in DMF (1 ml) was added and the mixture was stirred at 20° for 18 h. Phosphate buffer solution (25ml, pH6.5) was added and the mixture was extracted with EtOAc. The extract was washed with water, dried (Na2S04) and the solvent evaporated in vacuo to give a residue. The residue was purified by chromatography on flash silica gel (30mm diameter column). Elution with EtOAc-cyclohexane (2:3) then (1:1) gave the title compound (400mg). LCMS RT = 4.43 min.
iii) 3-((2-r(6- r(2R)-2-(2,2-Dimethyl-4H-1.3-benzodioxin-6-vn-2- hvdroxyethvπamino)hexy0oxylethoxy)methyl)-N,N-bis{f2- (trimethylsilvDethoxylmethyllbenzenesulfonamide
A solution of 3-{[2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3- oxazol id in-3-yl] hexyl}oxy)ethoxy] methyl}-N , N-bis{[2-
(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (200mg) in THF (10ml) under nitrogen was treated with potassium trimethylsilanolate (125mg) and the mixture heated to 70° for 5 h. The mixture was cooled to 20° and phosphate buffer solution (25ml, pH6.5) was added. The mixture was extracted with EtOAc, the extract dried (Na2S04) and the solvent evaporated in vacuo to give the title compound (400mg). LCMS RT = 3.6 min.
iv) 3-r(2-(r6-«(2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenvHethyl|amino)hexylloxy)ethoxy)methyll benzenesulfonamide acetate
A solution of 3-({2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]ethoxy}methyl)-N,N-bis{[2-
(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (170mg) in acetic acid (8ml) and water (4ml) was heated to 70° for 6 h. The mixture was cooled to 20° and the solvent evaporated in vacuo. The reisidue was purified by preparative TLC. Elution with dichloromethane-EtOH-0.880 ammonia (25:8:1) gave the free base (35mg). This was dissolved in acetic acid (2ml) and the solvent evaporated in vacuo to give the title compound (40mg). LCMS RT = 2.13 min, ES +ve 497 (MH)+
Example 11 2-(Hvdroxymethyl)-4-((1 Rl-1 -hvdroxy-2- r6-(2- f(1 Rl-1 -phenylethylloxylethoxy)- hexyllamino)ethyl)phenol acetate. LCMS RT = 2.55 min, ES+ve 432 (MH)+.
Example 12 2-(Hvdroxymethyl)-4-((1R)-1-hvdroxy-2-(r6-(2-(r(1S)-1-phenylethylloxy ethoxy)- hexyllamino)ethyl)phenol acetate. LCMS RT = 2.45 min, ES+ve 432 (MH)+.
Example 13 4-((1 R)-2-r(6-(2-r(4-Chlorobenzyl)oxylethoxy)hexyπaminol-1-hvdroxyethyl)-2-
(hvdroxymethvQphenol acetate. LCMS RT = 2.61 min, ES+ve 452 (MH)+, 454 (MH)\
Example 14 2-(H yd roxymethyl )-4-(( 1 R)- 1 -hyd roxy-2-r(6-( 2-f(4-meth yl benzyl )oxyl- ethoxy)hexyl)aminolethyl)phenol acetate. LCMS RT = 2.56 min, ES+ve 432 (MH)+.
Example 15 4-((1 R)-2-r(6-(2-r(2.4-Dichlorobenzvnoxylethoxy hexyl)amino1-1-hydroxyethyl>-2-
(hvdroxymethyl)phenol acetate. LCMS RT = 2.77 min, ES+ve 486 (MH)+, 488 (MH)+, 490 (MH)+.
Example 16 2-(Hvdroxymethyl)-4-((1 R)-1-hvdroxy-2-(r6-(2-(r4-(trifluoromethyl)benzyll- oxy)ethoxy)hexyllamino)ethyl)phenol acetate LCMS RT = 2.60 min, ES+ve 486 (MH)+.
Example 17 4-1(1 R)-1-Hvdroxy-2-f(6-(2-r(3-hvdroxybenzvnoxylethoxy hexyl)aminolethyll-2-
(hvdroxymethyl)phenol acetate.
LCMS RT = 2.31 min, ES+ve 434 (MH)\
Example 18
N-(3-r(2-(r6-({(2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyl - amino)hexylloxy}ethoxy)methyllPhenyl}urea acetate. LCMS RT = 2.30 min, ES+ve 476 (MH)+.
Example 19
N-(3-r(2-(f6-( (2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenvπethyl>amino)hexylloxy>ethoxy)methyllphenyl)-4-
(methylsulfonyl)benzenesulfonamide acetate.
LCMS RT = 2.54 min, ES+ve 451 (MH)+.
Example 20
N-(3-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyl)- amino)hexyπoxy)ethoxy)methyllphenyl}methanesulfonamide acetate. LCMS RT = 2.42 min, ES+ve 511 (MH)+.
Example 21
Synthesis of N-(3-{f((3-r(2-(f6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)- phenyllethyl)amino)hexylloxy)ethoxy)methvnphenyl)amino)carbonyllamino)phenyl)pyridi ne-3-carboxamide
i) 2-{(3-NitrophenvQmethoxy)ethanol
Ethylene glycol (7.18g) in anhydrous DMF (50ml) was treated at 0° under nitrogen with sodium hydride (60% dispersion in mineral oil, 1.85g) and the mixture stirred for 30 min. 3-Nitrobenzyl bromide (5.00g) was added and the mixture was warmed to 20° over 1 h and stirred for a further 15 h. Phosphate buffer (pH 6.5, 100ml) and water (100ml) were added and the product was extracted with EtOAc (2x150ml). The combined organic layer was washed with water (2x200ml) and dried (Na2S04). Solvent evaporation in vacuo gave a residue that was purified by Biotage. Elution with EtOAc-PE (1 :1 then 2:1) followed by solvent evaporation in vacuo gave the title compound (16.34g) HPLC RT = 1.554min. TSP+ve 215 (MNH4)+. ii) 1 -r(2-r(6-Bromohexyl)oxylethoxy)methvn-3-nitrobenzene 2-{(3-Nitrophenyl)methoxy}ethanol (6.50g), 1 ,6-dibromohexane (24.2g) and tetrabutylammonium bromide (0.21 g) were stirred under nitrogen at 20° and treated with 50%w/v sodium hydroxide (10ml). The mixture was stirred vigorously for 19 h before water (150ml) was added. The product was extracted with dichloromethane (3x80ml) and the combined organic layer was dried (Na2S04). Solvent evaporation in vacuo gave a residue that was purified by Biotage. Elution with PE-EtOAc (1 :0 then 3:1 ) followed by solvent evaporation in vacuo gave the title compound (8.12g). HPLC RT = 3.238min.
iii) (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-3- 6-r2-((3-nitrophenyl)- methoxy}ethoxylhexyl)-1.3-oxazolidin-2-one
A solution of (5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (4.40g) in anhydrous DMF (75ml) was treated under nitrogen at 0° with sodium hydride (60% dispersion in mineral oil, 1.04g) and the mixture stirred for 40 min. A solution of 1-[(2-
[(6-bromohexyl)oxy]ethoxy)methyl]-3-nitrobenzene (8.12g) in DMF (10ml) was added and the mixture stirred at 20° for 2 h. Phosphate buffer (pH 6.5, 100ml) and water (100ml) were added and the product extracted with EtOAc (4x100ml). The combined organic layer was washed with water (3x100ml) and dried (Na2S04). The solvent was removed in vacuo to give a residue that was purified by Biotage. Elution with EtOAc-PE
(1 :1 then 3:2) followed by solvent evaporation in vacuo gave the title compound (9.50g). LCMS RT = 3.75min, ES +ve 529 (MH)+.
iv) (5R)-3- 6-r2-((3-Aminophenyl)methoxy)ethoxylhexyl -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)-3-{6-[2-{(3-nitro- phenyl)methoxy}ethoxy]hexyl}-1 ,3-oxazolidin-2-one (9.50g) in EtOAc (120ml) and EtOH (120ml) was hydrogentated over platinum oxide (0.20g) for 1.75 h. The mixture was filtered through celite and washed with EtOH. Solvent evaporation in vacuo gave the title compound (9.60g). LCMS RT = 3.25 min, ES +ve 499 (MH)+.
v) N-r3-((2-((6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- yllhexyl}oxy)ethoxy)methyl)phenvπ-N'-(3-nitrophenyl)urea
A solution of (5R)-3-{6-[2-{(3-aminophenyl)methoxy}ethoxy]hexyl}-5-(2,2-dimethyl-4H- 1 ,3-benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (1.00g) in anhydrous dichloromethane (15ml) was treated under nitrogen at 20° with 3-nitrophenyl isocyanate (0.43g) and the mixture stirred for 4 h. Isopropanol (20ml) was added and the mixture stirred for 17 h before the solvent was removed in vacuo to give a residue that was purified by Biotage. Elution with dichloromethane-EtOH-ammonia (325:8:1 ) followed by solvent evaporation in vacuo gave the title compound (1.13g). LCMS RT = 3.85 min, ES +ve 663 (MH)+.
vi) N-(3-Aminophenvn-N,-r3- 2-((6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-vn-2- oxo-1 ,3-oxazolidin-3-yllhexyl)oxy)ethoxy)methyl)phenvHurea A solution of N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3- oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]-N'-(3-nitrophenyl)urea (0.976g) in EtOH
(12ml) and EtOAc (12ml) was hydrogenated over platinum oxide (0.020g) for 2 h. The mixture was filtered through celite and washed with EtOH. Solvent evaporation in vacuo gave the title compound (0.93g). LCMS RT = 3.48 min, ES +ve 633 (MH)+.
vii) N- 3-[«r3-α2-«6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3- oxazolidin-3-yllhexyl)oxy)ethoxy)methyl)phenyllamino)carbonyl)aminol-phenyl)pyridine-
3-carboxamide
A solution of N-(3-aminophenyl)-N'-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-
6-yl)-2-oxo-1 ,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]-urea (0.20g) in pyridine (4ml) was treated under nitrogen at 20° with nicotinoyl chloride hydrochloride (0.118g) and the mixture stirred for 5.5 h. Sat. sodium bicarbonate solution (25ml) was added and the product was extracted with dichloromethane (3x20 ml). The combined organic layer was dried (Na2S04) and the solvent removed in vacuo to give a residue that was purified by SPE. Elution with dichloromethane-EtOAc (1 :0, 1 :1 , then 0:1 ), then MeOH- EtOAc (1:50), followed by solvent evaporation in vacuo gave the title compound
(0.209g). LCMS RT = 3.54 min, ES +ve 738 (MH)\
viii) N-(3-(r 3-r(2-r(6-(r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethyllamino>hexyl)oxylethoxy)methvπphenyl}amino)carbonyllamino)- phenyl)pyridine-3-carboxamide
A solution of N-{3-[({[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3- oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]amino}carbonyl)-amino]phenyl}pyridine- 3-carboxamide (0.209g) in anhydrous THF (10ml) was treated under nitrogen at 20° with potassium trimethylsilanolate (0.217g). The mixture was heated to 65° for 2.5 h before cooling to room temperature. Phosphate buffer (pH 6.5, 25ml) was added and the product extracted with EtOAc (3x20ml). Solvent evaporation in vacuo gave a residue that was purified by SPE. Elution with dichloromethane-EtOH-ammonia (100:8:1 then 50:8:1) followed by solvent evaporation in vacuo gave the title compound (0.109g). LCMS RT = 2.86 min, ES +ve 712 (MH)+.
ix) N-(3-(f((3-r(2- r6-( (2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyll- ethyl)amino)hexylloxy)ethoxy)methyllphenyl)amino)carbonyllamino)phenyl)-pyridine-3- carboxamide
A solution of N-(3-{[({3-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]ethoxy)methyl]phenyl}amino)carbonyl]amino}- phenyl)pyridine-3-carboxamide (0.109g) in acetic acid (4ml) and water (2ml) was heated to 68° for 30 min. The mixture was cooled to room temperature before concentrating in vacuo to leave a residue that was purified by Biotage. Elution with dichloromethane- EtOH-ammonia (25:8:1) followed by solvent evaporation in vacuo gave the title compound (0.089g). LCMS RT = 2.02 min, ES +ve 672 (MH)+.
Example 22
Synthesis of N-cvclohexyl-3-r(2-(r6- (2R)-2-hvdroχy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyllethyl amino)hexynoxylethoxy)methyllbenzenesulfonamide compound with (2E)-but-2-enedioic acid (2:1) i) 3-f(Cvclohexylamino)sulfonyllbenzoic acid
A mixture of 3-(chlorosulfonyl)benzoic acid (2.00g) and dichloromethane (20ml) under nitrogen at 0° was treated with cyclohexylamine (3.63ml) and the mixture was stirred at 0° for 0.5 h. The solvent was evaporated in vacuo and the residue was treated with 1 M potassium hydrogen sulfate solution (50ml) and extracted with EtOAc (3x50ml). The combined extracts were dried (Na2S04) and the solvent evaporated in vacuo to give the title compound (2.28g). LCMS RT = 3.16min, ES +ve 284 (MH)+.
ii) N-Cvclohexyl-3-(hvdroxymethyl)benzenesulfonamide A solution of 3-[(cyclohexylamino)sulfonyl]benzoic acid (2.25g) in THF (100ml) under nitrogen at 0° was treated dropwise with 1M borane-THF solution (23.82ml). The mixture was stirred at 0° for 0.5 h and then at 20° for 72 h. The mixture was cooled to 0° and MeOH (20ml) was added dropwise. The mixture was stirred for 15 min and then 2N hydrochloric acid (50ml) was added and the mixture was allowed to warm to 20°. The bulk of the organic solvents were removed by evaporation in vacuo and the residual aqueous phase was extracted with EtOAc (2x40ml). The combined extracts were dried (Na2S04) and the solvent evaporated in vacuo. The residue was purified by SPE on alumina (10g, activated, neutral, Brockmann 1). Elution with MeOH-dichloromethane (1 :20) gave the title compound (1.944g). LCMS RT = 2.95min, ES +ve 270 (MH)\
iii) N-Cvclohexyl-3-(hvdroxymethyl)-N-((2-(trimethylsilyl)ethoxy)methyl)- benzenesulfonamide
A solution of N-cyclohexyl-3-(hydroxymethyl)benzenesulfonamide (1.744g) in DMF
(30ml) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 311 mg) and the mixture stirred at 20° for 0.5 h. 2-(Trimethylsilyl)ethoxymethyl chloride
(1.15ml) was added and the mixture was stirred for a further 2 h at 20°. Phosphate buffer solution (pH 6.5, 50ml) and water (50ml) were added and the mixture was extracted with EtOAc (2x50ml). The combined extracts were washed with water (2x100ml) and dried (Na2S0 ). Solvent evaporation in vacuo gave a residue which was purified by flash chromatography on silica gel. Elution with EtOAc-PE (3:7) gave the title compound (1.917g). LCMS RT = 3.83min, ES +ve 417 (MNH4)+.
iv) 2-((6-r(5R)-5-(2.2-Dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yllhexyl)oxy)ethyl methanesulfonate A solution of (5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-{6-[2- hydroxyethoxy]hexyl}-1 ,3-oxazolidin-2-one (200mg) in dichloromethane (14ml) under nitrogen at 0° was treated with diisopropylethylamine (0.10ml) followed by methanesulfonyl chloride (0.04ml). The mixture was stirred at 0° for 0.5 h and sat. sodium bicarbonate solution (30ml) was then added. The mixture was extracted with dichloromethane (30ml) and the organic extract dried (Na2S04). The solvent was evaporated in vacuo to give the title compound (240mg). LCMS RT = 3.22min, ES +ve
472 (MH)+.
v) N-Cvclohexyl-3-( 2-((6-r(5Rl-5-(2.2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1.3- oxazolidin-3-yllhexyl)oxy)ethoxy)methyl)-N-({2-(trimethylsilyl)ethoxy)methyl)- benzenesulfonamide
A solution of N-cyclohexyl-3-(hydroxymethyl)-N-({2-(trimethylsilyl)ethoxy}- methyl)benzenesulfonamide (508mg) in DMF (8ml) under nitrogen at 20° was treated with sodium hydride (60% dispersion in mineral oil, 58mg) and the mixture was stirred 15 min. A solution of 2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3- oxazolidin-3-yl]hexyl}oxy)ethyl methanesulfonate (400mg) in DMF (2ml) was added and the mixture was stirred at 20° for 72h. Phosphate buffer solution (pH 6.5, 10ml) and water (20ml) were added and the mixture was extracted with EtOAc (30ml). The extract was washed with water (2x30ml), dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel. Elution with EtOAc-PE
(1 :1 ) gave the title compound (530mg). LCMS RT = 4.47min, ES +ve 793 (MH)+.
vi) N-Cvclohexyl-3-r(2-r(6- r(2R)-2-(2.2-dimethyl-4H-1.3-benzodioxin-6-vn-2- hvdroxyethyllamino)hexyl)oxy1ethoxy)methyll-N-((2- (trimethylsilyl)ethoxy)methyl)benzenesulfonamide
The title compound was prepared by a procedure similar to that described in Example 1xii). LCMS RT = 3.58min, ES +ve 749 (MH)+.
vi i ) N-Cvclohexyl-3-r(2-(r6-(((2R)-2-hvd roxy-2-r4-hvd roxy-3-(hvd roxymeth yl)- phenvnethyl)amino)hexylloxy)ethoxy)methyllbenzenesulfonamide compound with (2E)- but-2-enedioic acid (2:1 )
A solution of N-cyclohexyl-3-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]ethoxy)methyl]-N-({[2-(trimethylsilyl)- ethyl]oxy}methyl)benzenesulfonamide (350mg) in acetic acid (20ml) and water (10ml) was heated to 70° for 1 h. The mixture was cooled to 20° and the solvent was evaporated in vacuo. The residue was azeotroped with MeOH (2x10ml) and the residue was purified by preparative TLC. Elution with dichloromethane-EtOH-ammonia (25:8:1 ) gave the free base (200mg). This was dissolved in EtOH (5ml) and treated with a solution of fumaric acid (20mg) in EtOH (5ml). The solvent was evaporated in vacuo to give the title compound (216mg). LCMS RT = 2.70min, ES +ve 579 (MH)+.
Example 23
Synthesis of N 3-r(2-fr6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)- phenyllethyl)amino)hexynoxy)ethoxy)methyllphenyl)-3- r(phenylsulfonyl)aminolbenzamide compound with (2E)-but-2-enedioic acid (2:1 )
\) N-r3-((2-((6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vh-2-oxo-1 ,3-oxazolidin-3- yllhexyl)oxy)ethoxylmethyl)phenyll-3-nitrobenzamide A solution of (5R)-3-{6-[2-{[(3-aminophenyl)methyl]oxy}ethoxy]hexyl}-5-(2,2-dimethyl- 4H-1 ,3-benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (2.20g) in pyridine (20ml) under nitrogen was treated with 3-nitrobenzoyl chloride (819mg) and the mixture was stirred at 20° for 2.5 h. Sat. sodium bicarbonate solution (100ml) was added and the mixture was extracted with dichloromethane (2x50ml). The combined extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel. Elution with EtOAc-PE (2:1) gave the title compound (2.11 g). LCMS RT = 3.71 min, ES +ve 648 (MH)+.
ii) 3-Amino-N-r3-((2-((6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3- oxazolidin-3-yllhexyl}oxy)ethoxy)methyl)phenyllbenzamide A solution of N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3- oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]-3-nitrobenzamide (2.11g) in EtOAc (30ml) and EtOH (30ml) was hydrogenated over platinum oxide (100mg). After 1.25 h the mixture was filtered through celite and the filtrate evaporated in vacuo to give the title compound (1.955g). LCMS RT = 3.49min, ES +ve 618 (MH)+.
iii) N-r3-((2-((6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yllhexyl)oxy)ethoxy)methyl)phenyll-3-r(phenylsulfonyl)aminol-benzamide 3-Amino-N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3- oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]benzamide (200mg) in pyridine (5ml) under nitrogen was treated with benzenesulfonyl chloride (0.045ml) and the mixture was stirred at 20° for 2 h. Sat. sodium bicarbonate solution (30ml) was added and the mixture was extracted with dichloromethane (2x20ml). The combined extracts were dried (Na2S04) and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel. Elution with EtOAc-dichloromethane (1 :1 ) gave the title compound (155mg). LCMS RT = 3.72min, ES +ve 758 (MH)+.
iv) N- 3-r(2-r(6-(r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-hvdroxyethyll- amino)hexyl)oxylethoxy)methyllphenyl)-3-r(phenylsulfonyl)amino1benzamide
The title compound was prepared by a procedure similar to that described in Example 1xii). LCMS RT = 2.96min, ES +ve 732 (MH)+.
v) N-f3-f(2-(r6-( (2RV2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyll- ethyl>amino)hexylloχv ethoxy)methvnphenyl)-3-r(phenylsulfonyl)aminol-benzamide compound with (2EVbut-2-enedioic acid (2:1) The title compound was prepared by a procedure similar to that described in Example 22vii). LCMS RT = 2.71 min, ES +ve 692 (MH)+.
Example 24 Synthesis of 4-K1 R)-2-«6-r2-(f3-r(2,3-dihydroimidazor2.1-blH ,31thiazol-6- ylmethyl)aminolbenzyl)oxy)ethoxylhexyl)amino)-1-hvdroxyethyll-2- (hvdroxymethyl)phenol acetate (1 :2)
i) (5R)-3-r6-(2-r 3-r(2.3-Dihvdroimidazor2.1-biπ .3lthiazol-6-ylmethyl)aminol- phenyl)methyl)oxylethoxy)hexyn-5-(2,2-dimethyl-4H-1.3-benzodioxin-6-yl)-1.3- oxazolidin-2-one
A solution of (5R)-3-{6-[2-{[(3-aminophenyl)methyl]oxy}ethoxy]hexyl}-5-(2,2-dimethyl- 4H-1 ,3-benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (200mg) and 2,3-dihydroimidazo[2,1- b][1 ,3]thiazole-6-carboxaldehyde (62mg) (WO94/10178) in dichloromethane (10ml) was treated under nitrogen with sodium triacetoxy borohydride (340mg) and stirred at 20° for
1.5 h. The mixture was cooled to 0°, phosphate buffer solution (pH6.5, 20ml) was added and the mixture was extracted with EtOAc (3x30ml). The combined organic extracts were dried (Na2S04) and the solvent evaporated in vacuo to give a residue which was purified by SPE. Elution with dichloromethane, dichloromethane-EtOH- ammonia (400:8:1) then (225:8:1 ) gave the title compound (172mg). LCMS RT =
3.16min, ES +ve 637 (MHf.
ii) (1 R)-2-(r6-(2-r(3-r(2.3-Dihvdroimidazor2.1-bin .3lthiazol-6-ylmethyl)aminol- phenyl)methoxy1ethoxy)hexyπamino>-1-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)ethanol The title compound was prepared by a procedure similar to that described in Example
21 viii) . LCMS RT = 2.46min, ES +ve 611 (MHf.
iii) 4-r(1 R)-2-((6-r2- 3-r(2.3-Dihvdroimidazor2,1-biπ .31thiazol-6-ylmethyl)aminol- benzyl}oxy)ethoxylhexyl>amino)-1-hvdroxyethyll-2-(hvdroxymethyl)phenol acetate (1 :2) The title compound was prepared by a procedure similar to that described in Example
22vii). LCMS RT = 2.25min, ES +ve 571 (MHf. Example 25
Synthesis of N-cvclopropyl-3'-r(2-(r6-(((2R)-2-hvdroxy-2-r4-hvdroχy-3-(hvdroxy- methyl)phenvnethyl)amino)hexyπoxy)ethoxy)methvn-1 , 1 '-biphenyl-2-sulfonamide acetate
i) (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-3-(6-(2-(r3-(4.4.5.5-tetramethyl-1.3.2- dioxaborolan-2-yl)phenyllmethoxy)ethoxy hexyl)-1.3-oxazolidin-2-one
A stirred mixture of (5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-{6-[2-{(3- iodophenyl)methoxy}ethoxy]hexyl}-1 ,3-oxazolidin-2-one (1.3g), bis(pinacolato)diboron (0.94g), potassium acetate (0.62g) and [1 , 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (complex with dichloromethane 1 :1 , 100mg) in DMF (25ml) under nitrogen was heated at 90° for 3.5 h. The mixture was cooled to 20°, poured into water (400ml) and extracted with EtOAc (3x50ml). The extracts were washed with water (200ml), dried (MgS04) and evaporated in vacuo to give a residue which was purified by Biotage. Elution with diethyl ether-PE (4:1 ) gave the title compound (920mg). LCMS RT = 3.93min, ES +ve 610 (MH)+.
ii) 1 ,1-Dimethylethyl (2-bromophenyl)sulfonyl(cyclopropyl)carbamate Cyclopropylamine (1.7g) was added to a stirred solution of 2-bromobenzenesulfonyl chloride (2.0g) in THF (25ml) under nitrogen. The mixture was stirred at 0° for 20 min and the solvent was then evaporated in vacuo. The residue was then triturated with cold water (20ml), the mixture filtered and the filter cake dried in vacuo. The filter cake was then dissolved in dichloromethane (30ml) and treated with triethylamine (1.53ml) and 4-(dimethylamino)pyridine (90mg) with stirring under nitrogen. The mixture was cooled to 0° and was treated with di-tert-butyl dicarbonate (2.4g). The mixture was then stirred at 5° for 1h and then washed with 1N hydrochloric acid (40ml), water (50ml) and was dried (Na2S04). The solvent was evaporated in vacuo and the residue was recrystallised from cyclohexane (30ml) to give the title compound (2.00g). LCMS RT = 3.52min, ES +ve 393 (MNH4)+, 395 (MNH4)+.
iii) 1 ,1-Dimethylethyl cvclopropyl(r3'-«2-((6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6- yl)-2-oxo-1.3-oxazolidin-3-yllhexyl)oxy)ethoxy>methyl)-1 ,1'-biphenyl-2- yllsulfonvDcarbamate
A stirred mixture of (5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-(6-{2-({[3-(4 ,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl}oxy)ethoxy}hexyl)-1 ,3-oxazolidin-2- one (420mg), 1 ,1-dimethylethyl (2-bromophenyl)-sulfonyl(cyclopropyl)carbamate (341 mg) and potassium carbonate (520mg) in dimethoxyethane (10ml) under nitrogen was treated with [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (complex with dichloromethane 1 :1 , 100mg) and the mixture heated under reflux for 18 h. The mixture was cooled to 20°, diluted with EtOAc (25ml) and filtered through celite. The filtrate was evaporated in vacuo to give a residue which was purified by Biotage. Elution with diethyl ether-PE (4:1) gave the title compound (262mg). LCMS RT = 4.15min, ES -ve 822 (MHC02)".
iv) N-Cvclopropyl-3'-r(2-r(6-(r(2R)-2-(2,2-dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethyllamino)hexyl)oxylethoxy)methyll-1.1'-biphenyl-2-sulfonamide A stirred mixture of 1 ,1-dimethylethyl cyclopropyl{[3'-({2-({6-[(5R)-5-(2,2-dimethyl-4H- 1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)-1 ,1'-biphenyl- 2-yl]sulfonyl}carbamate (260mg) and potassium trimethylsilanolate (420mg) in THF (10ml) was heated under reflux for 2 h. The mixture was cooled to 20°, poured into phosphate buffer solution (pH6.5, 50ml) and extracted with EtOAc (3x30ml). The combined organic extracts were washed with water (50ml), dried (MgSO4) and the solvent evaporated in vacuo to give a residue which was purified by Biotage. Elution with dichloromethane-ethanol-ammonia (100:8:1) gave the title compound (132mg). LCMS RT = 3.06min, ES +ve 653 (MH)+.
v) N-Cvclopropyl-3'-r(2-(f6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)- phenyllethyl)amino)hexylloxy}ethoxy)methyll-1.1'-biphenyl-2-sulfonamide acetate The title compound was prepared by a procedure similar to that described in Example 1xiii). LCMS RT = 2.75min, ES +ve 613 (MH)+.
Example 26
Synthesis of N-(3-f(2-(r6-(((2R)-2-hvdroxy-2-r4-hvdroχy-3-(hvdroxymethyl)- phenvnethyl)amino)hexylloxy>ethoxy)methyllphenyl)-N'-r3-(phenylethvnyl)phenyllurea
i) N-r3- 2-((6-r(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- yllhexyl)oxy)ethoxy)methyl)phenyll-N'-(3-iodophenyl)urea 3-lodophenylisocyanate (500mg) was added to a solution of (5R)-3-{6-[2-{[(3- aminophenyl)methyl]oxy}ethoxy]hexyl}-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-1 ,3- oxazolidin-2-one (700mg) in dichloromethane (14ml) and the mixture was stirred at 20° under nitrogen for 5h. Isopropanol (14ml) was added and the mixture was stirred for 16h. The solvent was evaporated in vacuo to give a residue that was purified by Biotage. Elution with EtOAc-PE (2:1 ) gave the title compound (800mg). LCMS RT = 4.02min, ES +ve 744 (MH)+.
ii) N-r3-((2-((6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- vnhexyl)oxy)ethoxy)methyl)phenyll-N'-r3-(phenylethynyl)phenyllurea
A solution of N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3- oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]-N'-(3-iodophenyl)urea (393mg) and phenylacetylene (77mg) in DMF (6ml) was treated with diisopropylethylamine (5ml) and nitrogen was passed through the solution for 5 min. Copper (I) iodide (10mg) and dichlorobis(triphenylphosphine)palladium(ll) (47mg) were added and the mixture was stirred under nitrogen at 20° for 21.5 h. The solvent was evaporated in vacuo and EtOAc (15ml) was added. The supematent solution was collected and the solvent evaporated in vacuo to give a residue which was purified by Biotage. Elution with dichloromethane-ethanol-ammonia (325:8:1) gave the title compound (328mg). LCMS RT = 3.93min, ES +ve 718 (MH)+.
iii) N-(3-r(2-r(6-(r(2R)-2-(2,2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-hvdroxyethyll- amino>hexyl)oxylethoxy)methyllphenyl>-N'-f3-(phenylethvnyl)phenvnurea The title compound was prepared by a procedure similar to that described in Example 25iv). LCMS RT = 3.35min, ES +ve 692 (MH)+.
iv) N-(3-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyl)- amino)hexylloxy)ethoxy)methvnphenyl)-N'-r3-(phenylethvnyl)phenvπurea A solution of N-{3-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]ethoxy)methyl]phenyl}-N'-[3-(phenylethynyl)-phenyl]urea (242mg) in MeOH (8ml) was loaded under gravity onto an SCX cartridge which had been pre-conditioned with MeOH. Elution with MeOH then ammonia-MeOH (15:100) gave a residue which was passed through an SCX cartridge as described above two more times. The resulting residue was purified by Biotage. Elution with dichloromethane-ethanol-ammonia (50:8:1) gave the title compound (145mg). LCMS RT = 3.34min, ES +ve 652 (MH)\ Example 27
Synthesis of N-(3-r(2-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)- phenyllethyl)amino)hexynoxy)ethoxy)methyllphenyl)-N'-r3-(2-phenylethyl)-phenyllurea compound with (2E)-but-2-enedioic acid (3:2)
A solution of N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)- phenyl]ethyl}amino)hexyl]oxy}ethoxy)methyl]phenyl}-N'-[3-(phenylethynyl)-phenyl]urea (70mg) in EtOH (15ml) was hydrogenated over 10% palladium on activated charcoal (70mg). After 2 h the mixture was filtered through celite and the solvent was partially evaporated in vacuo. Fumaric acid (6.2mg) was added and the solvent was evaporated in vacuo to give a residue. The residue was treated with hot MeOH (10ml) and was filtered. The filtrate was evaporated in vacuo to give the title compound (48mg). LCMS RT = 3.25min, ES +ve 655 (MH)+.
Example 28
Synthesis of cvclopentyl 3-r(2-(f6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyllethyl)amino)hexylloxy)ethoxy)methyllphenylcarbamate acetate
i) Cvclopentyl 3-«2-((6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3- oxazolidin-3-yllhexyl)oxy)ethoxy)methyl)phenylcarbamate
A stirred solution of (5R)-3-{6-[2-{[(3-aminophenyl)methyl]oxy}ethoxy]-hexyl}-5-(2,2- dimethyl-4H-1 ,3-benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (201 mg) and diisopropylethylamine (0.54ml) in dichloromethane (10ml) under nitrogen was treated with cyclopentychloroformate (0.348ml) and the mixture was stirred at 20° for 51 h. Sat. sodium bicarbonate solution (20ml) was added and the mixture was extracted with dichloromethane (3x20ml). The combined extracts were dried (Na2S04) and the solvent evaporated in vacuo to give a residue which was purified by Biotage. Elution with dichloromethane-ethanol-ammonia (275:8:1) gave the title compound (100mg). LCMS RT = 3.80min, ES +ve 611 (MH)+.
ii) Cvclopentyl 3-r(2-r(6-(r(2R)-2-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2- hvdroxyethyllamino)hexyl)oxylethoxy)methyllphenylcarbamate
The title compound was prepared by a procedure similar to that described in Example
25 iv). LCMS RT = 3.05min, ES +ve 585 (MH)+. iii) Cvclopentyl 3-r(2- r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyll- ethyl)amino)hexylloxy)ethoxy)methyllphenylcarbamate acetate The title compound was prepared by a procedure similar to that described in Example 1xiii). LCMS RT = 2.71min, ES +ve 545 (MH)\
Example 29
Synthesis of 5-{3'-r(2-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)- phenyllethyl)amino)hexylloxy}ethoxy)methyll-1 ,1'-biphenyl-3-yl>pyrimidine-2,4(1H,3H)- dione acetate
i) (5R)-3-(6-r2-(r(3'-(2,4-bis(1.1-Dimethylethyl)oxylpyrimidin-5-yl>-1.1'-biphenyl-3- yl)methoxy)ethoxylhexyl)-5-(2,2-dimethyl-4H-1.3-benzodioxin-6-yl)-1.3-oxazolidin-2-one The title compound was prepared by a procedure similar to that described in Example 25 iii). LCMS RT = 4.43min, ES +ve 782 (MH)+.
ii) (1 R)-2-(r6-(2-(r3'-(2.4-bisr(1.1-Dimethylethyl)oxylpyrimidin-5-yl)-1 ,1'-biphenyl-3- yllmethoxy)ethoxy)hexyllamino>-1-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)ethanol The title compound was prepared by a procedure similar to that described in Example 21viii). LCMS RT = 3.73min, ES +ve 756 (MH)+.
iii) 5- 3'-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyl1ethyl)- amino)hexylloxy)ethoxy)methvn-1 ,1'-biphenyl-3-yl)pyrimidine-2,4(1H,3H)-dione acetate The title compound was prepared by a procedure similar to that described in Example 1xiii)). LCMS RT = 2.57min, ES +ve 604 (MH)+.
Example 30
Synthesis of 4-1(1 R)-1-hvdroxy-2-f(6-(2-r(3-iodobenzyl)oxylethoxy)hexyl)amino]-ethyl)-2-
(hvdroxymethyl)phenol acetate
i) 2-((3-lodophenyl)methoxy)ethanol
The title compound was prepared by a procedure similar to that described in Example 21 i). LCMS RT = 2.84min, ES +ve 296 (MNH4)+.
ii) 1 -[(2-r(6-Bromohexyl)oxylethoxy)methvn-3-iodobenzene The title compound was prepared by a procedure similar to that described in Example 21 ii). LCMS RT = 4.12min.
iii) (5R)-5-(2.2-Dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-(6-f2-((3-iodophenyl)- methoxy)ethoxy1hexyl)-1.3-oxazolidin-2-one
The title compound was prepared by a procedure similar to that described in Example 21 iii). LCMS RT = 3.87min, ES +ve 610 (MH)+.
iv) (1 R)-1-(2.2-Dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-r(6-(2-r(3-iodobenzyl)oxyl- ethoxy)hexyl)amino1ethanol
The title compound was prepared by a procedure similar to that described in Example 21viii). LCMS RT = 3.07min, ES +ve 584 (MH)+.
v) 4-1(1 R)-1-Hvdroxy-2-r(6- 2-r(3-iodobenzyl)oxylethoxy)hexyl)aminolethyl)-2- (hvdroxymethyl)phenol acetate The title compound was prepared by a procedure similar to that described in Example 1xiii). LCMS RT = 2.73min, ES -ve 542 (M-H)".
Example 31
Synthesis of 3'-r(2-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenvn- ethyl)amino)hexylloxy>ethoxy)methyll-1 ,1'-biphenyl-3-ol acetate
i) (5R)-5-(2,2-Dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-(6-r2-(r(3'-hvdroxy-1 ,r-biphenyl-3- vDmethylloxylethoxyl hexyl)- 1.3-oxazol id in-2-one
A stirred mixture of (5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-3-{6-[2-{[(3- iodophenyl)methyl]oxy}ethoxy]hexyl}-1,3-oxazolidin-2-one (300mg), 3- hydroxyphenylboronic acid (102mg), tripotassium phosphate (417mg) and dichlorobis(triphenylphosphine)palladium(ll) (100mg) in dimethoxymethane (10ml) under nitrogen was heated under reflux for 4 h. The mixture was cooled to 20° and diluted with water (50ml). The mixture was extracted with EtOAc (2x25ml) and the combined extracts washed with water (50ml) and dried (Na2S04). Solvent evaporation in vacuo gave a residue which was purified by Biotage. Elution with diethyl ether gave the title compound (130mg). LCMS RT = 3.74min, ES +ve 593 (MNH4)+.
ii) 3'-r(2-r(6- r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-hvdroxyethvn- amino)hexyl)oxylethoxy)methvH-1 ,1'-biphenyl-3-ol The title compound was prepared by a procedure similar to that described in Example 21viii). LCMS RT = 2.99min, ES +ve 550 (MH)+.
iii) 3'-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyll- amino)hexynoxy)ethoxy)methyll-1 ,1'-biphenyl-3-ol acetate
The title compound was prepared by a procedure similar to that described in Example 1xiii). LCMS RT = 2.69min, ES +ve 510 (MH)+.
The following examples were prepared similarly:
Example 32
N-(3-Ethylphenyl)-N,- 3-r(2-(r6- (2R)-2-hvdroxy-2-f4-hvdroxy-3- (hvdroxymethyl)phenyllethyl|amino)hexylloxy>ethoxy)methyllphenyl)urea acetate LCMS RT =3.00 min, ES +ve 580 (MH)+ .
Example 33
N~f3-r(2-(r6- (2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenvnethyl amino)hexylloxy>ethoxy)methyllphenyl)-N'-(3- methylphenvDurea acetate LCMS RT =2.73 min, ES +ve 566 (MHf.
Example 34
N- 3-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyl1ethyl}amino)hexylloxy)ethoxy)methyllphenyl)-N'-r3- (trifluoromethyPphenyllurea acetate
LCMS RT = 2.91 min, ES +ve 620 (MHf.
Example 35
N-(3.5-Dichlorophenyl)-N'-(2-r(2-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyllethyl)amino)hexyπoxylethoxy)methyllphenyl>urea acetate
LCMS RT =3.19 min, ES +ve 620, 622, 623 (MHf.
Example 36 N-(3-Chlorophenyl)-N'-(3-r(2- r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyllethyl)amino)hexylloxy>ethoxy)methyllphenyl)urea acetate LCMS RT =3.01 min, ES +ve 586, 588 (MHf.
Example 37
N-(3-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyll- ethyl)amino)hexyπoxy)ethoxy)methyllphenyl)-N'-(3-iodophenyl)urea acetate LCMS RT =3.12 min, ES +ve 677 (MHf.
Example 38
4-1(1 R)-2-r(6-(2-r(3-Aminobenzyl)oxylethoxy hexyl)aminol-1-hydroxyethyl)-2-
(hvdroxymethyl)phenol acetate
LCMS RT =4.32 min, ES +ve 433 (MHf.
Example 39
N- 3-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyl}- amino)hexylloxy)ethoxy)methyllphenyl)pyridine-3-carboxamide acetate LCMS RT =2.31 min, ES +ve 538 (MHf.
Example 40
N-(3-f(2-(r6-( (2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyll- amino)hexyl1oxy}ethoxy)methyllphenylMhiophene-2-carboxamide acetate LCMS RT =2.69 min, ES +ve 543 (MHf.
Example 41
N-(3-r(2-(f6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyl)- amino)hexynoxy)ethoxy)methyllphenyl)benzamide acetate LCMS RT = 2.72min, ES +ve 537 (MHf.
Example 42
3-(Benzoylamino)-N- 3-r(2- r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)- phenvπethyl>amino)hexylloxy>ethoxy)methyllphenyl)benzamide acetate LCMS RT = 2.70 min, ES +ve 656 (MHf
Example 43 N-(3-f 3-r(2-(r6- (2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethylV amino)hexylloxy)ethoxy)methyllphenyl)amino)carbonyllphenyl>thiophene-2- carboxamide acetate LCMS RT =2.74 min, ES +ve 662 (MHf.
Example 44
N 3-r( 3-r(2-(r6-(((2R)-2-Hvdroxy-2-f4-hvdroxy-3-(hvdroxymethyl)phenyllethyl)- amino)hexynoxy)ethoxy)methyllphenyl}amino)carbonyllphenyl)nicotinamide acetate (1 :2) LCMS RT = 2.51 min, ES +ve 657 (MHf.
Example 45
N-(3-(r((3-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethviμ amino)hexylloxy)ethoxy)methyllphenyl)amino)carbonvnamino)phenyl)- benzenesulfonamide
LCMS RT = 2.80min, ES +ve 707 (MHf .
Example 46
4-r(1R)-2-( 6-r2-(1.1'-Biphenyl-2-ylmethoxy)ethoxylhexyl)amino)-1-hvdroxyethyll-2- (hydroxymethyl)phenol acetate
LCMS RT = 2.77min, ES +ve 494 (MHf.
Example 47
4-((1 R)-1-Hvdroxy-2-r(6- 2-r(4'-methoxy-1.1'-biphenyl-2-yl)methoxylethoxy)- hexyl)amino1ethyl)-2-(hvdroxymethyl)phenol acetate
LCMS RT = 2.79min, ES +ve 524 (MHf.
Example 48
4-((1 R)-2-r(6- 2-r(3-Bromobenzyl)oxylethoxy)hexyl)aminol-1-hvdroxyethyl)-2- (hvdroxymethyl)phenol acetate
LCMS RT = 2.68min, ES +ve 498 (MHf.
Example 49
2-(Hvdroxymethyl)-4- (1 R)-1-hvdroxy-2-r(6-(2-r(3-phenoxybenzyl)oxylethoxy>- hexyDaminolethv phenol acetate LCMS RT = 2.85min, ES +ve 510 (MHf.
Example 50
4-1(1 R)-1-Hvdroxy-2-r(6-(2-r(4-hvdroxybenzyl)oxylethoxy)hexyl)aminolethyl)-2- (hydroxymethyl)phenol
LCMS RT = 2.40 min, ES +ve 434 (MHf.
Example 51
5-(3-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyll- amino)hexyπoxy)ethoxy)methyllphenyl}pyrimidine-2,4-diol acetate
LCMS RT = 2.19 min, ES +ve 528 (MHf.
Example 52
4- (1 R)-2-r(6-{2-r(2,5-Dichlorobenzyl)oxylethoxy)hexyl)aminol-1-hvdroxyethyl>-2- (hvdroxymethyl)phenol acetate
LCMS RT = 2.86min, ES +ve 486 (MH)+, 488 (MHf.
Example 53
4-1(1 R)-2-r(6-(2-r(3,5-Dimethylbenzyl)oxylethoxy)hexyl)aminol-1-hvdroxyethyl)-2- (hvdroxymethyl)phenol acetate
LCMS RT = 2.76min, ES +ve 446 (MHf.
Example 54
4-((1 R)-2- r6-(2-(r2-Fluoro-6-(trifluoromethyl)benzylloχy)ethoxy)hexyllaminoM- hvdroxyethyl)-2-(hvdroxymethyl)phenol
LCMS RT = 2.65min, ES +ve 504 (MHf.
Example 55
2-(Hvdroxymethyl)-4-((1 R)-1-hvdroxy-2-(r6-(2-(r3-(trifluoromethoxy)benzyll- oxy)ethoxy)heχyllamino)ethyl)phenol acetate
LCMS RT = 2.89min, ES +ve 502 (MHf.
Example 56
2-(Hvdroxymethyl)-4-((1 R)-1-hvdroxy-2-r(6-(2-r(2-methyl-1.1'-biphenyl-3- yl)methoxylethoxy)hexyl)aminolethyl)phenol LCMS RT = 2.89min, ES +ve 508 (MHf.
Example 57
3-r(2.3-Dihvdroimidazof2.1-biri .3lthiazol-6-ylmethyl)aminol-N-(3-r(2-(r6-(((2R)-2- hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyl)amino)hexylloxy)ethoxy)- methyllphenvDbenzamide acetate (1 :3) LCMS RT = 2.43 min, ES +ve 690 (MHf.
Example 58
N-(3- r((3-r(2-(r6-( (2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethviμ amino)hexylloxy)ethoxy)methyllphenyl)amino)carbonyllamino>phenyl)benzamide
LCMS RT = 2.80 min, ES +ve 671 (MHf.
Example 59
N-(3-(r( 3-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyll- amino)hexylloxy)ethoxy)methyllphenyl>amino)carbonyllamino}phenyl)thiophene-2- carboxamide LCMS RT = 2.80 min, ES +ve 677 (MHf.
Example 60 N-(1.1'-Biphenyl-3-yl)-N'-{3-r(2-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyllethyl)amino)hexynoxy)ethoxy)methyllphenyl)urea LCMS RT =3.20 min, ES +ve 628 (MHf.
Example 61 N-(3-Aminophenyl)-N'-(3-r(2-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3-(hvdroxy- methyl)phenyllethyl)amino)hexylloxy)ethoxy)methyllphenyl)urea acetate LCMS RT =2.38 min, ES +ve 567 (MHf.
Example 62 3-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenvnethyl amino)- hexylloxy)ethoxy)methyll-N-methylbenzenesulfonamide compound with (2E)-but-2- enedioic acid (2:1 )
LCMS RT = 2.25min, ES +ve 511 (MHf. Example 63
N- 3-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenvnethyl)- amino)hexylloxy)ethoxy)methyllphenviμ3-r(thien-2-ylsulfonyl)aminolbenzamide compound with (2E)-but-2-enedioic acid (2:1 ) LCMS RT = min, 2.72ES +ve 698 (MHf.
Example 64
Λ/-(3-r(2-(r5-(((2f?)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyl) amino)pentylloxy>ethoxy)methvnphenv^-/V-phenylurea acetate
i) 1 -({2-r(5-Bromopentyl)oxylethoxy)methyl)-3-nitrobenzene
The title compound was prepared by a procedure similar to that described in example
21 ii). LCMS RT = 3.42min
ii) (5ff)-5-(2.2-Dimethyl-4r -1 ,3-benzodioxin-6-yl)-3-(5-(2-r(3-nitrobenzyl)oxyl ethoxy)pentyl)-1 ,3-oxazolidin-2-one
The title compound was prepared by a procedure similar to that described in example 21 iii). LCMS RT = 3.46min
iii) (5f?)-3-(5-(2-r(3-Aminobenzyl)oxylethoxy|pentyl)-5-(2.2-dimethyl-4H-1.3-benzodioxin-
6-yl)-1 ,3-oxazolidin-2-one
The title compound was prepared by a procedure similar to that described in example 21 iv). LCMS RT = 3.13min
iv) Λ/-(3-(r2-( 5-r(5R)-5-(2.2-Dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- yllpentyl)oxy)ethoxylmethyl)phenyl)-Λ/'-phenylurea
The title compound was prepared by a procedure similar to that described in example 21 v). LCMS RT = 3.58min
v) Λ/-f3-((2-f(5-(r(2f?)-2-(2.2-Dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-hvdroxyethyll amino)pentyl)oxylethoxy)methyl)phenyll-tV-phenylurea
The title compound was prepared by a procedure similar to that described in example 1 xii). LCMS RT = 2.79min vi) Λ/- 3-r(2-(r5- (2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl) phenyllethyl) amino)pentylloxy)ethoxy)methvnphenyiμA/'-phenylurea acetate
The title compound was prepared by a procedure similar to that described in example 1 xiii). LCMS RT = 2.42min, ES +ve 538 (MHf
Example 65
Λ/-(3-r(3-(r5-(((2f?)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenvnethyl) amino)pentylloxy>propoxy)methyllphenviμΛ/'-phenylurea acetate
i) 3-r(3-Nitrobenzyl)oxy1propan-1 -ol
The title compound was prepared by a procedure similar to that described in example
21 i). TSP +ve 229 (MHf
ii) 1 -((3-F(5-Bromopentyl)oxylpropoxy)methyl)-3-nitrobenzene
The title compound was prepared by a procedure similar to that described in example 21 ii). LCMS RT = 3.80min
iii) (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-3-(5-(3-r(3-nitrobenzyl)oxyl propoxy)pentyl)-1 ,3-oxazolidin-2-one
The title compound was prepared by a procedure similar to that described in example 21 iii) LCMS RT = 3.57min
iv) (5ffl-3-(5-(3-r(3-Aminobenzyl)oxy1propoxy>pentyl)-5-(2.2-dimethyl-4H-1.3- benzodioxin-6-yl)-1.3-oxazolidin-2-one
The title compound was prepared by a procedure similar to that described in example 21 iv). LCMS RT = 3.21 min
v) Λ/-(3-fr3-((5-r(5f?)-5-(2.2-Dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- yl1pentyl)oxy)propoxylmethyl)phenyl)-Λ/'-phenylurea
The title compound was prepared by a procedure similar to that described in example 21 v). LCMS RT = 3.62min vi) Λ/-r3-((3-U5-(r(2 )-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-hvdroxyethyll amino)pentyl)oxylpropoxy)methyl)phenyll-Λt;-phenylurea
The title compound was prepared by a procedure similar to that described in example 1 xii). LCMS RT = 2.94min
vii) Λ/-(3-r(3-(r5-(((2R)-2-Hvdroxy-2-f4-hvdroxy-3-(hvdroxymethyl)phenyllethyl) amino)pentylloxy}propoxy)methyllphenviμΛ/'-phenylurea acetate The title compound was prepared by a procedure similar to that described in example 1 xiii). LCMS RT = 2.50min, ES +ve 552 (MHf
Example 66
Λ/-(3-f(2-(r7-(((2f?)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyl) amino)heptvπoxy)ethoxy)methyllphenyl)-Λ/'-phenylurea acetate
i) 1 -((2-r(7-Bromoheptyl)oxylethoxy)methyl)-3-nitrobenzene
The title compound was prepared by a procedure similar to that described in example 21 ii). LCMS RT = 3.83min
ii) (5 )-5-(2,2-Dimethyl-4ry-1 ,3-benzodioxin-6-yl)-3-(7-(2-r(3-nitrobenzyl)oxyl ethoxy}heptyl)-1.3-oxazolidin-2-one
The title compound was prepared by a procedure similar to that described in example 21 iii). LCMS RT = 3.67min
iii) (5f?)-3-(7- 2-r(3-Aminobenzyl)oxylethoxy)heptyl)-5-(2.2-dimethyl-4H-1.3-benzodioxin- 6-yl)-1.3-oxazolidin-2-one
The title compound was prepared by a procedure similar to that described in example 21 iv). LCMS RT = 3.40min
iv) Λ/-(3-fr2-((7-r(5r?)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- yllheptyl)oxy)ethoxylmethyl)phenyl)-Λ/'-phenylurea
The title compound was prepared by a procedure similar to that described in example 21 v). LCMS RT = 3.74min v) Λ/-r3-( 2-r(7-(r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-hvdroxyethyll amino)heptyl)oxy1ethoxy methyl)phenyll-Λ/'-phenylurea
The title compound was prepared by a procedure similar to that described in example 1 xii). LCMS RT = 2.91 min
vii) Λ/-(3-r(2-(r7-( (2 ?)-2-Hvdroxy-2-r4-hvdroχy-3-(hvdroxymethyl)phenyllethyl> amino)heptylloxy)ethoxy)methyllphenyl)-Λ/'-phenylurea acetate
The title compound was prepared by a procedure similar to that described in example 1 xiii). LCMS RT = 2.58min, ES +ve 566 (MHf
Example 67
Λ/-(3-(r((3-r(2-(r5-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyll ethyl)amino)pentvnoxy)ethoxy)methyllphenyl)amino)carbonyllamino>phenyl) nicotinamide acetate
i) Λ/-(3-(r2-«5-r(5R)-5-(2.2-Dimethyl-4r7-1 ,3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yllpentyl)oxy)ethoxylmethyl>phenyl)-tV-(3-nitrophenyl)urea
The title compound was prepared by a procedure similar to that described in example 21 v) using 3-nitrophenyl isocyanate and purified using Biotage eluting with DCM-MeOH (50:1). LCMS RT = 3.67min
ii) Λ/-(3-Aminophenyl)-Λ/'-(3-(r2-((5-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-
1 ,3-oxazolidin-3-yllpentyl}oxy)ethoxylmethyl)phenyl)urea
The title compound was prepared by a procedure similar to that described in example 21 iv). LCMS RT = 3.22min
iii) Λ/-r3-( r(3-(f2-((5-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3- oxazolidin-3-vπpentyl>oxy)ethoxylmethyl)phenyl)aminolcarbonyl>amino) phenyllnicotinamide The title compound was prepared by a procedure similar to that described in example
21 vii). LCMS RT = 3.38min iv) Λ/-(3-r r3-((2-r(5-(r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethyllamino)pentyl)oxylethoxy)methyl)phenyllamino)carbonyl)aminol phenvDnicotinamide
The title compound was prepared by a procedure similar to that described in example 21 vii). It was purified using Prep. TLC (silica, 1 mm thick, 20x20cm) eluting with DCM-
EtOH : aqueous ammonia S.G. 0.880 (100:8:1) to yield the title compound (83mg). LCMS RT = 2.73min
v) Λ/-(3-(r((3-r(2-fr5-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenvn ethyl)amino)pentylloxy)ethoxy)methyllphenyl)amino)carbonyllamino)phenyl) nicotinamide acetate
The title compound was prepared by a procedure similar to that described in example 21 viii) LCMS RT = 2.45min, ES +ve 658 (MHf
Example 68
Λ/-(3- r((3-r(3-(r5-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyll ethyl)amino)pentvπoxy>propoxy)methvnphenyl)amino)carbonyllamino>phenyl)nicotinami de acetate
i) Λ/-(3-(r3-α5-r(5R)-5-(2.2-Dimethyl-4rY-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yllpentyl)oxy)propoxy1methyl>phenyl)-Λ/'-(3-nitrophenyl)urea
The title compound was prepared by a procedure similar to that described in example 21 v). LCMS RT = 3.75min
ii) /V-(3-Aminophenyl)-/V-(3-(r3-((5-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-
1.3-oxazolidin-3-vHpentyl)oxy)propoxylmethyl)phenyl)urea
The title compound was prepared by a procedure similar to that described in example 21 iv). LCMS RT = 3.31 min
iii) Λ/-r3-((r(3-(r3-((5-r(5R)-5-(2.2-Dimethyl-4r -1.3-benzodioxin-6-yl)-2-oxo-1.3- oxazolidin-3-yl1pentyl)oxy)propoxy1methyl)phenyl)aminolcarbonyl)amino) phenyllnicotinamide The title compound was prepared by a procedure similar to that described in example 21 vii). LCMS RT = 3.46min
iv) Λ/-(3-r((r3-((3-r(5-(r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethyllamino>pentyl)oxylpropoxy>methyl)phenyllamino}carbonyl)aminolphenyl)nic otinamide
The title compound was prepared by a procedure similar to that described in example 21 viii) LCMS RT = 2.80min
v) Λ/-(3-(r((3-r(3-(f5-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyll ethyl)amino)pentylloxy>propoxy)methyllphenyl)amino)carbonyllamino>phenyl)nicotinami de acetate
The title compound was prepared by a procedure similar to that described in example 1 xiii). LCMS RT = 2.51 min, ES +ve 672 (MHf
Example 69
Λ/-(3-(r( 3-r(3-(r7-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyll ethyl>amino)heptylloxy>propoxy)methvnphenyl>amino)carbonyllamino>phenyl) nicotinamide acetate
i) Λ/-(3-(r3-((7-f(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- vnheptyl)oxy)propoxylmethyl)phenyl)-/V-(3-nitrophenyl)urea
The title compound was prepared by a procedure similar to that described in example
21 v). LCMS RT = 3.84min
ii) A/-(3-Aminophenyl)-r -(3-ir3-((7-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-
1.3-oxazolidin-3-yllheptyl)oxy)propoxylmethyl>phenyl)urea
The title compound was prepared by a procedure similar to that described in example
21 iv). LCMS RT = 3.44min
iii) Λ/-r3-((r(3-(f3-((7-r(5R)-5-(2.2-Dimethyl-4rV-1 ,3-benzodioxin-6-yl)-2-oxo-1.3- oxazolidin-3-yllheptyl>oxy)propoxylmethyl)phenyl)aminolcarbonyl)amino) phenyllnicotinamide The title compound was prepared by a procedure similar to that described in example 21 vii). LCMS RT = 3.57min
iv) Λ/-(3-r((r3- 3-r(7-(f(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethyllamino)heptyl)oxylpropoxy)methyl)phenvnamino carbonyl)amino1phenyl)nic otinamide
The title compound was prepared by a procedure similar to that described in example 21 viii). LCMS RT = 2.83min
v) Λ/-(3-{r((3-r(3- f7-( (2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenvn ethyl)amino)heptvnoxy)propoxy)methyllphenyl>amino)carbonyllamino>phenyl)nicotinami de acetate
The title compound was prepared by a procedure similar to that described in example 1 xiii). LCMS RT = 2.58min, ES +ve 686 (MHf
Example 70
Λ/-(3-r(2-(r5-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenvnethyl) amino)pentylloxy)ethoxy)methvπphenyl)methanesulfonamide acetate
i) Λ/-(3-(r2-((5-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- vHpentyl)oxy)ethoxylmethyl)phenyl)methanesulfonamide
A solution of (5R)-3-(5-{2-[(3-aminobenzyl)oxy]ethoxy}pentyl)-5-(2,2-dimethyl-4H-1 ,3- benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (52mg) in pyridine (4ml) was treated with methanesulfonyl chloride (13mg) at 20°C for 3h. The mixture was quenched with sat. aqueous sodium bicarbonate (20ml) and partitioned with DCM. The organic layer was dried (Na2S04) and the solvent was removed in vacuo. The residue was purified using SPE eluting with DCM then EtOAc-PE (3:1 ). The selected fractions were evaporated in vacuo to yield the title compound (39mg). LCMS RT = 3.29min
ii) Λ/-r3-((2-r(5-(r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-hvdroxyethyll amino)pentyl)oxylethoxy)methyl)phenvHmethanesulfonamide The title compound was prepared by a procedure similar to that described in example 1 xii). LCMS RT = 2.53min
iii) Λ/- 3-r(2- r5-( (2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenvnethyl amino)pentylloxy)ethoxy)methyllphenyl>methanesulfonamide acetate
The title compound was prepared by a procedure similar to that described in example 1 xiii). LCMS RT = 2.12min, ES +ve 497 (MHf
Example 71 Λ/-(3-r(3-(r5-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyll amino)pentvnoxy)propoxy)methyllphenyllmethanesulfonamide acetate
i) 1 -((3-f(5-Bromopentyl)oxylpropoxy>methyl)-3-nitrobenzene
The title compound was prepared by a procedure similar to that described in example 24 ii). LCMS RT = 3.80min
ii) (5R)-5-(2.2-Dimethyl-4r -1.3-benzodioxin-6-yl)-3-(5- 3-r(3-nitrobenzyl)oxyl propoxy)pentyl)-1 ,3-oxazolidin-2-one
The title compound was prepared by a procedure similar to that described in example 21 iii). LCMS RT = 3.57min
iii] (5R)-3-(5-(2-r(3-Aminobenzyl)oxylethoxy pentyl)-5-(2.2-dimethyl-4H-1.3-benzodioxin- 6-yl)-1 ,3-oxazolidin-2-one
The title compound was prepared by a procedure similar to that described in example 21 iv). LCMS RT = 3.21 min
iv) Λ/-(3-(r3-((5-f(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- vπpentyl)oxy)propoxylmethyl)phenyl)methanesulfonamide
The title compound was prepared by a procedure similar to that described in example 70 i) purified using Biotage eluting with EtOAc-PE (3:1 ).
LCMS RT = 3.26min v) Λ/-r3-( 3-r(5-(r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-hvdroxy ethyllamino)pentyl)oxylpropoxy)methyl)phenyllmethanesulfonamide
The title compound was prepared by a procedure similar to that described in example 1 xii). LCMS RT = 2.57min
vi) Λ/-(3-r(3- r5-( (2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyll amino)pentvπoxy)propoxy)methvπphenyl)methanesulfonamide acetate The title compound was prepared by a procedure similar to that described in example 1 xiii). LCMS RT = 2.20min
Example 72
Λ/-(3-r(2-(r7-(((2R)-2-Hvdroxy-2-f4-hvdroχy-3-(hvdroxymethyl)phenyllethyl amino)heptylloxy)ethoxy)methyllphenyl)methanesulfonamide acetate
i) Λ/-(3-(r2-((7-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- vnheptyl)oxy)ethoxylmethyl}phenyl)methanesulfonamide
The title compound was prepared by a procedure similar to that described in example 70 i). LCMS RT = 3.48min
ii) Λ/-r3-((2-r(7-(r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-hvdroxyethyll amino)heptyl)oxylethoxy)methyl)phenyllmethanesulfonamide
The title compound was prepared by a procedure similar to that described in example 1 xii). LCMS RT = 2.69min
iii) Λ/-(3-r(2-(r7-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyl> amino)heptvnoxy)ethoxy)methyllphenyl)methanesulfonamide acetate The title compound was prepared by a procedure similar to that described in example 1 xiii). LCMS RT = 2.28min, ES +ve 525 (MHf
Example 73
Λ/-(3-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyl) amino)hexylloxy)ethoxy)methvnphenyl)benzenesulfonamide acetate i) Λ/-(3-(r2-«6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1 ,3-oxazolidin-3- vnhexyl)oxy)ethoxylmethyl)phenyl)benzenesulfonamide
The title compound was prepared by a procedure similar to that described in example 70 i) using benzenesulfonyl chloride and purified using SPE and eluting with DCM- MeOH (300:1 ) then at 100:1. LCMS RT = 3.51 min
ii) Λ/-(3-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyl amino)hexylloxy)ethoxy)methyllphenyl)benzenesulfonamide acetate
The title compound was prepared by a procedure similar to that described in example 1 xii). The product was purified using SCX-2 cartridge eluting with EtOH then EtOH-2M ammonia in MeOH (9:1). The resulting residue after solvent evaporation was further purified using SPE eluting with DCM then varying ratios of DCM-EtOH-aqueous ammonia S.G. 0.880. The selected fractions were evaporated in vacuo to yield the freebase. This was dissolved in AcOH (4ml) then azeotroped with MeOH (3χ8ml) to yield the title compound (214mg). LCMS RT = 2.50min, ES +ve 573 (MHf
Example 74
4-((1 R)-2-(r6-(2-(r3-(Dimethylamino)benzylloxy)ethoxy)hexyllamino)-1-hydroxyethyl)-2-
(hvdroxymethyl)phenol
i) (5R)-3-r6-(2-(r3-(Dimethylamino)benzylloxy>ethoxy)hexyll-5-(2.2-dimethyl-4/-/-1.3- benzodioxin-6-yl)-1.3-oxazolidin-2-one
A solution of 3-dimethylaminobenzyl alcohol (641 mg) in DMF (3ml) under nitrogen was treated with sodium hydride (220mg, 60% in oil) and the mixture stirred at 20° for 15 min. A solution of 2-({6-[(5R)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3- oxazolidin-3-yl]hexyl}oxy)ethyl methanesulfonate (2.00g) in DMF (5ml) was added and the mixture was stirred at 20° for 21 h. Phosphate buffer solution (15ml, pH6.5) was added, the mixture stirred for 15 min and then extracted with EtOAc. The combined organic layers were washed with water, dried (Na2S04) and the solvent evaporated in vacuo. The residue was purified by Biotage (40g). Elution with EtOAc - PE (1 :2) gave the title compound (2.125g). LCMS RT = 3.47 min. ii] (1 R)-2-(r6-(2-(r3-(Dimethylamino)benzylloxy)ethoxy)hexyllaminoμi-(2.2-dimethyl-4r - 1 ,3-benzodioxin-6-yl)ethanol
The title compound was prepared by a procedure similar to that described in Example 1xii). LCMS RT = 2.38 min.
iii) 4-((1 R)-2-(r6-(2-{r3-(dimethylamino)benzvnoxy>ethoxy)hexyllaminoμi -hydroxyethyl)-
2-(hydroxymethyl)phenol
The title compound was prepared by a procedure similar to that described in Example
1xiii). LCMS RT = 2.17 min, ES +ve 461 (MHf
Example 75
3-r(2- r6-( (2R)-2-Hvdroxy-2-f4-hvdroxy-3-
(hvdroxymethyl)phenyllethyl)amino)hexyπoxy)ethoxy)methyll-N,N,N- trimethylbenzenaminium acetate compound with acetic acid (1 :1)
i] Benzyl 6-(2-(f3-(dimethylamino)benzvnoxy ethoxy)hexyir(2R)-2-(2.2-dimethyl-4H-1.3- benzodioxin-6-yl)-2-hvdroxyethyllcarbamate
A solution of (1 R)-2-{[6-(2-{[3-(dimethylamino)benzyl]oxy}ethoxy)hexyl]aminoμi-(2,2- dimethyl-4r7-1 ,3-benzodioxin-6-yl)ethanol (200mg) in dichloromethane (10ml) was treated under nitrogen with diisopropylethylamine (0.09ml) followed by benzyl chloroformate (0.099ml) and the mixture was stirred at 20° for 4 h. Saturated sodium bicarbonate solution was added and the mixture extracted with dichloromethane. The extract was dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by SPE (silica, 10g). Elution with dichloromethane - ethanol - 0.880 ammonia (250:8:1 ) gave the title compound (220mg). LCMS RT = 3.87 min.
ii) 3-112-r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-hvdroxyethyl1-13-oxo-15- phenyl-2.5.14-trioxa-12-azapentadec-1-yiμN.N,N-trimethylbenzenaminium iodide A solution of benzyl 6-(2-{[3-(dimethylamino)benzyl]oxy}ethoxy)hexyl[(2R)-2-(2,2- dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-hydroxyethyl]carbamate (571 mg) in DMF (9ml) was treated with iodomethane (0.09ml) and the mixture was stirred 20° for 16 h. The solvent was evaporated in vacuo and the residue was purified by SPE (silica, 10g). Elution with methanol - 0.880 ammonia (19:1) gave the title compound (346mg). LCMS RT = 2.79 min.
iii) 3- 2-r(6- [(2R)-2-(2.2-Dimethyl-4r -1.3-benzodioxin-6-yl)-2- hvdroxyethyllamino>heχyl)oxylethoxy)methyl)-N.N.N-trimethylbenzenaminium iodide
A solution of 3-{12-[(2R)-2-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-hydroxyethyl]-13- oxo-15-phenyl-2,5,14-trioxa-12-azapentadec-1-yiμN,N,N-trimethylbenzenaminium iodide (195mg) in ethanol (15ml) was hydrogenated over 10% palladium on carbon (194mg) for 5 h. The mixture was filtered through celite and the solvent evaporated in vacuo. The residue was purified by mass directed autopreparative HPLC to give the title compound (7mg). LCMS RT = 2.13 min.
iv) 3-r(2-(r6-( (2R)-2-Hvdroxy-2-f4-hvdroxy-3- (hvdroxymethyl)phenyllethyl)amino)hexylloxy)ethoxy)methyll-N.N.N- trimethylbenzenaminium acetate compound with acetic acid (1 :1 )
The title compound was prepared by a procedure similar to that described in Example 1xiii). LCMS RT = 1.87 min, ES +ve 475 M+
Example 76 N-(4-r(2-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyllethyl)amino)hexylloxy)ethoxy)methyllphenyl>-N'-phenylurea acetate
i) (5R)-3-(6-f2-r(4-Bromobenzyl)oxy1ethoxylhexyl)-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)-3-{6-[(2- hydroxyethyl)oxy]hexyl}-1 ,3-oxazolidin-2-one (2.00g) in DMF (25ml) under nitrogen was treated with sodium hydride (244mg, 60% in oil) and the mixture was stirred at 20° for 15 min. 4-Bromobenzyl bromide (1.40g) was added and the mixture was stirred at 20° for 18 h. Phosphate buffer solution (50ml, pH6.5) and water (50ml) were added and the mixture was extracted with EtOAc. The extract was washed with water, dried (Na2SO4) and the solvent evaporated in vacuo to give a residue. The residue was purified by chromatography on flash silica gel (40mm diameter column). Elution with EtOAc - PE (1 :1 ) gave the title compound (2.125g). LCMS RT = 3.77 min.
ii) (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-3-(6-r2-( 4- [(diphenylmethylene)aminolbenzyl)oxy)ethoxylhexyiμi .3-oxazolidin-2-one
A mixture of palladium (II) acetate (40mg), racemic-2,2'-bis(diphenylphosphino)-1 ,1 '- binaphthyl (166mg) and cesium carbonate (811mg) under nitrogen was treated with toluene (15ml) and benzophenone imine (0.36ml) followed by a solution of (5R)-3-(6-{2- [(4-bromobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-1 ,3- oxazolidin-2-one (1 ,00g) in toluene (10ml). The stirred mixture was heated to 100 ° for
18 h. The mixture was cooled to 20°, dichloromethane (25ml) was added and the mixture was filtered. The filtrate was evaporated in vacuo and the residue purified by chromatography on flash silica gel (30mm diameter column). Elution with EtOAc - PE (3:2) gave the title compound (890mg). LCMS RT = 4.07 min.
iii) (5R)-3-(6- 2-r(4-Aminobenzyl)oxy1ethoxy)hexyl)-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)-3-{6-[2-({4- [(diphenylmethylene)amino]benzyl}oxy)ethoxy]hexyl}-1 ,3-oxazolidin-2-one (860mg) in MeOH (13ml) was treated with sodium acetate (255mg) followed by hydroxylamine hydrochloride (162mg) and the mixture was stirred at 20° for 0.5 h. Phosphate buffer solution (30ml, pH6.5) was added and the mixture was extracted with EtOAc. The combined extracts were dried (Na2S0 ) and the solvent evaporated in vacuo. The residue was purified by SPE (silica, 10g). Elution with EtOAc - cyclohexane (1 :1 ) then (4:1) gave the title compound (321 mg). LCMS RT = 3.18 min.
iv) N-(4-(r2-«6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yllhexyl)oxy)ethoxylmethyl>phenyl)-N'-phenylurea
A solution of (5R)-3-(6-{2-[(4-aminobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1 ,3- benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (150mg) in dichloromethane (5ml) under nitrogen was treated with phenyl isocyanate (0.07ml) and the mixture stirred at 20° for 5 h. Isopropyl alcohol (5ml) was added and the solution was stirred for a further 18 h. The solvent was evaporated in vacuo and the residue purified by SPE (silica, 10g). Elution with EtOAc - cyclohexane (3:7) then EtOAc gave the title compound (159mg). LCMS RT = 3.68 min.
v) N-r4-((2-r(6-(r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethyllamino)hexyl)oxy1ethoxy)methyl)phenyll-N'-phenylurea
The title compound was prepared by a procedure similar to that described in Example 1xii). LCMS RT = 3.68 min.
vi) N-(4-r(2- r6-(((2R)-2-Hvdroxy-2-r4-hvdroχy-3- (hvdroxymethyl)phenvnethyl}amino)hexyπoxy>ethoxy)methyllphenyl)-N'-phenylurea acetate
The title compound was prepared by a procedure similar to that described in Example 1xiii). LCMS RT = 2.54 min, ES +ve 552 (MHf
Example 77
4-((R)-2- 6-r2-(2,6-Dichlorobenzyloxy)-ethoxyl-hexylaminoμi-hvdroxyethyl)-2- hydroxymethyl-phenol
i) 2-(2.6-Dichlorobenzyloxy)ethanol Sodium methoxide (104.4g, 1.93mol) was added portionwise to ethylene glycol (3.74L) under N2, keeping the temperature below 35°C. After 1-2 h, 2,6-dichlorobenzylbromide (400g, 1.67mol) was added and the mixture heated to 55-60°C for 1 h. On cooling to 20°C water (2.14L) was added and the mixture extracted with ethyl acetate (2.14L). The aqueous layer was separated and extracted twice with ethyl acetate (2.14L, 1.28L). The combined organic extracts were washed with water (2.14L) then evaporated to dryness to afford a colourless oil (371.8g) - LC RT = 4min. This may be chromatographed on silica (Biotage) eluting with 10% ethyl acetate in 60/80 petrol to afford the title compound.
1H NMR (500MHz, CDCI3) δ 7.33 (d, 2H, J=8.2Hz), 7.20 (t, 1 H, J=8.2Hz), 4.83 (s, 2H),
3.75 (m, 2H), 3.68 (m, 2H), 2.18 (t, 1 H, J=6.3Hz)
ii) 2-f2-(6-Bromo-hexyloxy)-ethoxymethyll-1 ,3-dichloro-benzene 50% aq NaOH (1.89L), 2-(2,6-dichlorobenzyloxy)ethanol (473.2g), 1 ,6-dibromohexane (2.44kg, 5eq) and tetrabutylammonium bromide (34.1g, 5mol%) in toluene (1.89L) was heated to 55-60°C for 8-20 h. On cooling water (558mL) and toluene (558mL) were added. The aqueous phase was separated and diluted with water (1 L) then back extracted with toluene (1.1L). The combined toluene extracts were washed twice with water (2.2L), then evaporated to dryness on a rotary evaporator. The excess 1 ,6- dibromohexane was removed using a wiped film evaporator, and the resulting crude product chromatographed on silica (5kg Biotage), eluting with 5% ethyl acetate in petrol 60/80, to give the title compound (503.2g) - LC RT = 7.0min.
iii) (R)-3-(6-r2-(2.6-Dichlorobenzyloxy)-ethoxy1-hexyl)-5-(2.2-dimethyl-4H- benzoπ .31dioxin-6-yl)-oxazolidin-2-one
Potassium te/t-butoxide (4.38g, 39mmol) was added to a solution of (5R)-5-(2,2- dimethyl-4H-1 ,3-benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (9.3g, 39mmol) in anhydrous DMF (100mL) under N2 and the reaction stirred for 1 h at ambient temperature. A solution of 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]-1 ,3-dichloro-benzene (15g, 39mmol) in anhydrous DMF (25mL) was added and the reaction allowed to stir at ambient temperature for 20 h. The reaction mixture was poured into ice/water (350mL) and extracted with ethyl acetate (300mL). The organic layer was separated then washed successively with water/saturated brine (250ml_/25mL), water/brine (25mL/10mL) and finally brine (150mL), before drying over sodium sulfate. The solution was concentrated to dryness under vacuum to afford the title compound as an oil (21.6g) - LC RT = 6.8min.
iv) (R)-2-(6-r2-(2.6-Dichlorobenzyloxy)-ethoxy1-hexylaminoμi-(2.2-dimethyl-4H- benzoH ,31dioxin-6-yl)-ethanol
The title compound was prepared by a procedure similar to that described in Example 4 (ii).
(v) 4-((R)-2-f6-r2-(2.6-Dichlorobenzyloχy)-ethoxyl-hexylamino)-1-hvdroxyethyl)-2- hydroxymethyl-phenol
1 N HCI (295mL) was added to a solution of (R)-2-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]- hexylamino}-1-(2,2-dimethyl-4/-/-benzo[1 ,3]dioxin-6-yl)-ethanol (52g, 0.099mol) in ethanol (312mL), and the reaction stirred at ambient temperature for 1.5 h. Saturated sodium bicarbonate solution (500mL) was added followed by dichloromethane (500mL). The aqueous layer was separated and extracted with further dichloromethane (500mL). The combined organic solutions were washed with water/brine mixture (500ml_/100mL), then evaporated. The residue (50g) was chromatographed on silica (800g, Biotage) eluting with a dichloromethane/ethanol/ammonia mixture (50/8/1 ), to afford the title compound as an oil (35.2g) - LC RT = 4.1 min.
1H NMR (300MHz, MeOH-d4) δ 7.47 (m, 2H), 7.38 (m, 2H), 7.19 (dd, 1H, J=8.3, 2.3Hz), 6.84 (d, 1 H, J=8.3Hz), 4.90 (s, 2H), 4.78 (dd, 1 H, J=8.7, 4.5Hz), 4.74 (s, 2H), 3.78 (m, 2H), 3.68 (m, 2H), 3.55 (t, 2H, J=6.4Hz), 2.87 (dd, 1 H, J=12.1 , 8.7Hz), 2.79 (dd, 1 H,
J=12.1, 4.5Hz), 2.69 (m, 2H), 1.63 (m, 4H), 1.44 (m, 4H)
Example 78 Salts of 4-((R)-2-(6-r2-(2.6-Dichlorobenzyloxy)-ethoxyl-hexylamino -1 -hvdroxyethyl)-2- hvdroxymethyl-phenol
i) Triphenylacetate salt
Triphenylacetic acid (1.81g, 1eq) was added to a solution of 4-((R)-2-{6-[2-(2,6- dichlorobenzyloxy)-ethoxy]-hexylamino}-1-hydroxyethyl)-2-hydroxymethyl-phenol
(3.28g) in ethanol (20mL) and the mixture heated to 80°C to obtain a solution. The mixture was allowed to cool to ambient temperature, and the resulting product filtered, washed with a little ethanol, then dried in vacuo at 50°C to afford the title compound as a white crystalline solid (4.3g). m.pt. (DSC) 131.9-134.2°C. The XRPD pattern of this product is shown in Figure 1. ii) α-Phenylcinnamate salt α-Phenylcinnamic acid (0.249g) was added to a solution of 4-((R)-2-{6-[2-(2,6- dichlorobenzyloxy)-ethoxy]-hexylaminoμi-hydroxyethyl)-2-hydroxymethyl-phenol (0.54g) in isopropanol (5mL). The solution was seeded with product and allowed to stir at ambient temperature for 20 h. The product was filtered, washed with a little isopropanol, then dried in vacuo at 50°C to afford the title compound as a crystalline white solid (0.56g). m.pt. (DSC) 116.1-117.9°C. The XRPD pattern of this product is shown in Figure 2. iii) 1-Naphthoate salt
1-Naphthoic acid (0.16g, 0.97mmol) was added to a solution of 4-((R)-2-{6-[2-(2,6- dichlorobenzyloxy)-ethoxy]-hexylamino}-1-hydroxyethyl)-2-hydroxymethyl-phenol (0.46g) in MIBK (5mL) and the resulting suspension warmed to 80°C. The resulting solution was allowed to cool slowly to ambient temperature and left to stir for 20h. The product was filtered, washed with MIBK, then dried in vacuo at 50°C to afford the title compound as a solid (0.49g). m.pt. (DSC) 91.4-95.2°C. The XRPD pattern of this product is shown in Figure 3.
iv) (R)-Mandelate salt
(R)-Mandelic acid (0.15g) was added to a solution of 4-((R)-2-{6-[2-(2,6- dichlorobenzyloxy)-ethoxy]-hexylamino}-1-hydroxyethyl)-2-hydroxymethyl-phenol (0.48g) in MIBK (5mL) and the resulting suspension warmed to 80°C. The resulting solution was allowed to cool slowly to ambient temperature and left to stir for 20h. The product was filtered, washed with MIBK, then dried in vacuo at 50°C to afford the title compound as a solid (0.44g). The XRPD pattern of this product is shown in Figure 4.
Example 79
4-1(1 R)-2-r(5-(2-r(2.6-Dichlorobenzyl)oxylethoxy>pentyl)aminol-1-hvdroxyethviμ2- (hvdroxymethyl)phenol acetate
i) 2-((2-[(5-Bromopentyl)oxylethoxy)methyl)-1 ,3-dichlorobenzene Prepared from 2-[(2,6-dichlorobenzyl)oxy]ethanol using method described in
Example 77 ii) LCMS RT=3.91 min
ii) (5R)-3-(5-(2-r(2,6-Dichlorobenzyl)oxy1ethoxy>pentyl)-5-(2.2-dimethyl-4H-1.3- benzodioxin-6-yl)-1 ,3-oxazolidin-2-one
Prepared using method described in Example 21 iii) LCMS RT=3.75min iii) (1 R)-2-r(5- 2-r(2.6-Dichlorobenzyl)oxylethoxy)pentyl)amino1-1 -(2.2-dimethyl-4H-1.3- benzodioxin-6-yl)ethanol
Prepared using method described in Example 1 xii)
LCMS RT=2.71 min
iv) 44(1 R)-2-r(5-(2-r(2.6-Dichlorobenzyl)oxylethoxy)pentyl)aminol-1 -hvdroxyethvfl-2-
(hvdroxymethyl)phenol acetate
Prepared using method described in Example 1 xiii)
LCMS RT=2.38min ES+ve 472, 474 and 476 (MHf
Example 80
4-((1R)-2-(r6-(2-(r3-(Cvclopentylsulfonyl)benzylloxy>ethoxy)hexyllaminoμi- hvdroxyethyl)-2-(hvdroxymethyl)phenol acetate
i) Tert-butyl(f3-(cvclopentylthio)benzvHoxy}dimethylsilane
Tert-butyl[(3-iodobenzyl)oxy]dimethylsilane (WO9513095) (1.44g) in dry 1-methyl-2- pyrrolidone (15ml) and triethylamine (4ml) was stirred at room temperature under nitrogen. 1-1'Bis(diphenylphosphino)ferrocene (110mg) and ths(dibenzylideneacetone)dipalladium(0) (258mg) were added and the mixture was stirred for 15min. Cyclopentyl mercaptan (0.42g) was then added, and the reaction mixture stirred at 60°C for 2h. The reaction mixture was cooled to room temperature, poured onto water and extracted with diethyl ether. The combined organic extracts were dried (MgS04) and the solvent evaporated in vacuo. The residue was purified on a 50g SPE, eluting with a stepped gradient of 10 to 100% dichloromethane- cyclohexane to give the title compound (1.09g) LCMS RT= 4.67min
ii) r3-(Cvclopentylthio)phenyllmethanol
A solution of tetrabutylammonium fluoride in THF (1 M, 6ml) was added to a solution of tert-butyl{[3-(cyclopentylthio)benzyl]oxy}dimethylsilane (1.09g) in dry THF (10ml). The solution was stirred for 18h under nitrogen and the solvent was evaporated in vacuo.
The residue was partitioned between dichloromethane and water. The organic phase was separated and washed with water. The organic phase was separated and the solvent evaporated in vacuo. The residue was purified on a 10g silica SPE cartridge, eluting with a stepped gradient of 10% to 100% dichloromethane- cyclohexane to give the title compound (0.65g). LCMS RT= 3.3min
iii) (5R)-3-r6-(2- f3-(Cvclopentylthio)benzvnoxy)ethoxy)hexyll-5-(2.2-dimethyl-4H-1.3- benzodioxin-6-yl)-1 ,3-oxazolidin-2-one
A solution of [3-(cyclopentylthio)phenyl]methanol (270mg) in dry DMF (10ml) under nitrogen was treated with sodium hydride (60% dispersion on mineral oil, 57mg) and the mixture stirred for 1 h. 2-({6-[(5R)-5-(2,2-Dimethyl-4H-1 ,3-benzodioxin-6-yl)-2-oxo-1 ,3- oxazolidin-3-yl]hexyl}oxy)ethyl methanesulfonate (0.4g) in dry DMF (2ml) was then added and the mixture stirred for 18h. Phosphate buffer solution (pH6.5) was added and the mixture extracted with ethyl acetate. The combined extracts were washed with water and dried (MgS04), filtered, and evaporated in vacuo. The residue was purified on a 10g silica SPE cartridge, eluting with 10% to 20% ethyl acetate- cyclohexane to give the title compound (0.23g). LCMS RT= 4.08min.
iv) (5R)-3-r6-(2-(r3-(Cvclopentylsulfinyl)benzvπoxy)ethoxy)hexyll-5-(2.2-dimethyl-4H-1.3- benzodioxin-6-yl)-1.3-oxazolidin-2-one
Sodium periodate (333mg) was added to a solution of (5R)-3-[6-(2-{[3-
(cyclopentylthio)benzyl]oxy}ethoxy)hexyl]-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-1 ,3- oxazolidin-2-one (230mg) in ethanol (12ml) and water (4ml). The mixture was stirred at room temperature under nitrogen for 3h. and the ethanol evaporated in vacuo. The aqueous phase was diluted with water and extracted with ethyl acetate. The combined ethyl acetate extracts were dried (MgS04) filtered, and evaporated in vacuo. The residue was purified on a 10g silica SPE cartridge, eluting with a stepped gradient of 10% to 100% ethyl acetate- cyclohexane, to give the title compound (201 mg). LCMS
RT=3.54min.
v) (5R)-3-r6-(2-(r3-(Cvclopentylsulfonyl)benzylloxy)ethoxy)hexyll-5-(2.2-dimethyl-4H- 1 ,3-benzodioxin-6-yl)-1 ,3-oxazolidin-2-one 3-Chloroperbenzoic acid (60mg;57%purity) was added to a solution of (1 R)-2-{[6-(2-
{[3(5R)-3-[6-(2-{[3-(cyclopentylsulfinyl)benzyl]oxy}ethoxy)hexyl]-5-(2,2-dimethyl-4H-1 ,3- benzodioxin-6-yl)-1 ,3-oxazolidin-2-one (106mg) in dry DCM (5ml) stirring under nitrogen at 0°C. The solution was allowed to warm up to room temperature and stirred for 2.5h. The reaction mixture was quenched with aqueous sodium sulphite solution. The organic layer was separated and washed twice with aqueous sodium sulphite, dried (MgS04) filtered and evaporated in vacuo. The residue was purified on a 5g silica SPE cartridge, eluting with a stepped gradient of 20% to 100% ethyl acetate - cyclohexane to give the title compound (96mg). LCMS RT= 3.68min.
vi) (1 R)-2- r6-(2-(r3-(Cvclopentylsulfonyl)benzylloxy)ethoxy)hexyllaminoμi-(2.2- dimethyl-4H-1 ,3-benzodioxin-6-yl)ethanol The title compound was prepared from (5R)-3-[6-(2-{[3- (cyclopentylsulfonyl)benzyl]oxy}ethoxy)hexyl]-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-
1 ,3-oxazolidin-2-one by a procedure similar to that described in example_4ii. The residue was purified on a SPE cartridge, eluting with methanol- dichloromethane- ammonia (10:90:1), to give the title compound. LCMS RT = 2.80min.
vii) 4-((1 R)-2-(r6-(2-fr3-(Cvclopentylsulfonyl)benzvπoxy)ethoxy)hexyllaminoμi- hvdroxyethyl)-2-(hvdroxymethyl)phenol acetate The title compound was prepared from (1R)-2-{[6-(2-{[3- (cyclopentylsulfonyl)benzyl]oxy}ethoxy)hexyl]aminoμi-(2,2-dimethyl-4H-1 ,3- benzodioxin-6-yl)ethanol, by a procedure similar to that described in example 4iii. LCMS RT= 2.41 min. ES+ve 548 (M+Hf
Example 81
4-((1 R)-2-(r6-(2-(r3-(Cvclopentylsulfinyl)benzvnoxy)ethoxy)hexyllaminoμi- hvdroxyethyl)-2-(hvdroxymethyl)phenol acetate
i) (1 R)-2-fr6-(2-(r3-(Cvclopentylsulfinyl)benzylloxy>ethoxy)hexyllamino -1-(2.2-dimethyl-
4H-1 ,3-benzodioxin-6-yl)ethanol
The title compound was prepared from (5R)-3-[6-(2-{[3-
(cyclopentylsulfinyl)benzyl]oxy}ethoxy)hexyl]-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)- 1 ,3-oxazolidin-2-one (example 80iv) by a procedure similar to that described in example
4 ii) LCMS RT= 2.69min.
ii) 4-((1 R)-2-(r6-(2-(r3-(Cvclopentylsulfinyl)benzylloxy ethoxy)hexyllamino)-1 - hvdroxyethyl)-2-(hvdroxymethyl)phenol acetate The title compound was prepared from (1 R)-2-{[6-(2-{[3-
(cyclopentylsulfinyl)benzyl]oxy}ethoxy)hexyl]aminoμi-(2,2-dimethyl-4H-1 ,3- benzodioxin-6-yl)ethanol by a procedure similar to that described in example 4 iii).
LCMS RT= 2.43min ES+ve 534 (M+Hf
Example 82
4-((1 R)-2-(r6-(2-(r3-(Cvclopentylthio)benzylloxy>ethoxy)hexyllaminoμi-hvdroxyethyl)-2-
(hvdroxymethyl)phenol acetate
i) (1 R)-2-(r6-(2-(r3-(Cvclopentylthio)benzylloxy ethoxy)hexyllaminoμi-(2.2-dimethyl-4H-
1.3-benzodioxin-6-yl)ethanol
The title compound was prepared from (5R)-3-[6-(2-{[3-
(cyclopentylthio)benzyl]oxy}ethoxy)hexyl]-5-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)-1 ,3- oxazolidin-2-one by a procedure similar to that described in example 4 ii). LCMS RT= 3.18min
ii) 4-((1 R)-2-ff6-(2-(r3-(Cvclopentylthio)benzylloxy>ethoxy)hexyl1amino)-1-hydroxyethyl)- 2-(hydroxymethyl)phenol acetate The title compound was prepared from (1 R)-2-{[6-(2-{[3- (cyclopentylthio)benzyl]oxy}ethoxy)hexyl]amino}-1 -(2,2-dimethyl-4H-1 ,3-benzodioxin-6- yl)ethanol by a procedure similar to that described in example 4 iii). LCMS RT= 2.82min ES+ve m/z= 518 (M+Hf
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 and 4 to 82 had IC50 values below 1 μM.
Potency at human betal and beta3 adrenoceptors was determined in functional studies using Chinese hamster ovary cells transfected with either the human betal adrenoceptor or the human beta3 adrenoceptor. Agonist activity was assessed by measuring changes in intracellular cyclic AMP. For particularly preferred compounds of the invention, selectivity for beta2 adrenoceptors over betal adrenoceptors was typically 10 fold or greater. Selectivity for beta2 adrenoceptors over beta3 adrenoceptors was typically 5 fold or greater.
The onset of action and duration of action in vitro was assessed on isolated superfused airway preparations (human or guinea pig). Tissues were contracted either electrically or by spasmogen. Agonist was perfused over the tissue until maximum relaxation was achieved, and onset of action determined. Perfusion of the agonist was then ceased and duration determined by the time taken for the contractile response to re-establish. For particularly preferred compounds of the invention, onset was typically less than
30min. Duration was typically >3h.
Particularly preferred compounds of the invention are potent and long-acting inhibitors of histamine-induced bronchospasm in conscious guinea pigs. They also demonstrate an improved therapeutic index in conscious guinea pigs (bronchoprotective effects vs blood pressure lowering effects) relative to established long-acting beta2 agonist bronchodilators. The particularly preferred compounds of the invention show low oral bioavailability in rat and dog. In human hepatocyte cultures they are metabolised to products that are significantly less potent at the beta2 adrenoceptor than the parent compound.
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

Claims
1. A compound of formula (I)
Figure imgf000102_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 2 to 5; with the proviso that m + n is 4 to 10;
R1 is selected from hydrogen, C1-6alkyl, hydroxy, halo, C ehaloalkyl, -XC(0)NR9R °, -XNR8C(0)R9, -XNR8C(0)NR9R1°, -XNR8S02R9, -XS02NR11R12, XNR8S02R9R1°, -XNR9R10, XN+R8R9R10, -XNR8C(0)OR9, -XC02R9, -XNR8C(0)NR8C(0)NR9R1°, -XSR9, XSOR9, and -XS02R9; or R1 is selected from -X-aryl, -X-hetaryl, and -X-(aryloxy), each optionally substituted by 1 or 2 groups independently selected from hydroxy, C^alkoxy, halo, C1-6alkyl, Cβhaloalkyl, -NHC(O)(C1-6alkyl), -S02(C1.βalkyl), -S02(aryl), -S02NH2, -S02NH(C1-6alkyl), -S02NH(C3.7cycloalkyl), -C02H, -C02(C1-6alkyl), -S02NH(C3.7cycloalkylC1-6alkyl), -NH2, -NH(C1-6alkyl), or hetaryl optionally substituted by 1 or 2 groups independently selected from hydroxy, C1-6alkoxy, halo, C1-6alkyl, or Ci.6haloalkyl;
X is -(CH2)P- or C2-6 alkenylene;
p is an integer from 0 to 6,
R8 and R9 are independently selected from hydrogen, C1-6alkyl, C3.7cycloalkyl, aryl, hetaryl, hetaryl(C1-6alkyl)- and aryl(C1-6alkyl)- and R8and R9 are each independently optionally substituted by 1 or 2 groups independently selected from halo, Chalky!, C-βhaloalkyl, -NHC(0)(C1-6alkyl), -S02(C1-6alkyl), -S02(aryl), -C02H, -C02(C1-4alkyl), -NH2, -NH(C1-6alkyl), aryl(C1-6alkyl)-, aryl(C2-6alkenyl)-, aryl(C2-6alkynyl)-, hetaryl(C1-6alkyl)-, -NHS02aryl, -NH(hetarylC1-6alkyl), -NHS02hetaryl, -NHS02(C1-6alkyl), -NHC(0)aryl, or -NHC(0)hetaryl:
R is selected from hydrogen, d.6alkyl and C3-7 cycloalkyl;
R11 and R12 are independently selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, aryl, hetaryl, hetaryl(Cι-6alkyl)- and aryl(C1-6alkyl)-, or R11 and R12 , together with the nitrogen to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring; and R 1 and R12are each optionally substituted by one or two groups independently selected from halo, C1-6alkyl, and C^haloalkyl;
where R1 is -XNR8C(0)NR9R1° , R8 and R9 may, together with the -NC(0)N- portion of the group R1 to which they are bonded, form a 5-, 6- or 7- membered saturated or unsaturated ring;
where R1 is -XNR8C(0)OR9, R8 and R9 may, together with the -NC(O)O- portion of the group R1 to which they are bonded, form a 5-, 6- or 7- membered saturated or unsaturated ring;
where R1 is -XC(O)NR9R10 or -XNR8C(O)NR9R10 , R9 and R10 may, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring;
R2 is selected from hydrogen, hydroxy, C1-6alkyl, C1-6alkoxy, halo, aryl, aryl(C1-6alkyl)-, C1-6haloalkoxy, and C1-6 haloalkyl;
R3 is selected from hydrogen, hydroxy, C^alkyl, C1-6alkoxy, halo, aryl, aryl(C1-6alkyl)-, C1-6haloalkoxy, and Cι.6haloalkyl;
R4 and R5 are independently selected from hydrogen and C1-4 alkyl with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4; and, R6 and R7 are independently selected from hydrogen and
Figure imgf000104_0001
with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4.
2. A compound of formula (I)
Figure imgf000104_0002
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 2 to 5; with the proviso that m + n is 4 to 10;
R1 is selected from hydrogen, C1-6alkyl, hydroxy, halo, C^haloalkyl, -XC(0)NR9R10,
-XNR8C(0)R9, -XNR8C(0)NR9R1°, -XNR8S02R9, -XS02NR11R12; -XNR9R10, -XNR8C(0)OR9, or R1 is selected from -X-aryl, -X-hetaryl, or -X-(aryloxy), each optionally substituted by 1 or 2 groups independently selected from hydroxy, C1-6alkoxy, halo, C1-6alkyl, CL 6haloalkyl, -NHC(0)(C1-6alkyl), -S02(C1-6alkyl), -S02(aryl),
-S02NH2,
Figure imgf000104_0003
-S02NH(C3-7cycloalkyl), -C02H, -C02(C1-6alkyl), -S02NH(C3-7cycloalkylC1-6alkyl), -NH2, -NH(Cι-6alkyl), or hetaryl optionally substituted by 1 or 2 groups independently selected from hydroxy, d-βalkoxy, halo, Cι-6alkyl, or C^ 6haloalkyl;
X is -(CH2)P- or C2.6 alkenylene;
p is an integer from 0 to 6, preferably 0 to 4;
R8 and R9 are independently selected from hydrogen, C1-6alkyl, C3.7cycloalkyl, aryl, hetaryl, hetaryl(Cι-salkyl)- and aryl(C1-6alkyl)- and R8and R9 are each independently optionally substituted by 1 or 2 groups independently selected from halo, C1-6alkyl, CL βhaloalkyl, -NHC(0)(C1-6alkyl), -S02(C1-6alkyl), -S02(aryl), -C02H, and -C02(C1-4alkyl), - NH2, -NH(C1-6alkyl), aryl(C1-6alkyl)-, aryl(C2-6alkenyl)-, aryl(C2-6alkynyl)-, hetaryl(Cι. 6alkyl)-, -NHSO2aryl, -NH(hetarylC1-6alkyl), -NHS02hetaryl, -NHSO^C^alkyl), - NHC(0)aryl, or -NHC(0)hetaryl:
R10 is selected from hydrogen, C^alkyl and C3-7 cycloalkyl;
R11 and R12are independently selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, aryl, hetaryl, hetaryl(C1-6alkyl)- and aryl(Cι-6alkyl)-, or R1 and R12 , together with the nitrogen to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring; and R11 and R12are each optionally substituted by one or two groups independently selected from halo, C1-6alkyl, and C1-6haloalkyl;
where R1 is -XNR8C(0)NR9R ° , R8 and R9 may, together with the portion -NC(0)N- of the group R1 to which they are bonded, form a 5-, 6-, or 7- membered saturated or unsaturated ring;
where R1 is -XNR8C(0)OR9, R8 and R9 may, together with the portion -NC(0)O- of the group R1 to which they are bonded, form a 5-, 6-, or 7- membered saturated or unsaturated ring;
where R1 is -XC(0)NR9R1° or -XNR8C(0)NR9R10 , R9 and R10 may, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring;
R2 is selected from hydrogen, hydroxy, C1-6alkyl, C1-6alkoxy, halo, aryl, aryl(C1-6alkyl)-, C1-6haloalkoxy, and Cι-6 haloalkyl;
R3 is selected from hydrogen, hydroxy, Chalky!, C1-6alkoxy, halo, aryl, aryl(C1-6alkyl)-,
C1-6haloalkoxy, and C1-6haloalkyl;
R4 and R5 are independently selected from hydrogen and C1- alkyl with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4; and, R6 and R7 are independently selected from hydrogen and C1-4alkyl with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4.
3. A compound according to claim 1 or claim 2 of formula (la)
Figure imgf000106_0001
or a salt, solvate, or physiologically functional derivative thereof, wherein R1, R2, R3, R6 and R7 are as defined for claim 1 and m is 4 or 5.
4. A compound according to any of claims 1 to 3 which is selected from:
N-{3-[(2-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}-N'-phenylurea;
4-{(1 R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-
(hydroxymethyl)phenol;
N-(3-{[({3-[(2-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}ethoxy)methyl]phenyl}amino)carbonyl]amino}phenyl)pyridine-3- carboxamide;
4-{(1 R)-1-Hydroxy-2-[(6-{2-[(3-hydroxybenzyl)oxy]ethoxy}hexyl)amino]ethyl}-2-
(hydroxymethyl)phenol;
4-{(1 R)-2-[(6-{2-[(3,5-Dimethylbenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-
(hydroxymethyl)phenol; Λ/-{3-[(2-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl} amino)pentyl]oxy}ethoxy)methyl]phenyiμ/V-phenylurea;
and salts, solvates, and physiologically functional derivatives thereof.
5. A compound of formula (I) which is: 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-
(hydroxymethyl)phenol; or a salt or solvate thereof.
6. A pharmaceutical formulation comprising a compound of formula (I) or (la) according to any one of claims 1 to 5 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.
7. A combination comprising a compound of formula (I) or (la) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and one or more other therapeutic ingredients.
8. A combination according to claim 7 wherein the other therapeutic ingredient is a PDE4 inhibitor, a corticosteroid or an anti-cholinergic agent.
9. A combination according to claim 7 wherein the additional therapeutic ingredient is 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy-16α-methyl-3-oxo-androsta- 1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester.
10. The use of a compound of formula (I) or (la) according to any one of claims 1 to 5, 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.
11. A method for the prophylaxis or treatment of a clinical condition in a mammal, for which a selective β2-adrenoreceptor agonist is indicated, which comprises administration of a therapeutically effective amount of a compound of formula (I) or (la) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
12. A compound of formula (I) or (la) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for use in medical therapy.
13. A process for preparing a compound of formula (I) or (la) which comprises: deprotection of a protected intermediate of formula (II):
Figure imgf000108_0001
or a salt or solvate thereof, wherein R4, R5, R6, R7, m, and n are as defined for the compound of formula (I) or (la), and R a, R2a, and R3a are each independently either the same as R1, R2, and R3 respectively as defined for the compound of formulae (I) or (la) or a precursor for said group R1, R2, or R3, and R13, R14, and R15 are each independently either hydrogen or a protecting group provided that at least one of R13, R14, and R15 is a protecting group, and R 9 is hydrogen or a protecting group.
(B) alkylation of an amine of formula (XIX):
Figure imgf000108_0002
(XIX)
wherein R13, R14, R15 and R19 are as hereinbefore defined, with a compound of formula (VI): L1CR4R5(CH2)m — O— (CH2)n— O — (VI)
Figure imgf000109_0001
wherein L1 represents a leaving group such as halo, followed by removal of any protecting groups present by conventional methods.
(C) by reacting an amine of formula (XIX) as defined hereinabove, with a compound of formula (XX):
,2a
Figure imgf000109_0002
(XX)
wherein R4, R6, R7, R1a, R2a, R3a, m and n are as hereinbefore defined; under conditions suitable to effect reductive amination,
followed where necessary or desired by one or more of the following steps in any order: (i) optional removal of any protecting groups;
(ii) optional separation of an enantiomer or diastereoisomer from a mixture of enantiomers or diastereoisomers;
(iii) optional conversion of the product to a corresponding salt, solvate, or physiologically functional derivative thereof. (iv) optional conversion of a group R1a, R2a and/or R3a to a group R1, R2 and/or
R3 respectively.
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