WO2009011655A1 - Splropiperidine compounds, a process of their preparation, pharmaceutical compositions containing them, and their use in the treatment of airway diseases, inflammatory diseases, copd or asthma - Google Patents

Splropiperidine compounds, a process of their preparation, pharmaceutical compositions containing them, and their use in the treatment of airway diseases, inflammatory diseases, copd or asthma Download PDF

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WO2009011655A1
WO2009011655A1 PCT/SE2008/050878 SE2008050878W WO2009011655A1 WO 2009011655 A1 WO2009011655 A1 WO 2009011655A1 SE 2008050878 W SE2008050878 W SE 2008050878W WO 2009011655 A1 WO2009011655 A1 WO 2009011655A1
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Prior art keywords
chloro
compound
benzofuran
oxy
spiro
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PCT/SE2008/050878
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French (fr)
Inventor
Martin Hemmerling
Svetlana Ivanova
Marguerite Mensonides-Harsema
Håkan SCHULZ
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Astrazeneca Ab
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Priority claimed from PCT/SE2007/000694 external-priority patent/WO2008010765A1/en
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to PCT/SE2008/050878 priority Critical patent/WO2009011655A1/en
Publication of WO2009011655A1 publication Critical patent/WO2009011655A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • Splropiperidine compounds a process of their preparation, pharmaceutical compositions containing them, and their use in the treatment of airway diseases, inflammatory diseases, COPD or asthma
  • the present invention relates to new polymorphs of compounds 2- ⁇ 2-Chloro-5- ⁇ [(25)-3- (5-chloro- 1 'H,3H-spiro[l -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -A- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid, and the hydrochloride and sodium hydroxide salts thereof, and compound 2- ⁇ 2-Chloro-5- ⁇ [(2i?)-3-(5-chloro-l'H,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -A- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid.
  • the invention further relates to pharmaceutical composition containing said compounds and to the use of said compounds in therapy.
  • the present invention also relates to processes for the preparation of said compounds.
  • the compounds of the invention inhibit the CCRl receptor.
  • a desirable property for a drug acting at the CCRl receptor is that it has high potency e.g. as determined by its ability to inhibit the activity of the CCRl receptor. It is also desirable for such drugs to possess good selectivity and pharmacokinetic properties in order to further enhance drug efficacy. As an example, it can be advantageous for such drugs to exhibit low activity against the human ether-a-go-go-related gene (hERG)-encoded potassium channel. In this regard, low activity against hERG binding in vitro is indicative of low activity in vivo.
  • hERG human ether-a-go-go-related gene
  • the drug compound In the formulation of drug compositions, it is important for the drug compound to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially- viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical compositions comprising the active compound.
  • the manufacture of drug compositions it is important that a reliable, reproducible and constant plasma concentration profile of the drug is provided following administration of the compounds of the invention to a patient.
  • some crystalline forms may be more suitable for certain ways of administration e.g. inhalation, than others.
  • the dosing profile of some crystalline forms may differ from others.
  • Chemical stability, solid state stability, and "shelf life" of the active ingredients are also very important factors.
  • the drug compound, and compositions containing it should preferably be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the active component's physico-chemical characteristics (e.g. its chemical composition, density, hygroscopicity and solubility).
  • the compounds of the invention or salt thereof are in a substantially pure crystalline form e.g. at least 40% crystalline, at least 50% crystalline, at least 60% crystalline, at least 70% crystalline or at least 80% crystalline. Crystallinity can be estimated by conventional X-ray diffractometry techniques.
  • the compounds of the invention or salt thereof are from 40% to 100%, or 50 to 100%, or 60 to 100%, or 70 to 100% or 80 to 100%, or 70 to 99%, or 80 to 99%, or 85 to 99%, or 90 to 97%, or 90 to 96%, or 90% to 95% crystalline.
  • the compounds are 80% crystalline.
  • the compounds are 90% crystalline.
  • the compounds are 92% crystalline.
  • the compounds are 93% crystalline.
  • the compounds are 94% crystalline.
  • the compounds are 95% crystalline.
  • the compounds are 96% crystalline.
  • the compounds are 97% crystalline.
  • the compounds are 98% crystalline.
  • the compounds are 99% crystalline.
  • the compounds are 100% crystalline.
  • One embodiment relates to compounds 2- ⁇ 2-Chloro-5- ⁇ [(25)-3-(5-chloro-l'H,3H-spiro[l- benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -4-
  • Another embodiment relates to the compounds of the invention, whereby the compounds are 90% crystalline.
  • Figure 1 The X-ray powder diffractogram S-enantiomer of 2- ⁇ 2-Chloro-5- ⁇ [(25)-3-(5- chloro- 1 'H,3H-spiro[l -benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy ⁇ -A- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid Form A.
  • Figure 2 The X-ray powder diffractogram S-enantiomer of 2- ⁇ 2-Chloro-5- ⁇ [(25)-3-(5- chloro- 1 'H,3H-spiro[l -benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy ⁇ -A- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid Form A.
  • Figure 2 The X-ray powder diffractogram S-enantiomer of 2- ⁇ 2-
  • Figure 9 The X-ray powder diffractogram S-enantiomer of 2- ⁇ 2-Chloro-5- ⁇ [(25)-3-(5- chloro- 1 'H,3H-spiro[l -benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy ⁇ -4- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid sodium hydroxide.
  • One embodiment of the invention relates to the compound 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5- chloro-1 ⁇ ,3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -4- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ) (Form A): (1) 5.1, 10.2 and 12.9, or
  • Another embodiment relates to compound 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5-chloro-l ⁇ ,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -4-
  • One embodiment of the invention relates to the compound 2- ⁇ 2-Chloro-5- ⁇ [(2R)-3-(5- chloro-1 ⁇ ,3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -4- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ):
  • One embodiment of the invention relates to the compound 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5- chloro-1 ⁇ ,3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -4-
  • One embodiment of the invention relates to the compound 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5- chloro-1 ⁇ ,3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -4- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ) (Form C): (1) 4.5, 8.9 and 12.8, or (2) 4.5, 8.6 and 10.6, or
  • Another embodiment relates to compound 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5-chloro-l ⁇ ,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -A- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid (Form C), which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ):
  • One embodiment of the invention relates to the compound 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5- chloro-1 ⁇ ,3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -A- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ) (Form D): (1) 5.4, 12.3 and 21.3, or
  • Another embodiment relates to compound 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5-chloro-l ⁇ ,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -A- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid (Form F), which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ):
  • One embodiment of the invention relates to the compound 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5- chloro-l ⁇ ,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -4-
  • Another embodiment relates to compound 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5-chloro-l'H,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -A- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid (Form G), which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ): (1) 9.7, 15.6, 17.1 and 21.4 or (2) 9.7, 15.4, 15.6, 16.3, 17.1, 19.4, 19.7, 20.3 and 21.4.
  • Another embodiment of the invention relates to the compound 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5- chloro-1 ⁇ ,3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -A- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid hydrochloride, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ):
  • Another embodiment relates to compound 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5-chloro-l'H,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -A-
  • a further embodiment of the invention relates to the compound 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5- chloro-1 ⁇ ,3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -A- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid sodium hydroxide, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ): (1) 7.6, 8.6 and 18.4 or
  • Another embodiment relates to the substantially pure compound 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3- (5-chloro- 1 ⁇ ,3H-spiro[l -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -A- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid having an X-ray powder diffraction pattern substantially the same as that shown in Figure 1 and Figures 3 to 9.
  • One embodiment of the invention relates to a process for the preparation of polymorph Form A, comprising the following steps: a) compound 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5-chloro-l ⁇ ,3H-spiro[l-benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy ⁇ -4-[(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid is slurried in an organic solvent and heated to a temperature between 55 and 65°C for at least 25 to 35 minutes under continues stirring; b) addition of water over a period of 25 to 35 minutes and continues stirring for a further 30 minutes; c) cooling the mixture to room temperature and continued stirring for 25 to 35 minutes; d) cooling the mixture to a temperature between 0 and 4°C and continued stirring for 25 to 35 minutes, followed by filtration; e) washing the mixture in a 1:1 water/ethanol mixture, followed by drying at 50 to 70 0 C
  • stirring times are 30 minutes.
  • temperature in step a), b) and e) is 60 0 C.
  • Another embodiment relates to the preparation of polymorphic Form C, comprising steps a) to e) as described above followed by; f) micronizing Form A and dissolving in an organic solvent followed by stirring at a temperature between 25 to 35 0 C for around 24 hours; g) removal of the supernatant and drying the sediment at a temperature between 75 to 85 0 C for around 24 hours.
  • the solvent is Tetrahydrofuran.
  • step f) is 30 0 C and in step g) is 80 0 C.
  • a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compounds of the invention, or pharmaceutically acceptable salts thereof (also referred to as active ingredient or drug), in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.
  • the active ingredients of the present invention may be administered by oral or parenteral (e.g. intravenous, subcutaneous, intramuscular or intraarticular) administration using conventional systemic dosage forms, such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions and sterile injectable aqueous or oily solutions or suspensions.
  • the active ingredients may also be administered topically (e.g. to the lung and/or airways) in the form of solutions, suspensions, aerosols and dry powder formulations.
  • These dosage forms will usually include one or more pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants.
  • pharmaceutically acceptable ingredients may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants.
  • the most appropriate method of administering the active ingredients is dependent on a number of factors.
  • compositions of the present invention may be prepared by mixing the active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Therefore, in a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical composition, which comprises mixing a compound of the invention, or pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the active ingredient is conveniently administered via inhalation (e.g. topically to the lung and/or airways) in the form of solutions, suspensions, aerosols or dry powder formulations (also referred to as composition). Administration may be by inhalation orally or intranasally.
  • the active ingredient is preferably adapted to be administered, from a dry powder inhaler, pressurised metered dose inhaler, or a nebuliser.
  • the active ingredient may be used in admixture with one or more pharmaceutically acceptable additives, diluents or carriers. Examples of suitable diluents or carriers include lactose (e.g. the monohydrate), dextran, mannitol or glucose.
  • Metered dose inhaler devices may be used to administer the active ingredients, dispersed in a suitable propellant and with or without additional excipients such as ethanol, a surfactant, a lubricant, an anti-oxidant or a stabilising agent.
  • Suitable propellants include hydrocarbon, chlorofiuorocarbon and hydrofiuoroalkane (e.g. heptafiuoroalkane) propellants, or mixtures of any such propellants.
  • Preferred propellants are P 134a and P227, each of which may be used alone or in combination with other propellants and/or surfactant and/or other excipients.
  • Nebulised aqueous suspensions, solutions may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose formulations.
  • Dry powder inhalers may be used to administer the active ingredients, alone or in combination with a pharmaceutically acceptable carrier, in the later case either as a finely divided powder or as an ordered mixture.
  • the dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule.
  • the active ingredient When the active ingredient is adapted to be administered, via a nebuliser it may be in the form of a nebulised aqueous suspension or solution, with or without a suitable pH or tonicity adjustment, either as a single dose or multidose device.
  • Metered dose inhaler, nebuliser and dry powder inhaler devices are well known and a variety of such devices are available.
  • the present invention provides a pharmaceutical product comprising, the compounds of the present invention, formulated for inhaled administration.
  • the compounds of the present invention are administered by inhalation.
  • the compounds of the invention are administered orally. Medical use
  • the compounds of the invention have activity as pharmaceuticals, and are believed to be potent modulators of chemokine receptor (especially CCRl receptor) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases.
  • chemokine receptor especially CCRl receptor
  • a compound of the invention, or a pharmaceutically acceptable salt thereof, may be used in the treatment of: 1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications
  • osteoarthritides associated with or including osteoarthritis/osteoarthrosis both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection- related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue
  • arthitides for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy
  • other joint disease such as intervertebral disc degeneration or temporomandibular joint degeneration
  • bone remodelling disease such as osteoporosis, Paget's disease or osteonecrosis
  • polychondritits such as osteoporosis, Paget'
  • skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin
  • eyes blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial; 6.
  • gastrointestinal tract glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema);
  • abdominal hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;
  • nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);
  • allograft rejection acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease; 10.
  • CNS Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;
  • cardiovascular atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins; and
  • oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes.
  • the pharmaceutical product according to this embodiment may, for example, be a pharmaceutical composition comprising the first and further active ingredients in admixture.
  • the pharmaceutical product may, for example, comprise the first and further active ingredients in separate pharmaceutical preparations suitable for simultaneous, sequential or separate administration to a patient in need thereof.
  • the pharmaceutical product of this embodiment is of particular use in treating respiratory diseases such as asthma, COPD or rhinitis.
  • One embodiment of the invention relates to a pharmaceutical product comprising, in combination, a first active ingredient which is a compound of the invention, as hereinbefore described, and at least one further active ingredient selected from :
  • Examples of a phosphodiesterase inhibitor that may be used in the pharmaceutical product according to this embodiment include a PDE4 inhibitor such as an inhibitor of the isoform PDE4D, a PDE3 inhibitor and a PDE5 inhibitor.
  • PDE4 inhibitor such as an inhibitor of the isoform PDE4D
  • PDE3 inhibitor examples include the compounds (Z)-3-(3,5-dichloro-4-pyridyl)-2-[4-(2-indanyloxy-5-methoxy-2-pyridyl]propenenitrile, N-[9-amino-4-oxo-l-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,l-jk][l,4]benzodiazepin-3(R)- yl]pyridine-3-carboxamide (CI- 1044),
  • ⁇ 2 -adrenoceptor agonist examples include metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol (e.g. as sulphate), formoterol (e.g. as fumarate), salmeterol (e.g. as xinafoate), terbutaline, orciprenaline, bitolterol (e.g.
  • the ⁇ 2 -adrenoceptor agonist of this embodiment may be a long-acting ⁇ 2 -agonists, for example salmeterol (e.g. as xinafoate), formoterol (e.g. as fumarate), bambuterol (e.g.
  • carmoterol (TA 2005, chemically identified as 2(1H)-Quinolone, 8- hydroxy-5-[l-hydroxy-2-[[2-(4-methoxy-phenyl)-l-methylethyl]-amino]ethyl]- monohydrochloride, [R-(R*, R*)] also identified by Chemical Abstract Service Registry Number 137888-11-0 and disclosed in U.S. Patent No 4,579,854), indacaterol (CAS no 312753-06-3; QAB- 149), formanilide derivatives e.g.
  • Examples of an inhibitor of kinase function that may be used in the pharmaceutical product according to this embodiment include a p38 kinase inhibitor and an IKK inhibitor.
  • protease inhibitor examples include an inhibitor of neutrophil elastase or an inhibitor of matrix metalloproteases such as MMPl, MMP2, MMP7, MMP8, MMP9,MMP12 and/or MMP13.
  • Examples of a steroidal glucocorticoid receptor agonist that may be used in the pharmaceutical product according to this embodiment include budesonide, fluticasone (e.g. as propionate ester), mometasone (e.g. as furoate ester), beclomethasone (e.g. as 17- propionate or 17,21-dipropionate esters), ciclesonide, loteprednol (as e.g. etabonate), etiprednol (as e.g. dicloacetate), triamcinolone (e.g.
  • acetonide fiunisolide
  • zoticasone flumoxonide
  • rofleponide butixocort (e.g. as propionate ester)
  • prednisolone prednisone
  • tipredane steroid esters e.g.
  • a muscarinic receptor antagonist for example a Ml, M2 or M3 antagonist, such as a M3 antagonist
  • ipratropium e.g. as bromide
  • tiotropium e.g. as bromide
  • oxitropium e.g. as bro
  • a quinuclidine derivative such as 3(R)-(2-hydroxy-2,2- dithien-2-ylacetoxy)- 1 -(3 -phenoxypropyl)- 1 -azonia-bicyclo [2.2.2] octane bromide as disclosed in US 2003/0055080, quinuclidine derivatives as disclosed in WO 2003/087096 and WO 2005/115467 and DE 10050995; or GSK 656398 or GSK 961081.
  • Examples of a modulator of a non-steroidal glucocorticoid receptor agonist that may be used in the pharmaceutical product according to this embodiment include those described in WO2006/046916.
  • One embodiment of the present invention provides a compound of the invention, as hereinbefore defined for use in therapy.
  • Another embodiment of the present invention provides the use of a compound of the invention, as hereinbefore defined in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of CCRl activity is beneficial.
  • a further embodiment of the present invention provides the use of a compound of the invention, as hereinbefore defined in the manufacture of a medicament for treating respiratory diseases.
  • Yet another embodiment of the present invention provides the use of a compound of the invention, as hereinbefore defined in the manufacture of a medicament for treating airways diseases.
  • Yet a further embodiment of present invention provides the use of a compound of the invention, as hereinbefore defined in the manufacture of a medicament for treating inflammatory diseases.
  • One embodiment of the present invention provides the use of a compound of the invention, as hereinbefore defined in the manufacture of a medicament for treating chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Another embodiment of the present invention provides the use of a compound of the invention, as hereinbefore defined in the manufacture of a medicament for treating asthma.
  • a further embodiment of the present invention provides a method of treatment of respiratory diseases, airway diseases, inflammatory diseases, COPD and/or asthma, in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of the invention, as hereinbefore defined.
  • Another embodiment of the present invention provides the uses and methods above whereby the compound of the invention as defined above, is administered by inhalation.
  • One embodiment of the invention relates to an agent for the treatment of respiratory diseases, airway diseases, inflammatory diseases, COPD and/or asthma, which comprises as active ingredient a compound of the invention.
  • Another embodiment relates to the use of a pharmaceutical composition comprising the compound of the invention in the treatment of respiratory diseases, airway diseases, inflammatory diseases, COPD and/or asthma.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • inhibitor and “antagonist” mean a compound that by any means, partly or completely, blocks the transduction pathway leading to the production of a response by the agonist.
  • disorder means any condition and disease associated with CCRl receptor activity.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of the invention may be in the range from 0. 1 ⁇ g/kg to 30 mg/kg.
  • the compounds of the invention may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compound of the invention (active ingredient) is in association with a pharmaceutically acceptable adjuvants, diluents and/or carriers.
  • the pharmaceutical composition will preferably comprise from 0.01 to 100 %w (per cent by weight), more preferably from 0.01 to 80 %w, still more preferably from 0.05 to 70 %w, and even more preferably from 0.05 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • Instrument Agilent 1100 Column Waters Symmetry 2.1 x 30 mm; Mass APCI; Flow rate 0.7 ml/min; Wavelength 254 nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA; Gradient 15-95%/B 2.7 min, 95% B 0.3 min. Instrument Agilent 1100; Column Hi Chrom Ace Phenyl 3.0 x 50 mm; Mass APCI; Flow rate 1.25 ml/min; Wavelength 230 nm; Solvent A: water + 0..03% TFA; Solvent B: acetonitrile + 0.03% TFA; Gradient 5-95% B 6 min, 95% B 1.5 min.
  • Solvent A 0.1 %TF A/water
  • Solvent B 0.08%TFA/acetonitrile Flow: 1 ml/min
  • Method B Instrument Agilent 1100; Column: XTerra C8, 100 x 3 mm, 5 ⁇ particle size, Solvent A: 15 mM NH 3 /water, Solvent B: acetonitrile Flow: 1 ml/min, Gradient 10-100%
  • a standard copper lamp was used for X-ray measurements.
  • Step 1 5-Chloro-4- [(4-methoxybenzyl)oxy] -N-methyl-2- [(2S)-oxiran-2- ylmethoxyjbenzamide
  • Step 2 5-Chloro-2- ⁇ [(2S)-3-(5-chloro-l ⁇ ,3H-spiro[l-benzofuran-2,4'-piperidin]-l '-yl)-2- hydroxypropylJoxy ⁇ -4-hydroxy-N-methylbenzamide
  • a mixture of 5-chloro-3H-spiro[l-benzofuran-2,4'-piperidine] (172 mg, 0.77 mmol) and 5- chloro-4-[(4-methoxybenzyl)oxy]- ⁇ /-methyl-2-[(25)-oxiran-2-ylmethoxy]benzamide 290 mg, 0.77 mmol
  • ethanol (10 ml) was stirred at 80 0 C overnight.
  • Step 3 Ethyl 2- ⁇ 2-chloro-5- ⁇ [(2S)-3-(5-chloro-l ⁇ ,3H-spiro[l-benzofuran-2,4'-piperidin]- l '-yl)-2-hydroxypropyl] oxy ⁇ -4- [(methylamino)carbonyl] phenoxy ⁇ -2-methylpropanoate
  • Step 4 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5-chloro-l ⁇ ,3H-spiro[l-benzofuran-2,4'-pipe ⁇ dinJ-l '- yl)-2-hydroxypropyl]oxy ⁇ -4-[(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid
  • Step 1 l-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester
  • THF (10 L) was added to the concentrate and solvent was distilled off to leave a solution of l-oxa-6- aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester in THF, 1.8 kg, 51.2% w/w, 0.92 kg contained weight, 86% yield.
  • 2-Bromo-4-chloroanisole is treated with isopropylmagnesium chloride dissolved in THF to produce the Grignard reagent in situ.
  • a catalytic amount of copper (I) bromide dimethyl sulphide complex (CuBr 1 SMe 2 ) and a solution of l-oxa-6-aza-spiro[2.5]octane-6- carboxylic acid tert-butyl ester in THF are added to produce the desired piperidinol.
  • the reaction mixture was warmed to between 25 and 30 0 C and stirred at this temperature for around 20 min.
  • the layers were separated, the aqueous layer was extracted with ethyl acetate (8 kg) and the combined organic layers were washed with water 2 x 6 kg).
  • the organic phase was concentrated under vacuum at 40 - 45 0 C to 2-3 L total volume then heptane (8 kg) added to the solution over a period of 30 min.
  • 5-Chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl ester is heated under reflux in a mixture of hydrobromic acid and acetic acid to form the hydrobromic acid salt of the 5-chlorospiropiperidine.
  • Aqueous hydrobromic acid (48% w/w, 62 ml) was added dropwise to a stirred mixture of 4-(5-chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl ester (20 g, 56 mmol) and acetic acid (40 ml) over a period of 40 min at a temperature of between 40 and 50 0 C. Stirring was continued at this temperature for a further 30 - 40 min on completion of the addition. The reaction mixture was then heated to reflux for between 6 and 8 h when HPLC analysis showed complete reaction.
  • Chloro Phenol Aluminium chloride (531 g, 4.0 mol) and toluene (3.45 L) were charged to a reaction vessel and stirred.
  • Dodecanethiol (966 g, 4.8 mol) was added over 25 min and the mixture stirred to give a solution then heated to 40 to 50 0 C.
  • a solution of 5-chloro-2-hydroxy-4- methoxybenzoic acid methyl ester (345.0 g, 1.6 mol) in toluene (3.45L) was then added over 2 h at 40 to 50 0 C.
  • the reaction mixture was maintained at this temperature for a further 2 h following the addition when less than 1.0% starting material remained.
  • the crude product (53.5 g, 75%) was suspended in acetonitrile (250 ml), heated to reflux and held for 15 min, cooled to 40 0 C then held for 1 h.
  • the solid was collected by filtration, washed with acetonitrile (2 x 25 ml) then dried under vacuum at 50 0 C to provide 5-chloro-2-hydroxy-4-(4- methoxybenzyloxy)benzoic acid methyl ester as a solid 42.9 g (60%).
  • Step 8 5-Chloro-4-(4-methoxybenzyloxy)-N-methyl-2-((S)-l-oxiranylmethoxy)benzamide
  • Step 9 5-Chloro-2- ⁇ [(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-l '-yl)-2- hydroxypropyl]oxy ⁇ -4-hydroxy-N-methylbenzamide, trifluoroacetic acid salt
  • Step 10 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-l '-yl)-2- hydroxypropyl]oxy ⁇ -4-[(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid.
  • the filter cake was slurry washed with water (1 x 135 ml and 1 x 540 ml), ethanol (270 ml), TBME (135 ml), treated with ethanol (1 L) at 60 0 C for 18 h and then filtered. The filter cake was washed with ethanol (135 ml).
  • the resulting solid (5 g) was slurried in NMP (50 ml) and heated to 60 0 C and held at between 60 and 65 0 C for 30 min with stirring. Water (50 ml) was charged to the resulting solution over a period of 35 min, maintaining the temperature between 60 and 65 0 C, which caused crystallization of the product. After a further 30 min at this temperature the slurry was cooled to ambient temperature then held at this temperature for 30 min. The mixture was further cooled to between 0 and 4 0 C and held for 30 min. The solid was collected by filtration, washed with water (25 ml), ethanol (25 ml), pulled dry on the filter then dried in a vacuum oven at 60 0 C.
  • the diffractogram is shown in figure 1.
  • Step 1 4-(l-tert-butoxycarbonyl-l-methylethoxy)-5-chloro-2-hydroxybenzoic acid methyl ester
  • the pH of the combined filtrates was adjusted to around 4 using dilute HCl solution then water (100 ml, 10.0 rel vol) added.
  • the solution was extracted with dichloromethane (100 ml, 10 rel vol), the organic layer was washed with water (150 ml, 15.0 rel vol) then evaporated to dryness at 35 0 C under vacuum.
  • the excess of 2-bromo-2-methyl-propionic acid tert-butyl ester and 2-methylacrylic acid tert-butyl ester by product were removed by applying a high vacuum (20-25 mbar) at 60 - 65 0 C for approximately one h.
  • the resulting solution was diluted with water (240 ml, 19.56 rel vol) and the pH of the solution adjusted to 7.5 using 10% w/w hydrochloric acid solution (85 ml, 6.9 rel vol).
  • the resulting suspension was stirred for 1 to 2 h at 25-30 0 C.
  • the suspended solid was collected by filtration, washed with water (32 ml, 2.60 rel vol) then dried under vacuum (80-100 mbar) at 40-45 0 C to provide 2-(2-chloro-5-hydroxy-4-methylcarbamoylphenoxy)- 2-methylpropionic acid tert-butyl ester, weight 8.0 g (65.5%).
  • the reaction mixture was then further cooled to 5 0 C then the solid product collected by filtration and washed with water (20 ml, 4.0 rel vol).
  • the crude product was dissolved in toluene (20 ml, 4.0 rel vol) at 40 0 C then the solution was concentrated to 3.0 rel vol under vacuum (200 mbar) at around 50 0 C.
  • the concentrate was cooled to 20 to 25 0 C and stirred for approximately for 3 h.
  • the solid product was collected by filtration and dried under vacuum at 40-45 0 C to give 2-[2-chloro- 4-methylcarbamoyl-5-((5)-l-oxiranylmethoxy)-phenoxy]-2-methylpropionic acid tert- butyl ester weight 3.8 g (65.4%).
  • Trifluoroacetic acid (2.0 ml, 2.0 rel vol) was added to a stirred suspension of 2- ⁇ 2-chloro- 5- ⁇ [(25)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ - 4- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid tert-butyl ester (1.0 g, 0.0016 mol, 1.0 mol eq) in toluene (6.0 ml, 6.0 rel vol) at 20 to 25 0 C resulting in a clear solution and stirring continued for 12 h.
  • reaction mixture was evaporated to dryness under reduced pressure (10 mbar) at 40 0 C and the gummy residue was dissolved in water (10 ml, 10.0 rel vol).
  • a solution of ammonium acetate (3.0 g, 0.0389 mol, 24.32 mol eq, 3.0 rel wt) in water (15 ml, 15 rel vol) was added and the thick suspension stirred for 1 to 2 h.
  • the water layer was decanted and isopropanol (20 ml, 20.0 rel vol) added to the suspension and the mixture stirred for 30 min.
  • Form B exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2 ⁇ ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test ⁇ 941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089): 5.6, 7.6, 8.6, 13.1, 17.0, 18.4. The diffractogram is shown in figure 3.
  • XRPD characteristic X-ray powder diffraction
  • Form C exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2 ⁇ ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test ⁇ 941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089):
  • Form D exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2 ⁇ ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test ⁇ 941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089):
  • Form F exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2 ⁇ ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test ⁇ 941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089): (1) 7.5, 9.2 and 10.7, or
  • the diffractogram is shown in figure 6.
  • Form G exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2 ⁇ ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test ⁇ 941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089):
  • the title compound exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2 ⁇ ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test ⁇ 941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089):
  • Form G exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2 ⁇ ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test ⁇ 941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089): (1) 7.6, 8.6 and 18.4 or
  • HEK293 cells from ECACC, stably expressing recombinant human CCRl (HEK-CCRl) were used to prepare cell membranes containing CCRl .
  • the membranes were stored at -70 0 C.
  • the concentration of membranes of each batch was adjusted to 10% specific binding of 33 pM [ 125 I] MIP- l ⁇ .
  • NSB average cpm in the wells with membranes and MIP-Ia and [ 125 I] MIP- l ⁇ (nonspecific binding);
  • BO average cpm in wells with membranes and assay buffer and [ 125 I] MIP-Ia (maximum binding).
  • the molar concentration of compound producing 50% displacement (IC50) was derived using the Excel-based program XLf ⁇ t (version 2.0.9) to fit data to a 4-parameter logistics function.
  • CHO-Kl cells from ATCC, stably expressing recombinant human CCR3 (CHO-CCR3) were used to prepare cell membranes containing CCR3.
  • the membranes were stored at -70 0 C.
  • a membrane concentration was used which gave approximately 10% specific binding relative to the total amount of radioactivity of [ 3 H]-4-(2,4-dichloro-3- methylphenoxy)-r-[4-(methylsulfonyl)benzoyl]-l,4'-bipiperidine added to the assay.
  • Binding assay [ 3 H]-4-(2,4-dichloro-3-methylphenoxy)-r-[4-(methylsulfonyl)benzoyl]-l,4'-bipiperidine (20 ⁇ L, to a final concentration of 2 nM, pre-diluted in assay buffer from a 20 ⁇ M stock) and either vehicle (20 ⁇ L, 10% (v/v) DMSO in assay buffer: for determination of total binding (BO)), l,4'-bipiperidine, 4-(2,4-dichloro-3-methylphenoxy)-l '-[4- (methylsulfonyl)benzoyl] (20 ⁇ L, 100 ⁇ M solution in 10% (v/v) DMSO in assay buffer: for determination of non-specific binding (NSB)) or the appropriate solution of test compound (20 ⁇ L, 10% (v/v) DMSO in assay buffer) were added to the wells of a U- bottomed 96-well plate.
  • the plates were sealed and incubated for 2 h at room temperature.
  • the plates were then filtered onto GF/B filter plates, pre-soaked for 1 h in plate-coating solution, using a 96-well plate Tomtec cell harvester.
  • Four washes with wash buffer (200 ⁇ L) were performed at 4°C to remove unbound radioactivity.
  • the plates were dried either for at least 2 h at 50 0 C or over night at room temperature. Filtration plates were sealed from underneath using Packard plate sealers (supplied with plates) and of MicroScint-0 (50 ⁇ L) was added to each well.
  • the plates were sealed (TopSeal A) and filter-bound radioactivity was measured with a scintillation counter (TopCount, Packard BioScience) using a 1 minute counting protocol.
  • test compound producing 50% displacement (IC 50 ) of [ 3 H]4- (2,4-dichloro-3-methylphenoxy)- 1 ' -[4-(methylsulfonyl)benzoyl]- 1 ,4 ' -bipiperidine specific binding (BO-NSB) was derived utilising GraphPad Prism ® to fit data to a 4-parameter logistic function of the form: in which E and [B] are specific binding of [ 3 H]4-(2,4-dichloro-3-methylphenoxy)-l '-[4- (methylsulfonyl)benzoyl]-l,4'-bipiperidine, and concentration of the antagonist respectively; ⁇ , ⁇ , IC 50 and m are the asymptote, baseline, location and slope parameters, respectively.
  • the derived IC 50 values were transformed to the negative logarithm (pICso) and then corrected using the Cheng-Prusoff equation to give pKi values for calculation of
  • Example 14 hERG-encoded Potassium Channel Bindins Assay This assay, which is described in full detail in example 2, WO2005037052, determines the ability of a test compound to bind to the human ether-a-go-go-related-gene (hERG)- encoded potassium channel.
  • hERG human ether-a-go-go-related-gene
  • the assay comprises the following steps: a) incubation of HEK 293 cell membranes expressing the I KR channel in the presence of radioligand 3,7- bis[2-(4-nitro[3,5- 3 H]phenyl)ethyl]-3,7-diazabicyclo[3.3.1]nonane, in the presence or absence of a test compound; b) quantitation of specifically bound labeled compound in the presence or absence of a test compound; c) calculation of the inhibition of labeled compound binding by the test compound.
  • Similar protocols to determine affinity for the human ether-a-go-go-related-gene (hERG)-encoded potassium channel have been described by Finlayson, K. et al. [Eur. J. Pharmacol. 2001, 412, 203 and Eur. J. Pharmacol. 2001, 430, 147].
  • Example 15 hERG-encoded Potassium Channel Inhibition Assay This assay determines the ability of a test compound to inhibit the tail current flowing through the human ether-a-go-go-related-gene (hERG)-encoded potassium channel.
  • HEK Human embryonic kidney cells expressing the hERG-encoded channel were grown in Minimum Essential Medium Eagle (EMEM; Sigma- Aldrich catalogue number M2279), supplemented with 10% Foetal Calf Serum (Labtech International; product number 4-101-500), 10% Ml serum-free supplement (Egg Technologies; product number 70916) and 0.4 mg/ml Geneticin G418 (Sigma- Aldrich; catalogue number G7034).
  • EMEM Minimum Essential Medium Eagle
  • a glass coverslip containing the cells was placed at the bottom of a Perspex chamber containing bath solution (see below) at room temperature (-20 0 C). This chamber was fixed to the stage of an inverted, phase-contrast microscope. Immediately after placing the coverslip in the chamber, bath solution was perfused into the chamber from a gravity- fed reservoir for 2 min at a rate of ⁇ 2 ml/min. After this time, perfusion was stopped.
  • the pipette was connected to the headstage of the patch clamp amplifier (Axopatch 200B, Axon Instruments) via a silver/silver chloride wire.
  • the headstage ground was connected to the earth electrode. This consisted of a silver/silver chloride wire embedded in 3% agar made up with 0.85% sodium chloride.
  • the cell was recorded in the whole cell configuration of the patch clamp technique. Following “break- in”, which was done at a holding potential of -80 mV (set by the amplifier), and appropriate adjustment of series resistance and capacitance controls, electrophysiology software (Clampex, Axon Instruments) was used to set a holding potential (-80 mV) and to deliver a voltage protocol. This protocol was applied every 15 seconds and consisted of a 1 s step to +40 mV followed by a 1 s step to -50 mV. The current response to each imposed voltage protocol was low pass filtered by the amplifier at 1 kHz. The filtered signal was then acquired, on line, by digitising this analogue signal from the amplifier with an analogue to digital converter.
  • the digitised signal was then captured on a computer running Clampex software (Axon Instruments). During the holding potential and the step to + 40 mV the current was sampled at 1 kHz. The sampling rate was then set to 5 kHz for the remainder of the voltage protocol.
  • compositions, pH and osmolarity of the bath and pipette solution are tabulated below.
  • the amplitude of the hERG-encoded potassium channel tail current following the step from +40 mV to -50 mV was recorded on-line by Clampex software (Axon Instruments). Following stabilisation of the tail current amplitude, bath solution containing the vehicle for the test substance was applied to the cell. Providing the vehicle application had no significant effect on tail current amplitude, a cumulative concentration effect curve to the compound was then constructed.
  • test compound potency was determined by fitting the percentage inhibition values making up the concentration-effect to a four parameter Hill equation using a standard data- fitting package. If the level of inhibition seen at the highest test concentration did not exceed 50%, no potency value was produced and a percentage inhibition value at that concentration was quoted.

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Abstract

The present invention relates to new polymorphs of compounds 2-{2-Chloro-5-{[(2S)-3-(5-chloro-1'H,3H-spiro[1-benzofuran-2,4'-piperidin]-1'-yl)-2-hydroxypropyl]oxy}-4- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid, and the hydrochloride and sodium hydroxide salts thereof,and compound 2-{2-Chloro-5-{[(2R)-3-(5-chloro-1'H,3H-spiro[1-benzofuran-2,4'-piperidin]-1'-yl)-2-hydroxypropyl]oxy}-4- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid. The invention further relates to pharmaceutical composition containing said compounds and to the use of said compounds in therapy. The present invention also relates to processes for the preparation of said compounds.

Description

Splropiperidine compounds, a process of their preparation, pharmaceutical compositions containing them, and their use in the treatment of airway diseases, inflammatory diseases, COPD or asthma
The present invention relates to new polymorphs of compounds 2-{2-Chloro-5-{[(25)-3- (5-chloro- 1 'H,3H-spiro[l -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -A- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid, and the hydrochloride and sodium hydroxide salts thereof, and compound 2-{2-Chloro-5-{[(2i?)-3-(5-chloro-l'H,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -A- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid. The invention further relates to pharmaceutical composition containing said compounds and to the use of said compounds in therapy. The present invention also relates to processes for the preparation of said compounds.
The compounds 2-{2-Chloro-5-{[(21S)-3-(5-chloro-17/,3H-spiro[l-benzofuran-2,4'- piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid, and the hydrochloride and sodium hydroxide salts thereof, and compound 2-{2-Chloro-5-{[(2i?)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2 -methylpropanoic acid (hereinafter referred to as the 'compounds of the invention'), the preparation and the medical uses thereof, are described in detail in patent application WO2008/010765, which is hereby included by reference.
The compounds of the invention inhibit the CCRl receptor.
A desirable property for a drug acting at the CCRl receptor is that it has high potency e.g. as determined by its ability to inhibit the activity of the CCRl receptor. It is also desirable for such drugs to possess good selectivity and pharmacokinetic properties in order to further enhance drug efficacy. As an example, it can be advantageous for such drugs to exhibit low activity against the human ether-a-go-go-related gene (hERG)-encoded potassium channel. In this regard, low activity against hERG binding in vitro is indicative of low activity in vivo.
In the formulation of drug compositions, it is important for the drug compound to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially- viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical compositions comprising the active compound.
Further, in the manufacture of drug compositions, it is important that a reliable, reproducible and constant plasma concentration profile of the drug is provided following administration of the compounds of the invention to a patient. Furthermore, some crystalline forms may be more suitable for certain ways of administration e.g. inhalation, than others. Also, the dosing profile of some crystalline forms may differ from others. Chemical stability, solid state stability, and "shelf life" of the active ingredients are also very important factors. The drug compound, and compositions containing it, should preferably be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the active component's physico-chemical characteristics (e.g. its chemical composition, density, hygroscopicity and solubility). Moreover, it is also important to be able to provide drugs in a form, which is as chemically pure as possible. The skilled person will appreciate that, typically, if a drug can be readily obtained in a stable form, such as a stable crystalline form, advantages may be provided, in terms of ease of handling, ease of preparation of suitable pharmaceutical compositions, and a more reliable solubility profile. In an embodiment of the invention, the compounds of the invention or salt thereof are in a substantially pure crystalline form e.g. at least 40% crystalline, at least 50% crystalline, at least 60% crystalline, at least 70% crystalline or at least 80% crystalline. Crystallinity can be estimated by conventional X-ray diffractometry techniques.
In another embodiment of the invention, the compounds of the invention or salt thereof are from 40% to 100%, or 50 to 100%, or 60 to 100%, or 70 to 100% or 80 to 100%, or 70 to 99%, or 80 to 99%, or 85 to 99%, or 90 to 97%, or 90 to 96%, or 90% to 95% crystalline. In one embodiment the compounds are 80% crystalline. In another embodiment the compounds are 90% crystalline. In a further embodiment the compounds are 92% crystalline. In one embodiment the compounds are 93% crystalline. In one embodiment the compounds are 94% crystalline. In another embodiment the compounds are 95% crystalline. In one embodiment the compounds are 96% crystalline. In another embodiment the compounds are 97% crystalline. In one embodiment the compounds are 98% crystalline. In one another embodiment the compounds are 99% crystalline. In one embodiment the compounds are 100% crystalline.
One embodiment relates to compounds 2-{2-Chloro-5-{[(25)-3-(5-chloro-l'H,3H-spiro[l- benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy}-4-
[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid, or the hydrochloride and sodium hydroxide salts thereof, or compound 2-{2-Chloro-5-{[(2i?)-3-(5-chloro-l'H,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -A- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid in a substantially pure crystalline form.
Another embodiment relates to the compounds of the invention, whereby the compounds are 90% crystalline.
It should be noted that where X-ray powder diffraction peaks are expressed herein (in degrees 2Θ), the margin of error is consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test <941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089).
Description of the drawings;
Figure 1. The X-ray powder diffractogram S-enantiomer of 2-{2-Chloro-5-{[(25)-3-(5- chloro- 1 'H,3H-spiro[l -benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -A- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid Form A. Figure 2. The X-ray powder diffractogram R-enantiomer of 2-{2-Chloro-5-{[(2i?)-3-(5- chloro- 1 'H,3H-spiro[l -benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -A- [(methylamino)carbonyl]phenoxy } -2-methylpropanoic acid.
Figure 3. The X-ray powder diffractogram S-enantiomer of 2-{2-Chloro-5-{[(25)-3-(5- chloro- 1 'H,3H-spiro[l -benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -A- [(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form B. Figure 4. The X-ray powder diffractogram S-enantiomer of 2-{2-Chloro-5-{[(25)-3-(5- chloro- 1 'H,3H-spiro[l -benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid Form C. Figure 5. The X-ray powder diffractogram S-enantiomer of 2-{2-Chloro-5-{[(25)-3-(5- chloro- 1 'H,3H-spiro[l -benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid Form D. Figure 6. The X-ray powder diffractogram S-enantiomer of 2-{2-Chloro-5-{[(25)-3-(5- chloro- 1 'H,3H-spiro[l -benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid Form F. Figure 7. The X-ray powder diffractogram S-enantiomer of 2-{2-Chloro-5-{[(25)-3-(5- chloro- 1 'H,3H-spiro[l -benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid Form G. Figure 8. The X-ray powder diffractogram S-enantiomer of 2-{2-Chloro-5-{[(25)-3-(5- chloro- 1 'H,3H-spiro[l -benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid hydrochloride.
Figure 9. The X-ray powder diffractogram S-enantiomer of 2-{2-Chloro-5-{[(25)-3-(5- chloro- 1 'H,3H-spiro[l -benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid sodium hydroxide.
One embodiment of the invention relates to the compound 2-{2-Chloro-5-{[(2S)-3-(5- chloro-1 Η,3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy } -2-methylpropanoic acid, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ) (Form A): (1) 5.1, 10.2 and 12.9, or
(2) 5.1, 8.9 and 13.2, or
(3) 8.9, 10.2, 12.9, 15.1, 17.0 and 21.2 or
(4) 5.1, 8.9, 10.2, 14.6, 15.4, 21.2 and 25.8 or
(5) 5.1, 8.9, 10.2, 12.6, 14.6, 15.1 and 17.0 or (6) 5.1, 10.2, 12.6, 13.2, 14.6, 15.1, 17.0, 17.9, 21.2 and 21.8 or
(7) 5.1, 8.9, 10.2, 12.6, 13.2, 14.6, 14.9, 16.4, 19.2, 21.8 and 27.1 or (8) 5.1, 8.9, 10.2, 12.6, 12.9, 13.2, 14.6, 14.9, 15.1, 15.4, 16.4, 17.9, 19.2, 20.0, 21.8 and 25.8.
Another embodiment relates to compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-lΗ,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -4-
[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid (Form A), which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ):
(1) 10.2, 15.4 and 17.0, or
(2) 10.2, 15.4, 17.0, 20.0, 21.2 and 27.1.
One embodiment of the invention relates to the compound 2-{2-Chloro-5-{[(2R)-3-(5- chloro-1 Η,3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy } -2-methylpropanoic acid, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ):
(1) 15.5, 17.0, 20.0 and 21.3, or
(2) 10.3, 15.5, 17.0, 20.0, 21.3 and 27.6.
One embodiment of the invention relates to the compound 2-{2-Chloro-5-{[(2S)-3-(5- chloro-1 Η,3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -4-
[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid (Form B), which exhibits at least the following characteristic X-ray powder diffraction peaks
(expressed in degrees 2Θ):
(1) 7.6, 8.6 and 18.4, or (2) 5.6, 7.6, 8.6, 13.3, 17.0 and 18.4.
One embodiment of the invention relates to the compound 2-{2-Chloro-5-{[(2S)-3-(5- chloro-1 Η,3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy } -2-methylpropanoic acid, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ) (Form C): (1) 4.5, 8.9 and 12.8, or (2) 4.5, 8.6 and 10.6, or
(3) 4.5, 8.9, 10.6, 12.8, 14.8 and 17.6 or
(4) 8.6, 8.9, 12.8, 13.9, 15.7, 16.6 and 18.8 or
(5) 4.5, 8.6, 8.9, 10.6, 13.9, 15.7, 16.0, 16.6 and 17.9 or (6) 4.5, 8.9, 10.6, 12.8, 13.9, 14.8, 15.7, 17.6, 18.8 and 20.0 or
(7) 4.5, 8.6, 8.9, 10.6, 12.8, 13.9, 15.7, 16.0, 16.6, 17.9, 18.8, 20.0, 20.9 and 21.2.
Another embodiment relates to compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-lΗ,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -A- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid (Form C), which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ):
(1) 8.6, 8.9, 10.6 and 17.6, or
(2) 8.6, 8.9, 10.6, 12.8, 13.9, 17.6, 18.8 and 20.0.
One embodiment of the invention relates to the compound 2-{2-Chloro-5-{[(2S)-3-(5- chloro-1 Η,3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -A- [(methylamino)carbonyl]phenoxy } -2-methylpropanoic acid, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ) (Form D): (1) 5.4, 12.3 and 21.3, or
(2) 5.4, 12.3, 16,9, 19.2, 19.5 and 21.3
(3) 5.4, 9.8, 12.3, 13.6, 16,9, 19.2, 19.5 and 21.3.
Yet a further embodiment of the invention relates to the compound 2-{2-Chloro-5-{[(2S)- 3-(5-chloro- 1 Η,3H-spiro[ 1 -benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy}-4-
[(methylamino)carbonyl]phenoxy } -2-methylpropanoic acid, which exhibits at least the following characteristic X-ray powder diffraction peaks
(expressed in degrees 2Θ) (Form F):
(1) 7.5, 9.2 and 10.7, or (2) 7.5, 8.9 and 11.1, or
(3) 7.5, 8.9, 9.2, 11.1, 12.2 and 16.3 or
(4) 8.9, 9.2, 10.7, 11.1, 11.7, 12.2 and 15.1 or (5) 7.5, 8.9, 9.2, 10.7, 11.7, 12.2, 13.8, 15.1, 16.7 and 18.5 or
(6) 7.5, 8.9, 9.2, 11.1, 11.9, 13.8, 15.1, 16.3, 17.8, 18.3, 18.7 and 20.9 or
(7) 7.5, 8.9, 9.2, 10.7, 11.1, 11.7, 12.2, 13.8, 15.1, 18.3, 18.7, 19.7, 21.4, 22.3 and 24.0 or
(8) 7.5, 9.2, 10.7, 11.7, 11.9, 12.2, 13.8, 15.1, 16.3, 16.7, 17.8, 18.3, 19.2, 19.7, 20.9, 21.4 and 22.3.
Another embodiment relates to compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-lΗ,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -A- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid (Form F), which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ):
(1) 7.5, 11.7, 13.8, 18.3 and 21.4 or
(2) 7.5, 9.2, 11.7, 11.9, 13.8, 15.1, 16.7, 17.8, 18.3, 19.2, 20.9, 21.4 and 22.3.
One embodiment of the invention relates to the compound 2-{2-Chloro-5-{[(2S)-3-(5- chloro-lΗ,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy}-4-
[(methylamino)carbonyl]phenoxy } -2-methylpropanoic acid, which exhibits at least the following characteristic X-ray powder diffraction peaks
(expressed in degrees 2Θ) (Form G):
(1) 4.8, 12.2 and 15.4, or (2) 4.8, 9.7 and 13.7, or
(3) 9.7, 13.7, 14.5, 15.6, 17.1 and 20.3 or
(4) 4.8, 13.7, 14.5, 15.4, 16.3, 17.1 and 20.3 or
(5) 4.8, 9.7, 13.7, 14.5, 15.6, 16.3 and 19.7 or
(6) 9.7, 12.2, 13.7, 14.5, 15.6, 16.3, 19.4, 20.3, 21.4 and 23.1 or (7) 9.7, 13.7, 14.5, 15.6, 16.3, 19.7, 20.3, 20.8, 21.4, 23.1 and 25.5 or
(8) 4.8, 9.7, 12.2, 13.7, 15.4, 16.3, 17.1, 19.4, 19.7, 20.3, 20.8, 21.4, 23.1 and 25.5.
Another embodiment relates to compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-l'H,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -A- [(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid (Form G), which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ): (1) 9.7, 15.6, 17.1 and 21.4 or (2) 9.7, 15.4, 15.6, 16.3, 17.1, 19.4, 19.7, 20.3 and 21.4.
Another embodiment of the invention relates to the compound 2-{2-Chloro-5-{[(2S)-3-(5- chloro-1 Η,3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -A- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid hydrochloride, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ):
(1) 7.6, 7.9, 20.6, 21.3, 22.9 and 23.8 or
(2) 9.7, 13.7, 14.5, 16.2, 16.4, 19.6, 20.6, 21.3, 22.4, 22.9 and 23.8 or (3) 5.5, 7.6, 7.9, 13.4, 14.5, 15.2, 15.9, 16.2, 16.4, 19.6, 20.6, 21.3, 22.4, 22.9 and 23.8.
Another embodiment relates to compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-l'H,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -A-
[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid hydrochloride, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ):
(1) 7.6, 20.6 and 22.9 or
(2) 7.6, 7.9, 9.7, 13.4, 13.7, 15.2, 15.9, 20.6, 21.3, 22.4, 22.9 and 23.8.
A further embodiment of the invention relates to the compound 2-{2-Chloro-5-{[(2S)-3-(5- chloro-1 Η,3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -A- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid sodium hydroxide, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ): (1) 7.6, 8.6 and 18.4 or
(2) 5.6, 7.6, 8.6, 13.1, 17.0 and 18.4.
Another embodiment relates to the substantially pure compound 2-{2-Chloro-5-{[(2S)-3- (5-chloro- 1 Η,3H-spiro[l -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -A- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid having an X-ray powder diffraction pattern substantially the same as that shown in Figure 1 and Figures 3 to 9. Process
Compounds of the present invention can be prepared by routes, which are analogous to those described in WO2004/005295 and by the processes described in WO2008/010765, especially examples 5 to 14 and 17.
One embodiment of the invention relates to a process for the preparation of polymorph Form A, comprising the following steps: a) compound 2- {2-Chloro-5-{[(2S)-3-(5-chloro-lΗ,3H-spiro[l-benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid is slurried in an organic solvent and heated to a temperature between 55 and 65°C for at least 25 to 35 minutes under continues stirring; b) addition of water over a period of 25 to 35 minutes and continues stirring for a further 30 minutes; c) cooling the mixture to room temperature and continued stirring for 25 to 35 minutes; d) cooling the mixture to a temperature between 0 and 4°C and continued stirring for 25 to 35 minutes, followed by filtration; e) washing the mixture in a 1:1 water/ethanol mixture, followed by drying at 50 to 70 0C. In another embodiment the organic solvent is 7V-methyl-2-pyrrolidone.
In a further embodiment the stirring times are 30 minutes. In yet another embodiment the temperature in step a), b) and e) is 600C.
Another embodiment relates to the preparation of polymorphic Form C, comprising steps a) to e) as described above followed by; f) micronizing Form A and dissolving in an organic solvent followed by stirring at a temperature between 25 to 35 0C for around 24 hours; g) removal of the supernatant and drying the sediment at a temperature between 75 to 85 0C for around 24 hours.
In one embodiment the solvent is Tetrahydrofuran.
In yet another embodiment the temperature in step f) is 300C and in step g) is 800C.
The relative humidity in the laboratory was between 40 and 70% at rooms temperature. Pharmaceutical composition
According to one embodiment of the present invention there is provided a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compounds of the invention, or pharmaceutically acceptable salts thereof (also referred to as active ingredient or drug), in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.
The active ingredients of the present invention may be administered by oral or parenteral (e.g. intravenous, subcutaneous, intramuscular or intraarticular) administration using conventional systemic dosage forms, such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions and sterile injectable aqueous or oily solutions or suspensions. The active ingredients may also be administered topically (e.g. to the lung and/or airways) in the form of solutions, suspensions, aerosols and dry powder formulations. These dosage forms will usually include one or more pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants. As will be understood by those skilled in the art, the most appropriate method of administering the active ingredients is dependent on a number of factors.
The pharmaceutical compositions of the present invention may be prepared by mixing the active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Therefore, in a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical composition, which comprises mixing a compound of the invention, or pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable adjuvant, diluent or carrier.
The active ingredient is conveniently administered via inhalation (e.g. topically to the lung and/or airways) in the form of solutions, suspensions, aerosols or dry powder formulations (also referred to as composition). Administration may be by inhalation orally or intranasally. The active ingredient is preferably adapted to be administered, from a dry powder inhaler, pressurised metered dose inhaler, or a nebuliser. The active ingredient may be used in admixture with one or more pharmaceutically acceptable additives, diluents or carriers. Examples of suitable diluents or carriers include lactose (e.g. the monohydrate), dextran, mannitol or glucose.
Metered dose inhaler devices may be used to administer the active ingredients, dispersed in a suitable propellant and with or without additional excipients such as ethanol, a surfactant, a lubricant, an anti-oxidant or a stabilising agent. Suitable propellants include hydrocarbon, chlorofiuorocarbon and hydrofiuoroalkane (e.g. heptafiuoroalkane) propellants, or mixtures of any such propellants. Preferred propellants are P 134a and P227, each of which may be used alone or in combination with other propellants and/or surfactant and/or other excipients. Nebulised aqueous suspensions, solutions may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose formulations.
Dry powder inhalers may be used to administer the active ingredients, alone or in combination with a pharmaceutically acceptable carrier, in the later case either as a finely divided powder or as an ordered mixture. The dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule.
When the active ingredient is adapted to be administered, via a nebuliser it may be in the form of a nebulised aqueous suspension or solution, with or without a suitable pH or tonicity adjustment, either as a single dose or multidose device.
Metered dose inhaler, nebuliser and dry powder inhaler devices are well known and a variety of such devices are available.
One embodiment the present invention provides a pharmaceutical product comprising, the compounds of the present invention, formulated for inhaled administration. In one embodiment of the present invention, the compounds of the present invention are administered by inhalation.
In another embodiment of the present invention, the compounds of the invention, are administered orally. Medical use
The compounds of the invention, have activity as pharmaceuticals, and are believed to be potent modulators of chemokine receptor (especially CCRl receptor) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases.
A compound of the invention, or a pharmaceutically acceptable salt thereof, may be used in the treatment of: 1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus; 2. bone and joints: arthritides associated with or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection- related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle- Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies;
3. pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example sports injury] or disease: arthitides (for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as intervertebral disc degeneration or temporomandibular joint degeneration), bone remodelling disease (such as osteoporosis, Paget's disease or osteonecrosis), polychondritits, scleroderma, mixed connective tissue disorder, spondyloarthropathies or periodontal disease (such as periodontitis); 4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions; 5. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial; 6. gastrointestinal tract: glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema);
7. abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;
8. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);
9. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease; 10. CNS: Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;
11. other auto-immune and allergic disorders including Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome;
12. other disorders with an inflammatory or immunological component; including acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic syndromes; 13. cardiovascular: atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins; and
14. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes.
The pharmaceutical product according to this embodiment may, for example, be a pharmaceutical composition comprising the first and further active ingredients in admixture. Alternatively, the pharmaceutical product may, for example, comprise the first and further active ingredients in separate pharmaceutical preparations suitable for simultaneous, sequential or separate administration to a patient in need thereof. The pharmaceutical product of this embodiment is of particular use in treating respiratory diseases such as asthma, COPD or rhinitis.
One embodiment of the invention relates to a pharmaceutical product comprising, in combination, a first active ingredient which is a compound of the invention, as hereinbefore described, and at least one further active ingredient selected from :
• a phosphodiesterase inhibitor,
• a β2 adrenoceptor agonist,
• an inhibitor of kinase function,
• a protease inhibitor, • a steroidal glucocorticoid receptor agonist,
• an anticholinergic agent, and a
• a non-steroidal glucocorticoid receptor agonist.
Examples of a phosphodiesterase inhibitor that may be used in the pharmaceutical product according to this embodiment include a PDE4 inhibitor such as an inhibitor of the isoform PDE4D, a PDE3 inhibitor and a PDE5 inhibitor. Examples include the compounds (Z)-3-(3,5-dichloro-4-pyridyl)-2-[4-(2-indanyloxy-5-methoxy-2-pyridyl]propenenitrile, N-[9-amino-4-oxo-l-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,l-jk][l,4]benzodiazepin-3(R)- yl]pyridine-3-carboxamide (CI- 1044),
3-(benzyloxy)-l-(4-fluorobenzyl)-N-[3-(methylsulphonyl)phenyl]-lH-indole-2- carboxamide, (lS-exo)-5-[3-(bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl]tetrahydro-2(lH)- pyrimidinone (Atizoram),
N-(3,5,dichloro-4-pyridinyl)-2-[l-(4-fluorobenzyl)-5-hydroxy-lH-indol-3-yl]-2- oxoacetamide (AWD- 12-281), β-[3-(cyclopentyloxy)-4-methoxyphenyl]- 1 ,3-dihydro- 1 ,3-dioxo-2H-isoindole-2- propanamide (CDC-801),
N-[9-methyl-4-oxo-l-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,l-jk][l,4]benzodiazepin-3(R)- yl]pyridine-4-carboxamide (CI-1018), cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-l-carboxylic acid
(Cilomilast), 8-amino-l,3-bis(cyclopropylmethyl)xanthine (Cipamfylline),
N-(2,5-dichloro-3-pyridinyl)-8-methoxy-5-quinolinecarboxamide (D-4418),
5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-iminothiazolidin-4-one (Darbufelone),
2-methyl- 1 -[2-(I -methylethyl)pyrazolo[l ,5-a]pyridin-3-yl]- 1 -propanone (Ibudilast),
2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzofuran-6-yl methanesulphonate (Lirimilast), (-)-(R)-5-(4-methoxy-3-propoxyphenyl)-5-methyloxazolidin-2-one (Mesopram),
(-)-cis-9-ethoxy-8-methoxy-2-methyl- 1,2,3, 4,4a, 10b-hexahydro-6-(4- diisopropylaminocarbonylphenyl)-benzo[c][l,6]naphthyridine (Pumafentrine),
3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)benzamide
(Roflumilast), the N-oxide of Roflumilast,
5,6-diethoxybenzo[b]thiophene-2-carboxylic acid (Tibenelast),
2,3,6,7-tetrahydro-2-(mesitylimino)-9, 10-dimethoxy-3-methyl-4H-pyrimido[6, 1 - a]isoquinolin-4-one (trequinsin), and
3-[[3-(cyclopentyloxy)-4-methoxyphenyl]-methyl]-N-ethyl-8-(l-methylethyl)-3H-purine- 6-amine (V-11294A). Examples of a β2-adrenoceptor agonist that may be used in the pharmaceutical product according to this embodiment include metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol (e.g. as sulphate), formoterol (e.g. as fumarate), salmeterol (e.g. as xinafoate), terbutaline, orciprenaline, bitolterol (e.g. as mesylate), pirbuterol or indacaterol. The β2-adrenoceptor agonist of this embodiment may be a long-acting β2-agonists, for example salmeterol (e.g. as xinafoate), formoterol (e.g. as fumarate), bambuterol (e.g. as hydrochloride), carmoterol (TA 2005, chemically identified as 2(1H)-Quinolone, 8- hydroxy-5-[l-hydroxy-2-[[2-(4-methoxy-phenyl)-l-methylethyl]-amino]ethyl]- monohydrochloride, [R-(R*, R*)] also identified by Chemical Abstract Service Registry Number 137888-11-0 and disclosed in U.S. Patent No 4,579,854), indacaterol (CAS no 312753-06-3; QAB- 149), formanilide derivatives e.g. 3-(4-{[6-({(2R)-2-[3- (formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}-butyl)- benzenesulfonamide as disclosed in WO 2002/76933, benzenesulfonamide derivatives e.g. 3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxy-methyl)phenyl]ethyl}amino)- hexyl]oxy}butyl)benzenesulfonamide as disclosed in WO 2002/88167, aryl aniline receptor agonists as disclosed in WO 2003/042164 and WO 2005/025555, indole derivatives as disclosed in WO 2004/032921 and US 2005/222144, and compounds GSK 159797, GSK 159802, GSK 597901, GSK 642444 and GSK 678007.
Examples of an inhibitor of kinase function that may be used in the pharmaceutical product according to this embodiment include a p38 kinase inhibitor and an IKK inhibitor.
Examples of a protease inhibitor that may be used in the pharmaceutical product according to this embodiment include an inhibitor of neutrophil elastase or an inhibitor of matrix metalloproteases such as MMPl, MMP2, MMP7, MMP8, MMP9,MMP12 and/or MMP13.
Examples of a steroidal glucocorticoid receptor agonist that may be used in the pharmaceutical product according to this embodiment include budesonide, fluticasone (e.g. as propionate ester), mometasone (e.g. as furoate ester), beclomethasone (e.g. as 17- propionate or 17,21-dipropionate esters), ciclesonide, loteprednol (as e.g. etabonate), etiprednol (as e.g. dicloacetate), triamcinolone (e.g. as acetonide), fiunisolide, zoticasone, flumoxonide, rofleponide, butixocort (e.g. as propionate ester), prednisolone, prednisone, tipredane, steroid esters e.g. 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-l lβ-hydroxy- 16α-methyl-3-oxo-androsta-l,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 and 6α,9α-difluoro-l lβ-hydroxy- 16α-methyl- 17α-[(4-methyl- 1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta- 1 ,4-diene- 17β- carbothioic acid S-fluoromethyl ester, steroid esters according to DE 4129535, steroids according to WO 2002/00679, WO 2005/041980, or steroids GSK 870086, GSK 685698 and GSK 799943.
Examples of an anticholinergic agent that may be used in the pharmaceutical product according to this embodiment include for example a muscarinic receptor antagonist (for example a Ml, M2 or M3 antagonist, such as a M3 antagonist) for example ipratropium (e.g. as bromide), tiotropium (e.g. as bromide), oxitropium (e.g. as bromide), tolterodine, pirenzepine, telenzepine, glycopyrronium bromide (such as R,R- glycopyrronium bromide or a mixture of R,S- and S,R-glycopyrronium bromide); mepensolate (e.g. as bromide), a quinuclidine derivative such as 3(R)-(2-hydroxy-2,2- dithien-2-ylacetoxy)- 1 -(3 -phenoxypropyl)- 1 -azonia-bicyclo [2.2.2] octane bromide as disclosed in US 2003/0055080, quinuclidine derivatives as disclosed in WO 2003/087096 and WO 2005/115467 and DE 10050995; or GSK 656398 or GSK 961081.
Examples of a modulator of a non-steroidal glucocorticoid receptor agonist that may be used in the pharmaceutical product according to this embodiment include those described in WO2006/046916.
One embodiment of the present invention provides a compound of the invention, as hereinbefore defined for use in therapy.
Another embodiment of the present invention provides the use of a compound of the invention, as hereinbefore defined in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of CCRl activity is beneficial. A further embodiment of the present invention provides the use of a compound of the invention, as hereinbefore defined in the manufacture of a medicament for treating respiratory diseases.
Yet another embodiment of the present invention provides the use of a compound of the invention, as hereinbefore defined in the manufacture of a medicament for treating airways diseases.
Yet a further embodiment of present invention provides the use of a compound of the invention, as hereinbefore defined in the manufacture of a medicament for treating inflammatory diseases.
One embodiment of the present invention provides the use of a compound of the invention, as hereinbefore defined in the manufacture of a medicament for treating chronic obstructive pulmonary disease (COPD).
Another embodiment of the present invention provides the use of a compound of the invention, as hereinbefore defined in the manufacture of a medicament for treating asthma.
A further embodiment of the present invention provides a method of treatment of respiratory diseases, airway diseases, inflammatory diseases, COPD and/or asthma, in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of the invention, as hereinbefore defined.
Another embodiment of the present invention provides the uses and methods above whereby the compound of the invention as defined above, is administered by inhalation.
One embodiment of the invention relates to an agent for the treatment of respiratory diseases, airway diseases, inflammatory diseases, COPD and/or asthma, which comprises as active ingredient a compound of the invention. Another embodiment relates to the use of a pharmaceutical composition comprising the compound of the invention in the treatment of respiratory diseases, airway diseases, inflammatory diseases, COPD and/or asthma.
In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.
In this specification, unless stated otherwise, the terms "inhibitor" and "antagonist" mean a compound that by any means, partly or completely, blocks the transduction pathway leading to the production of a response by the agonist.
The term "disorder", unless stated otherwise, means any condition and disease associated with CCRl receptor activity.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of the invention may be in the range from 0. 1 μg/kg to 30 mg/kg.
The compounds of the invention may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compound of the invention (active ingredient) is in association with a pharmaceutically acceptable adjuvants, diluents and/or carriers. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.01 to 100 %w (per cent by weight), more preferably from 0.01 to 80 %w, still more preferably from 0.05 to 70 %w, and even more preferably from 0.05 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
Examples
The invention will now be further explained by reference to the following illustrative examples. Each exemplified compound represents a particular and independent aspect of the invention.
The following abbreviations are used: APCI-MS Atmospheric Pressure Chemical Ionisation Mass Spectroscopy;
DBU l,8-Diazabicyclo[5.4.0]undec-7-ene
DME 1 ,2-Dimethoxyethane
DMF 7V,7V-Dimethylformamide
DMSO Dimethylsulfoxide; HPLC High Performance Liquid Chromatography;
LC/MS Liquid Column Chromatography / Mass Spectroscopy;
NMP 7V-methyl-2-pyrrolidone
PMB /?-methoxybenzyl
PrCN n-Butyronitrile TBME tert-Butylmethyl ether
TFA Trifluoroacetic acid;
THF Tetrahydrofuran
ReI vol relative volume r.t, room temperature or ambient temperature a temperature between 16 and 25 0C eq. Equivalent aq. Aqeous vs. versus
General Methods 1H NMR and 13C NMR spectra were recorded on a Varian Inova 400 MHz or a Varian Mercury-VX 300 MHz or a Varian Unity Inova 400 MHz or a Varian Unity Inova 300 MHz instrument. The central peaks of chloroform-J (δπ 7.27 ppm), dimethylsulfoxide-Jή (δu 2.50 ppm), acetonitrile-Jj (δu 1.95 ppm) or methanol-^ (δu 3.31 ppm) were used as internal references. Flash chromatography was carried out using silica gel (0.040-0.063 mm, Merck). Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received. The following methods were used for LC/MS analysis:
Instrument Agilent 1100; Column Waters Symmetry 2.1 x 30 mm; Mass APCI; Flow rate 0.7 ml/min; Wavelength 254 nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA; Gradient 15-95%/B 2.7 min, 95% B 0.3 min. Instrument Agilent 1100; Column Hi Chrom Ace Phenyl 3.0 x 50 mm; Mass APCI; Flow rate 1.25 ml/min; Wavelength 230 nm; Solvent A: water + 0..03% TFA; Solvent B: acetonitrile + 0.03% TFA; Gradient 5-95% B 6 min, 95% B 1.5 min.
The following method was used for LC analysis: Method A. Instrument Agilent 1100; Column: Kromasil C18 100 x 3 mm, 5μ particle size,
Solvent A: 0.1 %TF A/water, Solvent B: 0.08%TFA/acetonitrile Flow: 1 ml/min,
Gradient 10-100% B 20 min, 100% B 1 min. Absorption was measured at 220, 254 and
280 nm.
Method B. Instrument Agilent 1100; Column: XTerra C8, 100 x 3 mm, 5 μ particle size, Solvent A: 15 mM NH3/water, Solvent B: acetonitrile Flow: 1 ml/min, Gradient 10-100%
B 20 min, 100% B 1 min. Absorption was measured at 220, 254 and 280 nm.
A standard copper lamp was used for X-ray measurements.
The following intermediates and starting materials can be prepared following the procedures described in WO2004005295: 5-chloro-3H-spiro[l-benzofuran-2,4'-piperidine], 5-chloro-2-hydroxy-4-[(4-methoxybenzyl)oxy]-Λ/-methylbenzamide, The other starting materials are either commercially available or the preparation thereof has been published.
Example 1
2-/2-Chloro-5-m2S)-3-(5-chloro-l Η,3H-sϋirofl-benzofuran-2,4'-ϋweήdin]-r-yl)-2- hydroxyyrovyl]oxy)-4-f(methylamino)carbonyllvhenoxy)-2-methylyroyanoic acid TFA
Figure imgf000024_0001
Step 1 : 5-Chloro-4- [(4-methoxybenzyl)oxy] -N-methyl-2- [(2S)-oxiran-2- ylmethoxyjbenzamide
A suspension of methyl 5-chloro-2-hydroxy-4-[(4-methoxybenzyl)oxy]benzoate (1.61 g, 5.0 mmol) in the solution of methylamine in ethanol (33 % wt, 25 ml) was stirred at room temperature overnight, then at 60 0C for 4 h to form a solution. The solvent was removed in vacuo, affording 5-chloro-2-hydroxy-4-[(4-methoxybenzyl)oxy]-N-methylbenzamide as red powder. This intermediate was dissolved in DMF (20 ml). To the solution were added cesium carbonate (1.96 g, 6.0 mmol) and (25)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (1.30 g, 5.0 mmol). The suspension was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, and filtered. The solvent was removed in vacuo to give the subtitled compound as red solid (1.71 g, 91 %). 1H-NMR (CDCl3, 400 MHz): δ 8.21(s, IH), 7.67 (d, J = 4.4, NH), 7.37 (d, J=8.76, 2H), 6.92 (d, J=8.76, 2H), 6.58 (s, IH), 5.11 (s, 2H), 4.44-4.39 (m, IH), 4.01-3.96 (m, IH), 3.82 (s, 3H), 3.39-3.34 (m, IH), 2.98 (d, J=4.9, 3H), 2.96-2.95 (m, IH), 2.82-2.79 (m, IH); APCI-MS: m/z 378 (MH+).
Step 2: 5-Chloro-2-{[(2S)-3-(5-chloro-l Η,3H-spiro[l-benzofuran-2,4'-piperidin]-l '-yl)-2- hydroxypropylJoxy}-4-hydroxy-N-methylbenzamide A mixture of 5-chloro-3H-spiro[l-benzofuran-2,4'-piperidine] (172 mg, 0.77 mmol) and 5- chloro-4-[(4-methoxybenzyl)oxy]-Λ/-methyl-2-[(25)-oxiran-2-ylmethoxy]benzamide (290 mg, 0.77 mmol) in ethanol (10 ml) was stirred at 80 0C overnight. Ethanol was then removed in vacuo. The residue was redissolved in dichloromethane (5 ml). Aq. TFA (95 %, 2.5 ml) was added, and the solution was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the residue was purified by HPLC to give the subtitle compound as TFA salt (382 mg, 72 %). 1H-NMR (DMSO-d6, 400 MHz): δ 8.05 (d, J=4.6, NH), 7.73 (s, IH), 7.30 (m, IH), 7.18- 7.14 (m, IH), 6.82-6.78 (m, IH), 6.73 (s, IH), 4.42 (m, IH), 4.05 (s, 2H), 3.57 (m, 2H), 3.45-3.40 (m, IH), 3.27-3.11 (m, 5H), 2.81 (d, J=4.8, 3H), 2.18-2.08 (m, 4H); APCI-MS: m/z 481 (MH+). Step 3: Ethyl 2-{2-chloro-5-{[(2S)-3-(5-chloro-l Η,3H-spiro[l-benzofuran-2,4'-piperidin]- l '-yl)-2-hydroxypropyl] oxy}-4- [(methylamino)carbonyl] phenoxy}-2-methylpropanoate To a stirred solution of 5-chloro-2-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'- piperidin]-r-yl)-2-hydroxypropyl]oxy}-4-hydroxy-Λ/-methylbenzamide , TFA salt, (Example 4 of WO 2008/010765, Step 2, 67 mg, 0.112 mmol) in DMF (1 ml) were added cesium carbonate (92 mg, 0.281 mmol) and ethyl 2-bromo-2-methylpropanoate (24 mg, 0.123 mmol). After stirring at 45 0C overnight another portion of ethyl 2-bromo-2- methylpropanoate (24 mg, 0.123 mmol) was added. The reaction mixture was stirred for an additional 4 h. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with brine, and dried with sodium sulfate. After evaporation of solvent the product was isolated by HPLC to afford the subtitle compound, as identified by APCI-MS (m/z 595 (MH+)), as colourless solid (TFA salt, 68 mg, 86 %). Step 4: 2-{2-Chloro-5-{[(2S)-3-(5-chloro-l Η,3H-spiro[l-benzofuran-2,4'-pipeήdinJ-l '- yl)-2-hydroxypropyl]oxy}-4-[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid To a solution of ethyl 2-{2-chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'- piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoate (33 mg, 55 μmol) in dioxane (2 ml) were added aq. NaOH (55 μl), and water (0.5 ml). The mixture was heated at 80 0C for 30 min. Then it was acidified with aq. HCl (2 M, 200 μl), and concentrated. The product was isolated by HPLC to give the title compound as colourless oil (TFA salt, 17 mg, 45 %). 1H-NMR (DMSO-J6, 400 MHz): δ 13.41 (br.s, IH), 9.60 - 9.35 (m, IH), 8.13 (d, J= 4.6 Hz, IH), 7.75 (s, IH), 7.30 (s, IH), 7.16 (d, J= 8.7 Hz, IH), 6.80 (d, J= 8.5 Hz, IH), 6.19 (s, IH), 4.40 (br.s, IH), 4.00 (d, J= 4.4 Hz, 2H), 3.62 - 3.15(m, 6H), 3.11 (s, 2H), 2.82 (d, J= 4.7 Hz, 3H), 2.50 (m, 4H), 1.60 (s, 6H); APCI-MS: m/z 567 (MH+). Result from assay: IC50 (μM) 0.001057.
Example 2, R-enantiomer 2-{2-Chloro-5-{[(2R)-3-(5-chloro-l 1H.3H-spiro[l-benzofuran-2.4 '-piperidin 1-1 '-yl)-2- hydroxypropylloxy}-4-[(methylam.ino)carbonyllphenoxy}-2-methylpropanoic acid This compound was prepared using the same process as described in example 1 but using 5-chloro-4-[(4-methoxybenzyl)oxy]-Λ/-methyl-2-[(2i?)-oxiran-2-ylmethoxy]benzamide. APCI-MS: m/z 567 (MH+).
The diffractogram is shown in figure 2. Result from assay: IC50 (μM) 0.01099.
Example 3 2-{2-Chloro-5-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2, 4 '-piperidinl-1 '-yl)-2- hydroxypropyl]oxy)-4-f(methylamino)carbonyllphenoxy)-2-methylpropanoic acid Method 1
Step 1: l-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester
Figure imgf000026_0001
Bocpiperidone Addition of 4-oxo-piperidine-l-carboxylic acid tert-butyl ester as a DMSO solution to a prepared solution of trimethylsulfoxonium iodide and potassium tert-butoxide (Corey- Chaykovsky reagent) in DMSO, provided the epoxy-piperidine.
Potassium tert-butoxide (660 g, 5.89 mol) and DMSO (5.5 L) were charged to a reaction vessel and the mixture cooled to around 20 0C with stirring. Trimethylsulfoxonium iodide (1.24 kg, 5.63 mol) was added in portions over a period of 15 - 20 min, maintaining the reaction temperature between 20 and 25 0C. On completion of the addition, the mixture was maintained at this temperature until a yellow solution was obtained (1 - 1.5 h). DME (1.5 L) was added to the reaction flask and the solution cooled to 0 - 5 0C. A pre-cooled solution of 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (1 kg, 5.02 mol) in a mixture of DME (1.5 L) and DMSO (500 ml) was transferred into the reaction mixture over a period of around 45 min, maintaining the reaction temperature between 0 and 5 0C. On completion of the addition, the reaction mixture was held at this temperature for a further 1 - 1.5 h. TBME (4 L) was added to the reaction mixture followed by water (6 L) over a period of 30 - 40 min, maintaining the reaction temperature between 0 and 10 0C, then stirring continued for a further 15 - 20 min at this temperature. The phases were separated and the aqueous layer was extracted with TBME (2 x 4 L). The combined organic layers were washed with water (2 x 6 L), dried over sodium sulphate, filtered and the solids washed with TBME (500 ml). The combined filtrates were concentrated under vacuum at below 45 0C to a small volume (1.5 kg). TBME (20 L) was added to the concentrate and solvent was distilled off at below 45 0C to leave a small volume (around 1.3 kg). THF (10 L) was added to the concentrate and solvent was distilled off to leave a solution of l-oxa-6- aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester in THF, 1.8 kg, 51.2% w/w, 0.92 kg contained weight, 86% yield.
1H NMR (399.824 MHz, CDCl3) δ 3.78 - 3.65 (m, 2H), 3.43 (ddd, J= 13.3, 9.5, 3.7 Hz, 2H), 2.69 (s, 2H), 1.85 - 1.74 (m, 2H), 1.50 - 1.40 (m, HH) APCI-MS: m/z 114 (MH+ - (CH3)3OCO). Step 2: 4-(5-Chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
Figure imgf000027_0001
Bromobenzene QMp ^^ Piperidinol
2-Bromo-4-chloroanisole is treated with isopropylmagnesium chloride dissolved in THF to produce the Grignard reagent in situ. A catalytic amount of copper (I) bromide dimethyl sulphide complex (CuBr1SMe2) and a solution of l-oxa-6-aza-spiro[2.5]octane-6- carboxylic acid tert-butyl ester in THF are added to produce the desired piperidinol.
A solution of isopropylmagnesium chloride in THF (2 M, 2.96 kg, 3036 ml, 6.07 mol) was added to a stirred solution of 2-bromo-4-chloro-l-methoxybenzene (1.26 kg, 5.69 mol) in THF (5.5 kg) at a temperature of between 15 and 25 0C and stirring continued at this temperature for 6 - 8 h. Copper(I) bromide dimethylsulphide complex (8.8 g, 42.8 mmol) was added to the reaction mixture and stirring continued at between 17 and 20 0C for 10 min. A solution of l-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester in THF (3.1 kg, 39% w/w, 1.21 kg contained weight, 5.67 mol) was added to the reaction over a period of 20 min, maintaining the temperature between 15 and 20 0C, followed by further THF (2.3 kg). After stirring at between 20 and 25 0C for 10 - 12 h, the reaction mixture was cooled to between 5 and 10 0C and a mixture of water (97 ml) and THF (220 g) added over 20 min followed by ethyl acetate (8 kg) and a solution of ammonium chloride (1.72 kg) in water (9.68 kg). The reaction mixture was warmed to between 25 and 30 0C and stirred at this temperature for around 20 min. The layers were separated, the aqueous layer was extracted with ethyl acetate (8 kg) and the combined organic layers were washed with water 2 x 6 kg). The organic phase was concentrated under vacuum at 40 - 45 0C to 2-3 L total volume then heptane (8 kg) added to the solution over a period of 30 min. After cooling to ambient temperature then further cooling to 0-5 0C and holding at this temperature, the solid was collected by filtration, washed with a mixture of ethyl acetate and heptane (1:5, 1.4 kg) followed by heptane (1.5 kg) then dried to afford 4-(5-chloro-2- methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl ester as a solid, 1.65 kg (82%).
1H NMR (399.824 MHz, CDCl3) δ 7.19 (dd, J= 8.7, 2.8 Hz, IH), 7.09 (d, J= 2.8 Hz, IH), 6.82 (d, J= 8.7 Hz, IH), 3.92 - 3.71 (m, 5H), 3.11 (t, J= 11.7 Hz, 2H), 2.80 (br s, 2H), 2.46 (s, exch D2O, IH), 1.60 - 1.42 (m, HH) APCI-MS: m/z 256/258 (MH+ - (CH3)3OCO). Step 3: 5-Chloro-3H-spiro[l-benzofuran-2,4 '-piperidine], hydrobromic acid salt
Figure imgf000028_0001
Piperidinol
5-Chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl ester is heated under reflux in a mixture of hydrobromic acid and acetic acid to form the hydrobromic acid salt of the 5-chlorospiropiperidine.
Aqueous hydrobromic acid (48% w/w, 62 ml) was added dropwise to a stirred mixture of 4-(5-chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl ester (20 g, 56 mmol) and acetic acid (40 ml) over a period of 40 min at a temperature of between 40 and 50 0C. Stirring was continued at this temperature for a further 30 - 40 min on completion of the addition. The reaction mixture was then heated to reflux for between 6 and 8 h when HPLC analysis showed complete reaction. After cooling to between 20 and 30 0C, ethanol (60 ml) was charged to the reaction and stirring continued at between 20 and 25 0C for 20 min. After cooling to between -10 and -15 0C and stirring for 30 min, the solid product was collected by filtration, washed with ethanol (2 x 20 ml) and dried to afford 5-chloro-3H-spiro[l-benzofuran-2,4'-piperidine], hydrobromic acid salt as an off- white solid, 13.5 g (79%). The combined filtrates were concentrated in vacuo to a volume of 40 ml then ethanol (20 ml) added and the mixture cooled to between -5 and -10 0C. The solid product was collected by filtration and washed with ethanol (2 x 10 ml). After drying, further 5-chloro-3H-spiro[l-benzofuran-2,4'-piperidine], hydrobromic acid salt, 1.4 g (8.2%) was obtained.
1H NMR (399.826 MHz, D6-DMSO) δ 8.57 (br s, 2 H), 7.28 (m, IH), 7.15 (dd, J= 8.5, 2.3 Hz, IH), 6.80 (d, J= 8.7 Hz, IH), 3.27 - 3.08 (m, 4H), 3.12 (s, 2H), 2.06 - 1.89 (m, 4H). APCI-MS: m/z 224/226 (MH+) Step 4: 5-chloro-2-hydroxy-4-methoxybenzoic acid methyl ester.
Figure imgf000029_0001
Methyl Ester Chloro Phenol
Sulfuryl chloride (274.8 g, 2.0 mol) was charged to a stirred solution of 2-hydroxy-4- methoxybenzoic acid methyl ester (308.2 g, 1.7 mol) in dichloromethane (3.18 L) maintained at between 25 and 30 0C. After stirring for 6 h the amount of starting material remaining was 2.3% by HPLC area. Acetic acid (203 g, 3.4 mol) was added to the reaction mixture followed by water (750 ml). The organic phase was separated then solvent distilled off at atmospheric pressure whilst adding methanol so as to maintain roughly constant reaction volume until a head temperature of 60 0C was achieved. A total of 3.5 L methanol was added. The product suspension was cooled to 0 to 5°C, the solid was collected by filtration, washed with methanol (2 x 200 ml) and dried under vacuum at 50 - 60 0C. The crude solid (342 g) was re-slurried in methanol (3.4 L) then collected by filtration and dried under vacuum at 50 - 60 0C to afford 5-chloro-2-hydroxy-4-methoxybenzoic acid methyl ester as a solid (316.6 g, 86.5%). 1H NMR (399.824 MHz, CDCl3) δ 10.92 (s, IH), 7.81 (s, IH), 6.50 (s, IH), 3.93 (s, 3H),
3.92 (s, 3H)
Step 5: 5-chloro-2,4-dihydroxybenzoic acid methyl ester
Figure imgf000030_0001
Chloro Phenol
Figure imgf000030_0002
Aluminium chloride (531 g, 4.0 mol) and toluene (3.45 L) were charged to a reaction vessel and stirred. Dodecanethiol (966 g, 4.8 mol) was added over 25 min and the mixture stirred to give a solution then heated to 40 to 50 0C. A solution of 5-chloro-2-hydroxy-4- methoxybenzoic acid methyl ester (345.0 g, 1.6 mol) in toluene (3.45L) was then added over 2 h at 40 to 500C. The reaction mixture was maintained at this temperature for a further 2 h following the addition when less than 1.0% starting material remained. The reaction was quenched by the slow portion wise addition of water (520 ml) (exothermic) and this was followed by a further water charge (3.45 L), resulting in two clear phases. The organic phase was separated off and filtered at 40 to 50 0C. A solvent replacement into heptane was performed under reduced pressure at 55 0C and the product suspension cooled. The solid was collected by filtration, washed with heptane and dried under vacuum to provide 5-chloro-2,4-dihydroxybenzoic acid methyl ester (281.3 g, 87.3%). 1H NMR (399.826 MHz, D6-DMSO) δ 11.29 (s, IH), 10.57 (s, IH), 7.69 (s, IH), 6.53 (s, IH), 3.85 (s, 3H). Step 6: 5-Chloro-2-hydroxy-4-(4-methoxybenzyloxy)benzoic acid methyl ester
Figure imgf000030_0003
4-Methoxybenzylchloride (37.3 g, 238 mmol) was added to a stirred suspension of 5- chloro-2,4-dihydroxybenzoic acid methyl ester (45.0 g, 222 mmol) and DBU (37.8 g, 248 mmol) in DMF (450 ml) over a period of 3 h at 25 0C with stirring. The reaction was then heated to 65 0C and held for 1 h. After cooling back to 20 0C, water (495 ml) was added, the product was collected by filtration, washed with water (2 x 50 ml) followed by acetonitrile (2 x 50 ml) then dried under vacuum at 50 0C. The crude product (53.5 g, 75%) was suspended in acetonitrile (250 ml), heated to reflux and held for 15 min, cooled to 40 0C then held for 1 h. The solid was collected by filtration, washed with acetonitrile (2 x 25 ml) then dried under vacuum at 50 0C to provide 5-chloro-2-hydroxy-4-(4- methoxybenzyloxy)benzoic acid methyl ester as a solid 42.9 g (60%). 1H-NMR (CDCl3, 300 MHz): δ 10.89 (s, IH), 7.83 (s, IH), 7.37 (d, J= 8.1 Hz, 2H), 6.93 (d, J= 8.1Hz, 2H), 6.56 (s, IH), 5.09 (s, 2H), 3.92 (s, 3H), 3.82 (s, 3H) APCI-MS (-ve): m/z 321 [M(-H)]~ Step 7: 5-Chloro-2-hydroxy-4-(4-methoxybenzyloxy)-N-methylbenzamide
Figure imgf000031_0001
O-PMB Ester O-PMB Amide
An aqueous solution of methylamine (40% w/w, 500 ml) was added to a stirred suspension of 5-chloro-2-hydroxy-4-(4-methoxybenzyloxy)benzoic acid methyl ester (100 g, 0.31 moles) in THF (500 ml). The mixture was heated to 50 - 56 0C and the resulting clear solution held at this temperature for 4 h, then cooled to ambient temperature and stirred overnight. Solvent was distilled off under reduced pressure until 600 ml had been removed, maintaining a roughly constant reaction volume by the dropwise addition of water (600 ml). The temperature of the reaction mixture increased from 22 0C to 47 0C during the course of the distillation. The resulting suspension was cooled to 5 0C and stirred for 30 min. The product was collected by filtration and dried under vacuum at 50 0C to leave 5- chloro-2-hydroxy-4-(4-methoxybenzyloxy)-7V-methylbenzamide as a solid (94.6 g, 95% yield).
1H NMR (399.826 MHz, D6-DMSO) δ 8.93 (br s, IH), 7.93 (s, IH), 7.39 (d, J= 9.5 Hz, 2H), 6.96 (d, J= 9.5 Hz, 2H), 6.69 (s, IH), 5.11 (s, 2H), 3.76 (s, 3H), 2.78 (s, 3H) APCI-MS: m/z 322/324 (MH+)
Step 8: 5-Chloro-4-(4-methoxybenzyloxy)-N-methyl-2-((S)-l-oxiranylmethoxy)benzamide
Figure imgf000032_0001
O-PMB Amide (S)-Glycidyl Ether
A solution of 3-nitrobenzenesulfonic acid (5)-l-oxiranylmethyl ester in butyronitrile (0.317 kg of a 28.2 % w/w solution, 89.4 g contained weight, 345 mmol, 1.1 eq) was diluted with butyronitrile (0.238 kg) and cooled to 7 0C with stirring. 5-Chloro-2-hydroxy-4-(4- methoxybenzyloxy)-7V-methylbenzamide (100 g, 0.311 mmol, 1.0 eq) was added followed by cesium carbonate (25.3 g, 77.7 mmol) and the mixture heated to 55 0C. Two further portions of cesium carbonate (25.3 g each, 77.7 mmol) were added to the reaction mixture after holding at 55 0C for 30 min and cooling the reaction mixture back to 7 0C prior to each addition. After 1 h 40 min further cesium carbonate (25.3 g, 77.7 mmol) was added to the reaction mixture and after an additional 1 h, a final portion of cesium carbonate (50.7 g 156 mmol) was added to the reaction mixture at 55 0C. On completion of the reaction, water (1 kg) added and the reaction mixture cooled to 7 0C. After stirring for 1 h, the solid product was collected by filtration, washed with water (150 ml) and methanol (100 ml) then dried under vacuum at 45 0C to leave 5-chloro-4-(4-methoxybenzyloxy)-7V-methyl-2- ((5)-l-oxiranylmethoxy)benzamide as a white solid, 93.6 g (79.7%). 1H NMR (399.826 MHz, D6-DMSO) δ 8.01 - 7.93 (m, IH), 7.78 (s, IH), 7.42 (d, J= 9.1 Hz, 2H), 7.03 (s, IH), 6.98 (d, J= 9.1 Hz, 2H), 5.20 (s, 2H), 4.55 (dd, J= 11.5, 2.6 Hz, IH), 4.12 (dd, J= 11.7, 6.0 Hz, IH), 3.76 (s, 3H), 3.49 - 3.44 (m, IH), 2.90 (t, J= 4.6 Hz, IH), 2.81 (d, J= 4.6 Hz, 3H), 2.78 - 2.74 (m, IH). APCI-MS: m/z 378/380 (MH+)
Step 9: 5-Chloro-2-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-l '-yl)-2- hydroxypropyl]oxy}-4-hydroxy-N-methylbenzamide, trifluoroacetic acid salt
Figure imgf000032_0002
(S)-Glycidyl Ether (S)-Phenol TFA
A suspension of 5-chloro-3H-spiro[l-benzofuran-2,4'-piperidine], hydrobromic acid salt (Step3; 42.85 g, 141 mmol) in toluene (440 ml) was stirred with aqueous ammonium hydroxide solution (28% w/w, 55 ml) for 30 min. The mixture was then filtered to remove a small amount of a solid and the layers allowed to separate. The aqueous phase was extracted with toluene (220 ml) and combined with the organic phase from the first separation to leave a solution of 5-chlorospiro[3H-benzofuran-2,4'-piperidine] in toluene. To this was added 5-chloro-4-(4-methoxybenzyloxy)-Λ/-methyl-2-((5)-l- oxiranylmethoxy)benzamide (Step 8; 50 g, 132 mmol) and the mixture heated at 80 0C for 22 h. The turbid solution was filtered at 80 0C then cooled to ambient temperature to leave 5-chloro-2-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy}-4-(p-methoxybenzyloxy)-7V-methylbenzamide as a suspension in toluene.
To this suspension was added trifiuoroacetic acid (220 g, 1.93 mol) at a temperature of between 20 and 25 0C with stirring. After stirring for 3 h at this temperature, the mixture was concentrated by distillation under vacuum until a residue of ca 200 ml remained. Isopropanol (150 ml) was added and solvent distilled off until the volume of the residue was ca 200 ml. This operation was repeated one more time. Methanol (200 ml) was added and solvent distilled off at atmospheric pressure until 200 ml of distillate had been removed. The residue was dissolved in methanol (400 ml) and stirred overnight. Some sticky solid was removed by filtration and the filtrate was distilled at atmospheric pressure, replacing the solvent removed with isopropanol (300 ml). The suspension was cooled in an ice-water bath then the solid product was collected by filtration, washed with isopropanol (2 x 50 ml) then dried in a vacuum oven at 50 0C to leave a 5-chloro-2-{[(25)-3-(5-chloro- 3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -4-hydroxy-7V- methylbenzamide, trifiuoroacetic acid salt as an off- white powder, 66.1 g (84% over 2 stages). 1H-NMR (D6-DMSO, 400 MHz): δ 8.05 (d, J=4.6, NH), 7.73 (s, IH), 7.30 (m, IH), 7.18- 7.14 (m, IH), 6.82-6.78 (m, IH), 6.73 (s, IH), 4.42 (m, IH), 4.05 (s, 2H), 3.57 (m, 2H), 3.45-3.40 (m, IH), 3.27-3.11 (m, 5H), 2.81 (d, J=4.8, 3H), 2.18-2.08 (m, 4H); APCI-MS: m/z 481 (MH+). APCI-MS: m/z 481/483/485 (MH+). Spectral data on an isolated sample of the intermediate PMB-protected compound:
1H NMR (399.826 MHz, D6-DMSO) δ 8.33 - 8.27 (m, IH), 7.83 (s, IH), 7.43 (dd, J= 6.7, 2.1 Hz, 2H), 7.25 - 7.22 (m, IH), 7.10 (dd, J= 8.6, 2.4 Hz, IH), 7.02 (s, IH), 6.98 (d, J = 6.7 Hz, 2H), 6.74 (d, J= 8.5 Hz, IH), 5.27 (s, exch D2O, IH), 5.23 (s, 2H), 4.29 - 4.22 (m,
IH), 4.11 - 4.02 (m, 2H), 3.76 (s, 3H), 3.00 (s, 2H), 2.80 (m, 3H), 2.70 - 2.56 (m, 2H), 1.88
- 1.70 (m, 4H). Remaining signals were coincident with DMSO at 2.5 ppm.
APCI-MS: m/z 601/603/605 (MH+)
Step 10: 2-{2-Chloro-5-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-l '-yl)-2- hydroxypropyl]oxy}-4-[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid.
Figure imgf000034_0001
(S)-Phenol TFA
Figure imgf000034_0002
polymorph A
Method 1 5-Chloro-2-{[(25)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy}-4-hydroxy-7V-methylbenzamide TFA (135.5 g) was placed in a 2 L jacketed vessel and treated sequentially with caesium carbonate (3.0 eq), ethyl-2- bromoisobutyrate (3.0 eq) and then DMF (675 ml). The mixture was heated to 60 0C and stirred overnight at this temperature. The mixture was cooled to 20 0C, treated with water (1.0 L) and then extracted with ethyl acetate (I x 600 ml and 1 x 400 ml). The ethyl acetate extracts were combined and evaporated to dryness to give an orange oil (221.07 g). The residue was redissolved in ethanol (675 ml) and treated with a solution of sodium hydroxide (27.2 g in 270 ml water) with stirring. After 30 min the solvent was evaporated and the residue was treated with ammonium acetate (140 g) in water (1.35 L). The resulting slurry was stirred overnight and then filtered. The filter cake was slurry washed with water (1 x 135 ml and 1 x 540 ml), ethanol (270 ml), TBME (135 ml), treated with ethanol (1 L) at 60 0C for 18 h and then filtered. The filter cake was washed with ethanol (135 ml). The solid was dried overnight in a vacuum oven at 500C to give the titled zwitterion as polymorph A (102.3 g; 80% over 2 steps) 1H-NMR (D6-DMSO, 400 MHz): δ 13.41 (br s, IH), 9.60 - 9.35 (m, IH), 8.13 (d, J= 4.6 Hz, IH), 7.75 (s, IH), 7.30 (s, IH), 7.16 (d, J= 8.7 Hz, IH), 6.80 (d, J= 8.5 Hz, IH), 6.19 (s, IH), 4.40 (br.s, IH), 4.00 (d, J= 4.4 Hz, 2H), 3.62 - 3.15(m, 6H), 3.11 (s, 2H), 2.82 (d, J= 4.7 Hz, 3H), 2.50 (m, 4H), 1.60 (s, 6H); APCI-MS: m/z 567 (MH+).
Spectral data for an isolated sample of the intermediate ester:
1H NMR (399.826 MHz, D6-DMSO) δ 8.27 (m, IH), 7.85 (s, IH), 7.23 (m, IH), 7.10 (dd, J= 8.5, 2.3 Hz, IH), 6.74 (d, J= 8.5 Hz, IH), 6.54 (s, IH), 5.26 (m, exch D2O, IH), 4.23 (q, J= 7.1 Hz, 2H), 4.16 - 4.02 (m, 3H), 3.92 (dd, J= 9.2, 6.2 Hz, IH), 3.00 (s, 2H), 2.80 (d, J= 4.9 Hz, 3H), 1.87 - 1.68 (m, 4H), 1.61 (s, 6H), 1.21 (t, J= 14.9 Hz, 3H). Remaining signals partially overlapping DMSO signal. APCI-MS: m/z 595/597/599 (MH+) Method 2 A solution of 5-chloro-2-{[(25)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)- 2-hydroxypropyl]oxy}-4-hydroxy-7V-methylbenzamide, trifluoroacetic acid salt (25.0 g, 42.0 mmol) in NMP (67 ml) was added over a period of 45 min to a stirred suspension of caesium carbonate (41.O g, 126 mmol) in NMP (67 ml), maintaining the temperature of the mixture below 30 0C, followed by an NMP line rinse (4 ml). Ethyl 2-bromoisobutyrate (24.6 g, 126 mmol) was then added to the reaction mixture over a period of 45 min followed by an NMP line rinse (4 ml). The reaction mixture was heated to 70 0C and stirred at this temperature for 11.5 h. After cooling to ambient temperature, the mixture was diluted with TBME (50 ml) then water (175 ml) was added over a period of around 1 h (exothermic addition). Further TBME (105 ml) was charged and the mixture stirred for around 30 min then the layers were allowed to separate. The aqueous layer was extracted with TBME (2 x 70 ml) and the combined organic layers were concentrated to a volume of approximately 90 ml. Ethanol (110 ml) was added and the volume reduced to 90 ml by evaporation. A further ethanol charge (110 ml) was added and the volume reduced again to 90 ml by evaporation to afford 2-{2-chloro-5-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran- 2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid ethyl ester as a solution in ethanol, total weight 81.31 g.
A solution of2-{2-chloro-5-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r- yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid ethyl ester in ethanol (952 g total weight, contained weight 366.2 g, 614 mmol) was diluted with ethanol (1.09 L) and warmed to 44 0C with stirring. To this was added a solution of sodium hydroxide (73.8 g, 1.85 mol) in water (732 ml) over a period of 30 min. After holding at 40 - 45 0C for 2.5 h, the solution was decanted away from the polymeric by product and filtered. A solution of citric acid (101 g) in water (1.46 L) was added to the filtrate over a period of 1 h 50 min. The solid was collected by filtration, washed with water (1.5 L), ethanol (1.5 L then 375 ml) and dried in a vacuum oven at 65 0C to yield crude 2-{2-chloro-5-{[(25)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy}-4-[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid as a pale yellow solid, weight 301.63 g (86%).
A slurry of crude 2-{2-chloro-5-{[(25)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid (9.0 g) in NMP (54 ml) was heated to 80 0C with stirring to dissolve the solid then cooled to around 65 0C. Ethanol (333 ml) was charged over a period of 35 min, maintaining the reaction temperature between 60 and 70 0C, which caused crystallization of the product. After a further 30 min at this temperature the slurry was cooled to between 10 and 15 0C over 1 hr, then held at this temperature for around 30 min. The solid was collected by filtration, washed with ethanol (45 ml), pulled dry on the filter then dried in a vacuum oven at 60 0C. 2-{2-Chloro-5-{[(25)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid was obtained as a white solid, weight 5.49 g (61%).
The resulting solid (5 g) was slurried in NMP (50 ml) and heated to 60 0C and held at between 60 and 65 0C for 30 min with stirring. Water (50 ml) was charged to the resulting solution over a period of 35 min, maintaining the temperature between 60 and 65 0C, which caused crystallization of the product. After a further 30 min at this temperature the slurry was cooled to ambient temperature then held at this temperature for 30 min. The mixture was further cooled to between 0 and 4 0C and held for 30 min. The solid was collected by filtration, washed with water (25 ml), ethanol (25 ml), pulled dry on the filter then dried in a vacuum oven at 60 0C. 2-{2-Chloro-5-{[(25)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'- piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid was obtained as a white solid (polymorph A), weight 4.82 g (96%). The title compound exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2Θ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test <941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089):
(1) 5.1, 10.2 and 12.9, or
(2) 5.1, 8.9 and 13.2, or
(3) 8.9, 10.2, 12.9, 15.1, 17.0 and 21.2 or (4) 5.1, 8.9, 10.2, 14.6, 15.4, 21.2 and 25.8 or
(5) 5.1, 8.9, 10.2, 12.6, 14.6, 15.1 and 17.0 or
(6) 5.1, 10.2, 12.6, 13.2, 14.6, 15.1, 17.0, 17.9, 21.2 and 21.8 or
(7) 5.1, 8.9, 10.2, 12.6, 13.2, 14.6, 14.9, 16.4, 19.2, 21.8 and 27.1 or
(8) 5.1, 8.9, 10.2, 12.6, 12.9, 13.2, 14.6, 14.9, 15.1, 15.4, 16.4, 17.9, 19.2, 20.0, 21.8 and 25.8
The diffractogram is shown in figure 1.
Example 4
2-{2-Chloro-5-{[(2S)-3-(5-chloro-l 'H, 3H-spiro[l-benzofuran-2, 4 '-piperidinl-1 '-yl)-2- hydroxypropylloxy}-4-[(methylam.ino)carbonyllphenoxy}-2-methylpropanoic acid. Preparation of chloro diol(5-Chloro,2,4-dihydroxy benzoic acid methyl ester) Synthetic scheme:-
mol.eq)
Figure imgf000038_0001
Figure imgf000038_0002
Chloro phenol-Crude Isomer Dichloro impurity
2-hydroxy, 4-Methoxy benzoic acid methyl ester
Methanol
Figure imgf000038_0003
Chloro phenol Chloro diol
(5- Chloro, 2,4- dihydroxy Benzoic acid methyl ester)
Step a) Preparation of Chloro phenol
To a solution of methyl ester (10.Og, 1.0 mol.eq) in DCM (110.0 ml, 11.0 rel.vol) add sulfuryl chloride (9.07g 8.89@100%, 1.20 mol.eq) drop wise over a period of 15 minutes. Reflux the reaction mixture (390C) until reaction is completed (approximately 17hrs). Cool the reaction mass to 250C and add water (50.0ml, 5.0 rel.vol). Separate the dichloromethane layer & evaporate it to dryness under vacuum (80-100 mbr) at 30- 350C. Slurry the crude chloro phenol in methanol (40.0ml 4.0 rel.vol) to remove isomer & dichloro impurity formed. Filter and wash the cake with methanol (10.0ml, 1.0 rel.vol). Dry the product under vacuum (80 -lOOmbr) at 400C until constant weight is obtained. Purity by HPLC: 99.7%, Isomer: 0.3%(By HPLC area%) Yield: 84%. Melting point: 130.8 - 132.10C.
1R NMR (200 MHz, CDC13): δ 10.93(s, IH), 7.81(s, IH), 6.50(s, IH), 3.93 (s, 3H), 3.92 (s, 3H) Step b) Preparation of Chloro diol:
Charge anhydrous aluminium chloride (153.87g 1.154 mol.eq) into R.B Flask. Charge Toluene (1000.0 ml, 10.0 rel.vol) at 25 to 270C and stir well. Reaction mass is a suspension. Slowly charge dodecanethiol (327.0ml 1.6156 mol.eq) Reaction mass becomes a clear solution. Raise the temperature of the reaction mixture to 40-500C. Dissolve Chloro Phenol (100.Og, 0.4616mol, 1.0 mol.eq) in toluene (1000.0ml, 10.0 rel.vol) and slowly add to the reaction mixture. Stir reaction mixture for 60-90 minutes at 40-500C. Monitor the reaction by HPLC. After the completion of reaction charge water (1.5 rel.vol) (Exothermic addition) to the reaction mixture at 500C. Stir the contents for 15 min. Again, charge water (10.0 rel. vol.) and stir for 30 minutes at 40-450C. Transfer the hot reaction mixture (40 to 500C) into separating funnel. Separate hot organic layer from reaction mixture at 40-450C (Solid precipitates out on cooling). Concentrated the organic layer up to « 10 rel. vol at 50- 550C under reduced pressure (150mbr). Charge n-heptane (10.0 rel.vol) slowly to solution containing chloro diol at 500C. Cool the contents to 300C. White solid precipitates out. Stir for 30 minutes. Further, cool the mixture to 0-50C. Stir for 30 minutes. Filter the solid in Buckner funnel and suck dry. Dry the material under vacuum (150mbr) at 45 to 500C until the constant weight is obtained. HPLC: 99.6%, (By HPLC area %) Yield: 85.6 %. Melting point: 116.8 -118.20C.
1U NMR (200 MHz, CDC13): δ 10.84(S, IH), 7.82(s, IH), 6.61(s, IH), 6.08(s, IH), 3.93(s, 3H).
Step 1. 4-(l-tert-butoxycarbonyl-l-methylethoxy)-5-chloro-2-hydroxybenzoic acid methyl ester
Figure imgf000039_0001
To a solution of 5-chloro-2,4-dihydroxybenzoic acid methyl ester (10.2 g, 10.0 g at 100% w/w, 0.0493 mol, 1.0 mol eq) in TV-methyl pyrrolidone (40 ml, 4.0 rel vol), was added potassium carbonate (17.40 g, 17.05 g at 100% w/w, 0.1233 mol, 2.5 mol eq) with stirring. 2-Bromo-2-methyl-propionic acid tert-butyl ester (67.42 g, 66.07 g at 100% w/w, 0.2961 mol, 6.0 mol eq) was added in one portion together followed by tetrabutylammonium bromide (3.25 g, 3.18 g at 100 % w/w, 0.0098 moles, 0.2 mol eq). The temperature of the reaction mass was raised to 60-650C and maintained at this temperature for 16 h. On completion, the reaction mixture was cooled 30-35 0C. The insoluble potassium salts were removed by filtration through Celite and the solids were washed with TV-methyl pyrrolidone (20 ml, 2.0 rel vol). The pH of the combined filtrates was adjusted to around 4 using dilute HCl solution then water (100 ml, 10.0 rel vol) added. The solution was extracted with dichloromethane (100 ml, 10 rel vol), the organic layer was washed with water (150 ml, 15.0 rel vol) then evaporated to dryness at 35 0C under vacuum. The excess of 2-bromo-2-methyl-propionic acid tert-butyl ester and 2-methylacrylic acid tert-butyl ester by product were removed by applying a high vacuum (20-25 mbar) at 60 - 65 0C for approximately one h. 4-(l-ter£-Butoxycarbonyl-l-methylethoxy)-5-chloro-2- hydroxybenzoic acid methyl ester was obtained as an oil, weight 16.0 g (72.2% yield). 1R NMR (300 MHz, CDCl3): δ 10.73 (s, IH), 7.82 (s, IH), 6.36 (s, IH), 3.92 (s, 3H), 1.66 (s, 6H), 1.44 (s, 9H). Step 2. 2-(2-Chloro-5-hydroxy-4-methylcarbamoylphenoxy)-2-methylpropionic acid tert- butyl ester
Figure imgf000040_0001
To an aqueous solution of methylamine (40% w/w, 160 ml, 12.6 rel vol) was added 4-(l- tert-butoxycarbonyl-l-methylethoxy)-5-chloro-2-hydroxybenzoic acid methyl ester (16.0 g, 12.27 g at 100%, 0.035 mol, 1.0 mol eq) and the mixture stirred for 1-2 h at 25 to 30 0C. After completion of the reaction, the reaction mixture was filtered through a Celite bed to separate some insoluble material. The Celite bed was washed with water (32 ml, 2.60 rel vol) and the combined filtrates de-gassed under vacuum (150 mbar) at 30-35 0C. The resulting solution was diluted with water (240 ml, 19.56 rel vol) and the pH of the solution adjusted to 7.5 using 10% w/w hydrochloric acid solution (85 ml, 6.9 rel vol). The resulting suspension was stirred for 1 to 2 h at 25-30 0C. The suspended solid was collected by filtration, washed with water (32 ml, 2.60 rel vol) then dried under vacuum (80-100 mbar) at 40-45 0C to provide 2-(2-chloro-5-hydroxy-4-methylcarbamoylphenoxy)- 2-methylpropionic acid tert-butyl ester, weight 8.0 g (65.5%). 1R NMR (300 MHz, CDCl3): δ 12.44 (s, IH), 7.33 (s, IH), 6.37 (s, IH), 6.15 (br s, IH), 2.98 (d, 3H), 1.65(s, 6H), 1.45 (s, 9H)
Step 3. 2-[2-Chloro-4-methylcarbamoyl-5-((S)-l-oxiranylmethoxy)phenoxy]-2- methylpropionic acid tert-butyl ester
Figure imgf000041_0001
2-(2-Chloro-5 -hydroxy-4-methylcarbamoylphenoxy)-2-methylpropionic acid tert-butyl ester (5.0 g, 0.0145 mol, 1.0 mol eq) was dissolved in acetonitrile (40 ml, 8.0 rel vol) and caesium carbonate (5.21 g, 5.18 g at 100%, 0.0159 mol, 1.10 mol eq) added. A solution of 3-nitrobenzenesulfonic acid (5)-l-oxiranylmethyl ester in butyronitrile (30.7% w/w, 12.89 g, 3.95 g at 100% w/w, 0.0152 mol, 1.05 mol eq) was diluted with acetonitrile (20 ml, 4.0 rel vol) and added to the reaction mixture. The reaction mixture was heated to 45-50 0C and held at this temperature for 4 h. After cooling the reaction mixture to 20 to 25 0C, acetonitrile (5.0 ml, 1.0 rel vol) and water (60 ml, 12.0 rel vol) were added. The reaction mixture was stirred for 12 h at 20 to 25 0C. The reaction mixture was then further cooled to 5 0C then the solid product collected by filtration and washed with water (20 ml, 4.0 rel vol). The crude product was dissolved in toluene (20 ml, 4.0 rel vol) at 40 0C then the solution was concentrated to 3.0 rel vol under vacuum (200 mbar) at around 50 0C. The concentrate was cooled to 20 to 25 0C and stirred for approximately for 3 h. The solid product was collected by filtration and dried under vacuum at 40-45 0C to give 2-[2-chloro- 4-methylcarbamoyl-5-((5)-l-oxiranylmethoxy)-phenoxy]-2-methylpropionic acid tert- butyl ester weight 3.8 g (65.4%).
IH NMR (300 mHz, CDC13): δ 8.20 (s, IH), 7.71-7.69 (broad d IH), 6.60 (s, IH), 4.39- 4.33 (d, IH), 4.00-3.92 (dd, IH), 3.41-3.34 (m, IH), 2.97-2.96 (d, 3H), 2.94-2.90 (IH, overlapping), 2.83-2.79 (m, IH), 1.63 (s, 6H), 1.43 (s, 9H).
Step 4. 2-{2-chloro-5-{[(2s)-3-(5-chloro-3h-spiro[l-benzofuran-2,4'-piperidin]-l '-yl)-2- hydroxypropyl]oxy}-4-[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid tert- butyl ester
Figure imgf000041_0002
A mixture of 5-chloro-l Η,3H-spiro[l-benzofuran-2,4'-piperidine], hydrobromic acid salt (3.2 g, 0.0105 mol, 1.05 mol eq) and potassium carbonate (1.52 g, 0.011 mol, 1.10 mol eq) in ethanol (40 ml, 10.0 rel vol) was stirred for 30 min at ambient temperature. 2-[2-Chloro- 4-methylcarbamoyl-5 -((S)- 1 -oxiranylmethoxy)phenoxy] -2-methylpropionic acid tert-butyl ester (4.0 g, 0.010 mol, 1.0 mol eq) was added and the temperature of the reaction mixture raised to 48-50 0C and held for 8 - 9 h. The reaction mixture was cooled to 20-25 0C, water (24 ml, 6.0 rel vol) was added and stirring continued for 1 h. The precipitated solid was collected by filtration and washed with water (8.0 ml, 2.0 rel vol). The solid was dissolved in ethyl acetate (30 ml, 7.5 rel vol), the resulting solution was washed with water (30 ml, 7.5 rel vol) then evaporated to dryness under vacuum (100 mbar) at 40-45 0C. n- Heptane (20 ml, 5.0 rel vol) was added to the residue and the slurry stirred for 30 min. The solid was collected by filtration then dried under vacuum (150 mbar) at 40-45 0C to afford 2-{2-chloro-5-{[(25)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid tert- butyl ester, weight 4.5 g (72.1%). 1HNMR (SOO mHz5 CDCl3)I o S-IQ (S, IH), 8.14-8.11 (broad d, IH), 7.10-7.04 (m, 2H), 6.70-6.65 (d, IH), 6.57 (s, IH), 4.12-4.08(d, 2H), 3.90-3.82 (m, IH), 2.99-2.76 (m, 7H), 2.66-2.51 (m, 4H), 2.04-1.78 (m, 4H), 1.62 (s,6H), 1.44 (s 9H).
Step 5. 2-{2-Chloro-5-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-l '-yl)-2- hydroxypropyl]oxy}-4-[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid.
Figure imgf000042_0001
Trifluoroacetic acid (2.0 ml, 2.0 rel vol) was added to a stirred suspension of 2-{2-chloro- 5-{[(25)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy}- 4- [(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid tert-butyl ester (1.0 g, 0.0016 mol, 1.0 mol eq) in toluene (6.0 ml, 6.0 rel vol) at 20 to 25 0C resulting in a clear solution and stirring continued for 12 h. The reaction mixture was evaporated to dryness under reduced pressure (10 mbar) at 40 0C and the gummy residue was dissolved in water (10 ml, 10.0 rel vol). A solution of ammonium acetate (3.0 g, 0.0389 mol, 24.32 mol eq, 3.0 rel wt) in water (15 ml, 15 rel vol) was added and the thick suspension stirred for 1 to 2 h. The water layer was decanted and isopropanol (20 ml, 20.0 rel vol) added to the suspension and the mixture stirred for 30 min. The solid was collected by filtration and dried under vacuum (150 mbar) at 40 0C to provide 2-{2-chloro-5-{[(25)-3-(5-chloro-3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -A- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid, weight 0.83 g (91.2%). APCI-MS: m/z 567 (MH+).
Example 5. Form B, S-enantiomer
2-/2-Chloro-5-m2S)-3-(5-chloro-l ΗJH-sϋirofl-benzofuran-2,4'-ϋweήdin]-r-yl)-2- hydroxypropyl]oxy)-4-f(methylamino)carbonyllphenoxy)-2-methylpropanoic acid Form B 2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form A (300 mg) was dissolved in chloroform (200 ml) by stirring at 300C for 3 h. The solvent was evaporated to air at 200C to give a solid white, moderately crystalline 2-{2-Chloro-5- {[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form B.
2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy}-4-[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid Form B exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2Θ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test <941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089): 5.6, 7.6, 8.6, 13.1, 17.0, 18.4. The diffractogram is shown in figure 3.
Example 6. Form C, S-enantiomer
2-{2-Chloro-5-{f(2S)-3-(5-chloro-l 'H,SH-spirofl-benzofuran-2,4'-piperidinl-l '-yl)-2- hydroxypropyl]oxy}-4-[(methylamino)carbonyllphenoxy}-2-methylpropanoic acid Form C Method A:
2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form A (micronized, 310 mg) was dissolved in THF (dried; 200 ml) and stirred at 300C for 24h. A white milky suspension was produced. The material was allowed to sediment at room temperature for 24h. The supernatant was removed and the sedimented material dried under vacuum (oil pump) at 800C for 24h to remove remaining THF, yielding 2-{2- Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form C.
Method B:
Equal amounts of 2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'- piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid Form A , Form C, and Form D (1 mg of each) were suspended in dichloromethane (0.65 ml). The mixture was shaken at 35°C for 2 days, yielding 2-{2- Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form C.
2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form C exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2Θ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test <941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089):
(1) 4.5, 8.9 and 12.8, or
(2) 4.5, 8.6 and 10.6, or (3) 4.5, 8.9, 10.6, 12.8, 14.8 and 17.6 or
(4) 8.6, 8.9, 12.8, 13.9, 15.7, 16.6 and 18.8 or
(5) 4.5, 8.6, 8.9, 10.6, 13.9, 15.7, 16.0, 16.6 and 17.9 or (6) 4.5, 8.9, 10.6, 12.8, 13.9, 14.8, 15.7, 17.6, 18.8 and 20.0 or
(7) 4.5, 8.6, 8.9, 10.6, 12.8, 13.9, 15.7, 16.0, 16.6, 17.9, 18.8, 20.0, 20.9 and 21.2 . The diffractogram is shown in figure 4.
Example 7. Form D, S-enantiomer
2-{2-Chloro-5-{f(2S)-3-(5-chloro-l 'H,3F[-spirofl-benzofuran-2,4'-piperidinl-l '-yl)-2- hydroxypropyljoxy] -4- 1 (methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form D Heating of 2- {2-Chloro-5- {[(25)-3-(5-chloro- 1 'H,3H-spiro[l -benzofuran-2,4'-piperidin]- 1 '- yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form B to 1400C under N2 atmosphere yields 2-{2-Chloro-5-{[(25)-3-(5-chloro-l'H,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form D.
2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form D exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2Θ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test <941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089):
5.4, 9.8, 12.3, 13.6, 16.9, 19.2, 19.5 and 21.3. The diffractogram is shown in figure 5.
Example 8. Form F, S-enantiomer
2-/2-Chloro-5-m2S)-3-(5-chloro-l Η,3H-sϋirofl-benzofuran-2,4'-ϋweridin]-r-yl)-2- hydroxypropyl]oxy)-4-f(methylamino)carbonyllphenoxy)-2-methylpropanoic acid Form F Method A
2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form A , Form C and Form D (37, 71 and 41 mg respectively) were suspended in methanol (4.0 ml). The slurry was stirred at 35°C for 4 days. The solid material was isolated by centrifugation (8000 rpm, 30 min, 22°C) and dried under vacuum for 18h, yielding 2-{2- Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form F. Method B
2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form A (658 mg) was suspended in methanol (20 ml). The suspension was heated to 600C with stirring for 18h. The temperature was adjusted to 35°C, thereafter 5 mg -{2-Chloro-5- {[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form F was added for seeding. The suspension was left at 35°C with stirring for 72h. The solid material was isolated by centrifugation and dried under vacuum at 400C for 24 h, yielding 2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl] oxy } -4- [(methylamino)carbonyl]phenoxy } -2-methylpropanoic acid Form F
2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl] oxy} -4- [(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form F exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2Θ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test <941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089): (1) 7.5, 9.2 and 10.7, or
(2) 7.5, 8.9 and 11.1, or
(3) 7.5, 8.9, 9.2, 11.1, 12.2 and 16.3 or
(4) 8.9, 9.2, 10.7, 11.1, 11.7, 12.2 and 15.1 or
(5) 7.5, 8.9, 9.2, 10.7, 11.7, 12.2, 13.8, 15.1, 16.7 and 18.5 or (6) 7.5, 8.9, 9.2, 11.1, 11.9, 13.8, 15.1, 16.3, 17.8, 18.3, 18.7 and 20.9 or
(7) 7.5, 8.9, 9.2, 10.7, 11.1, 11.7, 12.2, 13.8, 15.1, 18.3, 18.7, 19.7, 21.4, 22.3 and 24.0 or (8) 7.5, 9.2, 10.7, 11.7, 11.9, 12.2, 13.8, 15.1, 16.3, 16.7, 17.8, 18.3, 19.2, 19.7, 20.9, 21.4 and 22.3.
The diffractogram is shown in figure 6.
Example 9. Form G, S-enantiomer
2-{2-Chloro-5-{f(2S)-3-(5-chloro-l 'H,SH-spirofl-benzofuran-2,4'-piperidinl-l '-yl)-2- hvdroxypropyl]oxy}-4-[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid Form G 2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form A is dried under flow of dry N2 for 1 h yielding 2-{2-Chloro-5-{[(2i?)-3-(5-chloro-17/,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form G.
2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form G exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2Θ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test <941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089):
(1) 4.8, 12.2 and 15.4, or
(2) 4.8, 9.7 and 13.7, or
(3) 9.7, 13.7, 14.5, 15.6, 17.1 and 20.3 or (4) 4.8, 13.7, 14.5, 15.4, 16.3, 17.1 and 20.3 or
(5) 4.8, 9.7, 13.7, 14.5, 15.6, 16.3 and 19.7 or
(6) 9.7, 12.2, 13.7, 14.5, 15.6, 16.3, 19.4, 20.3, 21.4 and 23.1 or
(7) 9.7, 13.7, 14.5, 15.6, 16.3, 19.7, 20.3, 20.8, 21.4, 23.1 and 25.5 or
(8) 4.8, 9.7, 12.2, 13.7, 15.4, 16.3, 17.1, 19.4, 19.7, 20.3, 20.8, 21.4, 23.1 and 25.5. The diffractogram is shown in figure 7. Example 10
2-{2-Chloro-5-{f(2S)-3-(5-chloro-l 'H,SH-spirofl-benzofuran-2,4'-piperidinl-l '-yl)-2- hydroxypropylloxy}-4-[(methylam.ino)carbonyllphenoxy}-2-methylpropanoic acid hydrochloride
Figure imgf000048_0001
2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid (264 mg, 0.5 mmol) was dissolved in a mixture of 1 M hydrochloric acid (1.0 ml) in acetonitrile (1 ml). Water (2 ml) was added giving a sticky precipitate. More acetonitrile was added until a solution was obtained. The solution was diluted with water (2 ml) and set aside in the hood for slow evaporation of acetonitrile. The titled compound precipitated as a white solid (241 mg, 80%).
1H NMR (299.945 MHz, cd3od) 5 7.81 (s, IH), 7.22 - 7.20 (m, IH), 7.11 (dd, J= 8.6, 2.3 Hz, IH), 6.76 (s, IH), 6.75 (d, J= 8.5 Hz, IH), 4.55 - 4.46 (m, IH), 4.11 (dd, J= 7.5, 4.6
Hz, 2H), 3.75 - 3.35 (m, 6H), 3.16 (s, 2H), 2.94 (s, 3H), 2.34 - 2.13 (m, 4H), 1.66 (s,
6H)
APCI-MS m/z 567/569 (MH+)
Chloride analysis: mol ratio base/chloride 1/1
The title compound exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2Θ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test <941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089):
(1) 7.6, 7.9, 20.6, 21.3, 22.9 and 23.8 or
(2) 9.7, 13.7, 14.5, 16.2, 16.4, 19.6, 20.6, 21.3, 22.4, 22.9 and 23.8 or (3) 5.5, 7.6, 7.9, 13.4, 14.5, 15.2, 15.9, 16.2, 16.4, 19.6, 20.6, 21.3, 22.4, 22.9 and 23.8. The diffractogram is shown in figure 8.
Example 11 2-{2-Chloro-5-{f(2S)-3-(5-chloro-l 'H,SH-spirofl-benzofuran-2,4'-piperidinl-l '-yl)-2- hydroxypropyl]oxy}-4-f(methylamino)carbonyllphenoxy}-2-methylpropanoic acid sodium hydroxide
Figure imgf000049_0001
2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy}-4-[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid (770 mg) is dissolved in EtOH (680 ml) at 70 0C. NaOH (40 mg) is dissolved in water (5 ml). The aq. NaOH solution (1.7 ml) is added to the 2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid solution (170 ml). The precipitate is collected by filtration. APCI-MS: m/z 567 (MH+).
2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid Form G exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2Θ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test <941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089): (1) 7.6, 8.6 and 18.4 or
(2) 5.6, 7.6, 8.6, 13.1, 17.0 and 18.4. The diffractogram is shown in figure 9. Example 12
Human CCRl binding assay Membranes HEK293 cells, from ECACC, stably expressing recombinant human CCRl (HEK-CCRl) were used to prepare cell membranes containing CCRl . The membranes were stored at -700C. The concentration of membranes of each batch was adjusted to 10% specific binding of 33 pM [125I] MIP- lα.
Binding assay
100 μL of HEK-CCRl membranes diluted in assay buffer pH 7.4 ((137 mM NaCl (Merck, Cat No 1.06404), 5.7 mM Glucose (Sigma, Cat No G5400), 2.7 mM KCl (Sigma, Cat No P-9333), 0.36 mM NaH2PO4 x H2O (Merck, Cat No 1.06346), 10 mM HEPES (Sigma, Cat No H3375), 0.1% (w/v) Gelatine (Sigma, Cat No G2625)) with the addition of 17500 units/L Bacitracin (Sigma, Cat No B 1025) were added to each well of the 96 well filter plate (0.45 μm opaque Millipore cat no MHVB N4550). 12 μL of compound in assay buffer, containing 10% DMSO, was added to give final compound concentrations of 1x10" 5 5-lxl0"9 5 M. 12 μL cold human recombinant MIP- lα (270-LD-050, R&D Systems, Oxford, UK), 10 nM final concentration in assay buffer supplemented with 10% DMSO, was included in certain wells (without compound) as non-specific binding control (NSB). 12 μL assay buffer with 10% DMSO was added to certain wells (without compound) to detect maximal binding (BO).
12 μL [125I] MIP-Ia, diluted in assay buffer to a final concentration in the wells of 33 pM, was added to all wells. The plates with lid were then incubated for 1.5 h at room temperature. After incubation the wells were emptied by vacuum filtration (MultiScreen Resist Vacuum Manifold system, Millipore) and washed once with 200 μl assay buffer. After the wash, all wells received an addition of 50 μL of scintillation fluid (OptiPhase "Supermix", Wallac Oy, Turko, Finland). Bound [125I] MIP- lα was measured using a Wallac Trilux 1450 MicroBeta counter. Window settings: Low 5-High 1020, 1-minute counting/well. Calculation of percent displacement and IC50
The following equation was used to calculate percent displacement.
Percent displacement = 1- ((cpm test - cpm NSB) / (cpm BO- cpm NSB)) where: cpm test = average cpm in wells with membranes and compound and [125I] MIP- lα;
NSB = average cpm in the wells with membranes and MIP-Ia and [125I] MIP- lα (nonspecific binding);
BO = average cpm in wells with membranes and assay buffer and [125I] MIP-Ia (maximum binding). The molar concentration of compound producing 50% displacement (IC50) was derived using the Excel-based program XLfϊt (version 2.0.9) to fit data to a 4-parameter logistics function.
Example 13 Human CCR3 bindins assay Membranes
CHO-Kl cells, from ATCC, stably expressing recombinant human CCR3 (CHO-CCR3) were used to prepare cell membranes containing CCR3. The membranes were stored at -700C. A membrane concentration was used which gave approximately 10% specific binding relative to the total amount of radioactivity of [3H]-4-(2,4-dichloro-3- methylphenoxy)-r-[4-(methylsulfonyl)benzoyl]-l,4'-bipiperidine added to the assay.
Binding assay [3H]-4-(2,4-dichloro-3-methylphenoxy)-r-[4-(methylsulfonyl)benzoyl]-l,4'-bipiperidine (20 μL, to a final concentration of 2 nM, pre-diluted in assay buffer from a 20 μM stock) and either vehicle (20 μL, 10% (v/v) DMSO in assay buffer: for determination of total binding (BO)), l,4'-bipiperidine, 4-(2,4-dichloro-3-methylphenoxy)-l '-[4- (methylsulfonyl)benzoyl] (20 μL, 100 μM solution in 10% (v/v) DMSO in assay buffer: for determination of non-specific binding (NSB)) or the appropriate solution of test compound (20 μL, 10% (v/v) DMSO in assay buffer) were added to the wells of a U- bottomed 96-well plate. Membranes pre-diluted in assay buffer (160 μL) were then added, giving a total incubation volume of 200 μL per well.
The plates were sealed and incubated for 2 h at room temperature. The plates were then filtered onto GF/B filter plates, pre-soaked for 1 h in plate-coating solution, using a 96-well plate Tomtec cell harvester. Four washes with wash buffer (200 μL) were performed at 4°C to remove unbound radioactivity. The plates were dried either for at least 2 h at 500C or over night at room temperature. Filtration plates were sealed from underneath using Packard plate sealers (supplied with plates) and of MicroScint-0 (50 μL) was added to each well. The plates were sealed (TopSeal A) and filter-bound radioactivity was measured with a scintillation counter (TopCount, Packard BioScience) using a 1 minute counting protocol.
Calculation of percent displacement and IC50
The molar concentration of test compound producing 50% displacement (IC50) of [3H]4- (2,4-dichloro-3-methylphenoxy)- 1 ' -[4-(methylsulfonyl)benzoyl]- 1 ,4 ' -bipiperidine specific binding (BO-NSB) was derived utilising GraphPad Prism® to fit data to a 4-parameter logistic function of the form:
Figure imgf000052_0001
in which E and [B] are specific binding of [3H]4-(2,4-dichloro-3-methylphenoxy)-l '-[4- (methylsulfonyl)benzoyl]-l,4'-bipiperidine, and concentration of the antagonist respectively; α, β, IC50 and m are the asymptote, baseline, location and slope parameters, respectively. The derived IC50 values were transformed to the negative logarithm (pICso) and then corrected using the Cheng-Prusoff equation to give pKi values for calculation of descriptive statistics (mean±SEM).
Example 14 hERG-encoded Potassium Channel Bindins Assay This assay, which is described in full detail in example 2, WO2005037052, determines the ability of a test compound to bind to the human ether-a-go-go-related-gene (hERG)- encoded potassium channel. The assay comprises the following steps: a) incubation of HEK 293 cell membranes expressing the IKR channel in the presence of radioligand 3,7- bis[2-(4-nitro[3,5-3H]phenyl)ethyl]-3,7-diazabicyclo[3.3.1]nonane, in the presence or absence of a test compound; b) quantitation of specifically bound labeled compound in the presence or absence of a test compound; c) calculation of the inhibition of labeled compound binding by the test compound. Similar protocols to determine affinity for the human ether-a-go-go-related-gene (hERG)-encoded potassium channel have been described by Finlayson, K. et al. [Eur. J. Pharmacol. 2001, 412, 203 and Eur. J. Pharmacol. 2001, 430, 147].
Example 15 hERG-encoded Potassium Channel Inhibition Assay This assay determines the ability of a test compound to inhibit the tail current flowing through the human ether-a-go-go-related-gene (hERG)-encoded potassium channel.
Human embryonic kidney (HEK) cells expressing the hERG-encoded channel were grown in Minimum Essential Medium Eagle (EMEM; Sigma- Aldrich catalogue number M2279), supplemented with 10% Foetal Calf Serum (Labtech International; product number 4-101-500), 10% Ml serum-free supplement (Egg Technologies; product number 70916) and 0.4 mg/ml Geneticin G418 (Sigma- Aldrich; catalogue number G7034). One or two days before each experiment, the cells were detached from the tissue culture flasks with Accutase (TCS Biologicals) using standard tissue culture methods. They were then put onto glass coverslips resting in wells of a 12 well plate and covered with 2 ml of the growing media. For each cell recorded, a glass coverslip containing the cells was placed at the bottom of a Perspex chamber containing bath solution (see below) at room temperature (-20 0C). This chamber was fixed to the stage of an inverted, phase-contrast microscope. Immediately after placing the coverslip in the chamber, bath solution was perfused into the chamber from a gravity- fed reservoir for 2 min at a rate of ~ 2 ml/min. After this time, perfusion was stopped.
A patch pipette made from borosilicate glass tubing (GC 120F, Harvard Apparatus) using a P-97 micropipette puller (Sutter Instrument Co.) was filled with pipette solution (see hereinafter). The pipette was connected to the headstage of the patch clamp amplifier (Axopatch 200B, Axon Instruments) via a silver/silver chloride wire. The headstage ground was connected to the earth electrode. This consisted of a silver/silver chloride wire embedded in 3% agar made up with 0.85% sodium chloride.
The cell was recorded in the whole cell configuration of the patch clamp technique. Following "break- in", which was done at a holding potential of -80 mV (set by the amplifier), and appropriate adjustment of series resistance and capacitance controls, electrophysiology software (Clampex, Axon Instruments) was used to set a holding potential (-80 mV) and to deliver a voltage protocol. This protocol was applied every 15 seconds and consisted of a 1 s step to +40 mV followed by a 1 s step to -50 mV. The current response to each imposed voltage protocol was low pass filtered by the amplifier at 1 kHz. The filtered signal was then acquired, on line, by digitising this analogue signal from the amplifier with an analogue to digital converter. The digitised signal was then captured on a computer running Clampex software (Axon Instruments). During the holding potential and the step to + 40 mV the current was sampled at 1 kHz. The sampling rate was then set to 5 kHz for the remainder of the voltage protocol.
The compositions, pH and osmolarity of the bath and pipette solution are tabulated below.
Figure imgf000054_0001
Figure imgf000054_0002
The amplitude of the hERG-encoded potassium channel tail current following the step from +40 mV to -50 mV was recorded on-line by Clampex software (Axon Instruments). Following stabilisation of the tail current amplitude, bath solution containing the vehicle for the test substance was applied to the cell. Providing the vehicle application had no significant effect on tail current amplitude, a cumulative concentration effect curve to the compound was then constructed.
The effect of each concentration of test compound was quantified by expressing the tail current amplitude in the presence of a given concentration of test compound as a percentage of that in the presence of vehicle. Test compound potency (IC50) was determined by fitting the percentage inhibition values making up the concentration-effect to a four parameter Hill equation using a standard data- fitting package. If the level of inhibition seen at the highest test concentration did not exceed 50%, no potency value was produced and a percentage inhibition value at that concentration was quoted.

Claims

1. Compounds 2-{2-Chloro-5-{[(25)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'- piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid, or the hydrochloride and sodium hydroxide salts thereof, or compound 2-{2-Chloro-5-{[(2i?)-3-(5-chloro-rH,3H-spiro[l-benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2 -methylpropanoic acid in a substantially pure crystalline form.
2. Compounds according to claim 1 whereby the compounds are 90% crystalline.
3. Compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-lΗ,3H-spiro[l-benzofuran-2,4'- piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid (Form A), which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ):
(1) 10.2, 15.4 and 17.0, or
(2) 10.2, 15.4, 17.0, 20.0, 21.2 and 27.1.
4. Compound 2-{2-Chloro-5-{[(2R)-3-(5-chloro-lΗ,3H-spiro[l-benzofuran-2,4'- piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ):
(1) 15.5, 17.0, 20.0 and 21.3, or
(2) 10.3, 15.5, 17.0, 20.0, 21.3 and 27.6.
5. Compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-lΗ,3H-spiro[l-benzofuran-2,4'- piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid (Form B), which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ): (1) 7.6, 8.6 and 18.4, or
(2) 5.6, 7.6, 8.6, 13.3, 17.0 and 18.4.
6. Compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-lΗ,3H-spiro[l-benzofuran-2,4'- piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid (Form C), which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ): (1) 8.6, 8.9, 10.6 and 17.6, or
(2) 8.6, 8.9, 10.6, 12.8, 13.9, 17.6, 18.8 and 20.0.
7. Compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-lΗ,3H-spiro[l-benzofuran-2,4'- piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ) (Form D):
(1) 5.4, 12.3 and 21.3, or
(2) 5.4, 9.8, 12.3, 13.6, 16,9, 19.2, 19.5 and 21.3.
8. Compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-lΗ,3H-spiro[l-benzofuran-2,4'- piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid (Form F), which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ): (1) 7.5, 11.7, 13.8, 18.3 and 21.4 or (2) 7.5, 9.2, 11.7, 11.9, 13.8, 15.1, 16.7, 17.8, 18.3, 19.2, 20.9, 21.4 and 22.3.
9. Compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-lΗ,3H-spiro[l-benzofuran-2,4'- piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid (Form G), which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ):
(1) 9.7, 15.6, 17.1 and 21.4 or
(2) 9.7, 15.4, 15.6, 16.3, 17.1, 19.4, 19.7, 20.3 and 21.4.
10. Compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-lΗ,3H-spiro[l-benzofuran-2,4'- piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid hydrochloride, which exhibits at least the following characteristic X- ray powder diffraction peaks (expressed in degrees 2Θ): (1) 7.6, 20.6 and 22.9 or
(2) 7.6, 7.9, 9.7, 13.4, 13.7, 15.2, 15.9, 20.6, 21.3, 22.4, 22.9 and 23.8.
11. Compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-lΗ,3H-spiro[l-benzofuran-2,4'- piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid sodium hydroxide, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2Θ):
(1) 7.6, 8.6 and 18.4 or
(2) 5.6, 7.6, 8.6, 13.1, 17.0 and 18.4.
12. A substantially pure compound according to any one of claims 1 to 11 having an X-ray powder diffraction pattern substantially the same as that shown in Figure 1 to 9.
13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, in association with a pharmaceutically acceptable adjuvants, diluents and/or carriers.
14. A pharmaceutical product comprising, in combination, a compound according to any one of claims 1 to 12, and at least one further active ingredient selected from : • a phosphodiesterase inhibitor,
• a β2 adrenoceptor agonist,
• an inhibitor of kinase function,
• a protease inhibitor,
• a steroidal glucocorticoid receptor agonist, • an anticholinergic agent, and a
• a non-steroidal glucocorticoid receptor agonist.
15. A pharmaceutical device comprising a compound according to any one of claims 1 to 12 or a composition according to claim 13 or 14.
16. A compound of the invention, as claimed in any one of claims 1 to 12 for use in therapy.
17. Use of a compound of the invention, as claimed in any one of claims 1 to 12, in the manufacture of a medicament for treating respiratory diseases.
18. Use of a compound of the invention, as claimed in any one of claims 1 to 12, in the manufacture of a medicament for treating airway diseases, inflammatory diseases, COPD and/or asthma.
19. A method of treatment of respiratory diseases, airway diseases, inflammatory diseases, COPD and/or asthma, in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of the compound of the invention, as claimed in any one of claims 1 to 12.
20. The method according to claim 19 whereby the compound of the invention, as claimed in any one of claims 1 to 12 is administered by inhalation.
21. A process for the preparation of polymorph Form A according to claim 3, comprising the following steps: a) compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-lΗ,3H-spiro[l-benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid is slurried in an organic solvent and heated to a temperature between 55 and 65°C for at least 25 to 35 minutes under continues stirring; b) addition of water over a period of 25 to 35 minutes and continues stirring for a further 30 minutes; c) cooling the mixture to room temperature and continued stirring for 25 to 35 minutes; d) cooling the mixture to a temperature between 0 and 4°C and continued stirring for 25 to 35 minutes, followed by filtration; e) washing the mixture in a 1:1 water/ethanol mixture, followed by drying at 50 to 70 0C.
PCT/SE2008/050878 2007-07-17 2008-07-16 Splropiperidine compounds, a process of their preparation, pharmaceutical compositions containing them, and their use in the treatment of airway diseases, inflammatory diseases, copd or asthma WO2009011655A1 (en)

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