WO2005092841A1 - Compounds having beta-agonist activity - Google Patents

Compounds having beta-agonist activity Download PDF

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Publication number
WO2005092841A1
WO2005092841A1 PCT/IB2005/000637 IB2005000637W WO2005092841A1 WO 2005092841 A1 WO2005092841 A1 WO 2005092841A1 IB 2005000637 W IB2005000637 W IB 2005000637W WO 2005092841 A1 WO2005092841 A1 WO 2005092841A1
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phenyl
amino
hydroxy
alkyl
formula
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PCT/IB2005/000637
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French (fr)
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Alan Daniel Brown
Mark Edward Bunnage
Kenneth John Butcher
Paul Alan Glossop
Kim James
Charlotte Alice Louise Lane
Russell Andrew Lewthwaite
David Anthony Price
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Pfizer Limited
Pfizer Inc.
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Priority claimed from GB0408297A external-priority patent/GB0408297D0/en
Application filed by Pfizer Limited, Pfizer Inc. filed Critical Pfizer Limited
Publication of WO2005092841A1 publication Critical patent/WO2005092841A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/40—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen 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
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms

Definitions

  • This invention relates to ⁇ 2 agonists of general formula:
  • A, B, R 1 , R 2 , n and Q 1 have the meanings indicated below, and to processes for the preparation of, compositions containing and the uses of such derivatives.
  • Adrenoceptors are members of the large G-protein coupled receptor super-family.
  • the adrenoceptor subfamily is itself divided into the and ⁇ subfamilies with the ⁇ sub-family being composed of at least 3 receptor sub- types: ⁇ 1 , ⁇ 2 and ⁇ 3. These receptors exhibit differential expression patterns in tissues of various systems and organs of mammals.
  • ⁇ 2 adrenergic ( ⁇ 2) receptors are mainly expressed in smooth muscle cells (e.g.
  • ⁇ 3 adrenergic receptors are mainly expressed in fat tissues (therefore ⁇ 3 agonists could potentially be useful in the treatment of obesity and diabetes) and ⁇ 1 adrenergic receptors are mainly expressed in cardiac tissues (therefore ⁇ 1 agonists are mainly used as cardiac stimulants).
  • Glucocorticosteroids, anti-leukotrienes, theophylline, cromones, anti- cholinergics and ⁇ 2 agonists constitute drug classes that are currently used to treat allergic and non-allergic airways diseases such as asthma and chronic obstructive airways disease (COPD). Treatment guidelines for these diseases include both short and long acting inhaled ⁇ 2 agonists. Short acting, rapid onset ⁇ 2 agonists are used for "rescue" bronchodilation, whereas, long-acting forms provide sustained relief and are used as maintenance therapy.
  • Bronchodilation is mediated via agonism of the ⁇ 2 adrenoceptor expressed on airway smooth muscle cells, which results in relaxation and hence bronchodilation.
  • ⁇ 2 agonists can prevent and reverse the effects of all bronchoconstrictor substances,-including leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine and endothelins.
  • LTD4 leukotriene D4
  • acetylcholine acetylcholine
  • bradykinin prostaglandins
  • histamine and endothelins histamine and endothelins.
  • ⁇ 2 receptors are so widely distributed in the airway, ⁇ 2 agonists may also affect other types of cells that play a role in asthma. For example, it has been reported that ⁇ 2 agonists may stabilize mast cells.
  • the inhibition of the release of bronchoconstrictor substances may be how ⁇ 2 agonists block the bronchoconstriction induced by allergens, exercise and cold air. Furthermore, ⁇ 2 agonists inhibit cholinergic neurotransmission in the human airway, which can result in reduced cholinergic-reflex bronchoconstriction.
  • ⁇ 2 adrenoceptors are also expressed in other organs and tissues and thus ⁇ 2 agonists, such as those described in the present invention, may have application in the treatment of other diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.
  • diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.
  • ⁇ 2 agonists are limited in their use due to their low selectivity or adverse side-effects driven by high systemic exposure and mainly mediated through action at ⁇ 2 adrenoreceptors expressed outside the airways
  • novel ⁇ 2 agonists that would have an appropriate pharmacological profile, for example in terms of potency, selectivity, pharmacokinetics or duration of action.
  • the present invention relates to novel ⁇ 2 agonists.
  • EP0061907 discloses the following intermediate compound: N-Benzyl-4-
  • the invention relates to compounds of formula (1)
  • - A is selected from the following groups:
  • R 1 and R 2 are independently selected from H or C 1 -C 4 alkyl
  • n is an integer selected from 0, 1 or 2
  • Q 1 is a group selected from:
  • R 8 is selected from hydrogen or (C- ⁇ -C )alkyl optionally substituted by a hydroxy
  • - Q 2 is a bond or a C ⁇ -C alkylene optionally substituted with OH;
  • - Q 7 is C ⁇ -C 6 alkyl optionally substituted with NR 9 R 10 , OR 9 or phenoxy,
  • cycloalkyl being optionally bridged by one or more carbon atoms, preferably 1 2, 3 or 4 carbon atoms, and being optionally substituted with a group selected from hydroxy group and C-i- C 4 alkyl;
  • heterocycle optionally aromatic, containing from 1 to 3 heteroatoms, identical or different, selected from O, S or N, said heterocycle being optionally substituted with a group selected from (C C 4 )alkyl, cyclopropylmethyl and NR 9 R 10 , or, - a group of formula
  • R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are selected from H, C ⁇ -C 6 alkyl, benzyloxy, hydroxy(C 1 -C 6 )alkyl, OR 9 , SR 9 , SOR 9 , S0 2 R 9 , halo, CN, CF 3 , OCF 3 , (CH 2 ) m COOR 9 , NR 9 S02(CrC 4 )aIkyl, S0 2 NR 9 R 1 °, CONR 9 R 10 , NR 9 R 10 ,
  • - m is an integer selected from 0, 1 , and 2; - R 9 and R 10 are the same or different and are selected from H or C C ⁇ alkyl;
  • R 11 is selected from H and OH
  • - Q 3 is (CH 2 )t wherein t is an integer selected from 0 and 1 ;
  • - Q 5 is a single bond, a CrC alkylene optionally substituted with OH or a group (CH 2 ) q -0-(CH2)r wherein q and r are integers independently selected from 1 , 2 or 3; : i,s selected from
  • R 15 , R 16 , R 17 and R 18 are independently selected from H, d-C 4 alkyl, OR 19 , SR 19 , SOR ,1 ⁇ 9 a , S0 2 R 1'9 halo, CN, CF 3 , OCF 3 , COOR 20 , S0 2 NR 19 R 2 °, CONR 19 R 20 , -NR 19 S0 2 R 20 ,
  • R 20 is selected from H, C ⁇ -C 4 alkyl, benzyl optionally substituted with 1 , 2, 3 or 4 C-i-C 4 alkoxy, and a group
  • s is an integer selected from 0, 1 , 2 and 3; or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof, with the proviso that when B is selected from
  • the compounds of formula (1 ) are agonists of the ⁇ 2 receptors, that are particularly useful for the treatment of ⁇ 2-mediated diseases and/or conditions, by showing excellent potency, in particular when administered via the inhalation route.
  • CrC 4 alkyl and C ⁇ -C 4 alkylene denote a straight-chain or branched group containing 1 , 2, 3 or 4 carbon atoms. This also applies if they carry substituents or occur as substituents of other radicals, for example in 0-(CrC 4 )alkyl radicals, S-(C ⁇ -C 4 )alkyl radicals etc... .
  • C-i-C 6 alkyl denotes a straight-chain or branched group containing 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • Examples of suitable (CrC 4 )alkyl radicals are methyl, ethyl, n-propyl, /so-propyl, ⁇ -butyl, /so-butyl, sec-butyl, tert-buiy ⁇ ....
  • Examples of suitable 0-(C- ⁇ -C 4 )alkyl radicals are methoxy, ethoxy, ⁇ -propyloxy, /so-propyloxy, ⁇ -butyloxy, /so-butyloxy, sec-butyloxy and te/f-butyloxy....
  • the C 3 -C ⁇ o cycloalkyl wherein 2 carbon atoms or more are optionally bridged by one or more carbon atoms includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicy o[2.2.2]octane.
  • Preferred cycloalkyl groups are cyclohexyl and adamantyl.
  • Examples of preferred 5 to 10 membered heterocycle, optionally aromatic, containing from 1 to 3 heteroatoms are morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, thienyl, isothiazolyl, oxazolyl, pyridyl, pyrimidyl oxazolyl, isoxazolyl, thiazolyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, oxadiazolyl, triazinyl, indolyl, quinolyl, isoquinolyl, benzofuranyl, quinazolyi, quinoxalyl, phthalazinyl, benzothiazolyl, benzoxazoiyl, benzisothiazolyl, benzisoxazolyl, benzimadazolyl, ind
  • Preferred heterocyclic groups include 5 to 6 membered heterocyclic groups, optionally aromatic, containing one or two heteroatoms selected from O, N or S such as are morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, pyrazolyl, thienyl, furanyl, imidazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, pyridyl and pyrimidyl.
  • said heterocyclic groups contain one nitrogen, two nitrogens or one nitrogen and one oxygen atom.
  • Preferred aromatic 5 to 6 membered heterocyclic groups are pyrazolyl and pyridyl.
  • Preferred non aromatic 5 to 6 membered heterocyclic groups are morpholinyl, pyrrolidinyl, piperidyl and piperazinyl.
  • halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo in particular fluoro or chloro.
  • the amide derivatives of the formula (1 ) may be prepared by coupling an acid of formula (2):
  • NHR 8 -Q 2 -Z or NHR 8 -Q 7 are examples of NHR 8 -Q 2 -Z or NHR 8 -Q 7 .
  • the coupling is generally carried out in an excess of said amine as an acid receptor, with a conventional coupling agent (e.g. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride or N, A/'-dicyciohexylcarbodiimide), optionally in the presence of a catalyst (e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7- azabenzotriazole), and optionally in the presence of a tertiary amine base (e.g. /V-methylmorpholine, triethylamine or diisopropylethylamine).
  • a conventional coupling agent e.g. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride or N, A/'-dicyciohexylcarbodiimide
  • a catalyst e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy
  • the reaction may be undertaken in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at temperature comprised between 10°C and 40°C (room temperature) for a period of 1-24 hours.
  • a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate
  • Said amine is either commercially available or may be prepared by conventional methods well known to the one skilled in the art (e.g. reduction, oxidation, alkylation, transition metal-mediated coupling, protection, deprotection etc..) from commercially available material.
  • the acid of formula (2) may be prepared from the corresponding ester of formula (4):
  • Ra is a suitable acid protecting group, preferably a (C ⁇ -C 4 )alkyl group, which includes, but is not limited to, methyl and ethyl, according to any method well-known to the one skilled in the art to prepare an acid from an ester, without modifying the rest of the molecule.
  • the ester may be hydrolysed by treatment with aqueous acid or base (e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (e.g. water, 1 ,4-dioxan, tetrahydrofuran/water), at a temperature comprised between 20°C and 100°C, for a period of 1 to 40 hours.
  • aqueous acid or base e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide
  • solvent or mixture of solvents e.g. water, 1 ,4-dioxan, tetrahydrofur
  • the ester of formula (4) may be prepared by reaction of an amine of formula (5) :
  • the amine of formula (5) is reacted with a bromide of formula (6) optionally in the presence of a solvent or mixture of solvents (e.g. dimethylsulfoxide, toluene, N, ⁇ /-dimethylformamide, acetonitrile), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate) at a temperature comprised between 80°C and 120°C, for 12 to 48 hours.
  • a solvent or mixture of solvents e.g. dimethylsulfoxide, toluene, N, ⁇ /-dimethylformamide, acetonitrile
  • a suitable base e.g. triethylamine, diisopropylethylamine, potassium carbonate
  • the bromide of formula (6) may be prepared according method well known to the man skilled in the art.
  • the amine of formula (5) where R 1 is Me and R 2 is H, may be prepared as either the ⁇ R) or (S) enantiomer from the corresponding protected amine of formula (7) :
  • Ra and n are as previously defined and Rb and Re represent any suitable substituents so that HNRbRc is a chiral amine (for example, Rb may be hydrogen and Re may be ⁇ -methylbenzyl), provided that the bonds between N and Rb and N and Re can be easily cleaved to give the free amine of formula (5) using standard methodology for cleaving nitrogen protecting groups, such as those found in the text book T.W. GREENE, Protective Groups in Organic Synthesis , A. Wiley-lnterscience Publication, 1981.
  • the amine of formula (7) may be prepared as a single diastereomer by reaction of an amine of formula HNRbRc with a ketone of formula (8):
  • Ra, Rb, Re and n are as previously defined.
  • the reaction of the ketone of formula (8) with the amine of formula HNRbRc leads to a chiral intermediate which is in turn reduced by a suitable reducing agent (e.g. sodium cyanoborohydride of formula NaCNBH 3 or sodium triacetoxyborohydride of formula Na(OAc) 3 BH) optionally in the presence of a drying agent (e.g. molecular sieves, magnesium sulfate) and optionally in the presence of an acid catalyst (e.g. acetic acid) to give the amine of formula (7) as a mixture of diastereomers.
  • a suitable reducing agent e.g. sodium cyanoborohydride of formula NaCNBH 3 or sodium triacetoxyborohydride of formula Na(OAc) 3 BH
  • a drying agent e.g. molecular sieves, magnesium sulfate
  • an acid catalyst e.g. acetic acid
  • the reaction is generally done in a solvent such as tetrahydrofuran or dichloromethane at a temperature comprised between 20°C and 80°C for 3 to 72 hours.
  • a solvent such as tetrahydrofuran or dichloromethane
  • the resulting product is then converted to the hydrochloride salt and selectively crystallised from a suitable solvent or mixture of solvents (e.g. isopropanol, ethanol, methanol, diisopropyl ether or diisopropyl ether/methanol) to give (7) as a single diastereomer.
  • Ra is as previously defined and Hal represents an halogen atom, which includes, but is not limited to bromo and iodo, with an enolate or enolate equivalent.
  • the aryl halide of formula (9) is reacted with a tin enolate generated in-situ by treatment of isopropenyl acetate with tri-n-butyltin methoxide of formula Bu 3 SnOMe in the presence of a suitable palladium catalyst (palladium acetate/ tri-o/f jo-tolylphosphine of formula Pd(OAc) 2 /P(o- Tol) 3 ) in a non-polar solvent (e.g. toluene, benzene, hexane).
  • a non-polar solvent e.g. toluene, benzene, hexane.
  • the reaction is carried out at a temperature comprised between 80°C and 110°C for 6 to 16 hours.
  • the aryl halide of formula (9) may be obtained by esterification of the corresponding acid of formula (10):
  • Hal is as previously defined, according to any method well-known to the one skilled in the art to prepare an ester from an acid, without modifying the rest of the molecule.
  • the acid of formula (10) is reacted with an alcoholic solvent of formula RaOH, wherein Ra is as previously defined, in the presence of an acid such as hydrogen chloride at a temperature between 10°C and 40°C (room temperature) for 8 to 16 hours.
  • the acid of formula (10) is a commercial product.
  • the amine of formula (5), where R 1 and R 2 are both C C 4 alkyl, may be prepared according to the following scheme:
  • R 1 , R 2 and Ra are as previously defined.
  • ester of formula (11 ) is reacted with an "activated" alkyl (organometallic alkyl such as R 2 MgBr, R 2 MgCI or R 2 Li) to give the corresponding tertiary alcohol of formula (12) using the method described above.
  • an "activated" alkyl organometallic alkyl such as R 2 MgBr, R 2 MgCI or R 2 Li
  • Said tertiary alcohol of formula (12) is then treated with an alkyl nitrile (e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g. sulphuric acid, acetic acid) to give a protected intermediate which is in turn cleaved using standard methodology for cleaving nitrogen protecting group such as those mentioned in textbooks.
  • an acid e.g. sulphuric acid, acetic acid
  • the resulting amino acid is then esterified using the method described herein to give the amine of formula (5).
  • ester of formula (13) is reacted with an "activated" alkyl (organometallic alkyl such as R 2 MgBr, R 2 MgCI or R 2 Li) to give the corresponding tertiary alcohol of formula (14) using the method described above.
  • Said tertiary alcohol of formula (14) is then treated with an alkyl nitrile
  • the resulting bromo amine (15) is treated with a suitable palladium catalyst (e.g. [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)) under an atmosphere of carbon monoxide using RaOH as solvent (e.g. MeOH, EtOH) at elevated temperature (100°C) and pressure (100psi) to give the ester of formula (5).
  • a suitable palladium catalyst e.g. [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)
  • a solution of the olefin of formula (16) in a suitable solvent e.g. methanol, ethanol, ethyl acetate
  • a palladium catalyst e.g. 10% palladium on charcoal
  • elevated pressure e.g. 60 psi
  • the alkene of formula (16) may be prepared by a palladium mediated coupling of an activated olefin with an aryl halide of formula (17):
  • a suitable palladium catalyst e.g. tetrakis(triphenylphosphine)palladium(0) of formula Pd(PPh 3 ) 4 , palladium acetate/tri-ort 70-tolylphosphine of formula Pd(OAc) 2 /P(o-tol) 3 or (diphenylphosphino)ferrocenyl palladium chloride of formula dppfPdCI 2
  • a suitable solvent e.g. acetonitrile, N, / -dimethylforma ide, toluene
  • a base such as triethylamine at a temperature between 40°C and 110°C for 8 to 24 hours.
  • the ketone of formula (17) is a commercial product.
  • a compound of formula (1) may be prepared by reaction of a bromide of formula (6) and an amine of formula (18):
  • R 1 , R 2 , Q 1 and n are as previously defined for the compounds of the formula (1 ) unless otherwise stated.
  • the amine of formula (18) is reacted with a bromide of formula (6) optionally in the presence of a solvent or mixture of solvents (e.g. dimethylsulfoxide, toluene, N, / -dimethylformamide, acetonitrile), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate) at a temperature comprised between 80°C and 120°C, for 12 to 48 hours.
  • a solvent or mixture of solvents e.g. dimethylsulfoxide, toluene, N, / -dimethylformamide, acetonitrile
  • a suitable base e.g. triethylamine, diisopropylethylamine, potassium carbonate
  • the amide of formula (18) may be prepared by coupling an acid of formula (19) incorporating a suitable amine protecting group P1 :
  • the coupling is generally carried out in an excess of said amine as an acid receptor, with a conventional coupling agent (e.g. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride or N, A/'-dicyclohexylcarbodiimide), optionally in the presence of a catalyst (e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7- azabenzotriazole), and optionally in the presence of a tertiary amine base (e.g.
  • a conventional coupling agent e.g. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride or N, A/'-dicyclohexylcarbodiimide
  • a catalyst e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7- azabenzotriazole
  • a tertiary amine base e.g.
  • reaction may be undertaken in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at temperature comprised between 10°C and 40°C (room temperature) for a period of 1-24 hours.
  • a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate
  • Said amine is either commercially available or may be prepared by conventional methods well known to the one skilled in the art (e.g. reduction, oxidation, alkylation, transition metal-mediated coupling, protection, deprotection etc..) from commercially available material.
  • the acid of formula (19) may be prepared from the corresponding ester of formula (5).
  • the acid of formula (19), where R 1 and R 2 are both C ⁇ -C 4 alky ⁇ , may be prepared from the ester (5) incorporating a suitable amine protecting group P1 either before or after the acid formation:
  • Ra is a suitable acid protecting group, preferably a (CrC 4 )alkyl group, which includes, but is not limited to, methyl and ethyl, according to any method well-known to the one skilled in the art to prepare an acid from an ester, without modifying the rest of the molecule.
  • the ester may be hydrolysed by treatment with aqueous acid or base (e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (e.g. water, 1 ,4-dioxan, tetrahydrofuran/water), at a temperature comprised between 20°C and 100°C, for a period of 1 to 40 hours.
  • aqueous acid or base e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide
  • solvent or mixture of solvents e.g. water, 1 ,4-dioxan, tetrahydrofuran
  • the acid of formula (20) is preferentially reduced to the corresponding alcohol (21 ) in the presence of the ester.
  • This may be performed by formation of the acyl imidazole or mixed anhydride and subsequent reduction with sodium borohydride or another suitable reducing agent.
  • Said primary alcohol of formula (21 ) is then converted into a leaving group such as mesylate, tosylate, bromide or iodide and displaced with appropriate amine nucleophile.
  • the preferred nucleophile is azide ion which can then be reduced to the primary amine via hydrogenation or triphenylphosphine.
  • Alternative nucleophiles could include ammonia or alkylamines such as benzylamine or allylamine and subsequent cleavage of the alkyl group to furnish the amine.
  • a solvent or mixture of solvents e.g. dimethyl sulfoxide, toluene, N, / -dimethylformamide, acetonitrile, THF
  • a suitable base e.g. triethylamine, N, /V-diisopropylethylamine, potassium carbonate
  • a catalyst e.g. potassium iodide
  • the intermediate amino ketone can then be reduced using sodium borohydride or diisobutylaluminiumhydride to furnish the required aminoalcohol.
  • any compatible protecting radical can be used.
  • methods of protection and deprotection such as those described by T.W. GREENE ⁇ Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981) or by P. J. Kocienski ⁇ Protecting groups, Georg Thieme Verlag, 1994), can be used.
  • An alternative agent for deprotection would be one equivalent of triethylamine trihydrofluoride in tetrahydrofuran or suitable solvent at room temperature for 12 hours.
  • Q is a s ingle bond.
  • Z is selected from morpholinyl, pyrrolidinyl, piperidyl, piperazinyl or pyrazolyl, op-tionally susbstituted by a methyl group.
  • Z is selected from pyrazolyl optionally substituted by one or two C 1 -C 4 alkyl group.
  • Q 1 is *-NR 8 -Q 7 .
  • Q is a group selected from,
  • Q v 1 is a group *-NH-Q2-Z, wherein Z is C 3 -C 10 cycloalkyl, said cycloalkyl being optionally bridged by one or more carbon atoms, preferably 1 2, 3 or 4 carbon atoms.
  • Q 1 is a group *-NH-Q 2 -Z, wherein Z is cyclohexyl or adamantyl.
  • Q 1 is N
  • R 3 , R 4 . R 5 and R 6 are H.
  • Q 1 is a group *-NH-Q 2 -Z, wherein Z is a group
  • R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are selected from H, d-d alkyl, OR 9 , SR 9 , SOR 9 , S0 2 R 9 , CN, halo, CF 3 , OCF 3 , SO ⁇ NR 9 R 10 , CONR 9 R 10 , NR 9 R 10 , NHCOR 10 and phenyl provided at least 2 of R 3 to R 7 are equal to H; wherein R 9 and R 10 are the same or different and are selected from H or d-C 4 alkyl.
  • Q 1 is a group *-NH-Q 2 -Z, wherein Z is a group
  • R 3 , R 4 , R 5 , R ⁇ and R 7 are the same or different and are selected from H, OH, CH 3 , OCH 3 , OCH 2 -CH 3 , SCH 3 , halo, CF 3 , provided at least 2 of R 3 to R 7 are equal to H.
  • Q 5 is a bond, -CH 2 -, -(CH 2 ) 2 -, -C(CH 3 )2-CH 2 -, -CH(CH 3 )-CH( H)- or CH 2 -CH(CH 3 )-.
  • R , R , R , R and R 1 ⁇ are selected from H, d-C 4 alkyl, phenyl, phenoxy OR 16 , halo, CF 3 , OCF 3 ; and at least two of R 11 to R 15 represent H.
  • Q 2 is a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, or -C(CH 3 ) 2 -, preferably -CH 2 -.
  • R 1 is H or C 1 -C alkyl and R 2 is C ⁇ -C 4 alkyl. More preferably, R 1 is H or CH 3 and R 2 is CH 3 .
  • n is O or l .
  • R 1 is H and R 2 is CH 3 and n is 0 or 1.
  • R 1 is CH 3
  • R 2 is CH 3 and n is 0 or .
  • Pharmaceutically acceptable salts of the compounds of formula (1) include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, hydrogen phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methylsulphate, 2- napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen, phosphate/phosphate dihydrogen, pyroglutamate, sacchar
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • suitable salts see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non- stoichiometric amounts.
  • the resulting complexes may be ionised, partially ionised, or non-ionised.
  • references to compounds of formula (1 ) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • the compounds of the invention include compounds of formula (1 ) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula
  • 'pro-drugs' of the compounds of formula (1) are also within the scope of the invention.
  • certain derivatives of compounds of formula (1) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (1 ) having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E. B Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (1 ) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).
  • prodrugs in accordance with the invention include: (i) where the compound of formula (1) contains a carboxylic acid functionality (-COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (1 ) is replaced by (C ⁇ -Cs)alkyl; (ii) where the compound of formula (1) contains an alcohol functionality (- OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of formula (1 ) is replaced by (C ⁇ -C 6 )alkanoyloxymethyl; and (iii) where the compound of formula (1 ) contains a primary or secondary amino functionality (-NH 2 or -NHR where R ⁇ ), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula (1 ) is/are replaced by (C ⁇ -C ⁇ o)alkanoyl.
  • metabolites of compounds of formula (1) that is, compounds formed in vivo upon administration of the drug.
  • Some examples of metabolites in accordance with the invention include (i) where the compound of formula (1) contains a methyl group, an hydroxymethyi derivative thereof (-CH 3 -» -CH 2 OH):
  • Compounds of formula (1 ) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (1) contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (1) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (1 ) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (1 ) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
  • chromatography typically HPLC
  • a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine.
  • Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel (Wiley, New York, 1994).
  • the (R,R)-stereoisomer of the formula below wherein R 1 is hydrogen and R 2 is d-d alkyl, preferably methyl, and A, B, n and Q 1 are as defined above, is generally preferred:
  • the present invention includes all pharmaceutically acceptable isotopically- labelled compounds of formula (1) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 4C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of formula (1 ), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of formula (1 ) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, de-acetone, d 6 -DMSO.
  • the compounds of formula (1 ), their pharmaceutically acceptable salts and/or derived forms, are valuable pharmaceutically active compounds, which are suitable for the therapy and prophylaxis of numerous disorders in which the ⁇ 2 receptor is involved or in which agonism of this receptor may induce benefit, in particular the allergic and non-allergic airways diseases but also in the treatment of other diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • exeipient may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • the term "exeipient” is used herein to describe any ingredient other than the compound(s) of the invention. The choice of exeipient will to a large extent depend on factors such as the particular mode of administration, the effect of the exeipient on solubility and stability, and the nature of the dosage form.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995).
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).
  • the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, eroscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyi cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight %» of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylceilulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
  • ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % iubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • the formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
  • Consumable oral films for human or veterinary use are typically pliable water- soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (1), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent.
  • Some components of the formulation may perform more than one function.
  • the compound of formula (1 ) may be water-soluble or insoluble.
  • a water- soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes.
  • the compound of formula (1 ) may be in the form of multiparticulate beads.
  • the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydroeolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
  • ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.
  • Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intraeranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • compositions of formula (1) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug- coated stents and poly(cf/-lactic-coglycolic)acid (PGLA) nicrospheres.
  • PGLA poly(cf/-lactic-coglycolic)acid
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free ⁇ e.g. PowderjectTM, BiojectTM, etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules (made, for example, from gelatin or hy roxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ l to 100 /I.
  • a typical formulation may comprise a compound of formula (1 ), propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff containing from 0.001 mg to 10mg of the compound of formula (1 ).
  • the overall daily dose will typically be in the range 0.001 mg to 40mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the compounds of formula (1) are particularly suitable for an administration by inhalation.
  • the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema.
  • Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable ⁇ e.g. absorbable gel sponges, collagen) and non-biodegradable ⁇ e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyalu ronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
  • compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (1 ) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a container, divided bottle, or divided foil packet An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • the total daily dose of the compounds of the invention is typically in the range 0.001 mg to 5000mg depending, of course, on the mode of administration.
  • an intravenous daily dose may only require from 0.001 mg to 40mg.
  • the total daily dose may be administered in single or divided doses_and may, at the physician's discretion, fall outside of the typical range given herein.
  • dosages are based on an average human subject having a weight of about 65kg to 70kg.
  • the physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • references herein to "treatment” include references to curative, palliative and prophylactic treatment.
  • the compounds of the formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof can also be used as a combination with one or more additional therapeutic agents to be co-administered to a patient to obtain some particularly desired therapeutic end result such as the treatment of pathophysiologically-relevant disease processes including, but not limited to (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) signs and symptoms such as breathlessness, cough.
  • the second and more additional therapeutic agents may also be a compound of the formula (1), or a pharmaceutically acceptable salt, derived forms or compositions thereof, or one or more ⁇ 2 agonists known in the art. More typically, the second and more therapeutic agents will be selected from a different class of therapeutic agents.
  • co-administration As used herein, the terms “co-administration”, “co-administered” and “in combination with”, referring to the compounds of formula (1) and one or more other therapeutic agents, is intended to mean, and does refer to and include the following:
  • each part may be administered by either the same or different route.
  • Suitable examples of other therapeutic agents which may be used in combination with the compound(s) of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, include, but are by no means limited to :
  • LTRAs Leukotriene antagonists
  • PDE inhibitors e.g. PDE3, PDE4 and PDE5 inhibitors
  • Inhibitors of urokinase (t) Inhibitors of urokinase, (u) Compounds that act on dopamine receptors, e.g. D2 agonists,
  • (w) modulators of cytokine signalling pathyways such as p38 MAP kinase, syk kinase or JAK kinase inhibitor,
  • cytokine signalling pathyways such as p38 MAP kinase or syk kinase, or, - Leukotriene antagonists (LTRAs) including antagonists of LTB , LTd, LTD , and LTE4, are preferred.
  • LTRAs - Leukotriene antagonists
  • glucocorticosteroids in particular inhaled glucocorticosteroids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, and mometasone furoate, or
  • ipratropium salts namely bromide, tiotropium salts, namely bromide, oxitropium salts, namely bromide, perenzepine, and telenzepine
  • ipratropium salts namely bromide
  • tiotropium salts namely bromide
  • oxitropium salts namely bromide, perenzepine, and telenzepine
  • the compounds of formula (1 ) have the ability to interact with the ⁇ 2 receptor and thereby have a wide range of therapeutic applications, as described further below, because of the essential role which the ⁇ 2 receptor plays in the physiology of all mammals.
  • a further aspect of the present invention relates to the compounds of formula (1 ), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders, and conditions in which the ⁇ 2 receptor is involved. More specifically, the present invention also concerns the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders, and conditions selected from tine group consisting of :
  • asthma of whatever type, etiology, or pathogenesis in particular asthma that is a member selected from the group consisting of atopio asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE- mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, whez infant syndrome and bronchiolytis,
  • obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis in particular an obstructive or inflammatory airways disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary diseases (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airways hyper- reactivity consequent to other drug therapy and airways disea se that is associated with pulmonary hypertension,
  • COPD chronic osinophilic pneumonia
  • COPD chronic obstructive pulmonary diseases
  • COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD
  • COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS),
  • bronchitis of whatever type, etiology, or pathogenesis in particular bronchitis that is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphyloco ecus or streptococcal bronchitis and vesicular bronchitis,
  • bronchitis that is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphyloco ecus or streptococcal bronchit
  • bronchiectasis of whatever type, etiology, or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.
  • a still further aspect of the present invention also relates to the use of the compounds of formula (1 ), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug having a ⁇ 2 agonist activity.
  • the present inventions concerns the use of the compounds of formula (1 ), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug for the treatment of ⁇ 2- mediated diseases and/or conditions, in particular the diseases and/or conditions listed above.
  • the present invention provides a particularly interesting method to treat a mammal, including a human being, with an effective amount of a compound of formula (1), or a pharmaceutically acceptable salt, derived form or composition thereof. More precisely, the present invention provides a particularly interesting method for the treatment of a ⁇ 2-mediated diseases and/or conditions in a mammal, including a human being, in particular the diseases and/or conditions listed above, comprising admidministering said mammal with an effective amount of a compound of formula (1 ), its pharmaceutically acceptable salts and/or derived forms.
  • the reaction mixture was cooled to room temperature and filtered through arbocel to remove catalyst residues.
  • the filtrate was reduced in vacuo and the residue was partitioned between sat. aq. sodium chloride (20 ml) and dichloromethane (20 ml).
  • the organic phase was separated and the aqueous extracted with more dichloromethane (20 ml).
  • the combined organic extracts were dried (sodium sulphate) and the solvent removed in vacuo to give the title compound as a colourless oil (0.74 g).
  • Preparation 8 1-terf-butyl 2-methyl 5-(2-oxopropyl)-1H-indole-1 ,2- dicarboxylate
  • a solution of 1-terf-butyl 2-methyl 5-bromo-1H-indole-1 ,2-dicarboxylate (Preparation 9, 12.5 g, max 32.04 mmol), tributyltin methoxide (11.0 ml, 38.2 mmol), isoprenylacetate (5.3 ml, 48.1 mmol), palladium acetate (0.36 g, 5 mol%), tri-o-tolylphosphine (0.97 g, 10 mol%) in toluene (40 ml) was degassed and then heated at 100°C for 8 hours.
  • the reaction mixture was diluted with ethyl acetate (50 ml), 4M potassium fluoride (aqueous, 100 ml) and left to stir at room temperature overnight.
  • the resulting mixture was filtered through arbocel washing the precipitate thoroughly with ethyl acetate (100 ml) and the organic phase of the filtrate separated, dried (magnesium sulphate) and the solvent removed in vacuo.
  • the residue was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (95:5 changing to 90:10, by volume) to give the title compound (8.2 g) as a yellow oil.
  • the combined filtrate was evaporated under reduced pressure and the residual yellow solid was purified using a Biotage® silica gel column and dichloromethane:ethyl acetate (100:0 to 50:50 to 0:1 00) as the eluant.
  • the impure fractions were combined and purified again using a Biotage® silica gel column using toluene:dichloromethane (100:0 to 50:50 to 0:100) as the eluant, to provide the title compound as a solid.
  • Potassium cyanate (2.01 g, 24mmol) was added to a solution of the amine from preparation 18 (4g, 12mmol) in a solution of acetic acid:water (400mL, 1 :2 by volume), and the reaction stirred at room temperature for 1.5 hours. The solution was carefully basified by the addition of sodium hydroxide, and the resulting precipitate filtered off. The solid was washed with water (1600mL), then ether (500mL) and dried in vacuo for 18 hours, to afford the title compound, 2.44g.
  • the residual oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (99.7:0:0.3 to 96.7:3:0.3).
  • the impure fractions were further purified using a RediSEPTM flash silica gel column and an elution gradient of dichloromethane:methanol:0.88 ammonia (99.7:0:0.3 to 96.7:3:0.3).
  • the resulting oils were combined and triturated with ether, to afford the title compound as a pale yellow solid, 2.1g.
  • Preparation 30 ⁇ /-[2-(3-Bromophenyl)-1,1-dimethylethyl]-2- chloroacetamide Chloroacetonitrile (6.63 mL, 105 mmol) was added to a stirred solution of the product of preparation 29 (12.0 g, 52.0 mmol) in acetic acid (25 mL) at room temperature. The resulting solution was cooled to 0 °C and concentrated sulfuric acid (25 mL) was added whilst the temperature was maintained below 10 °C. The resulting solution was left to stir for 1 hour and was then poured onto ice and basified by the addition of solid potassium carbonate.
  • the product of preparation 31 (5.0g, 22mmol) was treated with di-fert-butyl dicarbonate (5.26g, 24mmol) in dichloromethane (50mL) and stirred for 20 hours.
  • the reaction mixture was washed with water (50mL) and the combined organic solution was dried over sodium sulfate and concentrated in vacuo.
  • the crude material was purified using a cation exchange column (methanol followed by 2M ammonia in methanol), followed by purification by flash column chromatography on silica gel eluting with dichloromethane to afford the title compound as a brown oil in quantitative yield, 7.23g.
  • Preparation 35 3- ⁇ 2-[(2R)-2-(3-Acetylamino-4-benzyloxyphenyl)-2-(ferf- butyldimethylsilanyloxy)ethylamino]-2-methylpropyI ⁇ benzoic acid benzyl ester
  • a mixture of preparation 28 (2.21 g, 4.79 mmol, containing some of the acetyl analogue) and the free-base of preparation 34 (2,69 g, 9.49 mmol) were heated to 95 °C for 24 h. The mixture was allowed to cool and then triturated with diethyl ether and the solid filtered off.
  • Example 1 5- ⁇ (2R)-2-[((2R)-2-Hydroxy-2- ⁇ 4-hydroxy-3-[(methylsulfonyl) amino]phenyl ⁇ ethyl)amino]propyl ⁇ -/V-[3-hydroxy-5-(trifluoromethyl) benzyl]-1 H-indole-2-carboxamide
  • reaction mixture was purified directly by HPLC using a Phenomenex Luna C18 column (150x10mm, 10 ⁇ m), at a flow rate of 8mL/min and detection at 225nm, using the following gradient system.
  • the ability of the compounds of the formula (1) to act as potent ⁇ 2 agonists therefore mediating smooth muscle relaxation may be determined by the measure of the effect of beta-2 adrenergic receptor stimulation on electrical field stimulated-contraction of guinea pig trachea strips.
  • Guinea-pig trachea Guinea-pig trachea
  • the strips are equilibrated, un-tensioned, for 20 minutes in a modified Krebs Ringer buffer (Sigma K0507) containing 3 ⁇ M Indomethacin (Sigma I7378), 10 ⁇ M Guanethidine (Sigma G8520) and 10 ⁇ M Atenolol (Sigma A7655), heated at 37°C and gassed with 95% 0 2 /5% C0 2 , before applying an initial tension of 1 g.
  • the preparations are allowed to equilibrate for a further 30- 45 minutes, during which time they are re-tensioned (to 1 g) twice at 15-minute intervals.
  • the organ baths are constantly perfused with the above-described Krebs Ringer buffer by means of a peristaltic pump system (pump flow rate 7.5 ml / minute) throughout the experiment, with the exception of when a beta-2 agonist according to the present invention is added, the pump is then stopped for the time of the cumulative dosing to the bath and started again after maximal response is reached for the wash-out period.
  • Experimental protocol for assessment of potency and efficacy Following equilibration to EFS, the peristaltic pump is stopped and the preparations 'primed' with a single dose of 300 nM isoprenaline (Sigma 15627) to establish a maximal response in terms of inhibition of the contractile EFS response.
  • the isoprenaline is then washed out over a period of 40 minutes.
  • a standard curve to isoprenaline is carried out on all tissues (Isoprenaline Curve 1) by means of cumulative, bolus addition to the bath using half log increments in concentration. The concentration range used is 1 e"9 to 1 e /3 e"6 M.
  • the preparations are washed again for 40 minutes before commencing a second curve, either to isoprenaline (as internal control) or a beta-2 agonist according to the present invention. Beta-2 agonist responses are expressed as percentage inhibition of the EFS response.
  • Data for beta-2 agonist are normalised by expressing inhibition as a percentage of the maximal inhibition induced by isoprenaline in Curve 1.
  • the EC 50 value for beta-2 agonist according to the present invention refers to the concentration of compound required to produce half maximal effect.
  • Data for beta-2 agonists according to the present invention are then expressed as relative potency to isoprenaline defined by the ratio (EC 5 o beta-2 agonist)/(EC50 Isoprenaline).
  • Beta-2 agonist activity of test compounds is confirmed using the protocol above, however, prior to constructing the curve to beta-2 agonist according to the present invention, the preparations are pre-incubated (for a minimum of 45 minutes) with 300 nM ICI 118551 (a selective ⁇ 2 antagonist) which results in the case of a beta-2 mediated effect in a rightward-shift of the test compound dose response curve.
  • the agonist potency for the ⁇ 2 receptor of the compounds of the formula (1) may also be determined by the measure of the concentration of compound according to the present invention required to produce half maximal effect (EC 50 ) for the ⁇ 2 receptor.
  • CHO Choinese Hamster Ovary cells recombinantly expressing the human ⁇ 2 adrenergic receptor (from Kobilka et al., PNAS 8 ⁇ 4: 46-50, 1987 and Bouvier et al., Mol Pharmacol 33: 133-139 1988 CHOh ⁇ 2) were grown in Dulbeccos MEM/ NUT MIX F12 (Gibco, 21331-020) supplemented with 10 % foetal bovine serum (Sigma, F4135, Lot 90K8404 Exp 09/04), 2 mM glutamine (Sigma, G7513), 500 ⁇ g/ml geneticin (Sigma, G7034) and 10 ⁇ g/rnl puromycin (Sigma, P8833). Cells were seeded to give about 90 % confluency for testing.

Abstract

The invention relates to compounds of formula (1) and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. The compounds according to the present invention are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions.

Description

COMPOUNDS HAVING BETA-AGONIST ACTIVITY
This invention relates to β2 agonists of general formula:
Figure imgf000002_0001
in which A, B, R1, R2, n and Q1 have the meanings indicated below, and to processes for the preparation of, compositions containing and the uses of such derivatives.
Adrenoceptors are members of the large G-protein coupled receptor super-family. The adrenoceptor subfamily is itself divided into the and β subfamilies with the β sub-family being composed of at least 3 receptor sub- types: β1 , β2 and β3. These receptors exhibit differential expression patterns in tissues of various systems and organs of mammals. β2 adrenergic (β2) receptors are mainly expressed in smooth muscle cells (e.g. vascular, bronchial, uterine or intestinal smooth muscles), whereas β3 adrenergic receptors are mainly expressed in fat tissues (therefore β3 agonists could potentially be useful in the treatment of obesity and diabetes) and β1 adrenergic receptors are mainly expressed in cardiac tissues (therefore β1 agonists are mainly used as cardiac stimulants).
The pathophysiology and treatments of airway diseases have been extensively reviewed in the literature (for reference see Barnes, PJ. Chest, 1997, 111 :2, pp 17S-26S and Bryan, S.A. et al, Expert Opinion on investigational drugs, 2000, 9:1 , pp25-42) and therefore only a brief summary will be included here to provide some background information.
Glucocorticosteroids, anti-leukotrienes, theophylline, cromones, anti- cholinergics and β2 agonists constitute drug classes that are currently used to treat allergic and non-allergic airways diseases such as asthma and chronic obstructive airways disease (COPD). Treatment guidelines for these diseases include both short and long acting inhaled β2 agonists. Short acting, rapid onset β2 agonists are used for "rescue" bronchodilation, whereas, long-acting forms provide sustained relief and are used as maintenance therapy.
Bronchodilation is mediated via agonism of the β2 adrenoceptor expressed on airway smooth muscle cells, which results in relaxation and hence bronchodilation. Thus, as functional antagonists, β2 agonists can prevent and reverse the effects of all bronchoconstrictor substances,- including leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine and endothelins. Because β2 receptors are so widely distributed in the airway, β2 agonists may also affect other types of cells that play a role in asthma. For example, it has been reported that β2 agonists may stabilize mast cells. The inhibition of the release of bronchoconstrictor substances may be how β2 agonists block the bronchoconstriction induced by allergens, exercise and cold air. Furthermore, β2 agonists inhibit cholinergic neurotransmission in the human airway, which can result in reduced cholinergic-reflex bronchoconstriction.
In addition to the airways, it has also been established that β2 adrenoceptors are also expressed in other organs and tissues and thus β2 agonists, such as those described in the present invention, may have application in the treatment of other diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.
However, numerous β2 agonists are limited in their use due to their low selectivity or adverse side-effects driven by high systemic exposure and mainly mediated through action at β2 adrenoreceptors expressed outside the airways
(muscle tremor, tachycardia, palpitations, restlessness). Therefore there is a need for improved agents in this class. Accordingly, there is still a need for novel β2 agonists that would have an appropriate pharmacological profile, for example in terms of potency, selectivity, pharmacokinetics or duration of action. In this context, the present invention relates to novel β2 agonists.
EP0061907 discloses the following intermediate compound: N-Benzyl-4-
[2-(2-hydroxy-2-phenyl-ethylamino)-propyl]-benzamide.
The invention relates to compounds of formula (1)
Figure imgf000004_0001
wherein:
- A is selected from the following groups:
Figure imgf000004_0002
Figure imgf000005_0001
wherein the dashed line represents an optional bond;
- R1 and R2 are independently selected from H or C1-C4 alkyl;
- B is selected from
Figure imgf000005_0002
wherein * represents the attachment points and
Figure imgf000005_0003
wherein ** represents the attachment point to the (CH2)nC(=0)Qι group and R is selected from hydrogen, (Cι-C4)alkyl and benzyl optionally substituted with 1 , 2 or 3 groups selected from hydroxy, hydroxy(Cι-C6)alkyl, (C-ι-C )alkyl, 0-(Cι-
C4)alkyl, halo, 0-CF3, NRaS02(Cι-C4)alkyl, S02NR 9aoR1'0u, trifluoromethyl and
NR9R10; n is an integer selected from 0, 1 or 2, Q1 is a group selected from:
Figure imgf000006_0001
Figure imgf000006_0002
wherein
- * represent the attachment point to the carbonyl group;
- p is 1 or 2 and q is 1 or 2,
- R8 is selected from hydrogen or (C-ι-C )alkyl optionally substituted by a hydroxy;
- Q2 is a bond or a Cι-C alkylene optionally substituted with OH;
- Q7 is Cι-C6 alkyl optionally substituted with NR9R10, OR9 or phenoxy,
- Z is selected from
- C3-Cιo cycloalkyl, said cycloalkyl being optionally bridged by one or more carbon atoms, preferably 1 2, 3 or 4 carbon atoms, and being optionally substituted with a group selected from hydroxy group and C-i- C4 alkyl;
- 5 to 10-membered heterocycle, optionally aromatic, containing from 1 to 3 heteroatoms, identical or different, selected from O, S or N, said heterocycle being optionally substituted with a group selected from (C C4)alkyl, cyclopropylmethyl and NR9R10 , or, - a group of formula
Figure imgf000007_0001
- R3, R4, R5, R6 and R7 are the same or different and are selected from H, Cι-C6 alkyl, benzyloxy, hydroxy(C1-C6)alkyl, OR9, SR9, SOR9, S02R9, halo, CN, CF3, OCF3, (CH2)mCOOR9, NR9S02(CrC4)aIkyl, S02NR9R1°, CONR9R10, NR9R10,
NHCOR 10.
- m is an integer selected from 0, 1 , and 2; - R9 and R10 are the same or different and are selected from H or C Cβ alkyl;
- R11 is selected from H and OH;
- R12 and R13 are the same or different and are selected from H, OR9, C1-C4 alkyl optionally susbstituted with OR9, C(=0)NH2, C(=0)CH3, N(CH3)C(=0)CH3, C(=0)OR9, phenyl optionally substituted with halogen, pyridyl optionally substituted with CN, oxadiazolyl optionally substituted with Cι-C4 alkyl, and
- Q3 is (CH2)t wherein t is an integer selected from 0 and 1 ;
- Q4 is a group selected from NH, -C(=0)NH-, -NHC(=0)-, NH-C(=0)-NH-, - NHS02- and -S02NH-; or
- Q5 is a single bond, a CrC alkylene optionally substituted with OH or a group (CH2)q-0-(CH2)r wherein q and r are integers independently selected from 1 , 2 or 3; : i,s selected from
Figure imgf000007_0002
wherein * represents the attachment point to Q5 and R14, R15, R16, R17 and R18 are independently selected from H, d-C4 alkyl, OR19, SR19, SOR ,1ι9a, S02R 1'9 halo, CN, CF3, OCF3, COOR20, S02NR19R2°, CONR19R20, -NR19S02R20,
NHR )1ι9arR-s20u, NHCOR20, CH2-NHC(=0)NH-R ,2z0u,
- RR1199 iiss sseelleecctteedd ffrroomm HH oorr CCιι--CC44 aallkkyyll aanndd F R20 is selected from H, Cι-C4 alkyl, benzyl optionally substituted with 1 , 2, 3 or 4 C-i-C4 alkoxy, and a group
Figure imgf000008_0001
wherein s is an integer selected from 0, 1 , 2 and 3; or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof, with the proviso that when B is selected from
Figure imgf000008_0002
then A is not
Figure imgf000008_0003
and with the exception of N-Benzyl-4-[2-(2-hydroxy-2-phenyl-ethylamino)- propyl]-benzamide.
The compounds of formula (1 ) are agonists of the β2 receptors, that are particularly useful for the treatment of β2-mediated diseases and/or conditions, by showing excellent potency, in particular when administered via the inhalation route.
In the here above general formula (1 ), CrC4 alkyl and Cι-C4 alkylene denote a straight-chain or branched group containing 1 , 2, 3 or 4 carbon atoms. This also applies if they carry substituents or occur as substituents of other radicals, for example in 0-(CrC4)alkyl radicals, S-(Cι-C4)alkyl radicals etc... . C-i-C6 alkyl denotes a straight-chain or branched group containing 1 , 2, 3, 4, 5 or 6 carbon atoms. Examples of suitable (CrC4)alkyl radicals are methyl, ethyl, n-propyl, /so-propyl, π-butyl, /so-butyl, sec-butyl, tert-buiy\.... Examples of suitable 0-(C-ι-C4)alkyl radicals are methoxy, ethoxy, π-propyloxy, /so-propyloxy, π-butyloxy, /so-butyloxy, sec-butyloxy and te/f-butyloxy....
The C3-Cιo cycloalkyl wherein 2 carbon atoms or more are optionally bridged by one or more carbon atoms includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicy o[2.2.2]octane. Preferred cycloalkyl groups are cyclohexyl and adamantyl.
Examples of preferred 5 to 10 membered heterocycle, optionally aromatic, containing from 1 to 3 heteroatoms are morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, thienyl, isothiazolyl, oxazolyl, pyridyl, pyrimidyl oxazolyl, isoxazolyl, thiazolyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, oxadiazolyl, triazinyl, indolyl, quinolyl, isoquinolyl, benzofuranyl, quinazolyi, quinoxalyl, phthalazinyl, benzothiazolyl, benzoxazoiyl, benzisothiazolyl, benzisoxazolyl, benzimadazolyl, indazolyl and benzotriazolyl.
Preferred heterocyclic groups include 5 to 6 membered heterocyclic groups, optionally aromatic, containing one or two heteroatoms selected from O, N or S such as are morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, pyrazolyl, thienyl, furanyl, imidazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, pyridyl and pyrimidyl. Preferably, said heterocyclic groups contain one nitrogen, two nitrogens or one nitrogen and one oxygen atom.
Preferred aromatic 5 to 6 membered heterocyclic groups are pyrazolyl and pyridyl.
Preferred non aromatic 5 to 6 membered heterocyclic groups are morpholinyl, pyrrolidinyl, piperidyl and piperazinyl.
Finally, halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo in particular fluoro or chloro.
The compounds of the formula (1 )
Figure imgf000010_0001
can be prepared using conventional procedures such as by the following illustrative methods in which Q1, R1, R2, A, B and n are as previously defined for the compounds of the formula (1 ) unless otherwise stated.
The amide derivatives of the formula (1 ) may be prepared by coupling an acid of formula (2):
Figure imgf000010_0002
with an amine of formula
Figure imgf000010_0003
Figure imgf000011_0001
NHR8-Q2-Z or NHR8-Q7.
The coupling is generally carried out in an excess of said amine as an acid receptor, with a conventional coupling agent (e.g. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride or N, A/'-dicyciohexylcarbodiimide), optionally in the presence of a catalyst (e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7- azabenzotriazole), and optionally in the presence of a tertiary amine base (e.g. /V-methylmorpholine, triethylamine or diisopropylethylamine). The reaction may be undertaken in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at temperature comprised between 10°C and 40°C (room temperature) for a period of 1-24 hours.
Said amine is either commercially available or may be prepared by conventional methods well known to the one skilled in the art (e.g. reduction, oxidation, alkylation, transition metal-mediated coupling, protection, deprotection etc..) from commercially available material.
The acid of formula (2) may be prepared from the corresponding ester of formula (4):
Figure imgf000011_0002
wherein Ra is a suitable acid protecting group, preferably a (Cι-C4)alkyl group, which includes, but is not limited to, methyl and ethyl, according to any method well-known to the one skilled in the art to prepare an acid from an ester, without modifying the rest of the molecule. For example, the ester may be hydrolysed by treatment with aqueous acid or base (e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (e.g. water, 1 ,4-dioxan, tetrahydrofuran/water), at a temperature comprised between 20°C and 100°C, for a period of 1 to 40 hours.
The ester of formula (4) may be prepared by reaction of an amine of formula (5) :
Figure imgf000012_0001
wherein Ra and n are as previously defined, with a bromide of formula (6) :
Figure imgf000012_0002
In a typical procedure, the amine of formula (5) is reacted with a bromide of formula (6) optionally in the presence of a solvent or mixture of solvents (e.g. dimethylsulfoxide, toluene, N, Λ/-dimethylformamide, acetonitrile), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate) at a temperature comprised between 80°C and 120°C, for 12 to 48 hours.
The bromide of formula (6) may be prepared according method well known to the man skilled in the art.
The amine of formula (5), where R1 is Me and R2 is H, may be prepared as either the {R) or (S) enantiomer from the corresponding protected amine of formula (7) :
Figure imgf000012_0003
wherein Ra and n are as previously defined and Rb and Re represent any suitable substituents so that HNRbRc is a chiral amine (for example, Rb may be hydrogen and Re may be α-methylbenzyl), provided that the bonds between N and Rb and N and Re can be easily cleaved to give the free amine of formula (5) using standard methodology for cleaving nitrogen protecting groups, such as those found in the text book T.W. GREENE, Protective Groups in Organic Synthesis , A. Wiley-lnterscience Publication, 1981.
The amine of formula (7) may be prepared as a single diastereomer by reaction of an amine of formula HNRbRc with a ketone of formula (8):
Figure imgf000013_0001
wherein Ra, Rb, Re and n are as previously defined.
In a typical procedure, the reaction of the ketone of formula (8) with the amine of formula HNRbRc leads to a chiral intermediate which is in turn reduced by a suitable reducing agent (e.g. sodium cyanoborohydride of formula NaCNBH3 or sodium triacetoxyborohydride of formula Na(OAc)3BH) optionally in the presence of a drying agent (e.g. molecular sieves, magnesium sulfate) and optionally in the presence of an acid catalyst (e.g. acetic acid) to give the amine of formula (7) as a mixture of diastereomers. The reaction is generally done in a solvent such as tetrahydrofuran or dichloromethane at a temperature comprised between 20°C and 80°C for 3 to 72 hours. The resulting product is then converted to the hydrochloride salt and selectively crystallised from a suitable solvent or mixture of solvents (e.g. isopropanol, ethanol, methanol, diisopropyl ether or diisopropyl ether/methanol) to give (7) as a single diastereomer.
The ketone of formula (8) where n=1 may be prepared by palladium mediated coupling of an aryl halide of formula (9):
Figure imgf000013_0002
wherein Ra is as previously defined and Hal represents an halogen atom, which includes, but is not limited to bromo and iodo, with an enolate or enolate equivalent. In a typical procedure, the aryl halide of formula (9) is reacted with a tin enolate generated in-situ by treatment of isopropenyl acetate with tri-n-butyltin methoxide of formula Bu3SnOMe in the presence of a suitable palladium catalyst (palladium acetate/ tri-o/f jo-tolylphosphine of formula Pd(OAc)2/P(o- Tol)3) in a non-polar solvent (e.g. toluene, benzene, hexane). Preferably, the reaction is carried out at a temperature comprised between 80°C and 110°C for 6 to 16 hours.
The aryl halide of formula (9) may be obtained by esterification of the corresponding acid of formula (10):
Figure imgf000014_0001
wherein Hal is as previously defined, according to any method well-known to the one skilled in the art to prepare an ester from an acid, without modifying the rest of the molecule.
In a typical procedure, the acid of formula (10) is reacted with an alcoholic solvent of formula RaOH, wherein Ra is as previously defined, in the presence of an acid such as hydrogen chloride at a temperature between 10°C and 40°C (room temperature) for 8 to 16 hours.
The acid of formula (10) is a commercial product.
The amine of formula (5), where R1 and R2 are both C C4 alkyl, may be prepared according to the following scheme:
Figure imgf000014_0002
wherein R1, R2 and Ra are as previously defined.
In a typical procedure, the ester of formula (11 ) is reacted with an "activated" alkyl (organometallic alkyl such as R2MgBr, R2MgCI or R2Li) to give the corresponding tertiary alcohol of formula (12) using the method described above.
Said tertiary alcohol of formula (12) is then treated with an alkyl nitrile (e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g. sulphuric acid, acetic acid) to give a protected intermediate which is in turn cleaved using standard methodology for cleaving nitrogen protecting group such as those mentioned in textbooks. The resulting amino acid is then esterified using the method described herein to give the amine of formula (5).
Alternatively, the amine of formula (5), where R1 are R2 both C-ι-C4 alkyl and n=0, may be prepared according to the following scheme:
Scheme 2
Figure imgf000015_0001
(13) ' (14)
Figure imgf000015_0002
(15) (5) wherein R1, R2 and Ra are as previously defined.
In a typical procedure, the ester of formula (13) is reacted with an "activated" alkyl (organometallic alkyl such as R2MgBr, R2MgCI or R2Li) to give the corresponding tertiary alcohol of formula (14) using the method described above. Said tertiary alcohol of formula (14) is then treated with an alkyl nitrile
(e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g. sulphuric acid, acetic acid) to give a protected intermediate which is in turn cleaved using standard methodology for cleaving nitrogen protecting group such as those mentioned in textbooks to give the bromo amine (15).
The resulting bromo amine (15) is treated with a suitable palladium catalyst (e.g. [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)) under an atmosphere of carbon monoxide using RaOH as solvent (e.g. MeOH, EtOH) at elevated temperature (100°C) and pressure (100psi) to give the ester of formula (5).
The ketone of formula (8) where n=2 may be prepared by reduction of an alkene of formula (16) :
Figure imgf000016_0001
In a typical procedure, a solution of the olefin of formula (16) in a suitable solvent (e.g. methanol, ethanol, ethyl acetate) is treated with a palladium catalyst (e.g. 10% palladium on charcoal) and stirred under an atmosphere of hydrogen, optionally at elevated pressure (e.g. 60 psi), at temperature between room temperature and 60°C for 8-24 hours.
The alkene of formula (16) may be prepared by a palladium mediated coupling of an activated olefin with an aryl halide of formula (17):
H3C^ B_ Ha| <17)
O
In a typical procedure, the aryl halide (1 7) is coupled with a vinyl ester
(e.g. methyl acrylate) in the presence of a suitable palladium catalyst (e.g. tetrakis(triphenylphosphine)palladium(0) of formula Pd(PPh3)4, palladium acetate/tri-ort 70-tolylphosphine of formula Pd(OAc)2/P(o-tol)3 or (diphenylphosphino)ferrocenyl palladium chloride of formula dppfPdCI2) in a suitable solvent (e.g. acetonitrile, N, / -dimethylforma ide, toluene), optionally in the presence of a base such as triethylamine at a temperature between 40°C and 110°C for 8 to 24 hours.
The ketone of formula (17) is a commercial product.
Alternatively a compound of formula (1) may be prepared by reaction of a bromide of formula (6) and an amine of formula (18):
Figure imgf000017_0001
where R1, R2, Q1and n are as previously defined for the compounds of the formula (1 ) unless otherwise stated.
In a typical procedure, the amine of formula (18) is reacted with a bromide of formula (6) optionally in the presence of a solvent or mixture of solvents (e.g. dimethylsulfoxide, toluene, N, / -dimethylformamide, acetonitrile), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate) at a temperature comprised between 80°C and 120°C, for 12 to 48 hours.
The amide of formula (18) may be prepared by coupling an acid of formula (19) incorporating a suitable amine protecting group P1 :
Figure imgf000017_0002
with an amine of formula
Figure imgf000017_0003
Figure imgf000018_0001
Z or NHR8-Q7.
The coupling is generally carried out in an excess of said amine as an acid receptor, with a conventional coupling agent (e.g. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride or N, A/'-dicyclohexylcarbodiimide), optionally in the presence of a catalyst (e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7- azabenzotriazole), and optionally in the presence of a tertiary amine base (e.g.
Λ/-methylmorpholine, triethylamine or diisopropylethylamine). The reaction may be undertaken in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at temperature comprised between 10°C and 40°C (room temperature) for a period of 1-24 hours.
Said amine is either commercially available or may be prepared by conventional methods well known to the one skilled in the art (e.g. reduction, oxidation, alkylation, transition metal-mediated coupling, protection, deprotection etc..) from commercially available material.
The acid of formula (19) may be prepared from the corresponding ester of formula (5).
The acid of formula (19), where R1 and R2 are both Cι-C4 alkyϊ, may be prepared from the ester (5) incorporating a suitable amine protecting group P1 either before or after the acid formation:
Figure imgf000018_0002
wherein Ra is a suitable acid protecting group, preferably a (CrC4)alkyl group, which includes, but is not limited to, methyl and ethyl, according to any method well-known to the one skilled in the art to prepare an acid from an ester, without modifying the rest of the molecule. For example, the ester may be hydrolysed by treatment with aqueous acid or base (e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (e.g. water, 1 ,4-dioxan, tetrahydrofuran/water), at a temperature comprised between 20°C and 100°C, for a period of 1 to 40 hours.
The amine of formula (5), where R1 and R2 are both H, may be prepared according to the following scheme:
Scheme 3
Figure imgf000019_0001
(5) wherein R1, R2 and Ra are as previously defined.
In a typical procedure, the acid of formula (20) is preferentially reduced to the corresponding alcohol (21 ) in the presence of the ester. This may be performed by formation of the acyl imidazole or mixed anhydride and subsequent reduction with sodium borohydride or another suitable reducing agent.
Said primary alcohol of formula (21 ) is then converted into a leaving group such as mesylate, tosylate, bromide or iodide and displaced with appropriate amine nucleophile. The preferred nucleophile is azide ion which can then be reduced to the primary amine via hydrogenation or triphenylphosphine. Alternative nucleophiles could include ammonia or alkylamines such as benzylamine or allylamine and subsequent cleavage of the alkyl group to furnish the amine.
In a typical procedure, the amine of formula (6) is reacted with a bromide of formula (7)
Figure imgf000020_0001
(7) optionally in the presence of a solvent or mixture of solvents (e.g. dimethyl sulfoxide, toluene, N, / -dimethylformamide, acetonitrile, THF), optionally in the presence of a suitable base (e.g. triethylamine, N, /V-diisopropylethylamine, potassium carbonate) and optionally in the presence of a catalyst (e.g. potassium iodide) at a temperature comprised between 60°C and 120°C, for 6 to 120 hours. The intermediate amino ketone can then be reduced using sodium borohydride or diisobutylaluminiumhydride to furnish the required aminoalcohol.
For some of the steps of the here above described process of preparation of the compounds of formula (1), it may be necessary to protect potential reactive functions that are not wished to react, and to cleave said protecting groups in consequence. In such a case, any compatible protecting radical can be used. In particular methods of protection and deprotection such as those described by T.W. GREENE {Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981) or by P. J. Kocienski {Protecting groups, Georg Thieme Verlag, 1994), can be used.
An alternative agent for deprotection would be one equivalent of triethylamine trihydrofluoride in tetrahydrofuran or suitable solvent at room temperature for 12 hours.
All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the examples and preparations hereto. Also, the compounds of formula (1) as well as intermediate for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatograph y.
The sub-groups of compounds of formula (I) are preferred:
Figure imgf000021_0001
In a preferred embodiment of the invention, Q is a s ingle bond.
In a preferred embodiment of the invention, Z is selected from morpholinyl, pyrrolidinyl, piperidyl, piperazinyl or pyrazolyl, op-tionally susbstituted by a methyl group.
In a preferred embodiment of the invention, Z is selected from pyrazolyl optionally substituted by one or two C1-C4 alkyl group. In a preferred embodiment of the invention, Q1 is *-NR8-Q7.
In a preferred embodiment of the invention, Q is a group selected from,
Figure imgf000022_0001
Subgroup of compounds of formula (1 ) containing the following substituents are preferred:
Preferably, Q v 1 is a group *-NH-Q2-Z, wherein Z is C3-C10 cycloalkyl, said cycloalkyl being optionally bridged by one or more carbon atoms, preferably 1 2, 3 or 4 carbon atoms.
Preferably Q1 is a group *-NH-Q2-Z, wherein Z is cyclohexyl or adamantyl.
Preferably, Q1 is
Figure imgf000022_0002
wherein R3, R4. R5 and R6 are H.
Preferably, Q1 is a group *-NH-Q2-Z, wherein Z is a group
Figure imgf000022_0003
wherein R3, R4, R5, R6 and R7 are the same or different and are selected from H, d-d alkyl, OR9, SR9, SOR9, S02R9, CN, halo, CF3, OCF3, SO≥NR9R10, CONR9R10, NR9R10, NHCOR10 and phenyl provided at least 2 of R3 to R7 are equal to H; wherein R9 and R10 are the same or different and are selected from H or d-C4 alkyl.
More preferably, Q1 is a group *-NH-Q2-Z, wherein Z is a group
Figure imgf000023_0001
wherein R3, R4, R5, Rδ and R7 are the same or different and are selected from H, OH, CH3, OCH3, OCH2-CH3, SCH3, halo, CF3, provided at least 2 of R3 to R7 are equal to H.
Other preferred compounds of formula (1 ) are those wherein Q1 is a group *- NH-CH2-Z, wherein Z is a group
Figure imgf000023_0002
Preferred compounds of formula (1 ) are those wherein Q3 is (CH2)t whe rein t is 0 and Q4 is -S02NH- or C(=0)NH-.
Other preferred compounds of formula (1 ) are those wherein Q3 is (CH≥ t wherein t is 1 and Q4 is -NH-C(=0)- or -NH-C(=0)-NH-.
Preferably, Q5 is a bond, -CH2-, -(CH2)2-, -C(CH3)2-CH2-, -CH(CH3)-CH( H)- or CH2-CH(CH3)-.
Preferably Q6 is
Figure imgf000024_0001
wherein R11, R12, R13, R14 and R15 are selected from H, C C4 alkyl, phenyl, phenoxy OR16, SR16, halo, CF3, OCF3, COOR17, S02NR16R17, C0NR16R17, NHR1δR17, NHCOR17, CH2-NHC(=0)NH-R17; and at least two of R11 to R15 represent H.
More preferably Q6 is
Figure imgf000024_0002
wherein R , R , R , R and R1ϋ are selected from H, d-C4 alkyl, phenyl, phenoxy OR16, halo, CF3, OCF3; and at least two of R11 to R15 represent H.
In the above groups of compounds, the following substituents are particularly preferred:
Q2 is a bond, -CH2-, -(CH2)2-, -(CH2)3-, or -C(CH3)2-, preferably -CH2-. R1 is H or C1-C alkyl and R2 is Cι-C4 alkyl. More preferably, R1 is H or CH3 and R2 is CH3. n is O or l .
R1 is H and R2 is CH3 and n is 0 or 1. R1 is CH3, R2 is CH3 and n is 0 or .
The following compounds are preferred: 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-benzylacetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-cyclopropylacetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[(1 R,2S)-2-
(hydroxymethyl)cyclohexyl]acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(3-morpholin-4- ylpropyl)acetamide;
2-(3-{2-[((2R)-2-{3~[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyI}phenyl)-/V-(pyridin-2-ylmethyl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyI)amino]-2-methylpropyl}phenyl)-/V-(2-morpholin-4- ylethyl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-isopropylacetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(4-chlorobenzyl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[2-
(dimethylamino)ethyl]acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[2- (diethylamino)ethyl]acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[3- (dimethylamino)propyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-pentylacetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(2-pyrrolidin-1-ylethyl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(2,4-dichlorobenzyl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(3,4-dichlorobenzyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(4-methoxybenzyI)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(2-hydroxyethyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-propylacetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(3-methoxypropyl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-cyclobutylacetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[(1 R)-1-(1- naphthyl)ethyl]acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-2,3-dihydro-1 H-inden-1 - ylacetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[2-(1-methylpyrrolidin-2- yl)ethyl]acetamide 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(4-fluorobenzyl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(4-phenylbutyl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(3-methoxybenzyl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(3-ethoxypropyl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(3,4,5- trimethoxybenzyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[4-
(trifluoromethyl)benzyl]acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[2- (trifluoromethyl)benzyl]acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(3,5- dimethoxybenzyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(2-phenoxyethyl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[(1 S)-2-hydroxy-1- methylethyljacetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[(1 S)-1-(hydroxymethyl)-2- methylpropyljacetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[(1 S,2S)-1-(hydroxymethyl)-2- methylbutyl]acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[(1R)-1-benzyl-2- hydroxyethyl]acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[(1 R)-1 - (hydroxymethyl)propyl]acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-[(1 S)-1-(hydroxymethyl)-2,2- dimethylpropyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-[(1S)-2-cyclohexyl-1- (hydroxymethyl)ethyI]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[(1 S,2R)-2-hydroxy-2,3-dihydro- 1 H-inden-1 -yl]acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(2-propoxyethyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(4-hydroxycyclohexyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-(3-propoxypropyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-ethyI-Λ/-(2- hydroxyethyl)acetamide;
1-[(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)acetyl]piperidine-4-carboxamide; Λ/-(5-{(1 R)-2-[(2-{3-[2-(4-acetylpiperazin-1 -yl)-2-oxoethyl]phenyl}-1 ,1 - dimethylethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)urea; Λ/-(5-{(1 R)-2-[(2-{3-[2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]phenyl}-1 ,1- dimethylethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)urea; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-benzyl-/V-methylacetamide;
A/-[2-hydroxy-5-((1 R)-1 -hydroxy-2-{[2-(3-{2-[4-(2-hydroxyethyl)piperazin-1 -yl]-2- oxoethyI}phenyl)-1 ,1-dimethylethyl]amino}ethyl)phenyl]urea; Λ/-[5-((1 R)-2-{[2-(3-{2-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2- oxoethyl}phenyl)-1 ,1-dimethylethyl]amino}-1-hydroxyethyl)-2- hydroxyphenyljurea;
Λ/-(5-{(1R)-2-[(1 ,1-dimethyl-2-{3-[2-(4-methylpiperazin-1-yl)-2- oxoethyI]phenyl}ethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)urea; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methyipropyI}phenyl)-/V-methyl-/V-(2- phenylethyl)acetamide;
Λ/-(5-{(1 R)-2-[(1 ,1-dimethyl-2-{3-[2-oxo-2-(4-pyridin-2-ylpiperazin-1- yl)ethyl]phenyl}ethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)urea; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[3-(dimethylamino)propyl]-/V- methylacetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(2-hydroxyethyl)-/V- propylacetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[2-(diethylamino)ethyl]-/V- methylacetamide; Λ/-(5-{(1R)-2-[(1 ,1-dimethyl-2-{3-[2-(4-methyl-1 ,4-diazepan-1-yl)-2- oxoethyl]phenyl}ethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)urea;
Λ/-{5-[(1R)-2-({1 ,1-dimethyl-2-[3-(2-morpholin-4-yl-2- oxoethyl)phenyl]ethyl}amino)-1-hydroxyethyl]-2-hydroxyphenyl}urea;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyI)-Λ/-methyl-/V-[(1 S)-1 - phenylethyl]acetamide;
Λ/-{5-[(1 R)-2-({1 ,1-dimethyl-2-[3-(2-oxo-2-piperidin-1- ylethyl)phenyl]ethyl}amino)-1-hydroxyethyl]-2-hydroxyphenyl}urea;
Λ/-[2-hydroxy-5-((1 R)-1 -hydroxy-2-{[2-(3-{2-[(3R)-3-hydroxypyrrolidin-1 -yl]-2- oxoethyl}phenyl)-1 ,1-dimethylethyl]amino}ethyl)phenyl]urea;
A/-[2-hydroxy-5-((1 R)-1-hydroxy-2-{[2-(3-{2-[(3R)-3-hydroxypiperidin-1-yl]-2- oxoethyl}phenyl)-1 ,1-dimethylethyl]amino}ethyl)phenyl]urea;
Λ/-(5-{(1 R)-2-[(2-{3-[2-(4-acetyl-1 ,4-diazepan-1-yl)-2-oxoethyl]phenyl}-1 ,1- dimethylethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)urea; Λ/-[2-hydroxy-5-((1 R)-1 -hydroxy-2-{[2-(3-{2-[4-(hydroxymethyl)piperidin-1 -yl]-2- oxoethyl}phenyl)-1 ,1-dimethylethyl]amino}ethyl)phenyl]urea; /-{1-[(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)acetyl]pyrrolidin-3-yl}-/V- methylacetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyI)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(2-methoxyethyl)-/V- propylacetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-ethyl-/V-(2- methoxyethyl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[3-(dimethylamino)-2,2- dimethylpropyl]acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-[3-fluoro-5-
(trifluoromethyl)benzyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-f(1 S)-1-(hydroxymethyl)-3- methylbutyl]acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-[(1 S)-2-hydroxy-1 - phenylethyl]acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/,/V-diethylacetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-1H-pyrazol-5-ylacetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(5-methyl-1H-pyrazol-3- yl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)- V-(cyclohexylmethyl)acetamide; ethyl 4-[(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)acetyl]piperazine-1-carboxylate;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)- V-(5-chloropyridin-2-yl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)- V-(6-methylpyridin-2-yl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(3-methylpyridin-2-yl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydrdxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-isoquinolin-1-ylacetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(4,6-dimethylpyridin-2- yl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(2-methoxybenzyl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[(1 S)-1-benzyi-2- hydroxyethyl]acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(1-ethyl-1/-/-pyrazol-5- yl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(1 ,3-dimethyl-1 H-pyrazol-5- yl)acetamide;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(3-fluorobenzyl)acetamide;
1-[(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)acetyl]-L-prolinamide;
Λ/-(5-{(1 R)-2-[(2-{3-[2-(5-amino-3-fe f-butyl-1 H-pyrazol-1 -yl)-2-oxoethyl]phenyl}- 1 ,1-dimethylethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)urea;
2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[(1 S)-1-phenylethyl]acetamide, Λ/-(5-{(1 R)-2-[(2-{3-[2-(1 ,4-dioxa-8-azaspiro[4. 5]dec-8-yi)-2-oxoethyl]phenyl}- 1 ,1-dimethylethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)urea, Λ/-benzyl-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetamide;
Λ/-cyclopropyl-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- [(1R,2S)-2-(hydroxymethyl)cyclohexyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- (3-morpholin-4-ylpropyl)acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- (pyridin-2-ylmethyl)acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- (2-morpholin-4-ylethyl)acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-Λ/- isopropylacetamide;
Λ/-(4-chlorobenzyI)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetamide;
/V-[2-(dimethylamino)ethyl]-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide;
Λ/-[2-(diethylamino)ethyl]-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}- 2-methylpropyl)phenyl]acetamide; Λ/-[3-(dimethylamino)propyl]-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyI]-/V- pentylacetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyI)ethyl]amino}-2-methylpropyl)phenyl]-/V- (2-pyrrolidin-1 -ylethyl)acetamide;
Λ/-(2,4-dichlorobenzyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetamide;
Λ/-(3,4-dichlorobenzyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- (4-methoxybenzyl)acetamide;
Λ/-(2-hydroxyethyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyi]amino}-2- methylpropyl)phenyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- propylacetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- (3-methoxypropyl)acetamide; Λ/-cyclobutyl-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyI)phenyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- [(1R)-1-(1-naphthyl)ethyl]acetamide; Λ/-2,3-dihydro-1 H-inden-1 -yl-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]- V- [2-(1-methylpyrrolidin-2-yl)ethyl]acetamide;
Λ/-(4-fluorobenzyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- (4-phenylbutyl)acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- (3-methoxybenzyl)acetamide; Λ/-(3-ethoxypropyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- (3,4,5-trimethoxybenzyl)acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- [4-(trifluoromethyl)benzyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- [2-(trifluoromethyl)benzyl]acetamide;
Λ/-(3,5-dimethoxybenzyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}- 2-methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyipropyl)phenyl]-/V- (2-phenoxyethyl)acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- [(1 S)-2-hydroxy-1 -methylethyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- [(1 S)-1 -(hydroxymethyl)-2-methylpropyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- [(1 S,2S)-1 -(hydroxymethyl)-2-methylbutyl]acetamide; Λ/-[(1 R)-1 -benzyl-2-hydroxyethyl]-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyI]amino}-2-methylpropyl)phenyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V-
[(1 R)-1 -(hydroxymethyl)propyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V-
[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]acetamide;
Λ/-[(1 S)-2-cyclohexyl-1-(hydroxymethyl)ethyl]-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide;
Λ/-[(1 S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-Λ/-
(2-propoxyethyl)acetamide;
Λ/-(4-hydroxycyclohexyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-A/-
(3-propoxypropyl)acetamide;
Λ/-ethyl-Λ/-(2-hydroxyethyl)-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide;
1-{[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]arnino}-2- methylpropyl)phenyl]acetyl}piperidine-4-carboxamide;
4-{2-[(2-{3-[2-(4-acetylpiperazin-1-yl)-2-oxoethyl]phenyl}-1 ,1- dimethylethyl)amino]-1-hydroxyethyl}phenol;
4-{2-[(2-{3-[2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]phenyl}-1 ,1- dimethylethy1)amino]-1-hydroxyethyl}phenol; A/-benzyl-2-[3-(2-{t2-hydroxy-2-(4-hydroxyphenyI)ethyI]amino}-2- methylpropyl)phenyl]-/V-methylacetamide;
4-(1-hydroxy-2-{[2-(3-{2-[4-(2-hydroxyethyl)piperazin-1-yl]-2-oxoethyI}phenyI)-
1 ,1-dimethylethyl]amino}ethyl)phenol;
4-(4-chlorophenyl)-1-{[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetyl}piperidin-4-ol;
4-{2-[(1 ,1-dimethyl-2-{3-[2-(4-methyipiperazin-1-yl)-2- oxoethyl]phenyl}ethyl)amino]-1-hydroxyethyl}phenol; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)eth'yl]amino}-2-methylpropyl)phenyl]-/V- methyl-/V-(2-phenylethyl)acetamide;
4-{2-[(1 ,1-dimethyl-2-{3-[2-oxo-2-(4-pyridin-2-ylpiperazin-1- yl)ethyl]phenyl}ethyl)amino]-1-hydroxyethyl}phenol; Λ/-[3-(dimethylamino)propyl]-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V-methylacetamide;
Λ/-(2-hydroxyethyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]-/V-propylacetamide; -[2-(diethylamino)ethyl]-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}- 2-methylpropyl)phenyl]-Λ/-methylacetamide;
4-{2-[(1 ,1-dimethyl-2-{3-[2-(4-methyl-1 ,4-diazepan-1-yl)-2- oxoethyl]phenyl}ethyl)amino]-1-hydroxyethyl}phenol;
4-[2-({1 , 1 -dimethyl-2-[3-(2-morpholin-4-yl-2-oxoethyl)phenyl]ethyl}amino)-1 - hydroxyethyljphenol; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- methyl-/V-[(1 S)-1 -phenylethyl]acetamide;
4-[2-({1 ,1-dimethyl-2-[3-(2-oxo-2-piperidin-1-ylethyl)phenyI]ethyI}amino)-1- hydroxyethyl]phenol;
(3R)-1-{[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetyl}pyrrolidin-3-ol;
(3R)-1-{[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methyIpropyl)phenyl]acetyl}piperidin-3-ol;
4-{2-[(2-{3-[2-(4-acetyl-1 ,4-diazepan-1-yl)-2-oxoethyl]phenyl}-1 ,1- dimethylethyl)amino]-1-hydroxyethyl}phenol; 4-(1-hydroxy-2-{[2-(3-{2-[4-(hydroxymethyl)piperidin-1-yl]-2-oxoethyi}phenyl)- 1 , 1 -dimethylethyl]amino}ethyl)phenol;
Λ/-(1-{[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetyl}pyrrolidin-3-yl)-/V-methylacetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]- V- (2-methoxyethyl)-/V-propylacetamide;
/V-ethyl-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]-/V-(2-methoxyethyl)acetamide; A/-[3-(dimethylamino)-2,2-dimethylpropyl]-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide;
/V-[3-fluoro-5-(trifluoromethyl)benzyl]-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V-
[(1 S)-1 -(hydroxymethyl)-3-methylbutyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V-
[(1 S)-2-hydroxy-1 -phenylethyl]acetamide;
Λ/,W-diethyl-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V-
1 /-/-pyrazol-5-ylacetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyI)ethyl]amino}-2-methylpropyl)phenyl]-/V-
(5-methyl-1H-pyrazol-3-yl)acetamide; /V-(cyclohexylmethyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetamide; ethyl 4-{[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyI)phenyl]acetyl}piperazine-1-carboxylate;
Λ/-(5-chloropyridin-2-yl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V-
(6-methylpyridin-2-yl)acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V-
(3-methylpyridin-2-yl)acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V- isoquinolin-1 -ylacetamide;
Λ/-(4,6-dimethylpyridin-2-yl)-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methyIpropyl)phenyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyI]-/V- (2-methoxybenzyl)acetamide;
Λ/-[(1 S)-1 -benzyl-2-hydroxyethyl]-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide; Λ/-(1 -ethyl-1 H-pyrazol-5-yl)-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpro pyl)phenyl]acetamide;
Λ/-(1 ,3-dimethyl-1 H-pyrazol-5-yl)-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpro pyl)phenyl]acetamide; Λ/-(3-fluorobenzyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetamide;
1 -{[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl )ethyl]amino}-2- methylpropyl)phenyl]acetyl}-L-prolinamide;
/V-(3-ferf-butyl-1H-pyrazol-5-yl)-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpro pyl)phenyl]acetamide;
2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-N- [(1 S)-1 -phenylethyl]acetamide; and,
4-{2-[(2-{3-[2-(1 ,4-dioxa-8-azaspiro[4. 5]dec-8-yl)-2-oxoethyl]phenyl}-1 ,1 ■ dimethylethyl)amino]-1-hydroxyethyl}phenol.
The following compounds are particularly preferred:
5-{(2R)-2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsuIfonyl) amino]phenyl}ethyl)amino]propyl}-/V-[3- ιydroxy-5-(trifluoromethyl) benzyl]-1H- indoIe-2-carboxamide;
N-(3,4-Dichloro-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-ureido-phenyl)- ethylamino]-2-methyl-propyl}-phenyl)-acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino]-2-methyl-propyl}- phenyl)-N-(4-phenyl-butyl)-acetamide;
N-(4-Chloro-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-ureido-phenyl)- ethy!amino]-2-methyl-propyl}-phenyl)-acetamide; N-(2,4-Dichloro-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-ureido-phenyl)- ethylamino]-2-methyl-propyl}-phenyl)-acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino]-2-methyl-propyl}- phenyl)-N-(1 -naphthalen-1 -yl-ethyl)-acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino]-2-methyl-propyl}- phenyl)-N-(4-methoxy-benzyl)-acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino]-2-methyl-propyl}- phenyl)-N-(3,4,5-trimethoxy-benzyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino]-2-methyl-propyI}- phenyl)-N-(3,4,5-trimethoxy-benzyl)-acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino]-2-methyl-propyl}- phenyl)-N-(3-methoxy-benzyl)-acetamide; N-(4-Fluoro-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-ureido-phenyl)- ethylamino]-2-methyl-propyl}-phenyl)-acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino]-2-methyl-propyl}- phenyl)-N-(4-trifluoromethyl-benzyl)-acetamide;
N-(3,5-Dimethoxy-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-ureido-pheny!)" ethylamino]-2-methyl-propyl}-phenyl)-acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino]-2-methyl-propyl}- phenyl)-N-(2-trifluoromethyl-benzyl)-acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino]-2-methyl-propyl}- phenyl)-N-(2-hydroxy-indan-1-yl)-acetamide; (5-{2-[2-(3-{2-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1 -yl]-2-oxo-ethyl}- phenyl)-1 ,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-urea;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino]-2-methyl-propyl}- phenyl)-N-methyl-N-phenethyl-acetamide;
{5-[2-(2-{3-[2-(3,4-Dihydro-1 H-isoquinolin-2-yl)-2-oxo-ethyl]-phenyl}-1 ,1- dimethyl-ethylamino)-1-hydroxy-ethyl]-2-hydroxy-phenyl}-urea;
N-Benzyl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino]-2- methyl-propyl}-phenyl)-N-methyl-acetamide;
{5-[2-(1 ,1-Dimethyl-2-{3-[2-oxo-2-(4-pyridin-2-yl-piperazin-1-yl)-ethyi]-phenyl}- ethylamino)-1-hydroxy-ethyl]-2-hydroxy-phenyl}-urea; {2-Hydroxy-5-[1-hydroxy-2-(2-{3-[2-(4-hydroxymethyl-piperidin-1-yl)-2-oxo- ethyl]-phenyl}-1 ,1-dimethyl-ethylamino)-ethyl]-phenyl}-urea;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino]-2-methyl-propyl}- phenyl)-N-methyl-N-(1-phenyl-ethyl)-acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino]-2-methyl-propyl}- phenyl)-N-(2-hydroxy-1 -phenyl-ethyl)-acetamide;
N-(3-FIuoro-5-trifluoromethyl-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-ureido- phenyl)-ethylamino]-2-methyl-propyl}-phenyl)-acetamide; N-(4,6-Dimethyl-pyridin-2-yl)-2-(3-{2-[2-hydroxy-2-(4-hydrox^-3-ureido-phenyl)- ethylamino]-2-methyl-propyl}-phenyl)-acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino]-2-methyl-propyl}- phenyl)-N-(5-propyl-1 H-pyrazol-3-yl)-acetamide; N-(3-Fluoro-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-ureido-phenyl)- ethylamino]-2-methyl-propyl}-phenyl)-acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino]-2-methyl-propyl}- phenyl)-N-(2-methoxy-benzyl)-acetamide;
N-(5-tert-Butyl-2H-pyrazol-3-yl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-ureido- phenyl)-ethylamino]-2-methyl-propyl}-phenyl)-acetamide;
N-Benzyl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-methyl-propyl}- phenyl)acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-meth yl-propyl}-phenyl)-
1 -(4-pyridin-2-yl-piperazin-1 -yl)-ethanone; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-metrιyl-propyl}-phenyl)-
N-(1 -naphthalen-1 -yl-ethyl)-acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-metr yl-propyl}-phenyl)-
N-pyridin-2-ylmethyl-acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-methyl-propyl}-phenyl)- N-pyridin-2-ylmethyl-acetamide;
N-(4-Fluoro-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-phenyl>-ethylamino]-2- methyl-propyl}-phenyl)-acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-met yl-propyl}-phenyl)-
N-methyl-N-(1-phenyl-ethyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-met yl-propyi}-phenyl)-
N-(2-methoxy-benzyl)-acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-methyl-propyl}-phenyl)-
N-(3-methoxy-benzyl)-acetamide;
N-(4-Chloro-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-phenyl )-ethylamino]-2- methyl-propyl}-phenyI)-acetamide;
1-(3,4-Dihydro-1 H-isoquinolin-2-yl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-phenyl)- ethylamino]-2-methyl-propyl}-phenyl)-ethanone; N-(3-Fluoro-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2- methyl-propyl}-phenyl)-acetamide;
2-(3-{2-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-methyl-propyl}-phenyl)- N-methyl-N-phenethyl-acetamide; N-(5-tert-Butyl-2H-pyrazol-3-yl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-phenyl)- ethylamino]-2-methyl-propyl}-phenyl)-acetamide, and, 3-{2-[(2R)-2-(3-AcetyIamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2- methylpropyl}-/V-[2-(2-chlorophenyl)ethyl]-benzamide.
According to one aspect of the present invention, the compounds of formula (1) wherein the (CH2)n-C(=0)Q1 group is in the meta position are generally preferred.
Pharmaceutically acceptable salts of the compounds of formula (1) include the acid addition and base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, hydrogen phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methylsulphate, 2- napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen, phosphate/phosphate dihydrogen, pyroglutamate, saccharate, stearate, succinate, tannate, D- and L-tartrate, 1-hydroxy-2- naphthoate tosylate and xinafoate salts.
Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
Pharmaceutically acceptable salts of compounds of formula (1 ) may be prepared by one or more of three methods:
(i) by reacting the compound of formula (1 ) with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (1) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of formula (1) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.
Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non- stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non-ionised. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).
Hereinafter all references to compounds of formula (1 ) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
The compounds of the invention include compounds of formula (1 ) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula
(1 ).
As indicated, so-called 'pro-drugs' of the compounds of formula (1) are also within the scope of the invention. Thus certain derivatives of compounds of formula (1) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (1 ) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E. B Roche, American Pharmaceutical Association).
Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (1 ) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).
Some examples of prodrugs in accordance with the invention include: (i) where the compound of formula (1) contains a carboxylic acid functionality (-COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (1 ) is replaced by (Cι-Cs)alkyl; (ii) where the compound of formula (1) contains an alcohol functionality (- OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of formula (1 ) is replaced by (Cι-C6)alkanoyloxymethyl; and (iii) where the compound of formula (1 ) contains a primary or secondary amino functionality (-NH2 or -NHR where R ≠ ), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula (1 ) is/are replaced by (Cι-Cιo)alkanoyl.
Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.
Moreover, certain compounds of formula (1) may themselves act as prodrugs of other compounds of formula (1 ).
Also included within the scope of the invention are metabolites of compounds of formula (1), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include (i) where the compound of formula (1) contains a methyl group, an hydroxymethyi derivative thereof (-CH3 -» -CH2OH):
-(ii) where the compound of formula (1) contains an alkoxy group, an hydroxy derivative thereof (-OR -» -OH); (iii) where the compound of formula (1) contains a tertiary amino group, a secondary amino derivative thereof (-NR1R2 -» -NHR1 or -NHR2); _(iv) where the compound of formula (1) contains a secondary amino group, a primary derivative thereof (-NHR1 - -NH2); (v) where the compound of formula (1 ) contains a phenyl moiety, a phenol derivative thereof (-Ph -» -PhOH); and (vi) where the compound of formula (1 ) contains an amide group, a carboxylic acid derivative thereof (-CONH2 → COOH).
Compounds of formula (1 ) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (1) contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (1) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (1 ), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, -lactate or /-lysine, or racemic, for example, c//-tartrate or c//-arginine.
Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (1 ) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel (Wiley, New York, 1994).
According to one aspect of the present invention, the (R,R)-stereoisomer of the formula below, wherein R1 is hydrogen and R2 is d-d alkyl, preferably methyl, and A, B, n and Q1 are as defined above, is generally preferred:
Figure imgf000045_0001
The present invention includes all pharmaceutically acceptable isotopically- labelled compounds of formula (1) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 4C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulphur, such as 35S.
Certain isotopically-labelled compounds of formula (1 ), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labeled compounds of formula (1 ) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D20, de-acetone, d6-DMSO.
The compounds of formula (1 ), their pharmaceutically acceptable salts and/or derived forms, are valuable pharmaceutically active compounds, which are suitable for the therapy and prophylaxis of numerous disorders in which the β2 receptor is involved or in which agonism of this receptor may induce benefit, in particular the allergic and non-allergic airways diseases but also in the treatment of other diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.
Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "exeipient" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of exeipient will to a large extent depend on factors such as the particular mode of administration, the effect of the exeipient on solubility and stability, and the nature of the dosage form.
Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995).
The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.
Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
The compounds of the invention may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).
For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, eroscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyi cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight %» of the dosage form.
Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylceilulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % iubricant.
Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
Consumable oral films for human or veterinary use are typically pliable water- soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (1), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.
The compound of formula (1 ) may be water-soluble or insoluble. A water- soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes. Alternatively, the compound of formula (1 ) may be in the form of multiparticulate beads.
The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydroeolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.
Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming. Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298.
The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intraeranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of compounds of formula (1) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug- coated stents and poly(cf/-lactic-coglycolic)acid (PGLA) nicrospheres.
The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free {e.g. Powderject™, Bioject™, etc.) injection.
Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
Capsules (made, for example, from gelatin or hy roxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1μg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1μl to 100 /I. A typical formulation may comprise a compound of formula (1 ), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff containing from 0.001 mg to 10mg of the compound of formula (1 ). The overall daily dose will typically be in the range 0.001 mg to 40mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
The compounds of formula (1) are particularly suitable for an administration by inhalation.
The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable {e.g. absorbable gel sponges, collagen) and non-biodegradable {e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyalu ronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.
Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148. Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (1 ) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
The kit of the invention is particularly suitable for administering different dosage forms, for example parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.
For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 0.001 mg to 5000mg depending, of course, on the mode of administration. For example, an intravenous daily dose may only require from 0.001 mg to 40mg. The total daily dose may be administered in single or divided doses_and may, at the physician's discretion, fall outside of the typical range given herein.
These dosages are based on an average human subject having a weight of about 65kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly. For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.
According to another embodiment of the present invention, the compounds of the formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, can also be used as a combination with one or more additional therapeutic agents to be co-administered to a patient to obtain some particularly desired therapeutic end result such as the treatment of pathophysiologically-relevant disease processes including, but not limited to (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) signs and symptoms such as breathlessness, cough. The second and more additional therapeutic agents may also be a compound of the formula (1), or a pharmaceutically acceptable salt, derived forms or compositions thereof, or one or more β2 agonists known in the art. More typically, the second and more therapeutic agents will be selected from a different class of therapeutic agents.
As used herein, the terms "co-administration", "co-administered" and "in combination with", referring to the compounds of formula (1) and one or more other therapeutic agents, is intended to mean, and does refer to and include the following:
• simultaneous administration of such combination of compound(s) of formula (1 ) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components at substantially the same time to said patient,
• substantially simultaneous administration of such combination of compound(s) of formula (1 ) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at substantially the same time by said patient, whereupon said components are released at substantially the same time to said patient, • sequential administration of such combination compound(s) of formula (1 ) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at consecutive times by said patient with a significant time interval between each administration, whereupon said components are released at substantially different times to said patient; and
• sequential administration of such combination of compound(s) of formula (1 ) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components in a controlled manner whereupon they are concurrently, consecutively, and/or overlapingly administered at the same and/or different times by said patient,
where each part may be administered by either the same or different route.
Suitable examples of other therapeutic agents which may be used in combination with the compound(s) of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, include, but are by no means limited to :
(a) 5-Lipdxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists,
(b) Leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4, LTD4> and LTE4,
(c) Histamine receptor antagonists including HI and H3 antagonists,
(d) α and α2-adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use,
(e) muscarinic M3 receptor antagonists or anticholinergic agents,
(f) PDE inhibitors, e.g. PDE3, PDE4 and PDE5 inhibitors,
(g) Theophylline,
(h) Sodium cromoglycate, (i) COX inhibitors both non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs),
(j) Oral and inhaled glucocorticosteroids, such as DAGR (dissociated agonists of the corticoid receptor), (k) Monoclonal antibodies active against endogenous inflammatory entities,
(I) Anti-tumor necrosis factor (anti-TNF-α) agents,
(m)Adhesion molecule inhibitors including VLA-4 antagonists,
(n) Kinin-B.1 - and B2 -receptor antagonists,
(o) Immunosuppressive agents, (p) Inhibitors of matrix metalloproteases (MMPs),
(q) Tachykinin NK-i, NK2 and NK3 receptor antagonists,
(r) Elastase inhibitors,
(s) Adenosine A2a receptor agonists,
(t) Inhibitors of urokinase, (u) Compounds that act on dopamine receptors, e.g. D2 agonists,
(v) Modulators of the NFi β pathway, e.g. IKK inhibitors,
(w) modulators of cytokine signalling pathyways such as p38 MAP kinase, syk kinase or JAK kinase inhibitor,
(x) Agents that can be classed as mucolytics or anti-tussive, (y) Antibiotics,
(z) HDAC inhibitors, and,
(aa) PI3 kinase inhibitors.
According to the present invention, combination of the compounds of formula (1 ) with :
- H3 antagonists,
- Muscarinic M3 receptor antagonists,
- PDE4 inhibitors,
- glucocorticosteroids, - Adenosine A2a receptor agonists,
- Modulators of cytokine signalling pathyways such as p38 MAP kinase or syk kinase, or, - Leukotriene antagonists (LTRAs) including antagonists of LTB , LTd, LTD , and LTE4, are preferred.
According to the present invention, combination of the compounds of formula (1 ) with :
- glucocorticosteroids, in particular inhaled glucocorticosteroids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, and mometasone furoate, or
- muscarinic M3 receptor antagonists or anticholinergic agents including in particular ipratropium salts, namely bromide, tiotropium salts, namely bromide, oxitropium salts, namely bromide, perenzepine, and telenzepine, are further preferred.
It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment. The description, which follows, concerns the therapeutic applications to which the compounds of formula (1 ) may be put.
The compounds of formula (1 ) have the ability to interact with the β2 receptor and thereby have a wide range of therapeutic applications, as described further below, because of the essential role which the β2 receptor plays in the physiology of all mammals.
Therefore, a further aspect of the present invention relates to the compounds of formula (1 ), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders, and conditions in which the β2 receptor is involved. More specifically, the present invention also concerns the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders, and conditions selected from tine group consisting of :
• asthma of whatever type, etiology, or pathogenesis, in particular asthma that is a member selected from the group consisting of atopio asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE- mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, wheezy infant syndrome and bronchiolytis,
• chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, and emphysema,
• obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis, in particular an obstructive or inflammatory airways disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary diseases (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airways hyper- reactivity consequent to other drug therapy and airways disea se that is associated with pulmonary hypertension,
• bronchitis of whatever type, etiology, or pathogenesis, in particular bronchitis that is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphyloco ecus or streptococcal bronchitis and vesicular bronchitis,
• acute lung injury, • bronchiectasis of whatever type, etiology, or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.
A still further aspect of the present invention also relates to the use of the compounds of formula (1 ), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug having a β2 agonist activity. In particular, the present inventions concerns the use of the compounds of formula (1 ), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug for the treatment of β2- mediated diseases and/or conditions, in particular the diseases and/or conditions listed above.
As a consequence, the present invention provides a particularly interesting method to treat a mammal, including a human being, with an effective amount of a compound of formula (1), or a pharmaceutically acceptable salt, derived form or composition thereof. More precisely, the present invention provides a particularly interesting method for the treatment of a β2-mediated diseases and/or conditions in a mammal, including a human being, in particular the diseases and/or conditions listed above, comprising admidministering said mammal with an effective amount of a compound of formula (1 ), its pharmaceutically acceptable salts and/or derived forms.
The following example illustrate the preparation of the indole derivatives of the formula (1) :
Preparation 1 : 5-{(2R)-2-[((2R)-2-{[fert-Butyl(dimethyl)silyl]oxy}-2-{4- hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}-Λf-[3- hydroxy-5«(trifluoromethyl)benzyl]-1H-indole-2-carboxamide
A solution of 5-{(2R)-2-[((2R)-2-{[tert-Butyl(dimethyl)silyljoxy}-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}-1 H-indole-2-carboxylic acid (Preparation 2, 0.27g, 0.48mmol), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (109mg, 0.57mmol), hydroxybenzotriazole (71 mg, 0.53mmol) in N, /V-dimethylformamide (5ml) was treated with N,N diethylisopropylamine (0.42ml, 0.24mmol) and 3-(aminomethyl)-5- (trifluoromethyl)phenol (Preparation 11 , 79mg, 0.58 mmol) and the resulting suspension left to stir at room temperature under a nitrogen atmosphere for 18 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (20 ml) and saturated aqueous sodium chloride (20 ml). The organic phase was separated, dried (sodium sulphate) and the solvent removed in vacuo. Partial purification by flash column chromatography on silica gel eluting with dichloromethane:methanol: 0.88 ammonia (98:2:0 changing to 93:7:1 , by volume) gave the title compound contaminated with inseparable material (360mg). The material was used without further purification.
Preparation 2 : 5-{(2R)-2-[((2R)-2-{[fert-Butyl(dimethyl)silyl]oxy}-2-{4- hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}-1H-indole-2- carboxylic acid
A solution of methyl 5-{(2R)-2-[((2R)-2-{[te/t-butyl(dimethyl)silyl]oxy}-2-{4- hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}-1 H-indole-2- carboxylate (Preparation 3, 0.74g, 1.28mmol) in tetrahydrofuran (15ml) was treated with 1M aqueous lithium hydroxide (2.6ml 2.6mmol) and the reaction mixture stirred at room temperature fro 48 hours. The reaction was neutraisied by addition of hydrochloric acid (2.6ml of 1 M solution) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : 0.88 ammonia (90:10:1 changing to 80:20:3, by volume) to give the title compound as a yellow foam (0.27g). 1H NMR (400MHz, CD3OD): δ = 7.42-7.37 (3H, m), 7.05-7.02 (1 H, m), 6.98- 6.94 (2H, m), 6.84 (1 H, d), 4.95-4.90 (1 H, m), 3.54-2.89 (8H, m), 1.30 (3H, d), 0.79 (9H, s), 0.01 (3H, s), -0.16 (s, 3H) ppm. LRMS (electrospray) : m/z [M+H]+ 562 Preparation 3 : Methyl 5-{(2/?)-2-[((2R)-2-{[fert-butyl(dimethyl)silyl]oxy}-2-
{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amϊno]propyl}-1H- indole-2-carboxylate
A solution of methyl 5-{(2R)-2-[((2R)-2-{4-(benzyloxy)-3- [(methylsulfonyl)amino]phenyl}-2-{[te/t-butyI(dimethyl)silyl]oxy}ethyl) amino]propyl}-1H-indole-2-carboxylate (Preparation 4, 0.90g, 1.35mmol) in ethanol (10 ml) was treated with ammonium formate (0.42g, 6.7 mmol) and palladium hydroxide on carbon (0.2g, 20% b/w palladium). The resulting suspension was purged with nitrogen and then heated to reflux for an hour. The reaction mixture was cooled to room temperature and filtered through arbocel to remove catalyst residues. The filtrate was reduced in vacuo and the residue was partitioned between sat. aq. sodium chloride (20 ml) and dichloromethane (20 ml). The organic phase was separated and the aqueous extracted with more dichloromethane (20 ml). The combined organic extracts were dried (sodium sulphate) and the solvent removed in vacuo to give the title compound as a colourless oil (0.74 g).
1H NMR (400MHz, CD3OD): δ = 7.39-7.35 (2H, m), 7.29 (1 H, m), 7.11 (1 H, s), 7.09-7.06 (1 H, m), 6.92-6.90 (1 H, m), 6.74 (1 H, d), 4.71-4.68 (1 H, m), 3.93 (3H, s), 3.01-2.85 (5H, m), 2.74-2.64 (3H, m), 1.12 (3H, d), 0.72 (9H, s), -0.07 (s, 3H), -0.23 (s, 3H) ppm.
LRMS (electrospray) : m/z [M+H]+ 576
Preparation 4 : Methyl 5-{(2R)-2-[((2R)-2-{4-(benzyloxy)-3-
[(methylsulfonyl)amino]phenyl}-2-{[fert-butyl(dimethyl)silyl]oxy}ethyl) amino]propyi}-1 H-indole-2 -carboxylate
A solution of methyl 5-[(2R)-2-aminopropyl]-1H-indole-2-carboxylate (Preparation 5, 1.12g, 4.8mmol) and N-[2-(benzyloxy)-5-((1 S)-2-bromo-{[/erf- butyl(dimethyl)silyl]oxy}ethyl)-phenyl]methanesulphonamide (WO 02/06258, pg. 36, example 14a) (0.80g, 1.6mmol) in dimethylsufoxide (2ml) was heated at 105°C for 3h. The reaction mixture was cooled to room temperature and partitioned between sat. aq. sodium chloride (50ml) and ethyl acetate (50ml). The organic phase was separated and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : 0.88 ammonia (98:2:0 changing to 95:5:0.5, by volume) to give the title compound as a yellow foam (0.90g). 1H NMR (400MHz, CD3OD): δ = 7.48-7.32 (8H, m), 7.12 (1H, s), 7.07 (1H, d), 6.92 (1 H, d), 5.07 (2H, s), 4.71-4.68 (1 H, m), 3.85 (3H, s), 2.96-2.90 (2H, m), 2.80-2.74 (4H, m), 2.67-2.58 (2H, m), 1.12 (3H, d), 0.74 (9H, s), -0.06 (3H, s), - 0.22 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]+ 666, [M-H] " 664.
Preparation 5 : Methyl 5-[(2R)-2-aminopropyl]-1H-indole-2 -carboxylate
A solution of methyl 5-((2R)-2-{[(1R)-1-phenylethyl]amino}propyl)-1H-indole-2- carboxylate (Preparation 6, 9.34 g, 25.0 mmol) in ethanol (125 ml) was treated with ammonium formate (7.90 g, 125 mmol) and palladium hydroxide on carbon (2.81 g, 20% b/w palladium). The resulting suspension was purged with nitrogen and then heated to reflux for an hour. The reaction mixture was cooled to room temperature and filtered through arbocel to remove catalyst residues. The filtrate was reduced in vacuo and the residue was partitioned between 0.88 ammonia (100 ml) and dichloromethane (100 ml). The organic phase was separated and the aqueous extracted with more dichloromethane (100 ml). The combined organic extracts were dried (sodium sulphate) and the solvent removed in vacuo to give the title compound as a colourless oil (6.25 g, trace solvent remaining by 1H NMR).
1H NMR (400MHz, CD3OD): δ = 7.44 (1 H, bs), 7.36 (1 H, d), 7.13 (1 H, d), 7.11 (1H, s), 3.90 (3H, s), 3.17-3.07 (1H, m), 2.77-2.61 (2H, m), 1.10 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]+ 233, [M+Na]+ 255.
Optical Rotation [α]D 25 = -22.58° 6.76mg/ml MeOH 589nm
Preparation 6 : Methyl 5-((2R)-2-{[(1R)-1-phenylethyl]amino}propyl)-1tf- indole-2 -carboxylate A solution of 1 -ferf-butyl 2-methyl 5-((2R)-2-{[(1 R)-1-phenylethyl]amino}propyl)- 1H-indole-1 ,2-dicarboxylate (Preparation 7, 20.48 g, 46.9 mmol) was treated with 4M hydrogen chloride in methanol and the resulting solution left to stir at room temperature for 16 hours and then heated at 50°C for a further 2 hours. The solvent was removed in vacuo to give a solid which was crystallised from a mixture of methanol (125 ml) and diisopropylether (50 ml) to give the title compound as a colourless crystalline solid (9.34 g, d.e.>98% as determined by 1H NMR).
1H NMR (400MHz, CD3OD): δ = 7.53-7.49 (5H, m), 7.40-7.38 (2H, m), 7.10, 1 H. bs), 6.97 (1 H, bd), 4.61 (1 H, q), 3.91 (3H, s), 3.42-3.37 (1 H, m), 3.26-3.19 (1 H, m), 2.72-2.66 (1 H, m), 1.69 (3H, d), 1.19 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]+ 337.
Preparation 7 : 1 -terf-butyl 2-methyl 5-((2R)-2-{[(1 R)-1 -phenylethyl] amino}propyl)-1 H-indole-1 ,2-dicarboxylate
A solution of 1-terf-butyl 2-methyl 5-(2-oxopropyl)-1H-indole-1 ,2-dicarboxylate (18.0 g, 54.32 mmol), (R)-α-methyl benzylamine (Preparation 8, 6.4 ml, 49.65 mmol), sodium triacetoxyborohydride (15.80 g, 74.55 mmol) and acetic acid (3.0 ml, 52.38 mmol) in dichloromethane (500 ml) was stirred at room temperature for 16 hours. The reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (200 ml) and allowed to stir until effervescence ceased. The organic phase was separated and the aqueous phase extracted with further dichloromethane (100 ml). The combined organic extracts were dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : 0.88 ammonia (99:1 :0.1 changing to 98:2:0.2, by volume) to give a 4:1 mixture of diastereomers {R,R major) as a pale yellow oil (20.48 g).
1H NMR (400MHz, CD3OD): δ = 7.97-7.92 (1 H, m), 7.41-7.02 (8H, m), 4.04- 3.99 (1 H, m), 3.96-3.94 (3H, m), 3.15-3.10 (1H, m), 2.80-2.70 (1H, m), 2.53- 2.48 (1 H, m), 1.66 (9H, s), 1.39-1.31 (3H, 2d), 1.10-0.95 (3H, 2d) ppm. LRMS (electrospray) : m/z [M+H]+ 437.
Preparation 8 : 1-terf-butyl 2-methyl 5-(2-oxopropyl)-1H-indole-1 ,2- dicarboxylate A solution of 1-terf-butyl 2-methyl 5-bromo-1H-indole-1 ,2-dicarboxylate (Preparation 9, 12.5 g, max 32.04 mmol), tributyltin methoxide (11.0 ml, 38.2 mmol), isoprenylacetate (5.3 ml, 48.1 mmol), palladium acetate (0.36 g, 5 mol%), tri-o-tolylphosphine (0.97 g, 10 mol%) in toluene (40 ml) was degassed and then heated at 100°C for 8 hours. The reaction mixture was diluted with ethyl acetate (50 ml), 4M potassium fluoride (aqueous, 100 ml) and left to stir at room temperature overnight. The resulting mixture was filtered through arbocel washing the precipitate thoroughly with ethyl acetate (100 ml) and the organic phase of the filtrate separated, dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (95:5 changing to 90:10, by volume) to give the title compound (8.2 g) as a yellow oil. 1H NMR (400MHz, CDCI3): δ = 8.05 (1 H, d), 7.44 (1 H, s), 7.25 (1 H, d), 7.05 (1H, s), 3.92 (3H, s), 3.78 (2H, s), 2.16 (3H, s), 1.61 (9H, s) ppm. LRMS (electrospray) : m/z [M-H]' 330, [M+Na]+ 354.
Preparation 9 : 1-ferf-butyl 2-methyl 5-bromo-1f/-indole-1 , 2-dicarboxylate
A solution of methyl 5-bromo-1H-indole-2-carboxylate (Preparation 10, 8.14 g, 32.04 mmol) in tetrahydrofuran (300 ml) was added to sodium hydride (1.35 g of a 40% dispersion in mineral oil, 33.7 mmol) at 0°C under nitrogen. The resulting mixture was left to stir until effervescence ceased (50 minutes). A solution of di-terf-butyldicarbonate in further tetrahydrofuran (30 ml) was added to the reaction and the resulting mixture stirred vigorously, warming gradually to room temperature overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (200 ml) and water (200 ml). The organic phase was separated and the aqueous extracted with more ethyl acetate (2-fold 200 ml). The combined organics were dried (magnesium sulphate) and the solvent removed in vacuo to give the title compound as a pale yellow oil (12.5 g - trace solvent remaining). 1H NMR (400MHz, CDCI3): δ = 7.98 (1 H, d), 7.74 (1 H, s), 7.50 (1 H, dd), 7.00 (1 H, s), 3.92 (3H, s), 1.61 (9H, s) ppm. LRMS (electrospray) : m/z [M+Hj+ 352 / 354, [M+Na]+ 376 / 378. Preparation 10 : Methyl 5-bromo-1H-indole-2 -carboxylate
A solution of 5-Bromp-1H-indole-2-carboxylic acid (commercial, 10.0 g, 41.6 mmol) in methanol (200 ml) was cooled to 0°C and saturated with HCI(g). The resulting solution was allowed to warm gradually to room temperature overnight. The solvent was removed in vacuo and the residue treated with 0.88 ammonia (500 ml). The resulting solution was extracted with dichloromethane (3-fold 150 ml) and the combined organics dried (magnesium sulphate) and the solvent removed in vacuo to give the required product as a colourless oil (8.35 g).
1H NMR (400MHz, CDCI3): δ = 8.96 (1 H, bs), 7.83 (1 H, s), 7.40 (1 H, d), 7.30 (1 H, d), 7.14 (1 H, s), 3.95 (3H, s) ppm. LRMS (electrospray) : m/z [M-H]" 252 / 254.
Preparation 11 : 3-(aminomethyl)-5-(trifluoromethyl)phenol
A solution of 3-hydroxy-5-(trifluoromethyl)benzamide (Preparation 12, 0.67g, 3.29mmol) in tetrahydrofuran (10ml) was cooled to 0°C and treated with borane.tetrahydrofuran complex (9.9ml of a 1 M solution in tetrahydrofuran, 9.9mmol). The resulting solution was allowed to warm to room temperature aover 20 minutes and then heated to relux for 16 hours. The reaction mixture was cooled to 0°C and quenched by addition of methanol (until effervescence ceased). The resulting solution was allowed to warm to room temperature over 2 hours and then the solvent was removed in vacuo. The residue was dissolved in dichloromethane (40ml) and washed with water (10ml x 2), sat. aq. sodium chloride (10ml), dried (sodium sulfate) and reduced in vacuo to give a colourless oil. Purification by column chromatography on silica gel eluting with dichloromethane:methanol (98:2 changing to 95:5) gave the title compound as a pale yellow oil. 1HNMR (400MHz, CD3OD) δ : 3.81 (s, 2H), 6.91 (s, 1 H), 6.98 (s, 1H), 7.09 (s, 1 H) ppm.
MS (electrospray) m/z 192 [M+H]+ Preparation 12 : 3-Hydroxy-5-(trifluoromethyl)benzamide
A solution of 3-hydroxy-5-(trifluoromethyl)benzoic acid {JACS, 1954, 76, 1051 , 2.26g, 9.99mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.11g, 10.98mmol), 1-hydroxybenzotriazole (1.48g, 10.98mmol) and ammonium carbonate (4.80g, 49.95mmol) in Λ/, -dimethylformamide (70ml) was left to stir at room temperature under a nitrogen atmosphere for 3 days. The solvent was removed in vacuo and the residue partitioned between saturated aqueous sodium hydrogen carbonate (50ml) and ethyl acetate (6 x 50ml). The combined organic extracts were washed with water (25ml), saturated aqueous sodium chloride (25ml), dried (sodium sulfate) and the solvent removed in vacuo. The solid was absorbed onto silica gel and purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.880 ammonia (95:5:0.5 changing to 90:10:1) to give the title compound as a pale yellow solid (1.1g). 1HNMR (400MHz, CD3OD) δ : 7.18 (t, 1 H), 7.50 (t, 1 H), 7.60-7.61 (m, 1 H) ppm. MS (electrospray) m/z 204 [M-H]"
Preparation 13
Diethyl 2,2"-(1 ,3-phenylene)diacetate 2,2'-(1 ,3-Phenylene)diacetic acid (10.0g, 51 mmol) was dissolved in ethanol (lOOmL) and the solution treated dropwise with catalytic acetyl chloride (2.5mL). The reaction mixture was stirred at reflux for 18 hours before being allowed to cool and concentrated under reduced pressure. The residue was taken up in ethyl acetate (100mL) and washed with sodium bicarbonate solution (3x50mL) and brine (3x50mL). The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was triturated with pentane to yield the title product, 1 1.8g. 1HNMR (CDCI3, 400MHz) δ: 1.31 (t, 6H), 3.65 (s, 4H), 4.20 (q, 4H), 7.24-7.36 (m, 4H). LRMS : m/z ES+ 251 [MH]+
Preparation 14 [3-(2-Ethoxy-2-oxoethyl)phenyl]acetic acid
A solution of the diester from preparation 13 (44.3g, 177mmol) and 2,2'-(1 ,3- phenylene)diacetic acid (59.2g, 308mmol) in ethanol (24mL) and dioxan (290mL) was treated dropwise with 12M hydrochloric acid (4.9mL, 58.8mmol). The reaction mixture was stirred at reflux for 18 hours before being allowed to cool and concentrated to low volume. The reaction mixture was diluted with toluene (125mL) and the resulting slurry filtered. The filtrate was concentrated under reduced pressure and the residue taken up in water and neutralised with sodium bicarbonate. The mixture was diluted with ethyl acetate (200mL) and the organic layer was separated and washed with sodium bicarbonate solution (5x30mL) and brine (50mL). The combined aqueous extracts were acidified to pH 3 with 6M hydrochloric acid and extracted with ether (3x30mL). The organics were combined, dried over magnesium sulphate and concentrated under reduced pressure. The residue was triturated with pentane giving the title compound as a colourless solid 10.8g.
1Hnmr (CD3OD, 400MHz) δ: 1.25 (t, 3H), 3.60 (m, 2H), 3.63 (m, 2H), 4.15 (q, 2H), 7.18-7.32 (m, 4H) LRMS : m/z ES" 245 [MNaj+
Preparation 15
[3-(2-Hydroxy-2-methyl-propyl)-phenyl]-acetic acid
A solution of the acid of preparation 14 (6.85g, 32mmol) in diethyl-ether (100mL) under an atmosphere of N2, was cooled to 0°C and treated with a 3M solution of methylmagnesium bromide in ether (23.5mL, 70.0mmol). The reaction mixture was allowed to warm gradually to room temperature. After 2 hours the reaction was quenched by addition of saturated aqueous ammonium chloride solution (200mL). The organic phase was separated and washed with brine (100mL), dried (MgSO4) and concentrated under reduced pressure. Purification by column chromatography on silica gel eluting with pentane:dichloromethane (60:40 to 0:100) gave the title compound as a colourless oil, 6.23g. 1H nmr (CDCI3, 400MHz) δ: 1.22 (s, 6H), 2.75 (s, 2H), 3.63 (s, 2H), 7.12-7.30
(m, 4H).
LRMS : m/z ES+ 209 [MH]+
Preparation 16
{3-[2-(2-Chloro-acetylamino)-2-methyl-propyl]-phenyl}-acetic acid
2-Chloroacetonitrile (8.8mL, 140mmol) was added to a solution of the alcohol from preparation 15 (16.0g, 70mmol), in acetic acid (33mL). The resulting solution was cooled to 0°C, treated with concentrated sulphuric acid (33mL), and the reaction mixture allowed to warm gradually to room temperature. After 4 hours the reaction mixture was poured onto ice and basified with solid sodium carbonate. The solution was extracted with ethyl acetate (2x500mL) and the combined organic extracts dried over magnesium sulphate and concentrated under reduced pressure to give the title product as a colourless solid, 19.0g. 1H nmr (CDCI3, 400MHz) δ : 1.36 (s, 6H), 3.02 (s, 2H), 3.62 (s, 2H), 3.95 (s, 2H), 6.19 (br s, 1 H), 7.06-7.31 (m, 4H) LRMS : m/z ES- 282, 284 [M- p
Preparation 17 Methyl [3-(2-amino-2-methylpropyl)phenyl]acetate
A solution of the amide from preparation 16 (5.1g, 18mmoi), thiourea (1.6g,
21 mmol) and acetic acid (18mL) in methanol (80mL) was heated to reflux under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure and the residue dissolved in methanol (150mL). The solution was saturated with hydrogen chloride gas and then heated to reflux for 16 hours. The solvent was reduced in vacuo and the residue partitioned between ethyl acetate (200mL) and 5% aqueous sodium carbonate (200mL). The organic extract was washed with saturated sodium chloride (100mL), dried over sodium sulphate and reduced in vacuo. The residue was purified on strong cation exchange resin, eluting with methanol and then 2N ammonia in methanol to elute the product. The eluant was concentrated in vacuo to give the title compound as a yellow oil, 2.68g. 1H nmr (CDCI3, 400MHz) δ :1.14 (s, 6H), 2.68 (s, 2H), 3.62 (s, 2H), 3.69 (s, 3H), 7.08-7.16 (m, 3H), 7.23-7.27 (m, 1 H). LRMS : m/z ES+ 236 [MH]+
Preparation 18
(1 R)-1 -[3-Amino-4-(benzyloxy)phenyl]-2-bromoethan ol
Platinum oxide (1g) was added to a solution of (R)-2-bromo-1-[4-(benzyloxy)-3- nitrophenoljethanol (Org. Proc. Res. And Dev. 1998; 2; 96-99) (50g, 142mmol) in toluene (100mL) and tetrahydrofuran (lOOmL) and the mixture was hydrogenated at 30 psi and room temperature for 18 hours. The reaction mixture was filtered through Arbocel®, washing through with dichloromethane (4x200mL). The combined filtrate was evaporated under reduced pressure and the residual yellow solid was purified using a Biotage® silica gel column and dichloromethane:ethyl acetate (100:0 to 50:50 to 0:1 00) as the eluant. The impure fractions were combined and purified again using a Biotage® silica gel column using toluene:dichloromethane (100:0 to 50:50 to 0:100) as the eluant, to provide the title compound as a solid.
1Hnmr (CDCI3, 400MHz) δ : 2.97-3.38 (br s, 2H), 3.55 (dd, 2H), 4.78 (m, 1 H), 5.03 (s, 2H), 6.63 (d, 1 H), 6.75 (s, 1 H), 6.80 (d, 1 H), 7.26-7.42 (m, 5H).
Preparation 19
Λ/-{2-(Benzyloxy)-5-[(1 R)-2-bromo-1 -hydroxyethyI]phenyl}urea
Potassium cyanate (2.01 g, 24mmol) was added to a solution of the amine from preparation 18 (4g, 12mmol) in a solution of acetic acid:water (400mL, 1 :2 by volume), and the reaction stirred at room temperature for 1.5 hours. The solution was carefully basified by the addition of sodium hydroxide, and the resulting precipitate filtered off. The solid was washed with water (1600mL), then ether (500mL) and dried in vacuo for 18 hours, to afford the title compound, 2.44g. 1Hnmr (CD3OD, 400MHz) δ : 3.58 (m, 2H), 4.71 (m, 1 H), 5.21 (s, 2H), 6.98 (m, 2H), 7.40 (m, 5H), 8.00 (s, 1 H). LRMS : m/z APCI+ 285 [MH]+ Preparation 20
W-[2-(Benzyloxy)-5-((1R)-2-bromo-1-{[fert-butyl(dimethyl)silyl]oxy}ethyl) phenyljurea Imidazole (1.24g, 18.2mmol) and fe/f-butyldimethylsilyl chloride (2.36g, 15.6mmol) were added to a solution of the alcohol from preparation 19 (4.75g, 13.0mmol) in N,N-dimethylformamide (30mL). 4-(Dimethylamino)pyridine (48mg, 0.39mmol) was then added and the reaction stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate (50mL), washed with water (2x25mL), dried over magnesium sulphate and evaporated under reduced pressure. The residual orange oil was purified on a Biotage® silica gel cartridge using dichloromethane as eluant to provide the title compound, 4.3g. 1Hnmr (CD3OD, 400MHz) δ: -0.10(s, 3H), 0.09(s, 3H), 0.91 (s, 9H), 3.50(m, 2H), 4.81 (m, 1 H), 5.20(s, 2H), 6.98(m, 2H), 7.40(m, 3H), 7.48(d, 2H), 8.05(s, 1 H). LRMS : m/z APCI+ 479, 481 [MH]+
Preparation 21
Methyl (3-{2-[((2R)-2-[3-[(aminocarbonyl)amino]-4-(benzyloxy)phenyl]-2- {[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyI}phenyl)acetate
A mixture of the bromide from preparation 20 (3.52g, 7.3mmol), the amine from preparation 17 (1.63g, 7.3mmol), potassium carbonate (2.O3g, 15mmol) and potassium iodide (1.22g, 7.3mmol) in acetonitrile (50mL) was stirred at 80°C for 5 days. The cooled mixture was concentrated under reduced pressure and the residue suspended in water and extracted with ethyl acetate (3x100mL). The combined organic extracts were washed with brine (3x50mL), dried over sodium sulphate and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (99.7:0:0.3 to 96.7:3:0.3). The impure fractions were further purified using a RediSEP™ flash silica gel column and an elution gradient of dichloromethane:methanol:0.88 ammonia (99.7:0:0.3 to 96.7:3:0.3). The resulting oils were combined and triturated with ether, to afford the title compound as a pale yellow solid, 2.1g.
1Hnmr (CDCI3, 400MHz) δ: -0.45 (s, 3H),-0.01 (s, 3H), 0.82 (s, 9H), 1.00 (s, 3 H), 1.03 (s, 3H), 2.60-2.68 (m, 3H), 2.78-2.84 (m, 1 H), 3.58 (s, 2H), 3.67 (s, 3H), 4.54 (s, 2H), 4.72 (m, 1 H), 5.06 (s, 2H), 6.78 (s, 1 H), 6.89 (d, 1 H), 6.96-7.18 (m, 6H), 7.38-7.41 (m, 5H). LRMS : m/z APCI+ 620 [MH]+
Preparation 22 Methyl (3-{2-[((2/?)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2-{[fe/-f- butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl)acetate
A mixture of the compound from preparation 21 (2.27g, 3.7mmol) and 1 0% palladium on charcoal (300mg) in methanol (40mL) was hydrogenated at 50 psi and room temperature for 18 hours. The reaction mixture was filtered through Arbocel®, and the filtrate evaporated under reduced pressure. The residual foam was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (99.7:0:0.3 to 95.7:4:0.3) to provide the title compound as a colourless foam, 1.45g.
1Hnmr (CDCI3, 400MHz) δ: -0.19 (s, 3H), -0.06 (s, 3H), 0.78 (s, 9H), 1.02 (s, 3H), 1.05 (s, 3H), 2.59-2.68 (m, 3H), 2.77-2.81 (m, 1 H), 3.61-3.66 (dd, 2H),
4.57-4.60 (m, 1 H), 5.03 (s, 2H), 6.79 (d, 1H), 6.86 (d, 1 H), 6.94-7.04 (m, 2H),
7.08-7.12 (m, 2H), 7.18-7.22 (m, 1 H), 7.39 (s, 1 H).
HRMS [C28H43N305Si] 530.3045 found 530.3042 [MH]+
Preparation 23
(3-{2-[((2/?)-2-{3-[(Aminocarbonyl)amino]-4-hydroxyphenyl}-2-{[terf- butyI(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl)acetic acid
Sodium hydroxide solution (5M, 2.74mL, 13.7mmol) was added to a solution of the ester from preparation 22 (1.45g, 2.74mmol) in dioxan (20mL) and water (2mL) and the reaction stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residual solution diluted with water. This solution was cooled in ice, acidified to pH 6 using 1M hydrochloric acid and the resulting precipitate filtered off, and dried in vacuo at 50°C for 4 days to afford the title compound as a white solid, 1.27g. 1Hnmr (CD3OD, 400MHz) δ: -0.11 (s, 3H), 0.05 (s, 3H), 0.83 (s, 9H), 1.32 (d, 6H), 2.91-2.99 (dd, 2H), 3.22-3.28 (m, 2H), 3.51 (s, 2H), 4.58-4.62 (m, 1 H), 6.82 (d, 1 H), 6.87-6.92 (m, 1 H), 7.05-7.09 (m, 1 H), 7.13 (s, 1 H), 7.25-7.29 (m, 2H), 7.76 (d, 1 H). LRMS : m/z APCI+ 516 [MH]+
Preparation 24 1 -[4-(Benzyloxy)phenyl]-2-bromoethanone
A solution of tetrabutylammonium tribromide (53g, 110mmol) in tetrahydrofuran (70mL) was added dropwise to a suspension of 4-benzyloxyacetophenone (27.38g, 121 mmol) in tetrahydrofuran (100mL) and methanol (25mL) over 1 hour. The reaction mixture was then left to stir for 48 hours and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (250mL) and washed with water (250mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2 x 100mL). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to give a solid. The crude residue was recrystallised using cyclohexane to afford the desired product, 22g (65%).
1H NMR (400 MHz, CDCI3) δ 4.38 (2H, s), 5.10 (2H, s), 7.00 (2H, m), 7.21-7.40 (5H, m), 7.9 (2H, m). LRMS: m/z APCI+ 305 [MH+].
Preparation 25
Methyl {3-[2-({2-[4-(benzyloxy)phenyl]-2-hydroxyethyl}amino)-2- methylpropyl]phenyl}acetate
A solution of the compound of preparation 24 (6.7g, 21.9mmol), the compound of preparation 17 (4.86g, 21.9mmol) and Λ/-ethyldiisopropylamine (3.8mL, 21.9mmol) in tetrahydrofuran (200mL) was heated under reflux for 24 hours. The reaction mixture was cooled to room temperatre and sodium borohydride (1.24g, 32.8mmol) was added and the solution stirred for 4 hours. The solution was quenched by the addition of methanol (30mL) and evaporated to a yellow gum. The yellow gum was partitioned between saturated sodium hydrogen carbonate solution (30mL) and dichloromethane (30mL). The phases were separated and the aqueous phase was extracted with dichloromethane (3 x 50mL). The organic extracts were combined and concentrated in vacuo to give the crude residue. Purification by column chromatography on silica gel using dichloromethane and then dichloromethane:methanol:0.88 ammonia (95:5:0.5) afforded the desired product, 2.72g (28%).
1H NMR (400 MHz, CDCI3) δ 1.05 (3H, s), 1.07 (3H, s), 2.66-2.78 (3H, m), 2.84- 2.89 (1 H, m), 3.60 (2H, s), 3.65 (3H, s), 4.65-4.68 (1 H, q), 5.06 (2H, s), 6.95- 6.97 (2H, d), 7.03-7.05 (1 H, d), 7.10-7.12 (2H, d), 7.17-7.21 (1 H, t), 7.27-7.31 (3H, m), 7.33-7.37 (2H, t), 7.41-7.43 (2H, d). LRMS: m/z APCI+ 448 [MH+j.
Preparation 26
Methyl [3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetate
A solution of the compound of preparation 25 (3.15g, 7.04mmol), ammonium formate (3.11g, 49.3mmol) and palladium hydroxide on carbon (320mg) in ethanol (70mL) was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature, filtered over Arbocel® and evaporated to give the crude residue. Purification by column chromatography on silica gel using dichloromethane and then dichloromethane:methanol:0.88 ammonia (90:10:1 ) afforded the desired product, 2.28g (91 %). 1H NMR (400 MHz, CDCI3) δ 1.06 (3H, s), 1.08 (3H. s), 2.53-2.78 (3H, m), 2.86- 2.91 (1 H, dd), 3.61 (2H, s), 3.66 (3H, s), 4.62-4.66 (1 H, dd), 6.75-6.77 (2H, d), 7.03-7.05 (1 H, d), 7.11-7.13 (2H, d), 7.18-7.20 (3H, d). LRMS: m/z APCI+ 358 [MH+].
Preparation 27
3-(2-{[2-Hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl] acetic acid A 1 M lithium hydroxide (12.8mL) solution was added dropwise to a solution of the compound of preparation 26 (2.28g, 6.38mmol) in tetrahydrofuran (20mL) at room temperature and stirred for 24 hours. The reaction was acidified with 1 M solution of hydrochloric acid and the solvent was evaporated in vacuo to give the crude residue as a gum. The crude residue was azeotrop ed with methanol and used without further purification.
1H NMR (400 MHz, DMSO-d6) δ 1.05 (6H, s), 2.76-2.88 (4H, m), 3.39 (2H, s), 4.69-4.71 (1 H, dd), 6.73-6.75 (2H, d), 6.95-6.97 (1 H, d), 7.07-7.09 (2H, d), 7.14-7.16 (3H, m). LRMS: m/z APCI+ 344 [MH+].
Preparation 28: Λ/-{2-Benzyloxy-5-[(7R)-2-bromo-1 -(fert-butyldimethyl silanyloxy)ethyl]phenyl}formamide
To a solution of A/-[2-benzyloxy-5-(2-bromo-1-hydroxyethyl)phenyl]formamide (Organic Process Research and Development 1998, 2, 96-9 S) (16.58 g, 47.4 mmol, containing about 20 % of the corresponding acetamide) in N,N- dimethylformamide (100 mL) at RT under N2 was added te/f-butyldimethylsilyl chloride (14.3 g, 94.7 mmol), imidazole (7.73 g, 113.7" mmol) and 4- (dimethylamino)pyridine (100 mg, 825 μmol). The resulting solution was stirred at RT overnight, the solvent was removed and the product taken up in ethyl acetate (200 mL). The organics were washed with 10% hy rochloric acid (2x 250 mL) brine (500 mL) and dried (MgSθ4). The crude material was purified by chromatography (0-30 % ethyl acetate in heptane) to yield a colourless oil (18.65 g). Major product : 1HNMR (CDCI3, 400 MHz) δ: -0.08 to -0.05 (3H, m), 0.09-0.11 (3H, s), 0.89-0.90 (9H, m), 3.38-3.55 (2H, m), 3.78-3.84 (1 H, rn), 5.06-5.11 (2H, m), 6.90-6.97 (1H, m), 7.03-7.12 (1 H, m), 7.24 (m), 7.36-7.-43 (5H, m), 7.67- 7.78 (m), 7.88 (d), 8.74 (d); LRMS ES m/z 486 [M+Na]+ Minor product : 1HNMR (CDCI3, 400 MHz) δ: distinguishing peak at 2.14 (3H, s); LRMS ES m/z 500 [M+Na]+
Preparation 29: 1-(3-Bromophenyl)-2-methylpropan-2-ol) Methylmagnesium bromide (3M solution in diethyl ether, 51.6 mL, 155 mmol) was slowly added to a solution of 1-(3-bromo-phenyl)propan-2-one (15.0 g, 70 mmol) in dry diethyl ether (200 mL) at 0 °C and the mixture was stirred for 3 hours. The reaction mixture was then re-cooled to 0 °C and slowly quenched with saturated aqueous ammonium chloride solution. The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residual yellow oil was then purified by column chromatography on silica gel eluting with dichloromethane:pentane:methanol, 90:5:5, to afford a pale yellow oil in 83% yield, 13.26 g. H NMR (400MHz, CDCI3) δ: 1.22 (6H, s), 1.42 (1 H, bs), 2.74 (2H, s), 7.15 (2H, m), 7.40 (2H, m)
Preparation 30: Λ/-[2-(3-Bromophenyl)-1,1-dimethylethyl]-2- chloroacetamide Chloroacetonitrile (6.63 mL, 105 mmol) was added to a stirred solution of the product of preparation 29 (12.0 g, 52.0 mmol) in acetic acid (25 mL) at room temperature. The resulting solution was cooled to 0 °C and concentrated sulfuric acid (25 mL) was added whilst the temperature was maintained below 10 °C. The resulting solution was left to stir for 1 hour and was then poured onto ice and basified by the addition of solid potassium carbonate. The product was extracted with ethyl acetate (2χ 500 mL) and the combined organic solution was washed with water (50mL), dried over sodium sulfate and the concentrated in vacuo to afford the title compound as an orange solid in quantitative yield, 16.08 g. ' "H NMR (400MHz, CDCI3) δ: 1.37 (6H, s), 3.02 (2H, s), 3.94 (2H, s), 6.17 (1H, bs), 7.08-7.03 (1 H, d), 7.10-7.13 (1 H, t), 7.26 (1 H, s), 7.39-7.32 (1 H d ,); LRMS ESI m/z 306 [M+H]+; Microanalysis: C12H15BrCINO requires: C 47.32; H 4.96; N 4.60; found C 47.26; H 4.87; N 4.65
Preparation 31 : 2-(3-Bromophenyl)-1,1-dimethylethylamine
A solution of the product of preparation 30 (32.0 g, 105 mmol), thiourea (9.60 g, 126 mmol) and acetic acid (50 mL) in ethanol (250 mL) was heated to reflux overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, basified using aqueous sod ium hydroxide solution (1M, 450 mL) and extracted with dichloromethane (2χ 500 mL). The combined organic solution was washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound as a black oil in 96% yield, 23 g.
1H NMR (400MHz, CDCI3) δ: 1.12 (6H, s), 1.84 (2H, bs), 2.62 (2H, s), 7.16-7.08 (2H, m), 7.36-7.32 (2H, m); LRMS ESI m/z 228 [M+H]+
Preparation 32: [2-(3-Bromophenyl)-1,1-dimethylethyl]carbamic acid tert- butyl ester
The product of preparation 31 (5.0g, 22mmol) was treated with di-fert-butyl dicarbonate (5.26g, 24mmol) in dichloromethane (50mL) and stirred for 20 hours. The reaction mixture was washed with water (50mL) and the combined organic solution was dried over sodium sulfate and concentrated in vacuo. The crude material was purified using a cation exchange column (methanol followed by 2M ammonia in methanol), followed by purification by flash column chromatography on silica gel eluting with dichloromethane to afford the title compound as a brown oil in quantitative yield, 7.23g. 1H NMR (400MHz, CDCI3) δ: 1.27 (6H, s) 1.50 (9H, s), 2.97 (2H, s), 4.24 <1 H, bs), 7.05 (1H, d), 7.15-7.11 (1H, t), 7.30 (1H, s), 7.35 (1 H, d); LRMS ESI m/z 350 [M+NH4]+
Preparation 33: Benzyl 3-{2-[(terf-butoxycarbonyl)amino]-2- methylpropyl}benzoate
A solution of the product of preparation 32 (3.9 g, 12 mmol), [ 1 ,1'- b/s(diphenylphosphino)ferrocene]dichloropalladium(ll) (1.00 g, 1.3 mmol) and triethylamine (3.3 mL, 24 mmol) in benzyl alcohol (60 mL) was heated to 10O °C under 100psi carbon monoxide for 5 hours. The cooled reaction mixture was then filtered through Arbocel® and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with sodium hydrogen carbonate solution (50 mL) and brine (2x 50 mL). The organic solution was "then dried over sodium sulfate and concentrated in vacuo to give a dark oil. This oil was purified by column chromatography on silica gel, eluting with hexane:ethyl acetate 100:0 to 84:16, to afford the title compound as a pale yellow oil in 61% yield, 2.81 g. 1H NMR (400MHz, CDCI3) δ: 1.25 (6H, s), 1.45 (9H, s), 3.05 (2H, s), 4.22 (1 H, bs), 5.35 (2H, s), 7.32-7.48 (7H, m), 7.86 (1 H, s), 7.93-7.97 (1 H, m)
Preparation 34: Benzyl 3-(2-amino-2-methylpropyl)benzoate hydrochloride
Hydrogen chloride (4M in dioxane, 25 mL, 10 mmol) was added to a solution of the product of preparation 33 (2.80 g, 7.30 mmol) in dioxane (10 mL) and the resulting solution stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was evaporated from diethylether (x3), then suspended in diethylether and filtered to yield a white precipitate in 91 % yield. 1H NMR (400MHz, CD3OD) δ: 1.33 (6H, s), 2.98 (2H, s), 5.37 (2H, s), 7.31-7.53 (7H, m), 7.93 (1 H, s), 8.00-8.04 (1 H, m); LRMS APCI m/z 284 [M+H]+
Preparation 35 : 3-{2-[(2R)-2-(3-Acetylamino-4-benzyloxyphenyl)-2-(ferf- butyldimethylsilanyloxy)ethylamino]-2-methylpropyI}benzoic acid benzyl ester A mixture of preparation 28 (2.21 g, 4.79 mmol, containing some of the acetyl analogue) and the free-base of preparation 34 (2,69 g, 9.49 mmol) were heated to 95 °C for 24 h. The mixture was allowed to cool and then triturated with diethyl ether and the solid filtered off. The filtrate was evaporated and purified by chromatography, eluting with dichloromethane:methanol:ammonia 100:0 to 96:4. A second chromatography eluting with ethyl acetate:hexane:triethylamine 30:70:1 furnished preparation 41 (1.70 g, 53 %) and an oil which was evaporated from diethylether (x3) to yield a colourless gum (283 mg, 10 %). 1H NMR (400MHz, CDCI3) δ: -0.17 (3H, s), -0.04 (3H, s), 0.80 (9H, s), 1.00 (3H, s), 1.04 (3H, s), 2.13 (3H, s), 2.64-2.84 (4H, m), 4.69-4.72 (1 H, m), 5.09 (2H, s), 5.35 (2H, s), 6.85 (1 H, d), 6.99 (1 H, d), 7.24-7.45 (12H, m), 7.72 (1 H, s), 7.87- 7.93 (2H, m), 8.37 (s); LCMS APCI m/z 681 [M+H]+. Preparation 36 : 3-{2-[(2R)-2-(3-Acetylamino-4-hydroxyphenyl)-2-(ferf- butyldimethylsilanyloxy)ethylamino]-2-methylpropyl}benzoic acid
The product of preparation 35 (283 mg, 420 μmol) and 10% Pd/C (300 mg) were suspended in methanol and the mixture was stirred under 50psi of hydrogen gas, at room temperature for 18 hours. The reaction mixture was then filtered through Filter aid® and the filtrate was concentrated in vacuo and evaporated from diethylether (x3) to yield an off-white foam (220 mg, 100 %). jH NMR (400MHz, CD3OD) δ: -0.13 (3H, s), -0.03 (3H, s), 0.81 (9H, s), 1.126 (3H: s), 1.27 (3H, s), 2.19 (3H, s), 2.94-3.24 (4H, m), 4.89-4.94 (1 H, m), 6.87 (1 H, d), 7.02 (1 H, d), 7.30-7.40 (2H, m), 7.78-7.95 (3H, m); LCMS APCI m/z 501 [M+H]+.
Preparation 37 : 3-{2-[(2R)-2-(3-Acetylamino-4-hydroxyphenyl)-2-(fert- butyldimethylsilanyloxy)ethylamino]-2-methylpropyl}-Λ/-[2-(2- chlorophenyl)ethyl]benzamide
A mixture of the product of preparation 36 (220 mg, 440 μmol), hydroxybenzotriazole hydrate (67 mg, 440 μmol), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (85 mg, 440 μmol) and triethylamine (120 μL, 880 μmol) in dichloromethane (20 mL was stirred at room temperature for 10 minutes. 2-chlorophenethylamine (69 mg, 440 μmol) was then added and the mixture was stirred at room temperature for 20 hours. The solvent was then removed in vacuo and the residue was diluted with ethyl acetate, washed with sodium hydrogen carbonate solution (20 mL) and brine (20 mL), dried over sodium sulfate. The crude material was purified by chromatography eluting with dichloromethane:methanol:ammonia 99.7:0:0.3 to 95.7:4:0.3. The fractions were concentrated in vacuo and evaporated from diethylether (x3) to yield an off-white foam (55 mg, 20 %).
1H NMR (400MHz, CDCI3) δ: -0.25 (3H, s), -0.11 (3H, s), 0.67 (9H, s), 1 .06 (3H, s), 1.07 (3H, s), 2.35 (3H, s), 2.60-2.82 (4H, m), 3.08-3.12 (2H, t), 3.72-3.82 (2H, m), 4.58-4.62 (1 H, m), 6.40 (1 H, bs), 6.89-7.00 (2H, m), 7.05 (1 H, s), 7.19- 7.32 (5H, m), 7.39-7.41 (2H, m), 7.81 (1 H, s), 9.45 (1 H, bs); LCMS APCI m/z 638 [M+H]+. Example 1 : 5-{(2R)-2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl) amino]phenyl}ethyl)amino]propyl}-/V-[3-hydroxy-5-(trifluoromethyl) benzyl]-1 H-indole-2-carboxamide
Figure imgf000082_0001
A solution of 5-{(2R)-2-[((2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}-Λ/-t3-hydroxy-5- (trifluoromethyl)benzyl]-1H-indole-2-carboxamide (Preparation 1 , crude, 0.48mmol assumed) in a mixture of methanol (10ml) and water (5ml) was treated with ammonium fluoride (100 mg, 2.7mmol) and the resulting suspension heated at 40°C for a period of 16 hours. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : 0.88 ammonia (95:5:0.5 changing to 85:15:1.5, by volume) to give the title compound. Crystallisation from aqueous methanol gave the title compound as a colourless solid (20mg). 1H NMR (400 MHz, CD3OD) : δ = 7.37-7.29 (3H, m), 7.11 (1 H, m), 7.05-7.00 (3H, m), 6.94-6.91 (2H, m), 6.71 (1 H, d), 4.65-4.61 (1 H, m), 3.05-2.68 (8H, m), 1.12 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]+ 621.
Examples 2 to 29
Figure imgf000082_0002
A solution of the acid from preparation 23 (12.5mg, 24μmol) in N,N- dimethylformamide (200μL) was added to the appropriate amine (HNRARB) (30μmoi) in N,N-dimethylformamide (150μL) and the reaction sealed and shaken. A solution of 0-benzotriazol-1-yl-/V,Λ/,/V',/V-tetramethyluronium hexafluorophosphate (9.19mg, 24μmol) in N,N-dimethylformamide (200μL) was added, the reaction mixture sealed and shaken and allowed to stand at room temperature for 48 hours. The solvent was removed in vacuo, and the residue re-dissolved in dichloromethane (200μL). Sodium bicarbonate solution (0.5M, 200μL) was added and the mixture sealed and shaken vigorously. The phases were separated using a phase separation tube, washing through with additional dichloromethane (200μL). The combined organic solutions were allowed to evaporate over 2 days. A solution of triethylamine trihydrofluoride (4μL, 0.024mmol) in dimethylsulphoxide (500μL) was added, the mixture sealed and shaken and allowed to stand for 48 hours. The reaction mixture was purified directly by HPLC using a Phenomenex Luna C18 column (150x10mm, 10μm), at a flow rate of 8mL/min and detection at 225nm, using the following gradient system. A-0.05% aqueous diethylamine B-acetonitrile
Figure imgf000083_0001
Each product was analysed using a Phenomenex Luna C18 (30 x 4.6mm, 5μm) column at a flow rate of 2.5mL/min using the gradient described in the table belnw.
A-5% 6.5mM ammonium acetate in wateπacetonitrile (95:5) B-acetonitrile
Figure imgf000083_0002
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
86
Figure imgf000087_0003
A= 3-amino-5-ethyl-1 H-pyrazole (WO 03/048133, method 6)
Example 30
Λ/-Benzyl-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetamide
Figure imgf000087_0001
A solution of the acid of preparation 27 (50mg, 0.12mmol), benzylamine (16mg, 0.15mmol) and 0-(1 H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (58mg, 0.15mmol) in N, /V-dimethylformamide (3mL) was stirred for 48 hours at room temperature. The solvent was removed iη vacuo to give the crude residue. Purification by column chromatography on silica gel using dichloromethane and then dichloromethane:methanol:0.88 ammonia (92.5:7.5:0.75) as eluent to give the desired product as a white foam, 17mg (34%).
1H NMR (400 MHz, CD3OD) δ 1.01 (3H, s), 1.04 (3H, s), 2.63-2.72 (3H, m), 2.82-2.87 (1 H, t), 3.51 (2H, s), 4.34 (2H, s), 4.59-4.62 (1 H, bq). LRMS: m/z APCI+ 433 [MH+].
Examples 31-42
Figure imgf000087_0002
A solution of the acid from preparation 9 (30μmol) in N,N-dimethylformamide (200μL) was added to the appropriate amine (HNRARB) (30μmol) in N,N- dimethylformamide (100μL) and the reaction sealed and shaken. A solution of 0-benzotriazoI-1-yl-/V,/V,/V',/V-tetramethyluronium hexafluorophosphate
(11.38mg, 30μmol) in N,N-dimethylformamide (100μL) was added, the reaction mixture sealed and shaken and allowed to stand at room temperature for 4 days. The reaction mixture was purified directly by HPLC using a Phenomenex Luna C18 column (150x10mm, 10μm), at a flow rate of 8mL/min and detection at 225nm, using the following gradient system.
A-0.05% aqueous diethylamine B-acetonitrile
Figure imgf000088_0001
Each product was analysed using a Phenomenex Luna C18 (30 x 4.6mm, 5μm) column at a flow rate of 2.5mL/min using the gradient described in the table below.
A-5% 6.5mM ammonium acetate in water.acetonitrile (95:5) B-acetonitrile
Figure imgf000088_0002
Figure imgf000088_0003
Figure imgf000089_0001
Figure imgf000090_0002
Example 43
3-{2-[(2R)-2-(3-Acetylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2- methylpropyl}-W-[2-(2-chlorophenyl)ethyl]-benzamide
Figure imgf000090_0001
The amide of preparation 37 and triethylamine trihydrofluoride (1 equivalent) in tetrahydrofuran (5 mL) were stirred at room temperature for 2 days. The mixture was then concentrated in vacuo and the residue treated with methanolic ammonia and evaporated (x3) to leave a foam which was taken up in dichloromethane:methanol:0.88 ammonia, 90:10:1 filtered, then purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 90:10:1 to afford the title compound as a film which was dissolved in methanol and evaporated (x3), then suspended in diethylether and evaporated (x3) to yield colourless foam (40 mg, 95 %)
1H NMR (400MHz, CD3OD) δ: 1.05 (3H, s), 1.11 (3H, s), 2.16 93H, s), 2.70-2.97 (4H, m), 3.05 (2H, t), 3.61-3.66 (2H, m), 4.62-4.66 (1 H, m), 6.83 (1 H, d), 7.03 (1 H, d), 7.18-7.20 (2H, m), 7.30-7.38 (4H, m), 7.61-7.65 (2H, m), 7.70 (1 H, d); LRMS APCI m/z 524 [M+H]+. The ability of the compounds of the formula (1) to act as potent β2 agonists therefore mediating smooth muscle relaxation may be determined by the measure of the effect of beta-2 adrenergic receptor stimulation on electrical field stimulated-contraction of guinea pig trachea strips. Guinea-pig trachea
Male, Dunkin-Hartley guinea pigs (475-525g) are killed by C02 asphyxiation and exsanguination from the femoral artery and the trachea is isolated. Four preparations are obtained from each animal, starting the dissection immediately below the larynx and taking 2.5 cm length of trachea. The piece of trachea is opened by cutting the cartilage opposite the trachealis muscle, then transverse sections, 3-4 cartilage rings wide, are cut. The resulting strip preparations are suspended in 5 ml organ baths using cotton threads tied through the upper and lower cartilage bands. The strips are equilibrated, un-tensioned, for 20 minutes in a modified Krebs Ringer buffer (Sigma K0507) containing 3 μM Indomethacin (Sigma I7378), 10 μM Guanethidine (Sigma G8520) and 10 μM Atenolol (Sigma A7655), heated at 37°C and gassed with 95% 02/5% C02, before applying an initial tension of 1 g. The preparations are allowed to equilibrate for a further 30- 45 minutes, during which time they are re-tensioned (to 1 g) twice at 15-minute intervals. Changes in tension are recorded and monitored via standard isometric transducers coupled to a data-collection system (custom-designed at Pfizer). Following the tensioning equilibration, the tissues are subjected to electrical field stimulation (EFS) using the following parameters : 10 s trains every 2 minutes, 0.1 ms pulse width, 10 Hz and just-maximal voltage (25 Volts) continuously throughout the length of the experiment. EFS of post-ganglionic cholinergic nerves in the trachea results in monophasic contractions of the smooth muscle and twitch height is recorded. The organ baths are constantly perfused with the above-described Krebs Ringer buffer by means of a peristaltic pump system (pump flow rate 7.5 ml / minute) throughout the experiment, with the exception of when a beta-2 agonist according to the present invention is added, the pump is then stopped for the time of the cumulative dosing to the bath and started again after maximal response is reached for the wash-out period. Experimental protocol for assessment of potency and efficacy Following equilibration to EFS, the peristaltic pump is stopped and the preparations 'primed' with a single dose of 300 nM isoprenaline (Sigma 15627) to establish a maximal response in terms of inhibition of the contractile EFS response. The isoprenaline is then washed out over a period of 40 minutes. Following the priming and wash-out recovery, a standard curve to isoprenaline is carried out on all tissues (Isoprenaline Curve 1) by means of cumulative, bolus addition to the bath using half log increments in concentration. The concentration range used is 1e"9 to 1e/3e"6 M. At the end of the isoprenaline curve the preparations are washed again for 40 minutes before commencing a second curve, either to isoprenaline (as internal control) or a beta-2 agonist according to the present invention. Beta-2 agonist responses are expressed as percentage inhibition of the EFS response. Data for beta-2 agonist are normalised by expressing inhibition as a percentage of the maximal inhibition induced by isoprenaline in Curve 1. The EC50 value for beta-2 agonist according to the present invention refers to the concentration of compound required to produce half maximal effect. Data for beta-2 agonists according to the present invention are then expressed as relative potency to isoprenaline defined by the ratio (EC5o beta-2 agonist)/(EC50 Isoprenaline).
Confirmation of beta-2 mediated functional activity
Beta-2 agonist activity of test compounds is confirmed using the protocol above, however, prior to constructing the curve to beta-2 agonist according to the present invention, the preparations are pre-incubated (for a minimum of 45 minutes) with 300 nM ICI 118551 (a selective β2 antagonist) which results in the case of a beta-2 mediated effect in a rightward-shift of the test compound dose response curve.
According to another alternative, the agonist potency for the β2 receptor of the compounds of the formula (1) may also be determined by the measure of the concentration of compound according to the present invention required to produce half maximal effect (EC50) for the β2 receptor. Compound Preparation
10 mM/100% DMSO (dimethylsulfoxide) stock of compound is diluted to required top dose in 4 % DMSO. This top dose is used to construct a 10-point semi-log dilution curve, all in 4 % DMSO. Isoprenaline (Sigma, I-5627) was used as a standard in every experiment and for control wells on each plate. Data was expressed as % Isoprenaline response.
Cell Culture
CHO (Chinese Hamster Ovary) cells recombinantly expressing the human β2 adrenergic receptor (from Kobilka et al., PNAS 8<4: 46-50, 1987 and Bouvier et al., Mol Pharmacol 33: 133-139 1988 CHOhβ2) were grown in Dulbeccos MEM/ NUT MIX F12 (Gibco, 21331-020) supplemented with 10 % foetal bovine serum (Sigma, F4135, Lot 90K8404 Exp 09/04), 2 mM glutamine (Sigma, G7513), 500 μg/ml geneticin (Sigma, G7034) and 10 μg/rnl puromycin (Sigma, P8833). Cells were seeded to give about 90 % confluency for testing.
Assay Method
25 μl / well each dose of compound was transferred into a cAMP- Flashplate® (NEN, SMP004B), with 1 % DMSO as basal controls and 100 nM Isoprenaline as max controls. This was diluted 1 :2 by the add ition of 25 μl / well PBS. Cells were trypsinised (0.25% Sigma, T4049), washed with PBS (Gibco, 14040-174) and resuspended in stimulation buffer (NEN, SMP004B) to give 1x106 cells / ml CHOhB2. Compounds were incubated with 50 μl / well cells for 1 hour. Cells were then lysed by the addition of 100 μl / well detection buffer (NEN, SMP004B) containing 0.18 μCi / ml 125l-cAMP (NEN, NEX-130) and plates were incubated at room temperature for a further 2 hours. The amount of ! 5l-cAMP bound to the Flashplate® was quantified using a Topcount NXT (Packard), normal counting efficiency for 1 minute. Dose-response data was expressed as % Isoprenaline activity and fitted using a four parameter sigmoid fit.
It has been found that the compounds of formula (1 ) according to the present invention that are illustrated in examples 1 to 43 above show a β2 cAMP EC50 below 10 nM.

Claims

1. A compound of formula (1)
Figure imgf000094_0001
wherein:
- A is selected from the following groups:
Figure imgf000094_0002
H
Figure imgf000095_0001
wherein the dashed line represents an optional bond;
- R1 and R2 are independently selected from H or C-1-C4 alkyl;
- B is selected from
Figure imgf000095_0002
wherein * represents the attachment points and
Figure imgf000095_0003
wherein ** represents the attachment point to the (CH2)nC(=0)Qι group and R is selected from hydrogen, (Cι-d)alkyl and benzyl optionally substituted with 1 , 2 or 3 groups selected from hydroxy, hydroxy(Cι-Cs)alkyl, (d-djalkyl, 0-(Cr d)alkyl, halo, 0-CF3, NR9S02(d-C4)alkyl, S02NR9R1°, trifluoromethyl and NR9R10; - n is an integer selected from 0, 1 or 2, - Q1 is a group selected from:
Figure imgf000096_0001
* M I->8 rsl -7
NR -Q -Z
Figure imgf000096_0002
wherein
- * represent the attachment point to the carbonyl group;
- p is an integer selected from 1 , 2 or 3;
- R8 is selected from hydrogen or (Cι-d)alkyl optionally substituted by a hydroxy;
- Q2 is a bond or a C1-C4 alkylene optionally substituted with OH;
- Q7 is d-C6 alkyl optionally substituted with NR9R10, OR9 or phenoxy,
- Z is selected from
- C3-Cιo cycloalkyl, said cycloalkyl being optionally bridged by one or more carbon atoms, preferably 1 2, 3 or 4 carbon atoms, and being optionally substituted with a group selected from hydroxy group and Cr d alkyl;
- 5 to 10-membered heterocycle, optionally aromatic, containing from 1 to 3 heteroatoms, identical or different, selected from O, S or N, said heterocycle being optionally substituted with a group selected from (Cι- d)alkyl, cyclopropylmethyl and NR9R10 , or,
- a group of formula
Figure imgf000096_0003
- R3, R4, R5, R6 and R7 are the same or different and are selected from H, d- C6 alkyl, benzyloxy, hydroxy(d-C6)alkyl, OR9, SR9, SOR9, S02R9, halo, CN, CF3, OCF3) (CH2)mCOOR9, NR9S02(C1-C4)alkyl, S02NR9R1°, CONR9R10, NR9R10, NHCOR10;
- m is an integer selected from 0, 1 , and 2;
- R9 and R10 are the same or different and are selected from H or Cι-C6 alkyl; - R ii i is selected from H and OH;
- R12 and R13 are the same or different and are selected from H, OR9, d-d alkyl optionally susbstituted with OR9, C(=0)NH2, C(=0)CH3, N(CH3)C(=0)CH3, C(=0)OR9, phenyl optionally substituted with halogen, pyridyl optionally substituted with CN, oxadiazolyl optionally substituted with d-d alkyl, and - Q3 is (CH2)t wherein t is an integer selected from 0 and 1 ;
- Q4 is a group selected from NH, -C(=0)NH-, -NHC(=0)-, NH-C(=0)-NH-, -
Figure imgf000097_0001
- Q5 is a single bond, a C1-C4 alkylene optionally substituted with OH or a group (CH2)q-0-(CH2)r wherein q and r are integers independently selected from 1 , 2 or 3;
Q is selected from
Figure imgf000097_0002
wherein * represents the attachment point to Q5 and R14, R15, R16, R17 and R18 are independently selected from H, d-d alkyl, OR19, SR19, SOR19, S02R19, halo, CN, CF3) OCF3l COOR20, S02NR19R20, CONR19R20, -NR19S02R2°,
NHR ι1ι9aRr>20 , NHCOR s20 ,
Figure imgf000097_0003
- RR1199 iiss sseelleecctteedd ffrroomm HH oorr d C1--dC4 aallkkyyll aannd R20 is selected from H, d-C4 alkyl, benzyl optionally substituted with 1 , 2, 3 or 4 C1-C4 alkoxy, and a group
Figure imgf000097_0004
wherein s is an integer selected from 0, 1 , 2 and 3; or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof, with the proviso that when B is selected from
Figure imgf000098_0001
then A is not
H
Figure imgf000098_0002
and with the exception of N-Benzyl-4-[2-(2-hydroxy-2-phenyl-ethylamino)- propylj-benzamide.
2. A compound according to claim 1 , wherein A is selected from
CH
3 and B is selected from
Figure imgf000098_0003
3. A compound according to claim 1 , said compound being of formula
Figure imgf000098_0004
4. A compound according to any one of claims 1 to 3 wherein Q1 is a group
*-NH-Q2-Z, wherein Z is cyclohexyl or adamantly,
Figure imgf000099_0001
-NH-Q -Z, wherein Z is a group
Figure imgf000099_0002
wherein R3, R4, R5, R6 and R7 are the same or different and are selected from
H, d-d alkyl, OR9, SR9, SOR9, S02R9, CN, halo, CF3, OCF3, S02NR9R10,
CONR9R10, NR9R10, NHCOR10 and phenyl provided at least 2 of R3 to R7 are equal to H; wherein R9 and R10 are the same or different and are selected from H or C1-C4 alkyl.
5. A compound according to any one of claims 1 to 4 wherein Q2 is a single bond, -CH2-, -(CH2)2-, -(CH2)3-, or -(CH(CH3))-.
6. A compound according to claim 1 wherein Q1 is a group *-NH-CH2-Z, wherein Z is a group
Figure imgf000099_0003
7. A compound according to claim 6 wherein Q3 is (CH2)P wherein p is 0 and Q4 is -SO2NH- or C(=0)NH- or wherein Q3 is (CH2)P wherein p is land Q4 is -NH- C(=0)- or -NH-C(=0)-NH-.
8. A compound according to any one of claims 1 , 6 or 7 wherein Q5 is a bond, CH2-, -(CH2)2-, -C(CH3)2-CH2-, -CH(CH3)-CH(OH)- or CH2-CH(CH3)-.
9. A compound according to any one of claims 1 or 6 to 8 wherein Q6 is
Figure imgf000100_0001
wherein R11, R 2, R13, R14 and R15 are selected from H, d-C4 alkyl, phenyl, phenoxy OR16, SR16, halo, CF3, OCF3, COOR17, S02NR16R17, CONR16R17, NHR16R17, NHCOR17, CH2-NHC(=0)NH-R17; and at least two of R11 to R15 represent H.
10. A compound according to any one of claims 1 to 9 wherein R1 is H or CH3 and R2 is CH3.
11. A compound according to claim 1 , selected from the group consisting of examples 1 to 43.
12. A pharmaceutical composition comprising at least an effective amount of a compound of the formula (1) as described in any one of claims 1 to 13 or a pharmaceutically acceptable salt or derived form thereof.
13. A compound of the formula (1 ) as described in any one of claims 1 to 19 or a pharmaceutically acceptable salt, derived form or composition thereof, for use as a medicament.
14. The use of a compound of the formula (1 ) as described in claim 1 or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a drug for the treatment of diseases, disorders, and conditions in which the β2 receptor is involved.
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