WO2004085420A1 - Composes bicycliques utiles en tant qu'agonistes d'angiotensine ii - Google Patents

Composes bicycliques utiles en tant qu'agonistes d'angiotensine ii Download PDF

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WO2004085420A1
WO2004085420A1 PCT/GB2003/001251 GB0301251W WO2004085420A1 WO 2004085420 A1 WO2004085420 A1 WO 2004085420A1 GB 0301251 W GB0301251 W GB 0301251W WO 2004085420 A1 WO2004085420 A1 WO 2004085420A1
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compound
formula
alkyl
alkoxy
compounds
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PCT/GB2003/001251
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Anders Hallberg
Mathias Alterman
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Vicore Pharma Ab
Mcneeney, Stephen, Phillip
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Priority to PCT/GB2003/001251 priority Critical patent/WO2004085420A1/fr
Priority to AU2003219291A priority patent/AU2003219291A1/en
Publication of WO2004085420A1 publication Critical patent/WO2004085420A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention relates to novel pharmaceutically -useful compounds, in particular compounds that are angiotensin II (Angll) agonists, more particularly agonists of the Angll type 2 receptor (hereinafter the AT2 receptor), and especially agonists that bind selectively to that receptor.
  • Angll angiotensin II
  • AT2 receptor Angll type 2 receptor
  • the invention further relates to the use of such compounds as medicaments, to pharmaceutical compositions containing them, and to synthetic routes to their production.
  • the endogenous hormone Angll is a linear octapeptide (Asp -Arg -Val -
  • Tyr -lie -His -Pro -Phe is the active component of the renm- angiotensin system (RAS). It is produced by the sequential processing of the pro-hormone angiotensinogen by renin and angiotensin converting enzyme (ACE).
  • ACE angiotensin converting enzyme
  • the renin-angiotensin system plays an important role in the regulation of blood pressure, body fluid and electrolyte homeostasis.
  • Ang II exerts these physiological actions in many organs including the kidneys, the adrenal glands, the heart, blood vessels, the brain, the gastrointestinal tract and the reproductive organs (de Gasparo et al, Pharmacol. Rev. (2000) 52, 415-472).
  • Angll receptors Two main classes of Angll receptors have been identified, and designated as the type 1 receptor (hereinafter the ATI receptor) and the AT2 receptor.
  • the ATI receptor is expressed in most organs, and is believed to be responsible for the majority of the biological effects of Angll.
  • the AT2 receptor is more prevalent than the ATI receptor in fetal tissues, the adult ovaries, the adrenal medulla and the pancreas. An equal distribution is reported in the brain and uterus (Ardaillou, J. Am. Soc. NephroL, 10, S30-39 (1999)).
  • the AT2 receptor has also been shown to be involved in apoptosis and inhibition of cell proliferation (see de Gasparo et al, supra). Further, it seems to play a role in blood pressure control. For example, it has been shown in transgenic mice lacking AT2 receptors that their blood pressure was elevated. Furthermore, it has been concluded that the AT2 receptor is involved in exploratory behaviour, pain sensitivity and thermoregulation.
  • AT2 receptors have also been shown to increase during pathological circumstances, such as vascular injury, wound healing and heart failure (see de Gasparo et al, supra).
  • AT2 receptor agonists have been shown to be of potential utility in the treatment and/or prophylaxis of disorders of the alimentary tract, such as dyspepsia and irritable bowel syndrome, as well as multiple organ failure (see international patent application WO 99/43339).
  • International patent application WO 00/68226 and US patent number 6,235,766 disclose compounds comprising substituted imidazolyl groups, which groups are attached, via a methylene bridge, to a phenylthiophene moiety, as agonists of angiotensin-(l-7) receptors.
  • International patent application WO 02/072569 discloses similar compounds as agonists of the same receptors.
  • International patent application WO 01/44239 discloses biphenylsulfonamide compounds as combined angiotensin and endothelin receptor antagonists. The use of the compounds as Ang II receptor agonists is neither mentioned nor suggested in any of these documents.
  • Peptide and non-peptide AT2 receptor agonists unrelated structurally to those described herein, and potential uses thereof, have been disclosed in, for example, international patent applications WO 00/38676, WO 00/56345, WO 00/09144, WO 99/58140, WO 99/52540, WO 99/46285, WO 99/45945, WO 99/42122, WO 99/40107, WO 99/40106, WO 99/39743, WO 99/26644, WO 98/33813, WO 00/02905 and WO 99/46285; US patent number 5,834,432; and Japanese patent application JP 143695.
  • Angll antagonists (which bind to the ATI and/or AT2 receptors) have been disclosed in inter alia European patent application EP 512 675; international patent applications WO 94/27597, WO 94/02142, WO 95/23792 and WO 94/03435; and US patent numbers 5,091,390, 5,177,074, 5,412,097, 5,250,521, 5,260,285, 5,376,666, 5,252,574, 5,312,820, 5,330,987, 5,166,206, 5,932,575, 5,444,068, 5,635,525, 5,541,229, 5,864,043 and 5,240,928.
  • Angll agonists, and particularly AT2 receptor agonists are not contemplated in any of these documents.
  • US patent number 5,444,067 discloses compounds comprising a 5,7- dimethyl-2-ethylpyridinoimidazolyl group attached, via a methylene bridge, to a phenylthiophene moiety, as Angll agonists.
  • international patent application WO 02/96883 discloses compounds comprising certain monocyclic heterocyclic groups attached, via a methylene bridge, to substituted phenylthiophene and biphenyl moieties. The compounds disclosed therein are indicated as Angll agonists and in particular as selective AT2 receptor agonists.
  • X represents -0-, -C(O)- or -S(0) 2 -;
  • R , 1a and R , 1b independently represent H, C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, Ar 1 , Het 1 , C ⁇ _ 3 alkyl-Ar 2 , C 1-3 alkyl-Het 2 , C 1-3 alkoxy-Ar 3 or C 1-3 alkoxy- Het 3 ; or, in the case where X represents -C(O)- , R la may also represent C 1- alkoxy or -O-Ar 4 ;
  • Yi, Y 2 , Y 3 and Y independently represent -CH- or -CF-;
  • Z 2 represents -CH-, -0-, -S- or -N-; provided that:
  • R represents C ⁇ _ 6 alkyl, C 1-6 alkoxy or C 1-6 alkoxy-C ⁇ -6 -alkyl;
  • R 4 represents C 1-6 alkyl, C ⁇ . 6 alkoxy, C ⁇ _ 6 alkoxy-C ⁇ _ 6 -alkyl, C ⁇ _ alkylamino or di-C 1- alkylamino;
  • R 5 represents C 1-6 alkyl, or a pharmaceutically-acceptable salt thereof, which compounds and salts are referred to together hereinafter as "the compounds of the invention".
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo or by freeze-drying).
  • Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • alkyl groups, and the alkyl parts of alkoxy, alkoxyalkyl, alkylamino, alkyl-aryl, alkyl-heterocyclic groups, alkoxy-aryl and alkoxy-heterocyclic groups, as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic/acyclic.
  • alkyl groups, and alkyl parts of alkoxy, alkoxyalkyl, alkylamino, alkyl-aryl, alkyl-heterocyclic, alkoxy-aryl and alkoxy-heterocyclic groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated. Unless otherwise specified, such groups may also be substituted by one or more halo, and especially fluoro, atoms.
  • alkoxy and aryloxy (e.g. -O-Ar ) groups are attached to the rest of the molecule via the oxygen atom in that group
  • alkylamino groups are attached to the rest of the molecule via the nitrogen atom of the amino part of that group
  • alkoxyalkyl, alkyl-aryl and alkyl- heterocyclic groups are attached to the rest of the molecule via the alkyl part of that group
  • alkoxy-aryl and alkoxy-heterocyclic groups are attached to the rest of the molecule via the alkyl part of the alkoxy part of that group.
  • halo when used herein, includes fluoro, chloro, bromo and iodo.
  • C ⁇ -io ar yl groups include phenyl, naphthyl and the like (preferably phenyl).
  • Preferred optional substituents on aromatic groups include C 1-3 alkyl groups (such as methyl) or C 1-3 alkoxy groups.
  • Het (Het to Het ) groups that may be mentioned include those containing 1 to 4 heteroatoms (selected from the group oxygen, nitrogen and/or sulfur) and in which the total number of atoms in the ring system are between five and twelve. Het (Het to Het ) groups may be fully saturated, wholly aromatic, partly aromatic and/or bicyclic in character.
  • Heterocyclic groups that may be mentioned include benzodioxanyl, benzodioxepanyl, benzodioxolyl, benzofuranyl, benzofurazanyl, benzimidazolyl, benzomorpholinyl, benzothiophenyl, chromanyl, cinnolinyl, dioxanyl, furanyl, hydantoinyl, imidazolyl, imidazo[l,2-_.]pyridinyl, indolyl, isoquinolinyl, isoxazolyl, maleimido, morpholinyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimindinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl,
  • Het 1 that may be mentioned include thiophenyl, furanyl, pyridinyl and thiazolyl.
  • Values of Het 2 that may be mentioned include pyridinyl, furanyl, thiophenyl and thiazolyl.
  • Values of Het 3 that may be mentioned include pyridinyl.
  • Substituents on Het (Het 1 to Het 3 ) groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of Het (Het to Het ) groups may be via any atom in the ring system including (where appropriate) a heteroatom, or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • Het (Het 1 to Het 3 ) groups may also be in the N- or _?-oxidised fonn.
  • Preferred ring systems comprising the substituents Y ls Y 2 , Y 3 and Y 4 include phenyl groups.
  • the ring systems in compounds of formula I that comprise the groups Zi and Z 2 are aromatic in nature.
  • an additional H atom may necessarily be bonded to that CH group or N atom, in order to ensure that the rules of valency are adhered to.
  • Preferred ring systems comprising Zi and Z 2 include oxazole groups, thiazole groups, phenyl groups, pyridinyl groups, thiophenyl groups and furanyl groups.
  • Compounds of the invention also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.
  • Preferred compounds of the invention include those in which R la and R lb independently represent H, C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, Ar 1 , Het 1 , C 1-3 alkyl- Ar 2 , C 1-3 alkyl-Het 2 , C ⁇ -3 alkoxy-Ar 3 or C 1-3 alkoxy-Het 3 .
  • R la does not represent
  • More preferred compounds of the invention include those in which:
  • R la represents H, C 1-5 alkoxy, or, more preferably, C ⁇ _ 5 alkyl, Ar 1 or Het 1 ;
  • Het 1 represents thiophenyl
  • R represents H or, more preferably, C 1- alkyl, phenyl (optionally substituted by one or more . 2 alkyl groups), C 1-2 alkylphenyl, C ⁇ _ 2 alkyl-
  • Het 2 represents pyridinyl.
  • More preferred compounds of the invention include those in which: X represents -O- or, more preferably, -C(O)-;
  • R a represents H, C 1-3 alkoxy (e.g. ethoxy), or, more preferably, C 1-4 alkyl (e.g. methyl or n-butyl), phenyl or thiophenyl;
  • R represents H or, more preferably, Cj -3 alkyl (e.g. methyl or ethyl), phenyl (optionally substituted by one or more methyl groups), benzyl or methylpyridinyl;
  • Z 2 represents -CH-
  • R 2 represents -S(0) 2 N(H)C(0)R 4 ;
  • R represents n-butyl or, particularly, iso-butyl;
  • R represents n-butyl, n-butoxymethyl, .sobutoxy and especially, w-butoxy.
  • R la When X represents -0-, preferred values of R la include C ⁇ _ 3 alkyl, such as methyl. When X represents -C(O)-, preferred values of R la include H, C 1-3 alkoxy (e.g. ethoxy), C ⁇ _ 4 alkyl (e.g. methyl or /.-butyl), phenyl or thiophenyl. When X represents -S(0) 2 -, preferced values of R la include C 1-3 alkyl, such as methyl.
  • R 4 When R 2 represents -S(0) 2 N(H)C(0)R 4 , preferred values of R 4 include n- butoxymethyl, wo-butoxy and especially, n-butoxy.
  • R represents Ar or Het
  • those groups are not substituted with a cyano group, e.g. at the 2-position relative to the point
  • More preferred compounds of the invention include the compounds of the examples described hereinafter.
  • R la , R lb , X, Y ls Y 2 , Y 3 , Y 4 , Z l5 Z 2 and R 3 are as hereinbefore defined with a compound of formula III,
  • G represents C(O) or S(0) 2 (as appropriate)
  • L 1 represents a suitable leaving group, such as halo (e.g. chloro or bromo) and R 4 is as hereinbefore defined, for example at around room temperature or above (e.g. up to 60-70°C) in the presence of a suitable base (e.g. pyrollidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, di-zso-propylamine, 1 ,8-diazabicyclo[5.4.0]undec- 7-ene, sodium hydroxide, or mixtures thereof) and an appropriate solvent (e.g.
  • a suitable base e.g. pyrollidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, di-zso-propylamine, 1 ,8-diazabicyclo[5.4.0]
  • Preferred base/solvent systems for compounds of formula III in which G is C(O) include pyrollidinopyridine/pyridine, pyrollidinopyridine/triethylamine, dimethylaminopyridine/pyridme or dimethylaminopyridine/triethylamine.
  • Preferred base/solvent systems for compounds of formula III in which G is S(0) 2 include NaOH/THF; (ii) for compounds of formula I in which R 2 represents -S(0) 2 N(H)C(0)R 4 and R 4 represents _ 6 alkoxy-C 1-6 -alkyl, coupling of a compound of formula II as hereinbefore defined with a compound of formula IV,
  • R 4a represents C ⁇ _ 6 alkoxy-C ⁇ _ 6 -alkyl, for example under similar conditions to those described under process step (i) above, in the presence of a suitable coupling reagent (e.g. l, -carbonyl-diimidazole, N,N'- dicyclohexylcarbodiimide, N,N'-disuccinimidyl carbonate, benzotriazole-1- yloxytris(dimethylamino)phos ⁇ honiumhexafluorophosphate, 2-( 1 H- benzotriazole- 1 -yl)- 1,1,3 ,3 -tetramethyluronium hexafluorophosphate, benzotriazole- 1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate, bromo-tris-pynOlidinophosponium hexafluorophosphate or 2-(lH-
  • R la , R lb , X, Y l5 Y 2 , Y 3 , Y 4 , Z Z 2 and R 3 are as hereinbefore defined with a compound of formula VI,
  • R 4 is as hereinbefore defined, for example in the presence of a suitable coupling reagent (such as those described in process step (ii) hereinbefore), and under similar reaction conditions to those described hereinbefore for preparation of compounds of formula I in which R 4 represents C 1-6 alkoxy-C ⁇ _ 6 -alkyl;
  • R a , R , X, Y l5 Y 2 , Y 3 , Y , Z ls Z 2 and R are as hereinbefore defined with a compound of formula VIII,
  • R 4 is as hereinbefore defined, for example at around 50°C in the presence of a suitable base (e.g. sodium hydride) and an appropriate organic solvent (e.g. THF); (v) for compounds of formula I in which R 2 represents -N(H)S(0) 2 N(H)C(0)R 5 and R 5 is as hereinbefore defined, reaction of a compound of fomiula IX,
  • a suitable base e.g. sodium hydride
  • an appropriate organic solvent e.g. THF
  • R la , R lb , X, Y b Y 2 , Y 3 , Y 4 , Z l5 Z 2 and R 3 are as hereinbefore defined with a compound of formula X,
  • R 5 is as hereinbefore defined, for example at or around room temperature in the presence of a suitable base (e.g. sodium hydroxide or triethylamine) and a suitable organic solvent (e.g. benzene or dichloromethane) ;
  • a suitable base e.g. sodium hydroxide or triethylamine
  • a suitable organic solvent e.g. benzene or dichloromethane
  • R 5 S(0) 2 N(H)C(0)OR x XI wherein R x represents C ⁇ _ 2 alkyl and R is as hereinbefore defined, for example at or around room temperature in the presence of a suitable organic solvent (e.g. dichloromethane);
  • a suitable organic solvent e.g. dichloromethane
  • R 5 is as hereinbefore defined, for example at or around room temperature in the presence of a suitable organic solvent (e.g. dichloromethane) ;
  • a suitable organic solvent e.g. dichloromethane
  • R is C 1-6 alkyl, for example at or around room temperature in the presence of a suitable base (e.g. sodium hydroxide or potassium hydroxide and an appropriate organic solvent (e.g. acetone or acetonitrile);
  • a suitable base e.g. sodium hydroxide or potassium hydroxide and an appropriate organic solvent (e.g. acetone or acetonitrile);
  • R 4c and R 4d independently represent C 1-6 alkyl, for example at above room temperature (e.g. at between 70°C and 100°C) in the presence of an appropriate organic solvent (e.g. toluene); or
  • R a and R 1 are as hereinbefore defined under standard conditions (e.g. in the presence of a suitable organic solvent (e.g. methanol, ethanol, dichloromethane, dichloroethane, tetrahydrofuran or dioxane), and, subsequently, an appropriate reducing agent (e.g. sodium borohydride, sodium cyanoborohydride or NaBH(OAc) 3 )).
  • a suitable organic solvent e.g. methanol, ethanol, dichloromethane, dichloroethane, tetrahydrofuran or dioxane
  • an appropriate reducing agent e.g. sodium borohydride, sodium cyanoborohydride or NaBH(OAc) 3
  • R la , R l , X, Y Y 2 , Y 3 , Y 4 , Z l5 Z 2 and R 3 are as hereinbefore defined, for example under standard oxidation conditions in the presence of a suitable oxidising agent, such as potassium permanganate or chromium (VI) oxide.
  • a suitable oxidising agent such as potassium permanganate or chromium (VI) oxide.
  • R y represents -S0 2 NH 2 (in the case of a compound of formula II), -CONH 2 (in the case of a compound of formula VII), -NH 2 (in the case of a compound of formula IX), or -CHO (in the case of a compound of formula XVI), and R lb , Y Y 2 , Y 3 , Y 4 , Z,, Z 2 and R 3 are as hereinbefore defined, with a compound of formula XVIII,
  • X a represents -C(O)- or -S(0) 2 - and R la and L are as hereinbefore defined, for example at or around room temperature in the presence of a suitable base (e.g. triethylamine, 4-dimethylaminopyridine, pyrollidinopyridine, diisopropylethylamine or mixtures thereof) and an appropriate organic solvent (e.g. dichloromethane, chloroform, tetrahydrofuran, dioxane or dimethylformamide).
  • a suitable base e.g. triethylamine, 4-dimethylaminopyridine, pyrollidinopyridine, diisopropylethylamine or mixtures thereof
  • an appropriate organic solvent e.g. dichloromethane, chloroform, tetrahydrofuran, dioxane or dimethylformamide
  • compounds of formulae II, VII, IX and XVI in which R la represents H and X represents -C(O)- may be prepared in this way by reaction of a compound of formula XVII with ammonium formate, for example at above room temperature (e.g. between 80 to 120°C) in the presence of an appropriate organic solvent (e.g. acetonitrile, dioxane, dimethylformamide, ethylene glycol dimethyl ether, l-methyl-2-pyrrolidinone or dimethylsulphoxide).
  • an appropriate organic solvent e.g. acetonitrile, dioxane, dimethylformamide, ethylene glycol dimethyl ether, l-methyl-2-pyrrolidinone or dimethylsulphoxide.
  • compounds of formula XVII are protected at the R y position prior to carrying out the reaction with the compound of formula XVIII or ammonium formate. Suitable protecting groups for different values of R y are described hereinafter. If a protected version of a
  • L 1 , Y 1 ⁇ Y 2 , Y 3 , Y , Z l5 Z 2 , R 3 and R y are as hereinbefore defined (L 1 may, in particular, represent bromo), with a compound of formula XX,
  • R la , X a and R 1 are as hereinbefore defined, for example at around or below room temperature in the presence of a suitable base (e.g. potassium hydroxide, potassium tert-butoxide, triethylamine or ⁇ i-iso- propylethylamine) and an appropriate organic solvent (e.g. DMSO, DMF, THF or CH 2 C1 2 ).
  • a suitable base e.g. potassium hydroxide, potassium tert-butoxide, triethylamine or ⁇ i-iso- propylethylamine
  • an appropriate organic solvent e.g. DMSO, DMF, THF or CH 2 C1 2
  • compounds of formula XIX are preferably protected at the R y position prior to carrying out the reaction with the compound of formula XX. If a protected version of a compound of formula XIX is employed, this reaction may be followed by deprotection of the R y group under standard conditions, for example as described hereinafter.
  • L 2 represents a suitable leaving group, such as trimethylsulphonate, or halo, such as iodo or bromo
  • R a , R , X, Yj, Y 2 , Y 3 and Y 4 are as hereinbefore defined, with a compound of formula XXII,
  • R y , R 3 , Z 1 and Z 2 are as hereinbefore defined, or a protected derivative thereof, for example in the presence of an appropriate coupling catalyst system (e.g. a palladium catalyst, such as Pd(PPh 3 ) 4 or
  • Pd(OAc) 2 /ligand (wherein the ligand may be, for example, PPh 3 , P(o-Tol) 3 or l,l'-bis(diphenylphosphino) ferrocene)) and a suitable base (e.g. sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, triethylamine or di- ⁇ o-propylamine)), as well as a suitable solvent system (e.g. toluene, ethanol, dimethoxymethane, dimethylformamide, ethylene glycol dimethyl ether, water, dioxane or mixtures thereof). This reaction may be carried out at above room temperature (e.g. at the reflux temperature of the solvent system that is employed).
  • a suitable base e.g. sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, triethylamine or di- ⁇ o-propylamine
  • solvent system
  • R , R , Zi and Z 2 are as hereinbefore defined, for example under similar conditions to those decribed hereinbefore for preparation of compounds of formulae II, VII, IX and XVI (third process).
  • R 1 is as hereinbefore defined, with an appropriate oxidising agent
  • L 1 and R la are as hereinbefore defined, for example in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, sodium hydroxide or triethylamine) and an appropriate organic solvent (e.g. dioxane, dichloromethane, dimethylformamide and/or acetone).
  • a suitable base e.g. sodium hydride, sodium bicarbonate, sodium hydroxide or triethylamine
  • an appropriate organic solvent e.g. dioxane, dichloromethane, dimethylformamide and/or acetone.
  • R la is as hereinbefore defined, with chloramine (NH 2 C1), for example in the presence of an appropriate base (e.g. sodium hydride, sodium hydroxide or triethylamine) and a suitable solvent (such as diethyl ether, dioxane, dimethylformamide or dichloromethane), followed by reaction of the intermediate oxylamine (R la ONH 2 ) with a compound of formula XXIX,
  • an appropriate base e.g. sodium hydride, sodium hydroxide or triethylamine
  • a suitable solvent such as diethyl ether, dioxane, dimethylformamide or dichloromethane
  • L and R are as hereinbefore defined, for example in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, sodium hydroxide or triethylamine) and an appropriate organic solvent (e.g. dioxane, dichloromethane, dimethylformamide and/or acetone).
  • a suitable base e.g. sodium hydride, sodium bicarbonate, sodium hydroxide or triethylamine
  • an appropriate organic solvent e.g. dioxane, dichloromethane, dimethylformamide and/or acetone
  • Compounds of formula XVII may be prepared by reductive amination of a compound of formula XXIII as hereinbefore defined, or an appropriate protected derivative thereof, in the presence of an amine of formula XXVI as hereinbefore defined, for example under standard conditions, such as those described hereinbefore for preparation of compounds of fonnula I.
  • Y ls Y 2 , Y 3s Y 4 , Z l3 Z 2 , R 3 and R y are as hereinbefore defined, or an appropriate protected derivative thereof, to an appropriate leaving group, L 1 (e.g., in the case where L 1 is bromo, conversion may be carried out by reaction with CBr 4 , for example at or around room temperature in the presence of a base (e.g. triphenylphosphine) and a suitable organic solvent (e.g. DMF)).
  • a base e.g. triphenylphosphine
  • DMF suitable organic solvent
  • W 1 represents -CHO, -CH 2 OH or -CH 2 NH 2 and L 2 , Y Y 2 , Y 3 and Y 4 are as hereinbefore defined by way of standard techniques, for example by way of known techniques for the conversion of a -CHO, a -CH 2 OH or a -CH 2 NH 2 group into a
  • R 3 wherein R y , R 3 , Zi and Z 2 are as hereinbefore defined, or an appropriate protected derivative thereof, with a reagent system that will enable the introduction of -B(OH) 2 into the appropriate ring system.
  • Suitable reagent systems include trialkylborates (e.g. tri-t_?o-propylborate). Such reactions may be carried out, for example, at low temperature (e.g. between -100°C and 0°C, e.g. between -80°C (such as -78°C) and -10°C (such as -20°C)) in the presence of a suitable base (e.g. n-butyl lithium) and an appropriate organic solvent (e.g. THF), followed by acid hydrolysis (e.g. in the presence of dilute HCl).
  • a suitable base e.g. n-butyl lithium
  • an appropriate organic solvent e.g. THF
  • Compounds of formulae XXIII and XXX may be prepared by reaction of a compound of formula XXXI as hereinbefore defined (in which former case, W 1 represents -CHO and in which latter case, W 1 represents -CH 2 OH), with a compound of formula XXII as hereinbefore defined, or an appropriate protected derivative thereof, for example under similar conditions to those decribed hereinbefore for preparation of compounds of formulae II, VII, IX and XVI (third process).
  • R ya represents -S(0) 2 NH 2 , -C(0)NH 2 or -CHO and Zi and Z 2 are as hereinbefore defined, or a protected derivative thereof, with a compound of formula XXXIV,
  • L represents a suitable leaving group (such as toluenesulphonate, benzenesulphonate, methanesulphonate or halo, such as bromo or iodo) and R is as hereinbefore defined, for example at below room temperature (e.g. between around -35°C and around -85°C), in the presence of a suitable base (e.g. n-butyl lithium) and an appropriate solvent (e.g. THF).
  • a suitable leaving group such as toluenesulphonate, benzenesulphonate, methanesulphonate or halo, such as bromo or iodo
  • R , ⁇ and Z 2 are as hereinbefore defined with an appropriate reagent for introduction of a -S(0) 2 NH 2 group into the appropriate ring system (for example chlorosulphonic acid., or thionyl chloride in the presence of a suitable strong base (e.g. butyl lithium)), followed by reaction of the resultant intermediate with ammonia, or a protected derivative thereof (e.g. tert-butylamine), under conditions that are well known to those skilled in the art.
  • an appropriate reagent for introduction of a -S(0) 2 NH 2 group into the appropriate ring system for example chlorosulphonic acid., or thionyl chloride in the presence of a suitable strong base (e.g. butyl lithium)
  • ammonia or a protected derivative thereof (e.g. tert-butylamine)
  • R z represents an appropriate protecting group, such as an alkyl group, including C 1-6 alkyl, e.g. tert-butyl for example at around 0°C, in the presence of a suitable base (e.g. n-butyl lithium) and an appropriate solvent (e.g. THF).
  • a suitable base e.g. n-butyl lithium
  • an appropriate solvent e.g. THF
  • R 3 , Zi and Z 2 are as hereinbefore defined with a protected (e.g. an (e.g. C 1-6 ) alkyl, such as tert-butyl-protected) derivative of ammonia (e.g. tert-butylamine) under standard coupling conditions
  • a protected e.g. an (e.g. C 1-6 ) alkyl, such as tert-butyl-protected
  • ammonia e.g. tert-butylamine
  • XX, XXIV, XXVI, XXVII, XXVIII, XXIX, XXXI, XXXIII, XXXIV, XXXV and XXXVI are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.
  • Compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
  • Functional groups that it is desirable to protect include sulphonamido, amido, amino and aldehyde.
  • Suitable protecting groups for sulphonamido, amido and amino include tert-butyloxycarbonyl, benzyloxycarbonyl, 2- trimethylsilylethoxycarbonyl (Teoc) or tert-butyl.
  • Suitable protecting groups for aldehyde include alcohols, such as methanol or ethanol, and diols, such as 1,3-propanediol or, preferably, 1,2-ethanediol (so forming a cyclic acetal).
  • the protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
  • Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter.
  • protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques (e.g. using trifluoroacetic acid, sulfuric acid, toluenesulfonic acid or boron trichloride).
  • compounds of the invention are agonists of Angll, more particularly, are agonists of the AT2 receptor, and, especially, are selective agonists of that sub-receptor, for example as may be demonstrated in the tests described below.
  • the compounds of the invention are thus expected to be useful in those conditions in which endogenous production of Angll is deficient and/or where an increase in the effect of Angll is desired or required.
  • the compounds of the invention are further expected to be useful in those conditions where AT2 receptors are expressed and their stimulation is desired or required.
  • the compounds of the invention are further indicated in the treatment of conditions characterised by vasoconstriction, increased cell growth and/or differentiation, increased cardiac contractility, increased cardiovascular hypertrophy, and/or increased fluid and electrolyte retention.
  • the compounds of the invention are further indicated in the treatment of stress-related disorders, and/or in the improvement of microcirculation and or mucosa-protective mechanisms.
  • compounds of the invention are expected to be useful in the treatment of disorders, which may be characterised as indicated above, and which are of, for example, the gastrointestinal tract, the cardiovascular system, the respiratory tract, the kidneys, the eyes, the female reproductive (ovulation) system and the central nervous system (CNS).
  • disorders which may be characterised as indicated above, and which are of, for example, the gastrointestinal tract, the cardiovascular system, the respiratory tract, the kidneys, the eyes, the female reproductive (ovulation) system and the central nervous system (CNS).
  • disorders of the gastrointestinal tract that may be mentioned include oesophagitis, Barrett's oesophagus, gastric ulcers, duodenal ulcers, dyspepsia (including non-ulcer dyspepsia), gastro-oesophageal reflux, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatitis, hepatic disorders (such as hepatitis), gall bladder disease, multiple organ failure (MOF) and sepsis.
  • IBS irritable bowel syndrome
  • IBD inflammatory bowel disease
  • pancreatitis hepatic disorders (such as hepatitis)
  • gall bladder disease multiple organ failure (MOF) and sepsis.
  • MOF multiple organ failure
  • gastrointestinal disorders include xerostomia, gastritis, gastroparesis, hyperacidity, disorders of the bilary tract, coelicia, Crohn's disease, ulcerative colitis, diarrhoea, constipation, colic, dysphagia, vomiting, nausea, indigestion and Sj ⁇ gren's syndrome.
  • disorders of the respiratory tract include inflammatory disorders, such as asthma, obstructive lung diseases (such as chronic obstructive lung disease), pneumonitis, pulmonary hypertension and adult respiratory distress syndrome.
  • inflammatory disorders such as asthma, obstructive lung diseases (such as chronic obstructive lung disease), pneumonitis, pulmonary hypertension and adult respiratory distress syndrome.
  • kidneys disorders of the kidneys that may be mentioned include renal failure, nephritis and renal hypertension.
  • disorders of the eyes that may be mentioned include diabetic retinopathy, premature retinopathy and retinal microvascularisation.
  • Disorders of the female reproductive system that may be mentioned include ovulatory dysfunction.
  • Cardiovascular disorders that may be mentioned include hypertension, cardiac hypertrophy, cardiac failure, artherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial lesions, post- balloon dilatation stenosis, angiogenesis, diabetic complications, microvascular dysfunction, angina, cardiac arrhythmias, claudicatio intermittens, preeclampsia, myocardial infarction, reinfarction, ischaemic lesions, erectile dysfunction and neointima proliferation.
  • disorders of the CNS include cognitive dysfunctions, dysfunctions of food intake (hunger/satiety) and thirst, stroke, cerebral bleeding, cerebral embolus and cerebral infarction.
  • Compounds of the invention may also be useful in the modulation of growth metabolism and proliferation, for example in the treatment of hypertrophic disorders, prostate hyperplasia, autoimmune disorders, psoriasis, obesity, neuronal regeneration, the healing of ulcers, inhibition of adipose tissue hype ⁇ lasia, stem cell differentiation and proliferation, cancer (e.g. in the gastrointestinal tract, lung cancer, etc), apoptosis, tumours (generally) and hypertrophy, diabetes, neuronal lesions and organ rejection.
  • the compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above conditions.
  • a method of treatment of a condition in which endogenous production of Angll is deficient, and/or a condition where an increase in the effect of Angll is desired or required, and/or a condition where AT2 receptors are expressed and their stimulation is desired or required which method comprises administration of a therapeutically effective amount of a compound of the invention to a person suffering from, or susceptible to, such a condition.
  • the compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
  • preferred routes of administration are parenteral (e.g. by injection). Otherwise, the preferred route of administration for compounds of the invention is oral.
  • the compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice.
  • a pharmaceutical formulation including a compound of the invention, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Compounds of the invention may also be administered in combination with other AT2 agonists that are known in the art, as well as in combination with ATI receptor antagonists that are known in the art, such as losartan, or in combination with an inhibitor of angiotensin converting enzyme (ACE).
  • AT2 agonists that are known in the art
  • ATI receptor antagonists that are known in the art, such as losartan
  • ACE angiotensin converting enzyme
  • a combination product comprising:
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • Such combination products provide for the administration of compound of the invention in conjunction with an ATI receptor antagonist, or an ACE inhibitor, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises compound of the invention, and at least one comprises ATI receptor antagonist, or ACE inhibitor, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including compound of the invention and ATI receptor antagonist or ACE inhibitor).
  • a pharmaceutical formulation including a compound of the invention and an ATI receptor antagonist, or an ACE inhibitor, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier;
  • a pharmaceutical formulation including a compound of the invention in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation including an ATI receptor antagonist, or an ACE inhibitor, in admixture with a pharmaceutically- acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
  • the compounds of the invention may be administered at varying doses.
  • suitable daily doses are in the range of about 1 to 1000 mg per patient, administered in single or multiple doses. More preferred daily doses are in the range 2.5 to 250 mg per patient. Individual doses of compounds of the invention may be in the range 1 to 100 mg.
  • the physician or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the condition that is to be treated, as well as the age, weight, sex and response of the particular patient to be treated.
  • the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Compounds of the invention have the advantage that they bind selectively to, and exhibit agonist activity at, the AT2 receptor.
  • the affinity ratio for the relevant compound is at least 5:1, preferably at least 10:1 and more preferably at least 20: 1.
  • the compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art.
  • Test A The following test procedures may be employed. Test A
  • Myometrial membranes were prepared from porcine uteri according to the method by Nielsen et al (Clin. Exp. Pharm. Phys. (1997) 24, 309). Any possible interference that may be exhibited by binding of compound to ATi receptors was blocked by addition of 1 ⁇ M of a selective ATI inhibitor. Binding of [ I]Ang II to membranes was conducted in a final volume of 0.5 mL containing 50 mM Tris-HCl (pH 7.4), 100 mM NaCl, 10 mM MgCl 2 , 1 mM EDTA, 0.025% bacitracin, 0.2% BSA, homogenate
  • the specific binding was determined by subtracting the non-specific binding from the total bound [ I]Ang II.
  • the binding data were best fitted with a one-site fit. All experiments were performed at least in triplicate .
  • N-tert-Butylthiophene-2-sulfonamide (10 g, 0.046 mol, see step (a) above) was dissolved in THF (85 mL) under ⁇ 2 and then cooled to -78°C.
  • n-BuLi 1.6 M, 76.9 mL, 0.12 mol
  • the reaction mixture was stirred at -78°C for 30 min. and then at -40°C for 2 h.
  • Iodo-2- methylpropane (10.5 mL, 0.09 mol) was added dropwise to the reaction mixture.
  • the reaction mixture was stirred overnight at room temperature.
  • the reaction was quenched with NH 4 C1 (aq.) and extracted with EtOAc.
  • the catalyst was then transferred into a nitrogen- flushed mixture of 5- .5_)-butyl-2-(N-tert-butylaminosulfonyl)-thiophene-3-boronic acid (1.11 g, 3.13 mmol, based on 90% purity, see step (c) above), 4-bromobenzaldehyde (1.45 g, 7.84 mmol) and potassium carbonate (1.73 g, 12.5 mmol) in a solvent mixture of DME (10 mL), ethanol (3 mL), and water (2 mL). After stirring for 20 h at reflux under a N 2 atmosphere, the reaction mixture was diluted with 1M NaOH solution (20 mL) followed by ethyl acetate (70 mL).
  • Step I The appropriate amine (1.1 eqv., 0.09 mmol, see below) was added to a solution of 3-(4-formylphenyl)-5- ,sO-butyl-N-tert-butylthiophene-2- sulfonamide (30 mg, 0.08 mmol, see Preparation A above) in methanol (1.5 mL) in a sample vial (5 mL size). After being stirred for 2 h, sodium borohydride (6.1 mg, 0.16 mmol) was added and the stirring continued for 2 h.
  • the mixture was acidified with dilute HCl (5 N, 0.1 mL), stirred for 10 min, neutralised with saturated NaHC0 3 solution ( ⁇ 0.5 mL) and diluted with ethyl acetate (10 mL).
  • the contents were poured into diatomaceous earth (liquid-liquid extraction cartridge) in a polypropylene column (packed for 1.5 cm, 24 mL size) and eluted with ethyl acetate (30 mL). Concentration under vacuum afforded the crude product.
  • Step 2 The product from step 1 was dissolved in dry DCM (1.5 mL) in a sample vial (5 mL size). Triethylamine (0.033 mL, 0.24 mmol), DMAP (1 mg, 0.008 mmol) and the appropriate acid chloride or alkyl chloroformate (2 eqv., 0.16 mmol, see below) were then added sequentially. The sample vial was tightly closed. The mixture was stirred overnight, quenched with aqueous saturated NaHC0 3 solution (0.5 mL), stirred for 30 min, and filtered through diatomaceous earth (packed for 1.5 cm in the column of 24 mL capacity) on elution with DCM (30 mL). Concentration in vacuo afforded the crude product.
  • Step 3 The mixture of the product from step 2 and anisole ( ⁇ 2 drops) in trifluoroacetic acid (1.5 mL) in a sample vial (5 mL size) was stirred at 30°C overnight. After the removal of the solvent in vacuo, the residue was dissolved in acetonitrile (2 mL) and evaporated (2 x).
  • Step 4 To a mixture of the product from step 3 in dry DCM (1.5 mL), pyrrollidinopyridine (17.8 mg, 0.12 mmol) and triethylamine (0.5 mL, 0.36 mmol), n-butyl chloroformate (0.04 mL, 0.3 mmol) were sequentially added. The solution was stirred for 12 h, concentrated in vacuo and the crude product purified by LCMS (30% acetonitrile to pure acetonitrile, reverse phase) to afford the title products indicated below:
  • the title compound was synthesised as stated in the above general procedure using benzylamine and valeroyl chloride.
  • the crude product from the final step was purified by LCMS (30% aqueous acetonitrile to pure acetonitrile, reverse phase) to afford a colourless solid (26 mg, 55%).
  • the title compound was synthesised as stated in the above general procedure using 3-picolylamine and benzoyl chloride.
  • the crude product from the final step was purified by LCMS (45% aqueous acetonitrile to pure acetonitrile, reverse phase) to afford a colourless solid (45 mg, 92%).
  • the title compound was synthesised as stated in the above general procedure using 3- ⁇ icolylamine and acetyl chloride.
  • the crude product from the final step was purified by LCMS (45% aqueous acetonitrile to 90% acetonitrile, reverse phase) to afford a colourless syrup (38 mg, 86%).
  • the title compound was synthesised as stated in the above general procedure using ethylamine and acetyl chloride.
  • the crude product in the final step was purified by LCMS (25% aqueous acetonitrile to 90% acetonitrile, reverse phase) to afford a colourless solid (18 mg, 46%).
  • the title compound was synthesised as stated in the above general procedure using methylamine and methanesulfonyl chloride.
  • the crude product from the final step was purified by LCMS (35% aqueous acetonitrile to 70% acetonitrile, reverse phase) to afford a colourless syrup (40 mg, 59%).
  • step (a) The product from step (a) was treated in accordance with Steps 3 and 4 of the General Procedure for Examples 1 to 12.
  • the crude product was purified by LCMS (45% to 85% aqueous acetonitrile) to afford pure title product as a colourless solid (36 mg, 79%). mp 101-102°C
  • Example 17 Title compounds of the Examples are tested in Test C above and are found to stimulate markedly mucosal alkalisation. This effect is blocked by co- administration of the selective AT2 receptor antagonist PD 123319 (Sigma Chemical Company).

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Abstract

L'invention concerne des composés représentés par la formule (I) dans laquelle R1a, R1b, X, Y1, Y2, Y3, Y4, Z 1, Z2, R2 et R3 possèdent les significations indiquées dans le descriptif, ainsi que leurs sels acceptables sur le plan pharmaceutique. Ces composés sont utiles en tant qu'agonistes sélectifs du récepteur AT2 et, en particulier, pour traiter des états gastro-intestinaux entre autre, tels que la dyspepsie, le syndrome du colon irritable, le déficit organique multiple ou des maladies cardio-vasculaires.
PCT/GB2003/001251 2003-03-24 2003-03-24 Composes bicycliques utiles en tant qu'agonistes d'angiotensine ii WO2004085420A1 (fr)

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US8461209B2 (en) 2007-06-20 2013-06-11 Mitsubishi Tanabe Pharma Corporation Malonic acid sulfonamide derivative and pharmaceutical use thereof
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US10071099B2 (en) 2014-04-03 2018-09-11 National Cerebral And Cardiovascular Center Medicament for suppressing malignant tumor metastasis
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US11426407B2 (en) 2014-10-06 2022-08-30 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
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