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WO2004046137A1 - Nouveaux agonistes tricycliques de l'angiotensine ii - Google Patents

Nouveaux agonistes tricycliques de l'angiotensine ii Download PDF

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Publication number
WO2004046137A1
WO2004046137A1 PCT/GB2003/005013 GB0305013W WO2004046137A1 WO 2004046137 A1 WO2004046137 A1 WO 2004046137A1 GB 0305013 W GB0305013 W GB 0305013W WO 2004046137 A1 WO2004046137 A1 WO 2004046137A1
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compound
formula
alkyl
compounds
alkoxy
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Mathias Alterman
Anders Hallberg
Yiqian Wan
Kannan Mahalingam
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Vicore Pharma AB
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Vicore Pharma AB
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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
    • C07D409/10—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 carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

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 1 -Arg 2 -Val 3 - Tyr 4 -Ile 5 -His 6 -Pro 7 -Phe 8 ), and is the active component of the renin- angiotensin system (RAS). It is produced by the sequential processing of the pro-hormone angiotensinogen by renin and angiotensin converting enzyme (ACE).
  • 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.
  • Angll antagonists (which bind to the ATI and/or AT2 receptors) have been disclosed in inter alia European patent applications EP 409 332, EP 512 675, EP 516 392, EP 542 059 and EP 624 583; international patent applications WO 92/20662, WO 93/01177, 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, 5,262,412, 5,312,820, 5,330,987, 5,166,206, 5,932,575, 5,240,928 and 6,235,766.
  • 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.
  • 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 -C(R la )(R lb )-, -N(R la )- or -O-; the dotted line signifies an optional double bond; and in the case when the dotted line does not signify a double bond, X 2 and X 3 independently represent -C(R lc )(R ld , -N(R le )-, -0-, -C(O)- or -C(R lf )(R lg )-C(R lh )(R lj )- provided that:
  • R la , R lb , R lc , R ld , R le , R lf , R lg , R lh and R lj independently represent H, C ⁇ - 6 alkyl, C ⁇ _ 6 alkoxy-Cj-g alkyl, Ar 1 , Het 1 , C 1 . 3 alkyl-Ar 2 , C ⁇ . 3 alkyl-Het 2 , C ⁇ - 3 alkoxy- Ar 3 or C i - 3 alkoxy-Het 3 ;
  • Z 2 represents -CH-, -O-, -S- or -N-; provided that:
  • R 3 represents C ⁇ - 6 alkyl, C ⁇ - 6 alkoxy, C ⁇ - 6 al oxy- -e-alkyl or di-C ⁇ - 3 - alkylamino-C ⁇ - -alkyl;
  • R 4 represents C ⁇ - 6 alkyl, C ⁇ - 6 alkoxy C ⁇ - 6 alkoxy-C ⁇ - 6 -alkyl, C 1 . 3 alkoxy-C ⁇ - 6 -alkoxy, C ⁇ - 6 alkylamino or di- - ⁇ alkylamino;
  • R 5 represents C ⁇ - 6 alkyl, or a pharmaceutically-acceptable salt thereof, which compounds and salts are referred to together hereinafter as "the compounds of the invention".
  • Pharmaceutically-acceptable 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, alkoxyalkoxy, alkylamino, alkylaminoalkyl, 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, alkoxyalkoxy, alkylamino, alkylaminoalkyl, 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 alkoxyalkoxy groups are attached to the rest of the molecule via the/an 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, alkylarninoalkyl, 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 6 - ⁇ o aryl groups include phenyl, naphthyl and the like (preferably phenyl).
  • Preferred optional substituents on aromatic groups include C ⁇ _ 3 alkyl groups (such as methyl) or C ⁇ - 3 alkoxy groups.
  • Het (Het 1 to Het 3 ) 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
  • 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,
  • 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 1 to Het 3 ) 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 ) groups may also be in the N- or S-oxidised form.
  • Preferred ring systems comprising the substituents Yi, Y 2 , Y 3 and Y 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 ⁇ 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 may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
  • 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: the dotted line does not signify a double bond;
  • Xi represents -C(R la )(R lb )- or -N(R la )-;
  • X 2 represents -0-, -N(R le )- or, more preferably, -C(R lc )(R ld )-;
  • X 3 represents -O-, -C(R lf )(R lg )-C(R lh )(R lj )- or, more preferably, -C(R lc )(R ld )- or -C(O)-;
  • R la represents H or C ⁇ - 3 alkyl, such as methyl
  • R lb represents C ⁇ _ 3 alkyl, such as methyl, or, especially, H;
  • R lc represents H or C ⁇ - 3 alkyl, such as methyl
  • R ld represents H or C ⁇ - 3 alkyl, such as methyl.
  • More preferred compounds of the invention include those in which:
  • Xi represents -CH 2 - or -N(CH 3 )-;
  • X 2 represents -CH 2 - or -C(CH 3 ) 2 -;
  • X 3 represents -CH 2 - or -C(O)-;
  • A represents -CH 2 -;
  • Z 2 represents -CH-;
  • R 2 represents S(0) 2 N(H)C(0)R 4 ;
  • R 3 represents n-butyl or, particularly, t-? ⁇ -butyl;
  • R 4 represents n-butoxymethyl, ⁇ -butoxy and especially, n-butoxy.
  • Preferred ring systems comprising the groups X X 2 and X 3 include optionally substituted 2-pyrrolidinon-l-yl groups, 2-imidazolidinon-l-yl and hydantoin-3 -yl groups .
  • More preferred compounds of the invention include the compounds of the examples described hereinafter.
  • 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. pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimemylamine, 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. pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimemylamine, dimethylaminopyridine, di-zso-propylamine, 1 ,8-diazabic
  • Preferred base/solvent systems for compounds of formula III in which G is C(O) include pyrrolidinopyridine/pyridine, pyrrolidinopyridine/triethylamine, dimethylaminopyridine/pyridine 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 C ⁇ - 6 alkoxy-C ⁇ - 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, NJ - dicyclohexylcarbodiimide, 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-disuccinimidyl carbonate, benzotriazole-1- yloxyhis(dimemyla ⁇ ino)phosphoniumhexafluorophosphate, 2-(l H- benzotriazole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphate, benzotriazole- 1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate, brom
  • 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 ⁇ - 6 alkoxy-C ⁇ - 6 -alkyl;
  • a suitable base e.g. sodium hydride
  • an appropriate organic solvent e.g. THF
  • 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 x represents . 2 alkyl and 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 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 4b is - 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); or (ix) for compounds of formula I in which R 2 represents -S(0) 2 N(H)C(0)R 4 and R 4 represents di-C ⁇ - 6 alkylamino, reaction of a corresponding compound of formula I in which R 2 represents -S(0) 2 N(H)C(O)R 4 and R 4 represents C ⁇ - 6 alkoxy with an amine of formula XIV,
  • a suitable base e.g. sodium hydroxide or potassium hydroxide and an appropriate organic solvent (e.g. acetone or acetonitrile)
  • an appropriate organic solvent e.g. acetone or acetonitrile
  • R 4c and R 4d independently represent C ⁇ - 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).
  • an appropriate organic solvent e.g. toluene
  • dotted line, Xi, X 2 , X 3 , A, Y l9 Y 2 , Y 3 , Y , Z 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.
  • Compounds of formulae II, VII, IX and XV may be prepared by reaction of a compound of formula XVI,
  • R y represents -SO 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 XV) and R , Z and Z are as hereinbefore defined, or a protected derivative thereof, with a compound of formula XVII,
  • L 2 represents a suitable leaving group, such as trimethylsulphonate, or halo, such as iodo or bromo
  • Xi, X 2 , X 3 , A, Yi, Y 2 , Y 3 and Y 4 are as hereinbefore defined, 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, -bis(diphenylphosphino)ferrocene)) and a suitable base (e.g.
  • a suitable 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
  • A, Yi, Y 2 , Y 3 , Y , Z l5 Z 2 , R y , R and L are as hereinbefore defined (L 1 , in particular, may represent bromo), or a protected (at the R y part) derivative thereof, for example at around or below room temperature in the presence of a suitable base (e.g. potassium hydroxide, potassium tert- butoxide, triethylamine or di-w ⁇ -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 di-w ⁇ -propylethylamine
  • an appropriate organic solvent e.g. DMSO, DMF, THF or CH 2 C1 2
  • suitable bases include potassium hydroxide and potassium tert- butoxide and suitable solvents include DMSO, THF, DMF, dioxane or DCM.
  • suitable bases include triethylamine and di-wo-propylemylamine and suitable solvents include DMSO, DMF, THF and CH 2 C1 2 .
  • Suitable protecting groups for different values of R y are described hereinafter. 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.
  • R y , R 3 , Z ⁇ and Z 2 are as hereinbefore defined, or an appropriate protected derivative thereof, with a reagent system that will enable the introduction of the -B(OH) 2 into the appropriate ring system.
  • Suitable reagent systems include trialkylborates (e.g. tri-t-ro-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.
  • a suitable base e.g. n-butyl lithium
  • an appropriate organic solvent e.g.
  • A, Y l5 Y 2 , Y 3 , Y 4 , L 1 and L 2 are as hereinbefore defined, for example under similar conditions to those described hereinbefore in respect of preparation of compounds of formulae II, VII, IX and XV (second process).
  • A, Y l5 Y 2 , Y 3 , Y 4 and L are as hereinbefore defined, for example under similar conditions to those described hereinbefore in respect of preparation of compounds of formulae II, VII, IX and XV (first process), followed by conversion of the OH group in the resultant intermediate to an appropriate leaving group, L 1 (e.g., in the case where A is -CH 2 - and 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); similarly, when A represents -C(O)- and L 1 represents Cl, the intermediate acid may be reacted with SOCl 2 in benzene or toluene, or with oxalyl chloride in DCM).
  • a base e.g. triphenylphosphine
  • DMF suitable organic solvent
  • R ya represents -S(O) 2 NH 2 , -C(O)NH 2 or -CHO and Z ⁇ and Z 2 are as hereinbefore defined, or a protected derivative thereof, with a compound of formula XXIV,
  • L 3 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. /.-butyl lithium) and an appropriate solvent (e.g. THF).
  • a suitable base e.g. /.-butyl lithium
  • an appropriate solvent e.g. THF
  • R 3 , Z ! 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 represents an appropriate protecting group, such as an alkyl group, including C ⁇ - 6 alkyl, e.g. tert-butyl, for example at low temperature (e.g. -78°C to around 0°C), in the presence of a suitable base (e.g. /--butyl lithium) and an appropriate solvent (e.g. THF).
  • an appropriate protecting group such as an alkyl group, including C ⁇ - 6 alkyl, e.g. tert-butyl, for example at low temperature (e.g. -78°C to around 0°C), in the presence of a suitable base (e.g. /--butyl lithium) and an appropriate solvent (e.g. THF).
  • XX in which R y represents -C(0)NH 2 may also be prepared by reaction of a compound of formula XXVII,
  • XXVII are known in the art or may be prepared by way of standard techniques, for example oxidation of a corresponding compound of formula XX in which R y is -CHO e.g. under those conditions described hereinbefore for preparation of compounds of formula V.
  • 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 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.
  • 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 hyperplasia, 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).
  • ACE angiotensin converting enzyme
  • 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 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.
  • Rat liver membranes were prepared according to the method of Dudley et al.
  • Binding of [ 125 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 (bovine serum albumin), liver homogenate corresponding to 5 mg of the original tissue weight, [ 125 I]Ang II (70 000 cpm, 0.03 nM) and variable concentrations of test substance.
  • 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 corresponding to 10 mg of the original tissue weight, [ 125 I]Ang II (70 000 cpm, 0.03 nM) and variable concentrations of test substance. Samples were incubated at 25°C for 1 h, and binding was terminated by filtration through Whatman GF/B glass-fiber filter sheets using a Brandel cell harvester. The filters were washed with 3 x 3 mL of Tris-HCl (pH 7.4) and transferred to tubes. The radioactivity was measured using a gamma counter. The characteristics of the Ang II binding AT 2 receptor was determined by using a gamma counter. The characteristics of the Ang II binding AT 2 receptor was determined by using a
  • Trifluoroacetic acid (5 mL) was added to 3-[4-(3-methyl-2,5- dioxoimidazolidin- 1 -ylmemyl)phenyl]-5-wo-butyl-N-tert-butylthiophene-2- sulfonamide (0.1 g, 0.24 mmol; see step (b) above).
  • Two drops (ca. 0.05 mL) of anisole were then added and the mixture was stirred under a ⁇ 2 atmosphere for 18 hours at ambient temperature.
  • the reaction mixture was evaporated and co-evaporated with acetonitrile (5 mL x 3) to give crude sub-title compound.
  • Trifluoroacetic acid (5 mL) was added to 3-[4-(3,4,4-trimethyl-2,5- dioxoi ⁇ nidazolidin-l-ylmethyl)phenyl]-5-t-?o-butyl-N-tert-butylthiophene-2- sulfonamide (0.12 g, 0.237 mmol; see step (b) above).
  • Two drops (ca. 0.05 mL) of anisole were also added and the mixture was stirred under a N 2 atmosphere for 18 hours at ambient temperature.
  • the reaction mixture was evaporated and co-evaporated with acetonitrile (5 mL x 3) to give crude sub-title compound.
  • step (c) above The crude product from step (c) above was dissolved in pyridine (3 mL). Pyrrolidinopyridine (0.035 g, 0.237 mmol) and n-butyl chloroformate (0.324 g, 2.37 mmol) were added. The reaction mixture was stirred overnight at room temperature under a ⁇ 2 atmosphere. The mixture was evaporated and co-evaporated with acetonitrile and the residue was taken up in chloroform (20 mL), washed with 10% aqueous citric acid, followed by water and then brine, and dried over MgS0 4 .

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Abstract

La présente invention porte sur des composés représentés par la formule (I) dans laquelle la ligne pointillée, X1, X2, X3, A, Y1, Y2, Y3, Y4, Z1, Z2, R2 et R3 sont tels que définis dans la description, ainsi que sur des sels pharmaceutiquement acceptables de ces composés. Les composés de cette invention sont utilisés comme agonistes sélectifs du récepteur AT2 et servent ainsi, en particulier, au traitement de troubles gastro-intestinaux inter alia tels que la dyspepsie, le syndrome du côlon irritable et l'insuffisance organique multiple, ainsi que de troubles cardiovasculaires.
PCT/GB2003/005013 2002-11-21 2003-11-19 Nouveaux agonistes tricycliques de l'angiotensine ii Ceased WO2004046137A1 (fr)

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Cited By (29)

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WO2006109056A1 (fr) * 2005-04-12 2006-10-19 Vicore Pharma Ab Nouveaux agonistes de l’angiotensine ii tricyclique
WO2006109058A1 (fr) 2005-04-12 2006-10-19 Vicore Pharma Ab Nouveaux agonistes de l’angiotensine ii bicyclique
US7504517B2 (en) 2006-06-20 2009-03-17 Wyeth Kv1.5 potassium channel inhibitors
JP2011520792A (ja) * 2008-05-01 2011-07-21 ヴァイティー ファーマシューティカルズ，インコーポレイテッド １１β−ヒドロキシステロイドデヒドロゲナーゼ１の環状インヒビター
US8080571B2 (en) 2005-04-12 2011-12-20 Vicore Pharma Ab Tricyclic angiotensin II agonists
US8114868B2 (en) 2008-07-25 2012-02-14 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8138178B2 (en) 2008-05-01 2012-03-20 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8202857B2 (en) 2008-02-11 2012-06-19 Vitae Pharmaceuticals, Inc. 1,3-oxazepan-2-one and 1,3-diazepan-2-one inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8242111B2 (en) 2008-05-01 2012-08-14 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8461209B2 (en) 2007-06-20 2013-06-11 Mitsubishi Tanabe Pharma Corporation Malonic acid sulfonamide derivative and pharmaceutical use thereof
US8575156B2 (en) 2007-07-26 2013-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8592410B2 (en) 2008-05-01 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11BETA-hydroxysteroid dehydrogenase 1
US8592409B2 (en) 2008-01-24 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8598160B2 (en) 2008-02-15 2013-12-03 Vitae Pharmaceuticals, Inc. Cycloalkyl lactame derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680281B2 (en) 2008-01-07 2014-03-25 Vitae Pharmaceuticals, Inc. Lactam inhibitors of 11-β-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
US8883778B2 (en) 2009-07-01 2014-11-11 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US10071099B2 (en) 2014-04-03 2018-09-11 National Cerebral And Cardiovascular Center Medicament for suppressing malignant tumor metastasis
US11186567B2 (en) 2017-02-10 2021-11-30 University College Cardiff Consultants Limited AMPA receptor potentiators
US11298345B2 (en) 2018-03-01 2022-04-12 University College Cardiff Consultants Limited Compounds that modulates AMPA receptor function
US11407733B2 (en) 2016-06-29 2022-08-09 Bristol-Myers Squibb Company Biarylmethyl heterocycles

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Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8067418B2 (en) 2005-04-12 2011-11-29 Vicore Pharma Ab Tricyclic angiotensin II agonists
WO2006109058A1 (fr) 2005-04-12 2006-10-19 Vicore Pharma Ab Nouveaux agonistes de l’angiotensine ii bicyclique
JP2008535899A (ja) * 2005-04-12 2008-09-04 ヴィコール・ファルマ・アーベー 新規な三環系アンジオテンシンｉｉアゴニスト
US8357710B2 (en) 2005-04-12 2013-01-22 Vicore Pharma Ab Bicyclic angiotensin II agonists
WO2006109056A1 (fr) * 2005-04-12 2006-10-19 Vicore Pharma Ab Nouveaux agonistes de l’angiotensine ii tricyclique
US8080571B2 (en) 2005-04-12 2011-12-20 Vicore Pharma Ab Tricyclic angiotensin II agonists
US7803827B2 (en) 2006-06-20 2010-09-28 Wyeth Llc Kv1.5 potassium channel inhibitors
US7504517B2 (en) 2006-06-20 2009-03-17 Wyeth Kv1.5 potassium channel inhibitors
US8461209B2 (en) 2007-06-20 2013-06-11 Mitsubishi Tanabe Pharma Corporation Malonic acid sulfonamide derivative and pharmaceutical use thereof
US8575156B2 (en) 2007-07-26 2013-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8680281B2 (en) 2008-01-07 2014-03-25 Vitae Pharmaceuticals, Inc. Lactam inhibitors of 11-β-hydroxysteroid dehydrogenase 1
US8592409B2 (en) 2008-01-24 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8202857B2 (en) 2008-02-11 2012-06-19 Vitae Pharmaceuticals, Inc. 1,3-oxazepan-2-one and 1,3-diazepan-2-one inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8598160B2 (en) 2008-02-15 2013-12-03 Vitae Pharmaceuticals, Inc. Cycloalkyl lactame derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
US8138178B2 (en) 2008-05-01 2012-03-20 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8569292B2 (en) 2008-05-01 2013-10-29 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8673899B2 (en) 2008-05-01 2014-03-18 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8242111B2 (en) 2008-05-01 2012-08-14 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8592410B2 (en) 2008-05-01 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11BETA-hydroxysteroid dehydrogenase 1
JP2011520792A (ja) * 2008-05-01 2011-07-21 ヴァイティー ファーマシューティカルズ，インコーポレイテッド １１β−ヒドロキシステロイドデヒドロゲナーゼ１の環状インヒビター
US8114868B2 (en) 2008-07-25 2012-02-14 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8883778B2 (en) 2009-07-01 2014-11-11 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
US9090605B2 (en) 2010-06-16 2015-07-28 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
US10071099B2 (en) 2014-04-03 2018-09-11 National Cerebral And Cardiovascular Center Medicament for suppressing malignant tumor metastasis
US11407733B2 (en) 2016-06-29 2022-08-09 Bristol-Myers Squibb Company Biarylmethyl heterocycles
US12037324B2 (en) 2016-06-29 2024-07-16 Bristol-Myers Squibb Company Biarylmethyl heterocycles
US11186567B2 (en) 2017-02-10 2021-11-30 University College Cardiff Consultants Limited AMPA receptor potentiators
US11298345B2 (en) 2018-03-01 2022-04-12 University College Cardiff Consultants Limited Compounds that modulates AMPA receptor function
US12383540B2 (en) 2018-03-01 2025-08-12 University College Cardiff Consultants Limited Compounds that modulates AMPA receptor function

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