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Definitions

• This invention relates to novel pharmaceutically-useful compounds, in particular compounds that are angiotensin II (Angll) agonists, more particularly agonists of the T 4 OIgII type 2 receptor (hereinafter the AT2 receptor), and especially agonists that bind selectively to that receptor.
• Angll angiotensin II
• AT2 receptor T 4 OIgII 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 -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 ⁇ l, 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).
• AngII antagonists (which bind to the ATI and/or AT2 receptors) have been disclosed in inter alia international applications WO 93/04045, WO 93/04046,
• A represents -CH 2 -, -C(O)-, -C(O)-CH 2 - (in which the -C(O)- group is attached to the ring bearing Y 1 , Y 2 , Y 3 and Y 4 ) or -CH 2 -CH 2 -;
• one OfX 1 and X 2 represents -N- and the other represents -C(R 1 )-;
• X 3 represents -N- or -C(R 2 )-;
• X 4 represents -N- or -C(R 3 )-;
• R 1 , R 2 and R 3 independently represent H, C 1-6 alkyl, C 1-6 alkoxy, 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 1-3 alkoxy- Ar 3 , C 1-3 alkoxy-Het 3 , halo, -C(O)-C 1-6 alkyl, -C(O)-Ar 4 or -C(O)-Het 4 ; or R 2 and R 3 may be linked to form, along with the carbon atoms to which they are attached, a 5- or 6-membered aromatic ring optionally containing one to three heteroatoms;
• R lla to R lld independently represent, on each occasion when used herein, C 1-6 alkyl
• R 12a to R 12p independently represent, on each occasion when used herein, H or C 1-6 alkyl; n represents 0, 1 or 2;
• Y 1 , Y 2 , Y 3 and Y 4 independently represent -CH- or -CF-;
• Z 2 represents -CH-, -O-, -S- or -N-; provided that:
• R 5 represents Ci -6 alkyl, Ci -6 alkoxy, Ci -6 alkoxy-Ci -6 -alkyl or di-Ci- 3 -alkylarnrno-
• R 6 represents Ci -6 alkyl, Ci -6 alkoxy, Ci -6 alkoxy-Ci -6 -alkyl, Ci -3 alkoxjr-Ci- ⁇ -alkoxy, Ci -6 alkylamino or di-Ci -6 alkylamino;
• R 7 represents Ci -6 alkyl, or a pharmaceutically-acceptable salt thereof
• 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-drymg).
• 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 allcoxy, alkoxyalkyl, alkoxyalkoxy, allcylamino, alkylaminoalkyl groups, alkyl- aryl, alkyl- heterocyclic groups, alkoxy-ar ⁇ 4 and alkoxy-heterocyclic groups, as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) 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.
• Such alkyl groups, and alkyl parts of allcoxy, alkoxyalkyl, alkoxyallcoxy, allcylamino, 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.
• allcoxy and alkoxyallcoxy groups are attached to the rest of the molecule via the/an oxygen atom in that group
• allcylamino groups are attached to the rest of the molecule via the nitrogen atom of the amino part of that group
• allcylamino alkyl, alkoxyalkyl alkyl- aryl and alky 1-hetero cyclic 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 allcoxy part of that group.
• halo when used herein, includes fluoro, chloro, bromo and iodo.
• Ci -6 alkyl groups the two alkyl groups in question may be the same or different.
• C 6-I o aryl groups include phenyl, naphthyl and the like (preferably phenyl).
• Preferred optional substituents on aromatic groups include halo, -OH, cyano, nitro, Ci- 6 (e.g. C J-3 ) alkyl groups (such as methyl) and C 1-6 (e.g. Ci -3 ) alkoxy groups.
• Het (Het 1 , Het 2 , Het 3 and Het 4 ) 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 1 , Het 2 , Het 3 and Het 4 ) 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, ci ⁇ nolinyl, 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 values of Het 1 that may be mentioned include furanyl, thiazolyl and, more particularly, thiophenyl (e.g. 2-thiophenyl or 3-thiophenyl) and pyridinyl (e.g. 2-pyridinyl).
• Values of Het 2 that may be mentioned include furanyl, thiophenyl, thiazolyl and pyridinyl.
• Values of Het 3 and Het 4 that may be mentioned include pyridinyl.
• Substituents on Het (Het 1 , Het 2 , Het 3 and Het 4 ) groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
• the point of attachment of Het (Het 1 , Het 2 , Het 3 and Het 4 ) 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 , Het 2 , Het 3 and Het 4 ) groups may also be in the N- or S-oxidised form.
• Preferred ring systems comprising the substituents Yi, Y 2 , Y 3 and Y 4 include phenyl groups.
• the ring systems in compounds of formula I that comprise the groups Z 1 and Z 2 are aromatic in nature.
• an additional H atom may necessarily be bonded to that N atom, in order to ensure that the rules of valency are adhered to.
• Preferred ring systems comprising Z 1 and Z 2 include oxazole groups, thiazole groups, pyridinyl groups, furanyl groups and, more particularly, thiophenyl groups and phenyl 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).
• AU stereoisomers are included within the scope of the invention.
• Preferred compounds of the invention include those in which: (i) when X 1 represents -C(R 1 )-, then:
• X 3 represents -C(R 2 )- and X 4 represents -N-;
• X 3 and X 4 both represent N; or, more preferably,
• X 3 represents -C(R 2 )- and X 4 represents -C(R 3 )-; or (ii) when X 1 represents -N-, then
• X 3 and X 4 both represent -N; or, more preferably, (c) X 3 represents -C(R 2 ) and X 4 represents -C(R 3 )-.
• Preferred compounds of formula I include those in which:
• A represents -CH 2 -, -C(O)-CH 2 - or -CH 2 -CH 2 -;
• X 3 represents -C(R 2 )-;
• X 4 represents -C(R 3 )-
• R 1 represents: hydrogen; halo (e.g. chloro); C 14 aJkyl, such as methyl, ethyl and butyl (e.g. ra-butyl), which allcyl group is optionally substituted by one or more fluoro atoms (so forming, for example, a trifluoromethyl group);
• halo e.g. chloro
• C 14 aJkyl such as methyl, ethyl and butyl (e.g. ra-butyl), which allcyl group is optionally substituted by one or more fluoro atoms (so forming, for example, a trifluoromethyl group);
• Ar 1 such as phenyl
• Het 1 such as thiophenyl (e.g. 2-thiophenyl or 3-thiophenyl) or pyridinyl (e.g. 2 ⁇ pyridinyl); or
• R 2 represents Ci -3 alkyl, or, especially, H;
• R 3 represents Ci -3 alkyl, or, especially, H;
• R 2 and R 3 are linked to form a further benzene ring, optionally containing one or two (e.g. one) heteroatoms (e.g. nitrogen), so forming, for example, a pyridine ring;
• Yi, Y 2 , Y 3 and Y 4 all represent -CH-; Zi represents -CH CH- or, especially, -S-; Z 2 represents -CH-; R 4 represents -S(O) 2 N(H)C(O)R 6 ;
• R 5 represents CM alkyl such as 77-butyl or, more particularly, zso-butyl;
• R 6 represents C 14 alkoxy-Ci -3 alkyl or C 14 aEcoxy (such as 77-butoxymethyl, iso- butoxy and especially, 77-butoxy).
• Preferred ring systems comprising the substituents Xi, X 2 , X 3 and X 4 include 1 ,2,4-triazole groups, tetrazole groups and, more particularly, pyrazole groups and imidazole groups.
• R 4 represents -S(O) 2 N(H)C(O)R 6 , -S(O) 2 N(H)S(O) 2 R 6 or -C(O)N(H)S(O) 2 R 6
• preferred values of R 6 include ⁇ -butoxymethyl, zs ⁇ -butoxy and especially, 77-butoxy.
• X 1 represents -C(R 1 )- and X 2 represents -N-; and/or the resultant biaryl ring system represents a 5,6-fused biaryl ring system, such as a benzoimidazolyl (e.g. benzoimidazol-1-yl) group or an azobenzoimidazolyl (e.g. imidazo[4,5-b]pyridine-3-yl or imidazo[4,5-b]pyridine-l-yl) group.
• a benzoimidazolyl e.g. benzoimidazol-1-yl
• an azobenzoimidazolyl e.g. imidazo[4,5-b]pyridine-3-yl or imidazo[4,5-b]pyridine-l-yl
• More preferred compounds of the invention include the compounds of the examples described hereinafter.
• G represents -C(O)- or -S(O) 2 - (as appropriate)
• L represents a suitable leaving group, such as halo (e.g. chloro or bromo) and R is as hereinbefore defined, for example at around room temperature or above (e.g. up to 60-70 0 C) in the presence of a suitable base (e.g. pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, di-zso-propylarnine, 1,8- diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, sodium carbonate, or mixtures thereof) and an appropriate solvent (e.g.
• a suitable base e.g. pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, di-zso-propylarnine, 1,
• Preferred base/solvent systems for compounds of formula III in which G is -C(O)- include pyrrolidinopyridine/pyridine, pyrrolidinopyridine/triethylamine, dimethylaminopyridine/pyridine, dimethylarnmopyridme/triethylarnine, sodium carbonate/dichloromethane/water or pyrrolidinopyridine/triethylamine/dicliloromethane.
• Preferred base/solvent systems for compounds of formula III in which G is -S(O) 2 - include NaOH/THF;
• R 6a represents C 1-6 alkoxy-Cj- ⁇ -alkyL for example under similar conditions to those described under process step (i) above, in the presence of a suitable coupling reagent (e.g. lj'-carbonyl-diimidazole, N 5 N'- dicyclohexylcarbodiimide, N,N'-disuccinimidyl carbonate, benzo triazo Ie-I- yloxytris(dimethylammo)phosphoniumhexafluorophosphate 5 2-( lH-benzo triazo Ie- 1 -yl)- 1 ,1,3 ,3 -tetramethyluronium hexafluorophosphate, benzotriazole- 1 -yl-oxy- tris-pyrrolidino-phosphonium hexafluorophosphate, bromo-tris- pyrrolidinophosponium hexafluorophosphate or 2-(lH-benz
• R 6 S(O) 2 NH 2 VI wherein R 6 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 -S(O) 2 N(H)C(O)R 6 and R 6 represents C 1-6 alkoxy-Ci -6 -a!kyl (i.e. process step ( ⁇ ));
• a suitable coupling reagent such as those described in process step (ii) hereinbefore
• R 6 is as hereinbefore, defined, for example at around 5O 0 C in the presence of a suitable base (e.g. sodium hydride) and an appropriate organic solvent (e.g. THF);
• a suitable base e.g. sodium hydride
• an appropriate organic solvent e.g. THF
• R 7 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 a suitable leaving group, such as a halo (e.g. chloro or bromo) group or alkoxy (e.g. -0-Cj -2 alley 1) and R 7 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 x may represent -OH, in which case the coupling reaction may be performed under conditions such as those hereinbefore described in respect of process (ii) above; (vii) for compounds of formula I in which R 4 represents -N(H)C(O)N(H)S(O) 2 R 7 and R 7 is as hereinbefore defined, reaction of a compound of formula IX as hereinbefore defined with an isocyanate compound of formula XII,
• R 7 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 6b 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 6c and R 6d independently represent C] -6 alley 1, for example at above room temperature (e.g. at between 7O 0 C and 10O 0 C) in the presence of an appropriate organic solvent (e.g. toluene); or (x) for compounds of formula I in which R 1 , R 2 or R 3 represent halo, reaction of a compound corresponding to a compound of formula I in which R 1 , R 2 and/or R represents an appropriate leaving group (such as a pyridinium group) with a source of halide (e.g. chloride, bromide or iodide) ions under reaction conditions known to those skilled in the art.
• a source of halide e.g. chloride, bromide or iodide
• R , Z and Z are as hereinbefore defined, or a N-protected derivative thereof, with a compound of formula XVI,
• L 2 represents a suitable leaving group, such as such as methylsulphonate (e.g. trifluoromethylsulphonate). or halo, such as iodo or brorno, and A, X 1 , X 2 , X 3 , X 4 , Y 1 , 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 /Iigand (wherein the ligand may be, for example, PPh 3 , P(o-Tol) 3 or l,r-bis(diphenylphosphino)ferrocene)
• a suitable base e.g. sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or di-fso-propylamine
• 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). If a protected version of a compound of formula XV is employed, this reaction may be followed by deprotection of the SO 2 NH-group under standard conditions, for example as described hereinafter.
• R q represents R 1 , R 2 or R 3 (as appropriate), provided that it does not represent H or halo, for example under similar conditions to those described above in respect of the first process for the preparation of compounds of formula II.
• a 5 Yi, Y 2 , Y 3 , Y 4 , Z 1 , Z 2 , R 5 and L 1 are as hereinbefore defined (L 1 , in particular, may represent bromo), or a N-protected derivative thereof, for example at around, below or, preferably, above room temperature (e.g. at 80°C), optionally in the presence of a suitable base (e.g. potassium ferf-butoxide, potassium hydroxide, sodium hydroxide, sodium carbonate, triethylamine or di-iso- propylethylamine) and an appropriate organic solvent (e.g. DMSO, dioxane, DMF, THF or CH 2 Cl 2 ).
• a suitable base e.g. potassium ferf-butoxide, potassium hydroxide, sodium hydroxide, sodium carbonate, triethylamine or di-iso- propylethylamine
• an appropriate organic solvent e.g. DMSO, dioxane, DMF,
• A, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , Y 4 , Z 1 , Z 2 and R 5 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.
• Z 1 , Z 2 and R 5 are as hereinbefore defined, or N-protected derivatives thereof, for example under similar conditions to those described B2006/001319
• Compounds of formula XVI in which A represents -CH 2 - or -CH 2 -CH 2 - may be prepared by reduction of a corresponding compound of formula XVI in which A represents -C(O)- or -C(O)-CH 2 , respectively.
• suitable reducing conditions e.g. using a chemo selective reducing agent
• appropriate reducing agents include borane and lithium aluminium hydride.
• suitable conditions include: employing NaBH 4 in the presence of an acid (e.g. CH 3 COOH or CF 3 COOH); Wolff-Kishner reduction conditions (Le.
• di-C 1-6 allcyl) phosphites or hypophosphorous acid all under reaction conditions known to those skilled in the art (for example in the case of reaction with (C 1-6 alkyl) 3 SnH and AIBN, in the presence of a suitable solvent (e.g. THF) at elevated temperature (e.g. reflux)), or reduction in the presence of hypophosphorous acid with iodine in acetic acid.
• a suitable solvent e.g. THF
• elevated temperature e.g. reflux
• R q2 represents C 1-6 alkyl, Ci -6 alkoxy-Ci -6 allcyl, Ci -3 alkyl-Ar 2 , C 1-3 alkyl- Het 2 , halo, -C(O)-C 1-6 allcyl, -C(O)-Ar 4 or -C(O)-Het 4 and L 1 is as hereinbefore defined.
• This reaction may be performed in the presence of an appropriate solvent, such as a polar aprotic solvent (e.g. THF) at, for example below room temperature (e.g. between O 0 C and -78 0 C), followed by the addition of an appropriate compound of formula XXIIa (e.g.
• THF polar aprotic solvent
• A, Y 1 , Y 2 , Y 3 , Y 4 and L 2 are as hereinbefore defined, for example under similar conditions to those described hereinbefore in respect of preparation of compounds of formula II (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 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)).
• the hydro xyl group may be converted to a sulfonate leaving group (e.g. mesylate or triflate) by employing a suitable reagent (e.g. a sulfonyl halide such as tosyl chloride, mesyl chloride or triflic anhydride).
• a suitable reagent e.g. a sulf
• Z 1 , Z 2 and R 5 are as hereinbefore defined, or a protected (at the aldehyde part) derivative thereof, for example under similar conditions to those described hereinbefore for preparation of compounds of formula II (first process). If a protected version of a compound of formula XXIV is employed, this reaction may be followed by deprotection of the CHO-group under standard conditions (e.g. acid hydrolysis).
• R y represents -S(O) 2 NH 25 -C(O)NH 2 , -NH 2 or -CHO (as appropriate) and R D , Z 1 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- ⁇ o-propylborate). Such reactions may be carried out, for example, at low temperature (e.g. between -100 0 C and O 0 C, e.g.
• a suitable base e.g. n-butyl lithium
• an appropriate organic solvent e.g. THF
• R ya represents -S(O) 2 NH 2 , -C(O)NH 2 or -CHO and Zi and Z 2 are as hereinbefore defined, or a protected derivative thereof, with a compound of formula XXVII,
• L 3 represents a suitable leaving group (such as toluenesulphonate, benzenesulphonate, methanesulphonate or halo, such as bromo or iodo) and R 5 is as hereinbefore defined, for example at below room temperature
• a suitable base e.g. r ⁇ -butyl lithium
• an appropriate solvent e.g. THF
• R 5 , Z 1 and Z 2 are as hereinbefore defined with an appropriate reagent for introduction of a -S(O) 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. t ⁇ t-butylamine), under conditions that are well known to those skilled in the art.
• an appropriate reagent for introduction of a -S(O) 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. t ⁇ t-butylamine)
• R z represents an appropriate protecting group, such as an allcyl group, including C 1-6 allcyl, e.g. tert-butyl, for example at low temperature (e.g. -78 0 C to around O 0 C), in the presence of a suitable base (e.g. ⁇ -butyl lithium) and an appropriate solvent (e.g. THF).
• an allcyl group including C 1-6 allcyl, e.g. tert-butyl, for example at low temperature (e.g. -78 0 C to around O 0 C)
• a suitable base e.g. ⁇ -butyl lithium
• an appropriate solvent e.g. THF
• R 5 , Zi and Zo are as hereinbefore defined with a protected (e.g. an (e.g. Ci -6 ) allcyl, such as tert-butyl-protected) derivative of ammonia (e.g. tert-butylamine) under standard coupling conditions (see, for example, those described hereinbefore for preparation of compounds of formula I (process step (iii))).
• a protected e.g. an (e.g. Ci -6 ) allcyl, such as tert-butyl-protected
• ammonia e.g. tert-butylamine
• Compounds of formula XXX are known in. the art or may be prepared by way of standard techniques, for example oxidation of a corresponding compound of formula XXV in which R y is -CHO e.g. under those conditions described hereinbefore for preparation of compounds of formula V.
• XXIIa 5 XXIII, XXVI, XXVII, XXVIII, XXIX and XXX 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 terf-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 a protic acid or a Lewis acid such as trifluoro acetic acid, sulfuric acid, toluenesulfonic acid, boron trichloride or Sc(OTf) 3 ).
• compounds of the invention are agonists of AngII, 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 AngII is deficient and/or where an increase in the effect of AngII 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 Sjogren'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, arthero sclerosis, 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 AngII is deficient, and/or a condition where an increase in the effect of AngII 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: (A) a compound of the invention.
• 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 Membrane AT ⁇ Receptor Rat liver membranes were prepared according to the method of Dudley et al (MoI. Pharmacol. (1990) 38, 370). 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, [ 123 I] Ang II (70 000 cpm, 0.03 nM) and variable concentrations of test substance.
• Tris-HCl pH 7.4
• BSA bovine serum albumin
• 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 ATj receptors was blocked by addition of 1 ⁇ M of a selective ATI inhibitor.
• 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 5 10 mM MgCl 2 , 1 mM EDTA 5 0.025% bacitracin, 0.2% BSA, homogenate corresponding to 10 mg of the original tissue weight, [ 125 I]AtIg 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.
• reaction mixture was diluted with CH 2 Cl 2 (30 mL) and washed with citric acid (10% aq), brine, water, dried (over anhydrous MgSO 4 ), concentrated in vacuo, and the residue purified by LCMS (Liquid Chromatography Mass Spectrum; 20-100% CH 3 CN in water) to give the title compound in 65% yield, over two steps, (33.2 mg, 0.0678 mmol).
• reaction mixture was diluted with CH 2 Cl 2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO 4 ), concentrated in vacuo, and the residue was purified by flash chromatography using MeOH:CH 2 Cl 2 (7:93) as eluent to give the title compound as a white solid in 72% yield, over two steps, (14.5 mg, 0.027 mmol).
• IRv (neat, cm '1 ): 3126, 3043, 2959, 2871, 1740, 1608, 1587, 1474, 1389, 1344.
• reaction mixture was diluted with CH 2 Cl 2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO 4 ), concentrated in vacuo, and the residue purified by flash chromatography using MeOHrCH 2 Cl 2 (6:94) as eluent to give the title compound as a white solid in 63% yield, over two steps, (32 mg, 0.058 mmol).
• reaction mixture was diluted with CH 2 Cl 2 (30 rnL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO 4 ), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH 2 Cl 2 (5:95) as eluent to give the title compound as a white solid in 87% yield, over two steps, (29.4 mg, 0.0533 mmol).
• reaction mixture was diluted with CH 2 Cl 2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO 4 ), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH 2 Cl 2 (5:95) as eluent to give the title compound as a white solid in 67% yield, over two steps, (28 mg, 0.050 mmol).
• IR v (neat, cm “1 ): 3126, 3096, 3064, 2965, 1700, 1588, 1568, 1496, 1419.
• reaction mixture was refluxed for 3 h and then a second portion Of Bu 3 SnH (11.2 mg, 0.0385 mmol) and AIBN (1 mg, 0.006 mmol) was added and the reaction was refluxed for an additional 40 min.
• the solvent was removed in vacuo and the residue dissolved in CH 3 CN (20 mL) and extracted with hexane.
• the solvent was removed in vacuo and the residue was purified by flash chromatography using MeOHiCH 2 Cl 2 (6:94) as eluent to give the sub-title compound as a colourless syrup in 74% yield (38.2 mg, 0.152 mmol).
• IRv (neat, cm “1 ): 3109, 3059, 2934, 1596, 1567, 1506, 1475.
• Example 21 Title compounds of the Examples were tested in Test C above and were found to stimulate markedly mucosal alkalisation. This effect was blocked by coadministration of the selective AT2 receptor antagonist PD 123319 (Sigma Chemical Company).

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