WO2011134019A1 - Nouveaux biphénylsartans - Google Patents

Nouveaux biphénylsartans Download PDF

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WO2011134019A1
WO2011134019A1 PCT/AU2011/000495 AU2011000495W WO2011134019A1 WO 2011134019 A1 WO2011134019 A1 WO 2011134019A1 AU 2011000495 W AU2011000495 W AU 2011000495W WO 2011134019 A1 WO2011134019 A1 WO 2011134019A1
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nitroxide
biphenyl
sartan
salt
stable
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PCT/AU2011/000495
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Carl Herbert Schiesser
Phei Hsin Tan
James Ziogas
Nitya Vipin Jani
Christine Eva Wright
Michelle Keily Taylor
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The University Of Melbourne
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Publication of WO2011134019A1 publication Critical patent/WO2011134019A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds and compositions useful in modulating the renin-angiotensin system (RAS) in cells, and in particular to compounds which, inter alia, act as angiotensin II antagonists by binding to angiotensin II receptors.
  • RAS renin-angiotensin system
  • the invention also relates to the use of these compounds and compositions in the treatment of conditions responsive to angiotensin II antagonists such as hypeitension, edema, renal failure, benign prostatic hypertrophy glaucoma, atherosclerosis, diabetes, Alzheimer's disease and congestive heart failure.
  • RAS renin-anigiotensin system
  • angiotensinogen a circulating protein
  • Angiotensin I is then cleaved to the octapeptide angiotensin II by the angiotensin coverting enzyme (ACE).
  • ACE angiotensin coverting enzyme
  • the receptors are a member of the superfamily of seven-transmembrane-domain G protein coupled receptors.
  • Angiotensin II interacts with the transmembrane domains of its ATi receptor, to bring about effects including vasoconstriction, vascular remodelling and salt/water retention, but has negligible or no stimulating action on the heart. The effects however all lead to a rise in blood pressure.
  • Hypertension is defined as a persistently high arterial blood pressure and is a well- established risk factor for cardiovascular disease, cerebral haemorrhage, stroke and kidney disease. The prevalence of hypertension in the western world in conjunction with its potentially lethal consequences makes treatment of the disease important.
  • Some antihypertensive drugs used in therapy target the enzymes renin and ACE in RAS.
  • inhibitors of ACE are known whose approved names generally end in "-pril” or in the case of active metabolites "-prilate”.
  • captopril and enalapril are both commercially available ACE inhibitors which are effective antihypertensive agents, ACE inhibitors, however, are unfortunately known to have adverse side effects such as dizziness and fainting, Skin rash, swelling to the face, mouth and hands, and may also cause a persistent dry cough.
  • antagonists at angiotensin receptors and more specifically AT
  • Such compounds typically have approved names which generally end in "-sartan”.
  • Examples include abitesartan, benzyllosartan, elisartan, embusartan, enoltasosartan, fonsartan, forasaitan, glycyllosartan, milfasartan, olmesartan, opomisartan, pratosartan, ripisartan, eprosartan, candesartan (including candersartan cilexetil), irbesartan, saprisartan, tasosartan, telmisartan, valsartan, zolasartan, and losartan (including losartan potassium).
  • the terra "sartan” is generally used to refer to any angiotensin II antagonist which blocks the action of angiotensin II at its AT, receptors and includes saralasin and saralasin acetate, CGP-63170, EMD-66397, T3-671 , LR-B/081, A-81282, BlBR-363, BIBS-222, B S-184698, CV-1 1 194, EXP-3174, KW- 3433, L-161 177, L-162154, LR-B/057, LY-235656, PD-150304, U-96849, U-97018, UP, 275-22, WAY-126227, WK-1492.2K.
  • Sartans like angiotensin II itself, interact with the uansmembrane domains of the AT, receptors, Since the sartans selectively bind to ATi receptors, angiotensin II is left with free access to its unblocked AT 2 receptors. This is beneficial as recent evidence suggests that many of the effects of the interaction between angiotensin II and its AT 2 receptors reduce blood pressure. Also, the sartans have been shown to lack the side effects demonstrated by other antihypertensives such as the ACE inhibitors. The sartans themselves, while all acting as angiotensin. II antagonists, are characterised with different molecular frameworks.
  • classes of sartans based on a 5 membered nitrogen containing heterocycle framework are described in EP 28,834-A, EP 253,310-A, EP 324,377-A, WO 91/14679, EP 392,317-A, EP 403,159-A, EP 503,162-A, EP 573,271-A, WO 94/03449, WO 94/08989, WO 94/08990, U.S. Pat. No. 4,576,958, U.S. Pat. No. 4,582,847, U.S. Pat. No. 4,207,324 and U.S, Pat. No. 4,340,598.
  • Sartans such as losartan, irbesartan, pratosartan, olmesartan, fonsartan, eprosartan, and saprisartan fall within this class.
  • sartans are derived from condensed heterocycles, in particular benzimidazoles and imidazpyridines (often also substituted with a substituted biphenyl group) and are described in EP 399,731 -A, EP 400,974-A, EP 392,317- ⁇ , ⁇ 260,613-A, EP 412,848-A, EP 420,237- ⁇ , ⁇ 502,314-A, EP 552,765-A, EP 546,358-A, EP 595,151 - A, EP 598,702-A, EP 245,637-A, U.S. Pat. No. 4,880.804, WO.93/190067, WO 94/01436 and WO 94/204,498. Candesartan and telmisartan fall within this class.
  • sartans are formed from optionally condensed 6-membered nitrogen containing heterocycles as described in EP 412,848-A, GB 2,234,748 ⁇ A, WO 91/07404, EP 487,252-A, EP 443,983-A, EP 500,409-A, WO 94/07492, WO 94/1 1379, WO 94/1 1369 and WO 95/002596.
  • Tasosartan falls within this class.
  • EP 434,249-A describes the benzofuran class of sartans to which saprisartan' and zolasartan belong.
  • saralasin and sarmesin represent peptide analogues of angiotensin ⁇ .
  • sartans As of 2000, six orally active sartans have been accepted by the US Food and Drug Administration and are available in the US and various other European countries for the • treatment of hypertension. These compounds include losartan, valsartan, irbesartan, candesartan, telmisartan and eprosartan. While, the mechanism of these compounds is relatively uniform, the pharmacodynamics and pharmacokinetics arc quite different. For instance, irbesartan displays longer activity than losartan and valsartan. Candesartan displays poor oral absorption and is therefore administered as the ester prodrug candesartan ciiexetil.
  • Telmisartan has a very long elimination half-life and causes an increase in serum diogix when used in combination therapy with digoxin. In contrast, eprosartan has a very short half-life (5-7 hr).
  • the above pharmacological variations have both beneficial and negative implications in therapy. It is thus desirable to develop novel sartans with improved and/or new pharmacological profiles.
  • the present invention provides a class of multi-functioning/multipotent biphenyl sartan compounds ('biphenyl sartans') which possess both traditional angiotensin antagonist activity but also antioxidant activity. More specifically the present invention provides biphenyl-sartans which comprise a stable nitroxide moiety which acts as a radical scavenger and in particular a reactive oxygen species (RQS) scavenger:
  • nitroxide-biphenyl sartans as herein retain their sartan activity (ie continue to act as angiotensin II antagonists) but also display other unique properties such as elevated antioxidant activity and ma also possess anti- inflammatory activity. Accordingly, the nitroxide-biphenyl sartans of the present invention may function as effective roultipotent (or multi-functioning) antihypertensive agents.
  • Such compounds have significant potential in treating, in addition to hypertension, diseases and conditions linked to, for instance, oxidative stress, such as neurodegenerative diseases (eg Alzheimer's disease, Parkinson's disease, Fredreich's Ataxia, Ataxia Telangiectasia, Wilson's disease, motor neurone disease, etc), mtDNA diseases (eg diabetes mellitus, epilepsy, renal failure, etc), as well as providing treatments for inflammation and ischaemic-reperfusion tissue injury in strokes, heart attacks, organ transplantation and surgery.
  • neurodegenerative diseases eg Alzheimer's disease, Parkinson's disease, Fredreich's Ataxia, Ataxia Telangiectasia, Wilson's disease, motor neurone disease, etc
  • mtDNA diseases eg diabetes mellitus, epilepsy, renal failure, etc
  • a method for the treatment of hypertension and/or conditions associated with oxidative stress by the administration of a nitroxide-biphenyl sartan, or a pharmaceutically acceptable salt thereof, or a composition containing a nitroxide-biphenyl sartan, or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of a nitroxide-biphenyl sartan, or a salt thereof, in the manufacture of a medicament for the treatment of hypertension and/or conditions associated with oxidative stress.
  • renin-angiotensin system RAS
  • a nitroxide-biphenyl sartan or a pharmaceutically acceptable salt thereof
  • compositions for use as an antihypertensive and/or antioxidant comprising an effective amount of a nitroxide-biphenyl sartan, or a pharmaceutically acceptable salt thereof and optionally a carrier or diluent.
  • FIG. 1 Bar graph of tissue-based doxorubicin antioxidant assay. ⁇ Force (g-min) for each of Vehicle control (A), Milfasartan (B, 1 ⁇ ), Nitroxyl-Milfasartan (C,
  • FIG. 1 Angiotensin II inhibition data. Plot of ⁇ RFU (Relative Fluorescence Units) as a function of logM angiotensin II concentration for compounds 6 and 5.
  • Figure 3 Bar graphs of tissue-based lucigenin antioxidant assay. Counts/mg for each of vehicle control, lucigenin, 1% DMSO and DPI (diphenylenciodonium sulphate) at 1 ⁇ , 10 ⁇ and ⁇ (above); lucigenin, DPI (10 ⁇ ) and the salt of compound 6 (Compound 7, Example 2) at 1 ⁇ , 3 ⁇ and 10 ⁇
  • Figure 4a Competitive inhibition of Angiotensin II-rnediated increases in intracellular calcium by Compound 7. Plot of ⁇ R tJ (Relative Fluorescence Units) as a function of lo M angiotensin U concentration for compound 7.
  • Figure 4b Schild plot for Compound 7 with a ⁇ of 8.14 determined using the intracellular calcium measurements in CHO cells stably expressing the ATJA rcceptor.
  • Figure 6 Persistent inhibition of vascular AT receptors following 7 day treatment with Compound 7 in SHR. Plot of % KPSS + NA ( ⁇ as a function of ATII concentration (log M).
  • Compound 7 in SHR Plot of change of right arterial rate (beats/min) as a function of AT II concentration (log ), Figure 8. Compound 7 prevents intlmal thickening of rubbed carotid arteries in SHR.
  • Figure 9 Compound 7 inhibits superoxide levels in rat abdominal aorta. Bar graph of luminescence counts (mg) when 30 mg/kg/day of nitroxide, compound 7, and milfasartan, is administered.
  • the present invention involves the incorporation of a stable nitroxide moiety unto a biphenyl sartan (i.e., angiotensin II antagonist) to form a nitroxide containing analogue of the angiotensin II antagonist with full or partial retention of the angiotensin antagonist activity.
  • a biphenyl sartan i.e., angiotensin II antagonist
  • biphenyl-sartan refers to any non-peptide angiotensin II antagonist which displays an in-vitro AT] -receptor affinity lC 5 o* in the range of about 0.1 nM to about 100 ⁇ (* ICso representing the concentration displacing specifically 50% of The binding of angiotensin) and is additionally characterised with a biphenyl moiety, that for the determination of ICjo values is described
  • biphenyl sartans examples include, but are not limited to, abitesartan, benryllosartan, clisartan, embusartan, enoltasosartan, fonsartan, forasartari, glycyllosartan, milfasartan, olmesartan, opomisartan, piatosartan, ripisartan, candesanan (including candersartan cilexetil), irbesartan, saprisartan, tasosartan, telmisartan, valsartan, zolasartan, and losartan (including losartan potassium), BMS-184698, L-162154, Y -31472, HN- 65021, ME-3221, D-8731, CL-329167, TAK-356, L-162234, L-162441 , L-163017, WJ- 464S8 and BIBS
  • nitroxide-biphenyl sartan refers to any non-peptide angiotensin II antagonist which displays an in-vitro AT r receptor affinity IC 5 o* in the range of about
  • the stable-nitroxide moiety may be any chemical moiety which bears a nitroxide free radical, which is stable in the sense that the nitroxyl group does not (to any great extent) decompose under physiological conditions.
  • Non-stable nitroxides are known to decompose to form hydroxylamines and nitrones. Accordingly, based on these decomposition products one of ordinary skill would be able to assess the suitability of any nitroxide moiety for the purposes of the present invention.
  • Suitable stable-nitroxide moieties include:
  • Ar represents an aryl group; 1 to R 4 in each occurrence may be independently aryl or G1-C3 alkyl, preferably C-O, alkyl;
  • n 1 or 2;
  • More specific suitable stable-nitroxide moieties include:
  • stable-nitroxide may optionally be substituted with one or more groups which do not (») adversely effect the moieties ability to act as a radical scavenger (i.e., for instance, reduce the stability of the moiety in vivo), or (ii) adversely effect the biphenyl sartans ability to function as an angiotensin antagonist.
  • the stable nitroxide moiety may be linked to the biphenyl sartan through a single bond or may be "fused" through multiple bonds. Again, the linking of the stable-nitroxide moiety to a biphenyl sartan (or biphenyl sartan precursor molecule) should not adversely interfere with the molecules ability to act as an angiotensin antagonist. To determine whether the linking of any stable-nitroxide moiety does or does not adversely effect this activity the skilled person would conduct comparable IC50 assays using the protocol described previously by Keenan et al., J. Med. Chem., 1992, 35, 3858-3872, and by Duncia et al., J. Med. Chem., 1990, 33, 1312-1329.
  • nitroxide-biphenyl sartan compound is represented by general formula (I) '
  • G represents a substituted heterocyclyl or substituted heteroaryl
  • L represents a divalent linker group selected from -0-, -CH2- or -O-CH2-;
  • A represents C(O)0R 3 (where R3 is H or lower alkyl), (where R is selected from NHC(0)0-lower alkyl, NHC(0)-optionally substituted heteroaryl, NHC(0)-optionally substituted heteroaryl, or NHC(0)-optlonally substituted heterocyclyl), optionally substituted heteroaryl, or optionally substituted heterocyclyl; and wherein at least one of the substituent groups on the substituted heterocycle or substituted heteroaryl of G is or comprises a stable-nitroxide moiety.
  • G represents a heterocyclyl or heteroaryl selected from the following:
  • L represents CH 2 , -0-CH 2 - (which includes -CH 2 -0-) or -0-
  • G represents a heteroaryl or heterocyclyl selected from the following:
  • each of which is further substituted and wherein a substituent group is or comprises a stable-nitroxide moiety.
  • substituent group is or comprises a stable-nitroxide moiety.
  • the following groups may be selected: where each R5 is independently lower alkyl;
  • R6 is selected from ⁇ C(lower alkyl) 2 OH, -S lower alkyl, -N (lower alkyl) C(0)CHC(lower alkyl) 2l or halogen;
  • R 7 is selected from -C0 2 H, -C(0)OCH(OC(0)0-lower alkyl) lower alkyl, or -CH 2 C(0)0-lower alkyl,
  • the selected group additionally comprises a stable-nitroxide moiety, or a stable nitroxide moiety is present in addition to or in place of the substituent group.
  • the G group may be selected from
  • R' is Ci-C 8 alkyl, and preferably R* is C 2 -C 6 alkyl, Cj-C 6 alkyl, C 4 -C 6 alkyl, n-butyl, pentyl, or hexyl; and wherein the selected group additionally comprises a stable nitroxide moiety, or a stable- nitroxide moiety is present in addition to or in place of the substituent group.
  • R' is n-butyl.
  • R' is methyl, ethyl, n-propyl or n-butyl.
  • X represents a divalent linking group selected from C1-C20 alkyiene, aryJene, - (CH2CH2-O),- (Svhere t is an integer from 2 to 20);
  • X I represents a divalent linking group selected from Ci-Cj alkyiene, O, S; and m is 1 or 2.
  • X and X 1 is preferably C 1 -C3 alkyiene, and more preferably CH 2 .
  • X Or. is C3 ⁇ 4 is selected from:
  • A is selected from the following groups;
  • each R $ is independently lower alk l, More preferably A is selected from:
  • nitroxide biphenyl sartan compounds of formula (1) are as follows:
  • R' is Ci-C 8 alkyl, and preferably R' is C 2 -Ci alkyl, C3-C alkyi, d-C ⁇ > alkyl, n-butyl, pentyl, or hexyl. Preferably R' is n-butyl. indicates potential attachmen points of the stable-nitroxide moiety group.
  • nitroxide-biphcny] sartan compounds are selected from:
  • R' is C)-Cg alkyl, for example, R' is C2-C6 alkyl, C3 ⁇ C ⁇ s alkyl, C4- ; alkyl, n-butyl, pentyl, or hexyl.
  • R' is methyl, ethyl, n-propyl, or n-butyl.
  • R' is butyl
  • the nitroxide-biphenyl sartan compounds are represented by formula (II):
  • R' is d-Ce alkyl, preferably methyl, ethyl, n-propyl, or n-butyl;
  • R 1' is selected from:
  • R 1 ' is selected from:
  • Thc term "substituted" means that the group includes one or more substituents.
  • One or more hydrogen atoms on the group may be replaced by substituent groups independently selected from halogens, alkyl, ⁇ _1 ⁇ 4. 6 alkenyl, Cu alkynyl, -(CH 2 ) P C3.7 cycloalkyl, - (CH 2 ) P C 4 .7 cycJoalkenyl, -(CH 2 ) P aryl, -(CH 2 ) P heterocyclyl, -(CH 2 ) P heteroaryl, -C 6 H 4 S(0) ⁇ ,C
  • each R, R' aritt R" is independently selected from H, Ci.g alkyl, C 2 .6 alkcnyl, C & alkynyl, C3.7 cycloalkyl, Co. ? cycloalkeny , aryl, heterocyclyl, heteroaryl, aryl C,-4 alkyl, hetero C
  • alkyl, heteroaryl C] _6 alkyl, or heterocyclyl Ci.i alkyl may be optionall substituted with one to six of same or different groups selected from halogen, hydroxy, lower alkyl, lower alkoxy, -C0 2 H, CF 3) CN, phenyl NH 2 and -N0 2 ; or when R' and R" are attached to the same nitrogen atom, they may, together with the atom to which they are attached, form a 5 to 7 membered nitrogen containing heterocyclic ring,
  • the substituent when the substituent is or contains an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkcnyl, aryl, heteroaryl or heterocyclyl group, the group may itself be optionally substituted with one to six of the same or different substituents selected from halogens, C
  • ⁇ alkyl refers to a straight or branched chain saturated hydrocarbon group.
  • C1-12 alkyl refers to such a group containing from one to twelve carbon atoms and the terms “C ⁇ alkyl” and “lower alkyl” refer to such groups containing from one to six carbon atoms, such as methyl ("Me”), ethyl ("Et”), n-propy.l (“n-Pr”), isopropyl (“i-Pr”), n-butyl (“n-Bu”), isobutyl (“i-Bu”), sec-butyl (“s-Bu”), tert-butyl ("t-Bu”) and the like.
  • aryl refers to carbocyclic (non-heterocyclic) aromatic rings Or ring systems.
  • the aromatic rings may be mono- or bi-cyclic ring systems.
  • the aromatic rings or ring systems are generally composed of 5 to 10 carbon atoms. Examples of suitable aryl groups include but are not limited to phenyl, biphenyl, naphthyl, tetrahydronaphthyl, and the ' like.
  • Preferred aryl groups include phenyl, naphthyl, indenyl, azulenyl, fluorenyl or anthracenyl.
  • arylalky refers to carbocyclic aromatic rings as previously described substituted by an alkyl group also as previously described.
  • Examples of arylalkyl groups include benzyl and the like.
  • Alkynyl refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 , and preferably from 1 -2, carbon to carbon, triple bonds.
  • alkynyl groups include ethynyl (-O CH), propargyl (-CH 2 C ⁇ CH), pent-2-ynyl (-CH 2 CsCCH 2 -C3 ⁇ 4), and the like.
  • Alkylene refers to divalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms, Examples of such alkylene groups include methylene (-CH2-), ethylene (-CH 2 CH 2 -), and the propylene isomers (e.g., -CH2CH2CH2- and -CH(CH 3 )CH 2 -), and the like.
  • Aryl refers to an unsaturated aromatic carbocyclic group having a single ring (eg. phenyl) or multiple condensed rings (eg. naphthyl or anthryl), preferably having from 6 to 14 carbon atoms.
  • aryl groups include phenyl, naphthyl and the like.
  • Arylene refers to a divalent aryl group wherein the aryl group is as described above.
  • Cycloalkyl refers to cyclic alkyl groups having a single cyclic ring or multiple condensed rings, preferably incorporating 3 to 8 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooetyl, and the like, or multiple ring structures such as adamantanyl, indanyl, and the like.
  • Cycloalkenyl refers to cyclic alkenyl groups having a single cyclic ring and at least one point of internal unsaturation, preferably incorporating 4 to 8 carbon atoms.
  • suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclohex-4»enyl, cyclooct-3-enyl and the like.
  • Halo or halogen refers to fluoro, chloro, brorno and iodo.
  • heteroaryl refers to a monovalent aromatic carbocyclic group, preferably of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring.
  • heterocyclic ring preferably of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring.
  • heterorocyolyl refers to a monovalent saturated or unsaturated grou having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen within the ring.
  • the heterocycle or heteroaryl may be fused to a carbocyclic ring such as phenyl, naphthyl, indenyl, aiulcnyl, fluorenyli and anthracenyl.
  • heterocyclyl and heteroaryl groups include, but are not limited to, oxazolyl, pyrrolyl, iraidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyi, indolizinyl, isoindolyl, indolyl, jndazolyl, purinyl, quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carba2olyl, carbolinyl, phenanthridiny], acridinyl, phenanthrolinyl, isothiazolyl, phenazinyl, isoxazolyl, isothiazolyl, phenoxazinyl, phenox
  • the compounds of the invention may be in crystalline form either as the free compounds or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention . .
  • Methods of solvation are generally known within the art. It will also be recognised that compounds of the invention may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form.
  • the invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres eg., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof.
  • Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or mixtures may be resolved by conventional methods, eg., chromatography, or use of a resolving agent.
  • the compounds of the present invention may be capable of undergoing tautomerism. Accordingly, all possible tautomers of a compound of the present invention fall within the scope and spirit of the invention.
  • biphenyl sartan compounds of the present invention can be prepared based on modification of the synthetic procedures described in, for example, US 6,573,288, US 5,889,020, US 6,335,451, US 5,087,634, US 6,004,989, EP 0475206, EP 0443983, EP 0500409, EP 0487252, EP 0412 848, WO 94/08989, EP 0502314 and EP 0392317.
  • the biphenyl compound (I)(c) may be prepared by reacting a compound of formula (I)(a) with a compound of formula (I)(b) under the palladium- catalysed coupling conditions described in Littke, A.F., and Fu, G.C., Angew. Chem. , Int. Ed., 2002, 1, 4176-421 1.
  • the preparation of compounds of formula (I) may take place by initiall halogcnating the L' group (eg with N-brornosuccinimide) and reacting the resultant alkylbromide with a suitably activated nucleophilic substituted heteroaromatic or heterocyclic compound.
  • the nucleophilic substituted heteroaromatie or heterocyclic compound may be a nucleophilic N-containmg substituted heteroaromatic or heterocyclic compound such as tertra2ole, piperidine, morpholine and the like, activated in the presence of a base
  • the GH group may be a nucleophilic substituted amine which can be subsequently cyclised to form a substituted heteroaryl or heterocyclyi.
  • the GH group may be a nucleophilic carbon moiety (e.g, an enolate) which can be subsequently cyclised to form the substituted heteroaryl or heterocyclyi.
  • R 1 is Cj-Ca alkyl, preferably CiC 6 alkyl.
  • Suitable protecting groups are well known in industry and have been described in many references such as Protecting Groups in Organic Synthesis, Greene T , Wiley-lnteiscience, New York, 1981.
  • the present invention provides pharmaceutical compositions for use as RAS modulators, more particularly as an antihypertensive, the composition comprising an effective amount of a nitroxide-biphenyl sartan of the present invention or a pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable derivative thereof, and optionally a pharmaceutically acceptable carrier or diluent.
  • composition is intended to include the formulation of an active ingredient with encapsulating material as earner, to give a capsule in which the active ingredient (with or without other carrier) is surrounded by carriers.
  • compositions or formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the biphenyl-sartans of the invention together with a conventional adjuvant, carrier, or diluent, may thus be placed into the fonn of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • a conventional adjuvant, carrier, or diluent may thus be placed into the fonn of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of
  • compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effectiv amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • Formulations containing ten (10) milligrams of active ingredient or, more broadly, 0.1 to one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms,
  • the biphenyl-sartans of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.
  • the compounds of the present invention may be administered to a subject as a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt also fall within the scope of the present invention since these may be useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts include, but are not limited to salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic, bena ic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benezenesulphonic, salicyclic sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, n
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium.
  • the present invention includes within its scope cationic salts eg sodium or potassium salts, or alky] esters (eg methyl, ethyl) of the phosphate group.
  • Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others,
  • prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group is converted into an ester, such as an acetate or phosphate ester, or where a free amino group is converted into an amide (eg. a-aminoacid amide).
  • esterifying, eg. acylating, the compounds of the invention are well known in the art and may include treatment of the compound with an appropriate carboxylic acid, anhydride or chloride in the presence of a suitable catalyst or base.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispensable granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilisers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material,
  • the carrier is a finely divided solid that is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oval administration.
  • a low melting wax such as an admixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.
  • the biphenyl-sartans according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily Or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, eg. sterile, pyrogen-free water, before use.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcelJulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcelJulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations ma contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents, and the like.
  • the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray, The formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension.
  • a spray this may be achieved for example by means of a metering atomising ; spray pump.
  • the compounds according to the invention may be encapsulated with cyclodextrins, or formulated with other agents expected to enhance delivery and retention in the nasal mucosa.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain
  • the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropyiroethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropyiroethyl cellulose and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the powder carrier will form a gel in the nasal cavity
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler,
  • the compound will generally have a small particle size for example of the order of 5 to 10 microns or less.
  • Such a particle size may be obtained by means known in the art, for example by micronisation.
  • formulations adapted to give sustained release of the active ingredient may be employed.
  • the pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.
  • the amount of the biphenyl-sartans administered may be in the range from about 10 mg to 2000 mg per day, depending on the activity of the compound and the disease to be treated.
  • Liquids or powders for intranasal administration, tablets or capsules for oral administration and liquids for intravenous administration are the preferred compositions.
  • compositions may furtlier contain one or more other antihypertensive compounds.
  • the compositions may contain a second antihypertensive agent such as a non- nitroxide containing antihypertensive sartan.
  • nitroxide containing biphenyl- sartan derivatives of saltans retain their ability to effectively act as AH antagonists. Accordingly, the biphenyl-sartans of the present invention may be used in therapies where existing sartans prove effective, and specifically, in the Treatment of hypertension. Yet the compounds of the present invention are predicted to also have added benefits due to the incorporation of the nitroxide moiety.
  • One of the main advantage lies in the ability of the nitroxide group to act as an antioxidant. For instance, the present inventors have found that the nitroxide-sartans possess favourable antioxidant properties. The implications of this means that the biphenyl sartan of the present invention, in addition to retaining All antagonist activity may also serve to treat conditions associated with oxidative stress where antioxidant treatment may be beneficial.
  • ROS reactive oxygen species
  • the main source of ROS within the arterial wall is a form of the enzyme NAD(P)H oxidase. This enzyme generated superoxide radicals by catalysing the reduction of O2 (see scheme 3). Superoxide radicals can subsequently be converted to more potent ROS. For example, dismutation provides hydrogen peroxide and reaction with nitric oxide affords peroxynitrite (see scheme 3).
  • ROS ONOO- Living organisms utilise ROS as inter- and intracellular mediators of signal transduction.
  • ROS can oxidise all major classes of biomolecules and are harmful at high concentrations.
  • Living organisms are protected against ROS by a group of antioxidant compounds and enzymes.
  • Notable antioxidant en2ymes are the enzymes glutathione peroxidase (GPx) and thioredoxin reductase which both contain selenium.
  • Antioxidants prevent the formation of ROS or intercept ROS and exclude them from further activity.
  • ROS production is counterbalanced by antioxidant defence networks and ROS levels are tightly regulated. However, sometimes the endogenous antioxidant defence network becomes overwhelmed by excess ROS.
  • ROS may activate genes and transcription factors mediated oxidation of arachidonic acid to F 2 -isoprostanes, which are prostaglandin-like compounds that are potent vasoconstrictors.
  • antioxidants constitute potential weapons against hypertension.
  • a group of mildly hypertensive patients received 200IU of vitamin E (a dietary antioxidant) per day (see Touyz, R. M. Expert Rev, Cardiovascular. Ther. , 1, 91., 2003). Over twenty-seven weeks the average systolic blood pressure of the group decreased by 24%.
  • Other antioxidants such as vitamin C and allopurinol, also reduce blood pressure in hypertensive humans.
  • the biphenyl-sartan compounds of the present invention may be effective multipotent drugs for the treatment of hypertension as well as other conditions and diseases linked to oxidative stress.
  • Multipotent drugs may be obtained by combining two different pharmacophore groups in a single molecule. Such drugs would be desirable for the treatment of hypertension, because hypertension has a complex pathogenesis and the treatment with one single-action drug often fails to sufficiently control the illness.
  • Multipotent drugs such as the biphenyi sartans of the present invention may provide similar benefits to combinations of single- action drugs without pharmacokinetic drug interactions and many of the other disadvantages associated with combination therapy.
  • the biphenyl-sartans of the present invention may be useful in the treatment of conditions associates with oxidative stress.
  • the biphenyl-sartans of the present invention may be useful in the treatment of neurodegenerative diseases and conditions such as Alzheimer's disease, Parkinson's disease, parkinsonian syndrome (multiple system atrophy and progressive supernuclear palsy), amyotrophic lateral sclerosis, dementia (including Lewy body dementia), Friedrich's ataxia, Wilson's disease, Ataxia Telangiectasia, Motor neurone disease, Alexander disease, Alper's disease, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington disease, Kennedy's disease, rabbe disease, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple sclerosis, Multiple System Atrophy
  • mtDNA diseases such as cardiomyopathy, heart failure, heart block, arrhythmia, diabetes, pancreatitis, retinopathy, optic neuropathy, renal failure, Kearns Sayre Syndrome, Sudden Infant Death Syndrome, dementia and epilepsy, stroke may also be effectively treated using the biphenyl-sartans of the present invention.
  • Other conditions such as inflammation, ischaemic-reperfusion tissue injury in strokes, heart attacks, organ transplantation and surgery, edema, atherosclerosis, may- also be beneficially treated with the biphenyl-sartans of the present invention.
  • each of the pharmacophoric subunits of the conjugated nitroxide-biphenyl sartan compounds of the present invention is preferably designed or arranged to ensure that each of the intended molecular targets is modulated to an appropriate degree in vivo.
  • This "matching" of activities is preferable as compounds with large differences in in viiro affinity for respective targets will only be able to act at both targets (in vivo) at high doses based on the lowest affinity target. This would increase the risk of side effects associated with the higher affinity target.
  • novel nitroxide-biphenyl sartan compounds of the present invention are characterised with in vitro antioxidant activity that is matched with the in vitro angiotensin II antagonist activity.
  • the compounds disclosed herein may be chemically modified.
  • matching may be facilitated through the elongation or reduction of the ' alkyl substituent in the embodiments discussed above.
  • the compounds of the present invention can be "tuned" in order to ensure maximum in vivo efficacy in relation to both antioxidant and antihypertensive activities.
  • Compound 13 was prepared as pale yellow foam (168 mg, 38 % over two steps) from 6- cthyl-a-mtthyl-S-CP'-i I -(triphenylmethyl)- 1 H-tetrazol-5-y][ 1 , 1 'bipheny l]-4- yl]methyl]pyrimidin-4(lH)-one (9) (640 mg, 1.04 rnmol) and 3-bromomethyl-2,2,5,5- tetramethyl-2,5-dihydropyrrole-l-oxyl (2) (360 mg, 1.56mmol).
  • Compound IS was prepared as pale yellow foam (1 5 mg,47 % overtwo steps) from 6- propyl- 2-methy]-5-[[2 '-[ 1 -(triphenylmethyl)- 1 H etrazo]-5 " y][l, ] 'biphenyl]-4.
  • Compound 16 was prepared as pale yellow foam, (262 mg, 56 % over two steps) from 6- propyl-2-methyl-5-[[2 H 1 -(triphenylmethyJ 1 H-tetrazol-5-y] [ 1 , l 'biphenyl]-4- yi]methyl]pyrimidin-4(lH)'One (10) (550 mg, 0.88mmol) and 2-(bromomethyl)-4,4,6,6- tetxamethyM.e-dihydro-SH-thienop ⁇ -cjpyrrol ⁇ -yloxyl (3) (450 mg, 3.00mmol);
  • mice 28 ⁇ 0,5 g, «-l 10) were used in this study. Mice were housed in the Department of Pharmacology Biological Research Facility and maintained at 22°C with a 12 h light/dark cycle. Animals were given free access to food and water. Experiments using animal tissues were undertaken with the approval of the University of Melbourne Animal Ethics Committee in accordance with the Code of practice of the National Health and Medical Research Council of Australia. Tissue preparation
  • mice were anaesthetised using spontaneous inhalation of halothane (5% in (Vroom air) and their hearts quickly excised. Left atria were dissected in gassed Krebs solution (in mM, Na* 144, K + 5.9, Mg 24 1.2, Ca 2+ 2.5, 3 ⁇ 4PCV 1.2, CT 128.7, S0 4 2" 1.2, HCOj 25, glucose II, EDTA 0.04).
  • the left auia were each mounted onto two 3QG S shaped hooks and set u in 10 ml organ baths that were positioned in a fume hood to scavenge aerated doxorubicin particles, rebs solution in the jacketed organ baths was kept at approximately 37°C with continuous bubbling of 95% Oz/5% C0 2 .
  • Left atria were stretched to 1 g of tension using an adjustable micrometer (Mitutoyo Manufacturing) and stimulated at 1 Hz, 0.3 ms at 120% of threshold voltage using a stimulator (S88, Grass Instruments, Warwick, RI, USA).
  • tissue was incubated with 10 ⁇ of milfasartan, compound 7 or sodium 2,2,5,5-tetramethyl-2,5-dihydropyriOle- l-oxyl-3-carboxylate (nitroxidc) for 30 min, Following this incubation period, doxorubicin (30 ⁇ ) was added to the bath and left for 90 min,
  • Drugs used and suppliers were: doxorubicin (Sigma, St. Louis, MO, USA), isoprenaline (Sigma), quercefin (Sigma), diphenyleneiodonium sulphate (DPI) (Sigma) and ebselen (Sigma). Analysis
  • the lucigenin probe is reduced by superoxide, (produced by a tissue sample stimulated with NADPH) resulting in the production of a cation radical and an unstable dioxetane.
  • the unstable dioxetane decomposes and emits a photon.
  • Photon emission can be measured using a scintillator or photometer (Janiszewski et al, "Overestimation of NADH-driven vascular oxidase activity due to hicigen artifacts", Free Radical Biol. Med 32(5):446-453, 2002).
  • the antioxidant status of a compound can be measured by quantifying the reduction ⁇ photon emission as compared to the control.
  • DPI diphenyleneiodonium sulphate
  • NADPH oxidase inhibitor is used as a positive control for the assay.
  • Rats Male Sprague Dawley rats (250-350 g body weight) were used in this study. Rats were housed in the Department of Pharmacology Biological Research Facility and maintained at 22°C with a 12 light/dark cycle, Animals were given free access to food and water. Experiments using animal tissues were undertaken with the approval of the University of Melbourne Animal Ethics Committee in accordance with the Code of practice of the National Health and Medical Research Council of Australia.
  • Rats were anaesthetised using spontaneous inhalation of halothane (5% in O ⁇ /room air) and killed using cervical dislocation.
  • Thoracic aorta were dissected out in rebs-Hepes buffer solution buffer (in mM NaCI, 99-01; KCl, 4.69; CaClj, 1.87; MgS0 4 , 1.20; 2 ⁇ 0 4 , 1.03; NaHC0 3 , 25.0; HEPES (4-(2-hydroxyethylH -piperazineeftancsu]fonic acid 20.0, and glucose, 1 1.1 , pB 7.4) and gassed with carbogen.
  • Aorta were cleared of fat and connective tissue and cut into approximately 3 mm segments.
  • Tissues were incubated at 37°C in a 6 well plates containing rebs-HEPES buffer solution, NADPH (nicotinamide adenine dinucleotide phosphate-oxidase 100 ⁇ ) and DETCA (diethylthiocarbamate 300 ⁇ ) for 45 min in 37°C oven (Forma Scientific; OH, USA). Control tissues were also incubated with the NADPH oxidase in inhibitor DPI (diphenyleneiodonium 0.1, 1 or 10 ⁇ see Tabic below for drug actions).
  • DPI diphenyleneiodonium 0.1, 1 or 10 ⁇ see Tabic below for drug actions.
  • aorta segments were placed in a 96 well Optiplate (Perkin Elmer; Downers Grove, IL, USA) containing NADPH (100 ⁇ ), lucigenin (5 ⁇ ) and DPI (0.1 ,1 or 10 ⁇ ). Photon emission was detected by a luminescence counter (Perkin Elmer; Downers Grove, IL, USA) which read each well 12 times over 25 min. Background photon emission counts of the 96 well Optiplate were also taken prior to addition of the tissue segments. Vessel segments were then dried in a 65°C oven (Daihan Scientific; Seoul, Korea) overnight in order to determine the dry weight of the vessel. Counts were expressed as average counts per mg of dry tissue weight.
  • vessel segments were incubated in a 6 well plates containing NADPHj DETCA, Krebs- HEPES buffer, vehicle (1% methanol or DMSO) and antioxidant moieties or novel biphenyl sartan (0.1 , 1 and 10 ⁇ ) for 45 min at 37 °C. Following an incubation period, aorta segments were transferred to a 96 well Optiplate containing NADPH (100 ⁇ ), lucigenin (5 ' ⁇ ) and antioxidant moieties or novel biphenyl sartans (0.1, 1 or 10 ⁇ ). Photon emission of the vessel segments were detected using a luminescence counter. Drug action of compounds used in the lucigenin enhanced chemiluminescence assay.
  • NADPH+ Stimulates NADPH oxidase 100 ⁇
  • Drugs used and suppliers were: nicotinamide adenine dinucleotide phosphate-oxidase (NADPH, Sigma, St. Louis, MO, USA), diethylthiocarbamate (DETCA, Sigma), 4-2- hydroxyethyl-l-piperazineethanesulfonic acid (HEPES, Sigma), diphenyleneiodonium (DPI, Sigma) and lucigenin (Sigma).
  • NADPH nicotinamide adenine dinucleotide phosphate-oxidase
  • DETCA diethylthiocarbamate
  • HEPES 4-2- hydroxyethyl-l-piperazineethanesulfonic acid
  • DPI diphenyleneiodonium
  • lucigenin Sigma
  • CHO cells stably expressing the AT )A receptor were loaded with Fluo4-AM and then incubated with 10, 30 or 100 nM Compound 7 for 30 min.
  • Compound 7 was evaluated using HPLC analysis. Compound 7 was incubated with CHO cells and buffered saline for 30 min or for 2 hrs. The 30 min incubations yielded a single peak that corresponded to the Compound 7 standards suggesting the antagonist activity in the CHO cell assay was attributable to Compound 7.
  • a telemetry transmitter (TL1 1M2-C50-PXT; Data Sciences International, St Paul, MN, USA) was implanted into the abdominal aorta under general anaesthesia and sterile surgical conditions (Huetteman. DA, Bogie, H (2009) Methods Mol Biol 573: 57-73). The- animals were allowed to recover and stabilise for 7 days. A baseline blood pressur measurement was recorded prior to the initiation of drug or vehicle treatment (Day 0).
  • the time frame from removing the arteries to testing the angiotensin II responsiveness was 2- 2.5 hrs.
  • responsiveness to angiotensin II was not different to the 50% DMSO solvent-treated animals.
  • animals treated with Compound 7 dissolved in 50% DMSO demonstrated persistent inhibition of angiotensin receptors.
  • rats were anaesthetised with a mixture of isoflurane/100% oxygen and the heart rapidly removed for determination of th responsiveness to angiotensin ⁇ .
  • the spontaneously beating right atrium was dissected free from the left atrium and ventricles, pierced by two hooks and mounted in an acrylic organ bath filled with Krebs' solution as described by Winkel, D, TibbaUs, J, Mo!enaar, P, Lambert, O, Coles, P, Ross-Smith, M, Wiltshire, C, Fenncr, PJ, Gershwin, LA, Hawdon, GM, Wright, CE, Angus, JA (2005) Clin Exp Pharmacol Physiol ' 32: 777-788.
  • Rubbing of the carotid artery is known to cause damage to the lining of blood vessels which develops over 14 days in SHR into a lesion of intimal thickening (Dalle Lucca, S, Dalle Lucca, J, Borges, A, Ihara, S, Paiva, T (2000) Brazilian J Med Biol Res 33: 1 - 927).
  • SH were anaesthetized and an osmotic mini-pum (model 2MD, Alzet, Cupertino, CA, USA) containing a 14 day drug treatment was implanted subcutaneous ly (s.c,).
  • the osmotic mini pump was filled'with either Compound 7, milfasartan, sodium 2,2,5, 5- tetramethyl-2,5-dihydropyrrole-l -oxyl-3-carboxylate (nitroxide) or saline solvent; the pump delivered a dose of 30 mg kg day. This dose was chosen based on previous reports where 30 mg kg/day losarfan was able to decrease blood pressure and the extent of vascular injury (De Blois, D, Tea, B-S, Dam, T-V, Tremblay, J, Harriet, P (1997) Hypertension 29: 340-344).
  • rats were perfusion-fixed (6% paraformaldehyde) at 150 mmHg and both injured and uninjured carotid arteries were excised and cut into 5 ⁇ thick sections. Sections were stained with haematoxylin and eosin and analysed to determine the extent of intimal thickening (Dalle Lucca, S, Dalle Lucca, J, Borgcs, A, Ihara, S, Paiva, T (2000) Brazilian J Med Biol Res 33: 919-927). A section of the abdominal aorta was removed prior to fixation to assess the effect of treatment on superoxide levels.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des composés et des compositions pouvant être employés dans la modulation du système rénine-angiotensine (SRA) dans les cellules, et en particulier des composés qui peuvent entre autres agir au titre d'antagonistes de l'angiotensine II en se liant aux récepteurs de l'angiotensine II. La présente invention concerne également l'emploi desdits composés et compositions dans le traitement des états pathologiques sensibles aux antagonistes de l'angiotensine II tels qu'hypertension, œdème, insuffisance rénale, hypertrophie bénigne de la prostate, glaucome, athérosclérose, diabète, maladie d'Alzheimer et insuffisance cardiaque congestive.
PCT/AU2011/000495 2010-04-30 2011-04-29 Nouveaux biphénylsartans WO2011134019A1 (fr)

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AU2010901858A AU2010901858A0 (en) 2010-04-30 Novel Biphenyl Sartans

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