Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
• • 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
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
  • C07C235/80—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms having carbon atoms of carboxamide groups and keto groups bound to the same carbon atom, e.g. acetoacetamides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms

Definitions

• the present invention relates to a process for preparing
• the invention also relates to a process for making intermediates useful in the formation of said compound, and to the intermediates, per se.
• Prolonged and excessive exposure of the myocardium to noradrenaline may lead to down-regulation of cardiac ⁇ -adrenoceptors, remodelling of the left ventricle, arrhythmias and necrosis, all of which can diminish the functional integrity of the heart.
• inhibitors of ⁇ may provide significant advantages over conventional ⁇ -blockers.
• nepicastat (RS-25560- 197, ICso 9nM) (Stanley, W.C., et al., Br. J Pharmacol., 121 : 1803- 1809, 1997), which was developed to early clinical trials.
• BBB blood brain barrier
• WO 2004/033447 discloses dopamine-P-hydroxylase inhibitors having high potency and significantly reduced brain access, giving rise to potent and peripherally selective DPH inhibitors.
• WO2008/ 136695 discloses a compound of formula 1:
• , R 2 and R 3 are the same or different and signify hydrogens, halogens, alkyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group;
• R 4 signifies -alkylaryl or - aikylheteroaryl;
• X signifies CH 2 , oxygen atom or sulphur atom; and
• n is 2 or 3.
• WO2008/I 36695 also discloses a compound of formula Y, its (R) or (S) enantiomer, or mixture of (R) and (S) enantiomer, or pharmaceutically acceptable salts or esters thereof.
• RY ⁇ which is the R-enantiomer of compound Y ⁇
• the present invention also relates to rivatives of compound RY', which derivatives have the formula RY.
• the present invention also provides intermediates for use in the processes, and processes for preparing and using the intermediates.
• , R 2 and R 3 are the same or different and signify hydrogen, halogen, alkyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group;
• X signifies CH 2 , oxygen atom or sulphur atom; which process comprises reducing a compound of formula D,
• the compound of formula D is prepared by condensing a compound of formula C,
• the compound of formula C is prepared by hydroxylating a compound of formula B,
• the compound of formula B is prepared brominating a compound of formula A
• the process comprises: brominating a compound of formula A to form a compound of formula B; hydroxylating a compound B to a compound of formula C; condensing the compound C with a compound of formula JT to form a compound of formula D; and reducing the compound D to form the compound of formula RY, and optionally converting compound RY to a pharmaceutically acceptable salt thereof;
• , R 2 and R 3 are the same or different and signify hydrogen, halogen, alkyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; and X signifies CH 2 , oxygen atom or sulphur atom.
• alkyl means hydrocarbon chains, straight of branched, containing from one to six carbon atoms, optionally substituted by aryl, alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl groups.
• aryl means a phenyl or naphthyl group, optionally substituted by alkyl, alkyloxy, halogen or nitro group.
• halogen means fluorine, chlorine, bromine or iodine
• heteroaryl means heteroaromatic group.
• one of Ri , R 2 and R 3 is hydrogen, and the others are fluorine.
• compound RY has the formula RY'
• the brominating step is carried out in the presence of a suitable brominating reagent such as N-bromosuccinimide (BS), dibromohydantoin or bromine.
• a suitable brominating reagent such as N-bromosuccinimide (BS), dibromohydantoin or bromine.
• the brominating step is carried out in the presence of bromine.
• the bromination is carried out at a temperature ranging from about 0°C to about 25°C, preferably from about 0°C to about 5°C.
• the reaction mixture is heated to room temperature, i.e. around 25°C, after addition of bromine. It has been observed that the bromination reaction may result in a mixture of isomers.
• the process may further comprise treating of the bromination product B (suitably after filtration thereof with DCM) with a suitable aqueous base such as aqueous bicarbonate solution, followed by extraction with a suitable solvent such as methyl /er/-butyl ether (MTBE) and crystallization from a further suitable solvent such as MTBE.
• a suitable aqueous base such as aqueous bicarbonate solution
• MTBE methyl /er/-butyl ether
• the conversion of the bromide B to the hydroxy ketone C is achieved by treatment with an alkaline metal formate, preferably sodium, potassium or cesium formate, most preferably potassium formate in a suitable solvent such as methanol, preferably boiling methanol.
• an alkaline metal formate preferably sodium, potassium or cesium formate, most preferably potassium formate in a suitable solvent such as methanol, preferably boiling methanol.
• crude bromide of formula B may be used without purification (i.e. either as the HBr salt or as the free base).
• the hydroxy ketone C was observed to be obtained as a stable crystalline material.
• the reaction temperature is about 50°C or higher, more preferably from about 50°C to the reflux temperature of the solvent used. Most preferably, the reaction is carried out under reflux.
• the alkaline metal formate is present in at least 3 molar equivalents.
• the free base is used for the conversion, the alkaline metal formate is present in at least 2 molar equivalents.
• Cyclisation of the hydroxy ketone C with compound JT is preferably carried out using an alkali metal thiocyanate such as potassium thiocyanate and a suitable acid such as acetic acid (AcOH) in a suitable solvent such as 2-propanol.
• an alkali metal thiocyanate such as potassium thiocyanate
• a suitable acid such as acetic acid (AcOH)
• AcOH acetic acid
• 2-propanol avoids the need for chromatographic purification of compound D.
• RY is carried out using a reducing agent comprising NaBH 4 -BF 3 complex such as NaBH 4 - BF 3 .Et 2 0, NaBH 4 -BF 3 .THF, preferably NaBH 4 -BF 3 .THF in a suitable solvent such as THF or Me-THF, preferably THF (it is believed that this results in in situ borane formation).
• a suitable solvent such as THF or Me-THF, preferably THF (it is believed that this results in in situ borane formation).
• Suitable amounts of reducing agent are 5 or 2.5 molar equivalents of each or 2.5 molar equivalents of NaBH 4 with 3.3 molar equivalents of BF 3 .Et 2 0 or BF 3 .THF, preferably 2.5 molar equivalents of NaBH 4 with 3.3 molar equivalents of BF 3 .THF.
• Alternative reducing agents are sodium bis(methoxyethoxy)alurninohydride) (RedAlTM), Borane
• the process further comprises converting the compound RY to a pharmaceutically acceptable salt thereof.
• Suitable pharmaceutically acceptable salts include acid addition salts.
• the pharmaceutically acceptable salt is the HCI salt.
• a process for preparing a compound of formula C from the compound of formula B is as described above.
• the present invention also provides the use of compound B in a process for preparing (R)-5-(2-(benzylamino)ethyl)- l -(6,8-difluorochroman-3-yl)- l H-imidazole-2(3H)- thione, or a pharmaceutically acceptable salt thereof, especially the hydrochloride salt.
• a process for preparing a compound of formula D from the compound of formula C is as described above.
• the present invention also provides the use of compound C in a process for preparing (R)-5-(2-(benzylamino)ethyl)-l -(6,8-difluorochroman-3-yl)- l H-imidazole-2(3H)- thione, or a pharmaceutically acceptable salt thereof, especially the hydrochloride salt.
• Ri, R 2 and R 3 are the same or different and signify hydrogen, halogen, alkyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; and X signifies CH 2 , oxygen atom or sulphur atom;
• alkyl means hydrocarbon chains, straight or branched, containing from one to six carbon atoms, optionally substituted by aryl, alkoxy, halogen, alkoxycarboriyl or hydroxycarbonyi groups;
• aryl means a phenyl or naphthyl group, optionally substituted by alkyl, alkyloxy, halogen or nitro group;
• halogen means fluorine, chlorine, bromine or iodine;
• heteroaryl means heteroaromatic group.
• X is O.
• , R 2 and R 3 is hydrogen, and the others are fluorine.
• compound D has the formula D'
• a process for preparing a compound of formula RY from the compound of formula D is as described above.
• the present invention also provides the use of compound D in a process for preparing (R)-5-(2-(benzylamino)ethyl)- 1 -(6,8-difluorochroman-3-yl)- 1 H-imidazoIe-2(3H)- thione, or a pharmaceutically acceptable salt thereof, especially the hydrochloride salt.
• the compound D' is used to prepare the compound RY'.
• , R 2 and R 3 are the same or different and signify hydrogen, halogen, alkyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group;
• X signifies CH 2 , oxygen atom or sulphur atom; which process comprises deprotecting a compound of formula
• the compound of formula I is prepared by reacting a compound of formula I,
• Ns signifies o-nitrophenylsulphonyl
• Ri, R 2 , R 3 and X are as hereinbefore defined in formula RY, X signifies CH 2 , an oxygen atom or a sulphur atom, and Z is selected from L-tartrate, hydrochloride, mesylate, tosylate, trifjuotoacetate, citrate, glycolate and oxalate.
• pound of formula I is prepared by hydroxylating a compound of formula G
• the compound of formula I is prepared by hydrolysing a compound of formula H,
• Ns signifies o-nitrophenylsulphonyl
• the compound of formula H is prepared by acylating a compound of formula G,
• the compound of formula G is prepared by brominating a compound of formula F,
• Ns signifies o-hitrophenylsulphonyl.
• the compound of formula F is prepared by reacting a compound of formula E, with o-nitrophenylsuplonyl chloride.
• the process comprises: converting benzylamine E to a compound of formula F in the presence of o-nitrophenylsulphonyl chloride and a suitable solvent such as methyl vinyl ketone (MVK); converting the compound F to a compound of formula G in the presence of a brominating agent; hydroxylating a compound G to a compound of formula 1 or acetylating compound G to form a compound of formula H followed by hydrolysing the compound H to form a compound of formula I; reacting the compound I with a compound of formula JZ to form a compound of formula ; and deprotecting compound to form compound RY, where Ns is o- nitrophenylsulphonyl, Z is selected from L-tartrate, hydrochloride, mesylate, tosylate, trifluotoacetate, citrate, glycolate and oxalate, R
• one of Ri, R 2 and R is hydrogen, and the others are fluorine.
• Z is L-tartrate.
• compound JZ has the formula JT and compound JZ' has the formula JT .
• the conversion of compound E to compound F is carried out in the presence of a base such as triethylamine, tributylamine, diisopropylethylamine, N-methyl morpholine, preferably triethylamine and a catalytic amount of a suitable alkali metal alkoxide such as potassium tert-butoxide (t-BuOK), sodium methoxide, sodium ethoxide or sodium tert- butoxide, preferably, potassium tert-butoxide.
• a base such as triethylamine, tributylamine, diisopropylethylamine, N-methyl morpholine, preferably triethylamine and a catalytic amount of a suitable alkali metal alkoxide such as potassium tert-butoxide (t-BuOK), sodium methoxide, sodium ethoxide or sodium tert- butoxide, preferably, potassium tert-butoxide.
• t-BuOK
• the bromination of compound F is achieved using Br 2 in the presence of MeOH.
• the acetylation of compound G is achieved using an alkaline metal acetate, such as potassium acetate (OAc), sodium acetate or cesium acetate, preferably potassium acetate, in the presence of a suitable acid such as acetic acid (AcOH).
• OAc potassium acetate
• AcOH acetic acid
• the hydrolysis of compound H is achieved using a suitable acid such as HCI in the presence of a suitable sol vent such as 2-propanol.
• the hydroxylation of compound G to a compound of formula 1 is achieved by treatment with an alkaline metal formate, such as sodium, potassium or cesium formate, preferably potassium formate in presence of formic acid in methanol.
• an alkaline metal formate such as sodium, potassium or cesium formate, preferably potassium formate in presence of formic acid in methanol.
• the reaction temperature is about 50°C or higher, preferably from about 50°C to the reflux temperature of the solvent used. Most preferably, the reaction is carried out under reflux.
• the compound of formula I was obtained in one step procedure from compound G.
• the condensation of compounds 1 and JZ is carried out in the presence of an alkaline metal thiocyanate, such as potassium thiocyanate (KSCN), sodium thiocyanate and cesium thiocyanate, preferably potassium thiocyanate or an tetraalkylammonium thiocyanate, such as tetrabutylammonium thiocyanate and an acid, such as acetic acid (AcOH) or propionic acid, preferably AcOH.
• an alkaline metal thiocyanate such as potassium thiocyanate (KSCN), sodium thiocyanate and cesium thiocyanate
• potassium thiocyanate or an tetraalkylammonium thiocyanate such as tetrabutylammonium thiocyanate
• an acid such as acetic acid (AcOH) or propionic acid, preferably AcOH.
• compound 1 can be condensed with the hydrochloride, mesylate, tosylate,
• deprotection of the nosyl compound K is achieved with thioglycolic acid in a polar aprotic solvent such as DMF, DMSO and NMP, preferably DMSO or DMF in the presence of a base, suitably LiOH, NaOH, KOH, CsOH or quaternary ammonium hydroxides, such as tetrabutylammonium hydroxide, preferably LiOH or KOH.
• a base suitably LiOH, NaOH, KOH, CsOH or quaternary ammonium hydroxides, such as tetrabutylammonium hydroxide, preferably LiOH or KOH.
• the deprotection is carried out at room temperature, i.e. about 25°C or at about 40°C.
• the isolated yield of compound RY ranges from 91 % to 96% and HPLC has shown the purity of the crude product to be around 98% area (Kromasil 100 5C4 250x4.6 column, mobile phase 0.1 %TFA - ACN 25:75 at 1 ml/min, 270 nm).
• the compound RY isolated from the deprotection step is then purified, in an embodiment, the purification is performed via a two-step procedure comprising formation of the HCl salt in MeOH with methanolic HCl and crystallisation of the HCl salt of compound RY from toluene after removal of MeOH, followed by isolation of the compound RY in free base form.
• the overall yield of the two-step purification process is about 85%.
• the purification is performed via a re-slurry in 2-butanone.
• the yield of the purification process is about 85%.
• the compound RY is RY'.
• a process for preparing a compound of formula G as described above from the compound of formula F is as described above.
• the present invention also provides the use of compound F in a process for preparing (R)-5-(2-(benzylamino)ethyi)-l-(6,8-difJuorochroman-3-yl)- l H- imidazole-2(3H)-thione, or a pharmaceutically acceptable salt thereof, especially the hydrochloride salt.
• a process for preparing a compound of formula H as described above from the compound of formula G is as described above.
• the present invention also provides the use of compound G in a process for preparing (R)-5-(2-(benzylamino)ethyl)-l-(6,8-difluorochroman-3-yl)-I H- imidazole-2(3H)-thione, or a pharmaceutically acceptable salt thereof, especially the hydrochloride salt.
• a process for preparing a compound of formula H is as described above.
• a process for preparing a compound of formula 1 as described above from the compound of formula H is as described above.
• the present invention also provides the use of compound H in a process for preparing (R)-5-(2-(benzylamino)ethyl)-l-(6,8-difluorochroman-3-yl)-l H- imidazole-2(3H)-thione, or a pharmaceutically acceptable salt thereof, especially the hydrochloride salt.
• Ns is o-nitrophenylsulphonyl
• , R 2 and R 3 are the same or different and signify hydrogen, halogen, alkyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group
• X signifies CH 2 , oxygen atom or sulphur atom
• alkyl means hydrocarbon chains, straight or branched, containing from one to six carbon atoms, optionally substituted by aryl, alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl groups
• aryl means a phenyl or naphthyl group, optionally substituted by alkyl, alkyloxy, halogen or nitro group
• halogen means fluorine, chlorine, bromine or iodine
• heteroaryl means heteroaromatic group.
• X is O.
• one of Ri, R 2 and R 3 is hydrogen, and the others are fluorine.
• compound K has the formula '
• a process for preparing a compound of formula RY as described above from the compound of formula K is as described above.
• the present invention also provides the use of compound K in a process for preparing (R)-5-(2-(benzylamino)ethyl)- l-(6,8- i difluorochroman-3-yl)- l H- imidazole-2(3H)-thione, or a pharmaceutically acceptable salt thereof, especially the hydrochloride salt.
• a process for preparing a compound of formula RY' as described above from the compound of formula ⁇ The process is as described above.
• the present invention also provides the use of compound K' in a process for preparing (R)-5-(2-(benzylamino)ethyl)- l-(6,8-difJuorochroman-3-yl)-l H- imidazole-2(3H)-thione, or a pharmaceutically acceptable salt thereof, especially the hydrochloride salt.
• a pharmaceutical composition comprising a compound RY or RY', or a pharmaceutically acceptable salt thereof, prepared as described above together with one or more pharmaceutieally- acceptable excipients.
• composition comprising RY or RY', or a pharmaceutically acceptable salt thereof, preferably a therapeutically effective amount of compound RY or RY', or a pharmaceutically acceptable salt thereof, prepared as described above in combination with a pharmaceutically effective carrier and one or more of the compounds selected from the classes described below.
• the compound RY or RY' as prepared by the present invention may be combined with one or more of the fol lowing classes of compounds: diuretics; beta-adrenergic antagonists; alpha2 -adrenergic agonists; alpha 1 -adrenergic antagonists; dual beta- and alpha- adrenergic antagonists; calcium channel blockers; potassium channel activators; antiarrhythmics; ACE inhibitors; ATI receptor antagonists; renin inhibitors; lipid lowerers, vasopeptidase inhibitors; nitrates; endothelin antagonists; neutral endopeptidase inhibitors; anti- angiotensin vaccines; vasodilators; phosphodiesterase inhibitors; cardiac glycosides; serotonin antagonists; and CNS acting agents.
• diuretics beta-adrenergic antagonists
• alpha2 -adrenergic agonists alpha 1 -adrenergic antagonists
• the most useful diuretics include:
• Loop diuretics in particular, furosemide, bumetanide, ethacrynic acid, torasemide, azosemide, muzolimine, piretanide, tripamide.
• hydrochlorothiazide hydroflumethiazide, methylclothiazide, polythiazide, trichlormethiazide.
• Aldosterone antagonists in particular, spirolactone, canrenone
• More than one of the aforementioned diuretics may be used.
• the most useful beta-adrenergic antagonists include: timolol, metoprolol, atenolol, propranolol, bisoprolol, nebivolol. More than one of the aforementioned beta- adrenergic antagonists may be used.
• the most useful alpha2-adrenergic agonists include: clonidine, guanabenz, guanfacine. More than one of the aforementioned alpha2 -adrenergic agonists may be used.
• the most useful alpha 1 -adrenergic antagonists include: prazosin, doxazosin, phentolamine. More than one of the aforementioned alpha 1 -adrenergic antagonists may be used.
• the most useful dual beta- and alpha-adrenergic antagonists include: carvedilol, labetalol. More than one of the aforementioned dual beta- and alpha-adrenergic antagonists may be used.
• Potassium channel activators include nicorandil.
• the most useful calcium channel blockers include: amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, verapamil. More than one of the aforementioned calcium channel blockers may be used.
• Anti-arrhythmics other than those mentioned elsewhere in the specification include: sodium channel blockers such as quinidine, procainamide, disopyramide, lidocaine, mexiletine, tocainide, phenytoin, encainide, flecainide, moricizine, and propafenone; potassium channel blockers such as: amiodarone, bretylium, ibutilide, dofetilide, azimilide, clofilium, tedisamil, sematilide, sotalol; and esmolol, propranolol, metoprolol. More than one of the antiarrhythmics mentioned in the specification may be used.
• the most useful ACE inhibitors include: benzepril, captopril, enalapril, fosinopril, lisinopril, imidapril, moexipril, perindopril, quinapril, ramipril, trandolapril. More than one of the aforementioned ACE inhibitors may be used.
• the most useful ATI receptor antagonists include: candesartan, irbesartan, losartan, telmisartan, valsartan, eprosartan. More than one of the aforementioned AT I receptor antagonists may be used.
• Lipid lowerers include: statins such as atorvastatin, cerivastatih, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin; bile acid sequestrants such as cholestyramine, colestipol and colesevelam; cholesterol absorption inhibitors such as ezetimibe; fibrates such as fenofibrate, gemfibrozil; niacin. More than one of the aforementioned lipid lowerers may be used.
• statins such as atorvastatin, cerivastatih, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin
• bile acid sequestrants such as cholestyramine, colestipol and colesevelam
• cholesterol absorption inhibitors such as ezetimibe
• fibrates such as fenof
• the most useful nitrates include organic nitrates such as: amyl nitrite, nitroglycerin, isosorbide dtnitrate, tsosorbide-5-mononitrate, erythrityl tetranitrate. More than one of the aforementioned organic nitrates may be used.
• Endothelin antagonists include: bosentan, sitaxsentan. More than one of the aforementioned endothelin antagonists may be used.
• the most useful vasodilators include: hydralazine, minoxidil, sodium nitroprusside, diazoxide. More than one of the aforementioned vasodilators may be used.
• the most useful phosphodiesterase inhibitors include: milrinone, inamrinone. More than one of the aforementioned phosphodiesterase inhibitors may be used.
• Cardiac glycosides include: allocar, corramedan, digitoxin, digoxin, lanoxin, purgoxin, cedilanid-D, crystodigin, lanoxicaps. More than one of the aforementioned cardiac glycosides may be used.
• Serotonin antagonists include: clozapine, loxapine, olanzapine, risperidone, ziprasidone, ritanserin, ketanserin, amoxapine. More than one of the aforementioned serotonin antagonists may be used.
• CNS acting agents other than those already mentioned elsewhere in this specification include imidazoline agonists such as moxonidine. The most useful CNS acting agent is methyidopa.
• the most useful renin inhibitors include: aliskiren, enalkiren, ditekiren, terlakiren, remikiren, zankiren, ciprokiren. More than one of the aforementioned renin inhibitors may be used.
• vasopeptidase inhibitors include: omapatrilat, sampatrilat, gemopatrilat. More than one of the aforementioned vasopeptidase inhibitors may be used.
• Other pharmaceuticals used in treating heart failure may also be combined with the compound RY or RY' as prepared by the present invention.
• These include calcium sensitisers; HMG CoA reductase inhibitors; vasopressin antagonists; adenosine A l receptor antagonists; atrial natriuretic peptide (ANP) agonists; chelating agents; corticotroph in-releasing factor receptor; glucagon-like peptide-1 agonists; sodium, potassium ATPase inhibitors; advanced glycosylation end-products (AGE) crosslink breakers; mixed neprilysin/endothel in- converting enzyme (NEP/ECE) inhibitors; nociceptin receptor (ORL- 1 ) agonists (e.g.
• alprazolam xanthine oxidase inhibitors
• benzodiazepine agonists cardiac myosin activators
• chymase inhibitors endothelial nitric oxide synthase (ENOS) transcription enhancers
• neutral endopeptidase inhibitors such as thiorphan.
• the invention also envisages the use of nepicastat with the classes of compounds described above.
• inert pharmaceutically acceptable carriers are admixed with the active compound.
• the pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules and capsules.
• a carrier can be one or more substances which may also act as diluents, flavouring agents, solubiiizers, lubricants, suspending agents, binders or tablet disintegrating agents; it may also be an encapsulating material.
• the pharmaceutical preparation is in unit dosage form, e.g. packaged preparation, the package containing discrete quantities of preparation such as packeted tablets, capsules and powders in vials or ampoules.
• the dosages may be varied depending on the requirement of the patient, the severity of the disease and the particular compound being employed. For convenience, the total daily dosage may be divided and administered in portions throughout the day. Suitable administration regimes for the compounds RY or RY' are thrice daily, twice daily, once daily, once every other day to once weekly. It is expected that once or twice per day administration will be most suitable. Determination of the proper dosage for a particular situation is within the skill of those in the medical art.
• the compound RY or RY' may also be used in conjunction with one or more compounds selected from the following classes of compounds: diuretics; beta-adrenergic antagonists; alpha2 -adrenergic agonists; alpha 1 -adrenergic antagonists; dual beta- and alpha- adrenergic antagonists; calcium channel blockers; potassium channel activators; antiarrhythmics; ACE inhibitors; ATI receptor antagonists; renin inhibitors; lipid lowerers, vasopeptidase inhibitors; nitrates; endothelin antagonists; neutral endopeptidase inhibitors; anti- angiotensin vaccines; vasodilators; phosphodiesterase inhibitors; cardiac glycosides; serotonin antagonists; CNS acting agents; calcium sensitisers; HMG CoA reductase inhibitors; vasopressin antagonists; adenosine A l receptor antagonists; atrial natriuretic peptide (ANP
• treatment and variations such as 'treat' or 'treating' refer to any regime that can benefit a human or non-human animal.
• the treatment may be in respect of an existing condition or may be prophylactic (preventative treatment).
• Treatment may include curative, alleviation or prophylactic effects.
• Treatment with a compound RY or RY' in combination with one of the other classes of compounds includes simultaneous and sequential administration of the two or more drugs.
• Anxiety disorders include but are not restricted to generalized anxiety disorders, social anxiety disorders, post-traumatic stress disorder, acute distress disorder, obsessive compulsive disorders, panic disorders such as panic attacks, and phobias such as agoraphobia, social phobias, specific phobias. Further, anxiety disorders treatable using compounds of the present invention may be found in on pages 429-484 of American Psychiatric Association: Diagnostic and Statistic Manual of Mental Disorders, 4th edition, Text Revision, Washington, DC, American Psychiatric Association, 2000. [00114] According to another aspect of the invention, there is provided the use of a compound RY or RY' prepared as described above, in the manufacture of a medicament for treating migraine. [00115] According to another aspect of the invention, there is provided the use of a compound RY or RY' prepared as described above, in the manufacture of a medicament for treating a subject afflicted by a cardiovascular disorder.
• a compound RY or RY' prepared as described above, in the manufacture of a medicament for treating one or more of the following indications: angina, arrhythmias, and circulatory disorders such as Raynaud's phenomenon.
• a method of treating anxiety disorders comprising administering a therapeutically effective amount of a compound RY or RY' prepared as described above to a patient in need thereof.
• a method of treating migraine comprising administering a therapeutically effective amount of a compound RY or RY' prepared as described above to a patient in need thereof.
• a method of treating cardiovascular disorders comprising administering a therapeutically effective amount of a compound RY or RY' prepared as described above to a patient in need thereof.
• a method of treating hypertension comprising administering a therapeutically effective amount of a compound RY or RY' prepared as described above to a patient in need thereof.
• a method of treating chronic or congestive heart failure comprising administering a therapeutically effective amount of a compound of RY or RY' prepared as described above to a patient in need thereof.
• a method of treating one or more of the following indications: angina, arrhythmias, and circulatory disorders such as Raynaud's phenomenon comprising administering a therapeutically effective amount of a compound RY or RY' prepared as described above to a patient i need thereof.
• the above-described methods of treatment may further comprise simultaneous or sequential administration of a drug from one of the following classes of compounds:
• beta-adrenergic antagonists alpha2-adrenergic agonists; alpha 1 -adrenergic antagonists; dual beta- and alpha-adrenergic antagonists; calcium channel blockers; potassium channel activators; anti-arrhythmics; ACE inhibitors; ATI receptor antagonists; renin inhibitors; lipid lowerers, vasopeptidase inhibitors; nitrates; endothelin antagonists; neutral endopeptidase inhibitors; anti-angiotensin vaccines; vasodilators; phosphodiesterase inhibitors; cardiac glycosides; serotonin antagonists; CNS acting agents; calcium sensitisers; HMG CoA reductase inhibitors; vasopressin antagonists; adenosine A I receptor antagonists; atrial natriuretic peptide (ANP) agonists; chelating agents; corticotrophin-releasing factor receptor; glucagon-like peptide- 1 agonists
• alprazolam xanthine oxidase inhibitors
• benzodiazepine agonists cardiac myosin activators
• chymase inhibitors endothelial nitric oxide synthase (ENOS) transcription enhancers
• neutral endopeptidase inhibitors such as thiorphan.
• NMR spectra were recorded at 20°C, on a Bruker Avance DPX 400MHz, or a 600 MHz Avance III spectrometer with solvent used as internal standard. Data are reported in the following order: approximate chemical shift (ppm), number of protons, multiplicity (br, broad; d d, doublet of doublet; d t, doublet of triplet; m, multiplet; m d, multiplet of doublet; m t, multiplet of triplet; s, singlet) and coupling constant (Hz).
• N-benzyl-4-bromo-3-oxobutanamide (compound B 50 g, 185.1 mmol) was dissolved in methanol (400 ml), and potassium formate (31.14 g, 370.2 mmol) was added. The resulting mixture was heated under reflux for 2 hours. Methanol was removed by distillation under reduced pressure; the residue was taken up into ethyl acetate (250 ml) under reflux, filtered hot, the filter cake washed with warm ethyl acetate (100 ml). The combined filtrate was cooled to - 10°C, aged for 1.5 hours.
• N-benzyl-4-hydroxy-3- oxobutanamide (1.854 g, 8.95 mmol) and potassium thiocyanate (0.870 g, 8.95 mmol) added, stirred for 1 hour.
• the mixture was heated with stirring at 100°C for 3 hours under HPLC control, cooled to 20 0 C, diluted with 2-propanol (55 ml), cooled to 0°C, aged for 1 hour. The precipitate collected, washed with cold 2-propanol (55 ml), dried to give 12.54 g.
• the solid was suspended in a mixture of water (38 ml) and ethanol (EtOH) ( 19 ml), solid sodium bicarbonate (2.255 g, 26.8 mmol) was added in portions with stirring at 20-25°C, stirred for 30 min.
• Example 20 N-benzyl-N-(4-hydroxy-3-oxobutyl)-ethyl methanoate (compound I with alternative protecting group - ethyl ethanoate instead of Ns)
• the vessel was charged with (R)-mt ⁇ y ⁇ 6,8-difluorochroman-3-ylcarbamate (1.0 wt) and methanol (12.66 vol.), the content temperature was adjusted to 65°C with stirring. A solution of potassium hydroxide (2.76 wt) in water (4.15 vol.) was transferred to the vessel while maintaining 65°C and the mixture was stirred for 24 hours. The content was adjusted to 35°C, water (5.6 vol.) was charged and the vessel was set up for atmospheric distillation. The content was distilled off at 70°C internal temperature and 80°C in doubled jacket until a residual volume reached 8- 10 vol.

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• 2012
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