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US20070078164A1 - 4-Phenylpiperidine derivatives as renin inhibitors - Google Patents

4-Phenylpiperidine derivatives as renin inhibitors Download PDF

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US20070078164A1
US20070078164A1 US10/580,296 US58029604A US2007078164A1 US 20070078164 A1 US20070078164 A1 US 20070078164A1 US 58029604 A US58029604 A US 58029604A US 2007078164 A1 US2007078164 A1 US 2007078164A1
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hydrogen
lower alkyl
halogen
hydroxy
combined
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Richard Sedrani
Juergen-Klaus Maibaum
Werner Breitenstein
Holger Sellner
Claus Ehrhardt
Nils Ostermann
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Priority to US12/163,038 priority patent/US7754727B2/en
Priority to US12/789,892 priority patent/US8362040B2/en
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/42—Oxygen atoms attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention provides compounds of the formula wherein
  • compounds of formula (I) may be employed for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.
  • diabetes such as nephropathy, vasculopathy and neuropathy
  • diseases of the coronary vessels restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.
  • optionally substituted alkyl refers to unsubstituted or substituted straight- or branched-chain hydrocarbon groups having 1-20 carbon atoms, preferably 1-7 carbon atoms.
  • exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like.
  • Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more of the following groups: halo, hydroxy, cycloalkyl, alkanoyl, alkoxy, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio, alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, carboxy, alkoxycarbonyl, aryl, alkenyl, alkynyl, aralkoxy, guanidino, heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and the like.
  • lower alkyl refers to those optionally substituted alkyl groups as described above having 1-7, preferably 1-4 carbon atoms.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • alkenyl refers to any of the above alkyl groups having at least two carbon atoms and further containing a carbon to carbon double bond at the point of attachment. Groups having 2-4 carbon atoms are preferred.
  • alkynyl refers to any of the above alkyl groups having at least two carbon atoms and further containing a carbon to carbon triple bond at the point of attachment. Groups having 2-4 carbon atoms are preferred.
  • alkylene refers to a straight-chain bridge of 2-5 carbon atoms connected by single bonds, e.g., —(CH 2 ) x —, wherein x is 2 to 5, which may be interrupted with one or more heteroatoms selected from O, S(O) 0-2 or —NR—, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, acyl, carbamoyl, sulfonyl, sulfamoyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl, or the alkylene may be substituted with one or more substituents selected from alkyl, cycloalkyl, oxo, halogen, hydroxy, carboxy, alkoxy, alkoxycarbonyl and the like.
  • cycloalkyl refers to optionally substituted monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, each of which may be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, carboxy, alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl, heterocyclyl and the like.
  • substituents such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, carboxy, alkoxycarbonyl, sulfon
  • Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like.
  • bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the like.
  • Exemplary tricyclic hydrocarbon groups include adamantyl and the like.
  • alkoxy refers to alkyl-O—.
  • alkanoyl refers to alkyl-C(O)—.
  • alkanoyloxy refers to alkyl-C(O)—O—.
  • alkylamino and “dialkylamino” refer to alkyl-NH— and (alkyl) 2 N—, respectively.
  • alkanoylamino refers to alkyl-C(O)—NH—.
  • alkylthio refers to alkyl-S—.
  • alkylaminothiocarbonyl refers to alkyl-NHC(S)—.
  • alkylthiono refers to alkyl-S(O)—.
  • alkylsulfonyl refers to alkyl-S(O) 2 —.
  • alkoxycarbonyl refers to alkyl-O—C(O)—.
  • alkoxycarbonyloxy refers to alkyl-O—C(O)O—.
  • carbamoyl refers to H 2 NC(O)—, alkyl-NHC(O)—, (alkyl) 2 NC(O)—, aryl-NHC(O)—, alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—, alkyl(heteroaryl)-NC(O)—, aralkyl-NHC(O)—, alkyl(aralkyl)-NC(O)— and the like.
  • sulfamoyl refers to H 2 NS(O) 2 —, alkyl-NHS(O) 2 —, (alkyl) 2 NS(O) 2 —, aryl-NHS(O) 2 —, alkyl(aryl)-NS(O) 2 —, (aryl) 2 NS(O) 2 —, heteroaryl-NHS(O) 2 —, aralkyl-NHS(O) 2 —, heteroaralkyl-NHS(O) 2 — and the like.
  • sulfonamido refers to alkyl-S(O) 2 —NH—, aryl-S(O) 2 —NH—, aralkyl-S(O) 2 —NH—, heteroaryl-S(O) 2 —NH—, heteroaralkyl-S(O) 2 —NH—, alkyl-S(O) 2 —N(alkyl)-, aryl-S(O) 2 —N(alkyl)-, aralkyl-S(O) 2 —N(alkyl)-, heteroaryl-S(O) 2 —N(alkyl)-, heteroaralkyl-S(O) 2 —N(alkyl)- and the like.
  • sulfonyl refers to alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like.
  • optionally substituted amino refers to a primary or secondary amino group which may optionally be substituted by a substituent, such as acyl, sulfonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, carbamoyl and the like.
  • aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6-12 carbon atoms in the ring portion, such as phenyl, biphenyl, naphthyl and tetrahydronaphthyl, each of which may optionally be substituted by 1-4 substituents, such as alkyl, trifluoromethyl, cycloalkyl, halo, hydroxy, alkoxy, acyl, alkanoyloxy, aryloxy, optionally substituted amino, thiol, alkylthio, arylthio, nitro, cyano, carboxy, alkoxycarbonyl, carbamoyl, alkylthiono, sulfonyl, sulfonamido, heterocyclyl and the like.
  • monocyclic aryl refers to optionally substituted phenyl as described under aryl.
  • aralkyl refers to an aryl group bonded directly through an alkyl group, such as benzyl.
  • aralkanoyl refers to aralkyl-C(O)—.
  • aralkylthio refers to aralkyl-S—.
  • alkoxy refers to an aryl group bonded directly through an alkoxy group.
  • arylsulfonyl refers to aryl-S(O) 2 —.
  • arylthio refers to aryl-S—.
  • aroyl refers to aryl-C(O)—.
  • aroyloxy refers to aryl-C(O)—O—.
  • aroylamino refers to aryl-C(O)—NH—.
  • aryloxycarbonyl refers to aryl-O—C(O)—.
  • heterocyclyl refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, e.g., which is a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized.
  • the heterocyclic group may be attached at a heteroatom or a carbon atom.
  • Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl
  • bicyclic heterocyclic groups include indolyl, dihydroidolyl, benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl, benzothiazinyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]-pyridinyl] or furo[2,3-b]pyr
  • Exemplary tricyclic heterocyclic groups include carbazolyl, dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl, carbolinyl and the like.
  • heterocyclyl refers to heterocyclic groups substituted with 1, 2 or 3 substituents selected from the group consisting of the following:
  • heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge.
  • heteroaryl or “heteroaromatic ring” refers to an aromatic heterocycle, e.g., monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl and the like, optionally substituted by, e.g., lower alkyl, lower alkoxy or halo.
  • heteroarylsulfonyl refers to heteroaryl-S(O) 2 —.
  • heteroaroyl refers to heteroaryl-C(O)—.
  • heteroaroylamino refers to heteroaryl-C(O)NH—.
  • heteroarylkyl refers to a heteroaryl group bonded through an alkyl group.
  • heteroaralkanoyl refers to heteroaralkyl-C(O)—.
  • heteroaralkanoylamino refers to heteroaralkyl-C(O)NH—.
  • acyl refers to alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl and the like.
  • acylamino refers to alkanoylamino, aroylamino, heteroaroylamino, aralkanoylamino, heteroaralkanoylamino and the like.
  • salts of any compound of the present invention refer to salts formed with acids, namely acid addition salts, such as of mineral acids, organic carboxylic and organic sulfonic acids, e.g., hydrochloric acid, maleic acid and methanesulfonic acid.
  • salts formed with bases namely cationic salts, such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris(hydroxymethyl)methylammonium salts and salts with amino acids, are possible provided an acidic group constitutes part of the structure.
  • bases namely cationic salts, such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris(hydroxymethyl)methylammonium salts and salts with amino acids, are possible provided an acidic group constitutes part of the structure.
  • the present invention provides piperidine derivatives of formula (I), pharmaceutical compositions containing them, methods for preparing said compounds, and methods of treating renin mediated conditions by administration of a therapeutically effective amount of a compound of the present invention, or a pharmaceutical composition thereof.
  • the compounds of the present invention possess two or more asymmetric centers depending on the choice of the substituents.
  • the preferred absolute configuration at the C-3 and C-4 asymmetric centers is maintained throughout the specification and the appended claims as indicated herein above.
  • any possible diastereoisomers, enantiomers and geometric isomers, and mixtures thereof, e.g., racemates, are encompassed by the instant invention.
  • a resulting compound of formula (III) may then be hydroxylated under appropriate reaction conditions, e.g., under conditions of hydroboration, to afford a compound of formula (IV) wherein Pg, R 5 , R 6 , R 7 and R 15 have meanings as defined above.
  • a resulting compound of formula (IV) is obtained as a racemic mixture according to the reaction sequence as outlined in Scheme 1. Racemic compounds, e.g., those of formula (IV) and (IC′), may be separated into their pure enantiomers using conventional methods known in the art.
  • compounds of formula (IV) wherein Pg, R 5 , R 6 , R 7 and R 15 have meanings as defined above may be obtained in high enantioselectivity from compounds of formula (III) by a reaction sequence involving asymmetric dihydroxylation followed by catalytic reduction, as described by Rich et al. in Organic Letters, 2001, 3, 2317-2320, or as described in International PCT Patent Application No. WO 00/63173.
  • compounds of formula (V) wherein Pg, X, R 5 , R 6 , R 7 and R 15 have meanings as defined above may be converted to compounds of formula (IC′) wherein R 5 , R 6 , R 7 , R 15 have meanings as defined herein above, and R 1 is —O—X in which X has a meaning as defined herein above, or a pharmaceutically acceptable salt thereof, by removal of the protecting group, e.g., when Pg is t-butoxycarbonyl by treatment with an acid such as trifluoroacetic acid (TFA) or hydrochloric acid (HCl), or when Pg is ethoxycarbonyl by treatment with a base such as aqueous sodium or potassium hydroxide.
  • TFA trifluoroacetic acid
  • HCl hydrochloric acid
  • compounds of formula (IC′) wherein R 5 , R 6 , R 7 , R 15 have meanings as defined herein above, and R 1 is —O—X in which X has a meaning as defined herein above, may be obtained from compounds of formula (IIb) following the reaction sequence as outlined in Scheme 2.
  • compounds of formula (IIb) wherein Pg represents a protecting group as described herein above, and R 16 and R 17 are lower alkyl, or R 16 and R 17 combined are alkylene which together with the boron and the oxygen atoms form a 5- or 6-membered ring, preferably, R 16 and R 17 combined are 1,1,2,2-tetramethylethylene, may be converted to compounds of formula (VIII) under conditions of Suzuki coupling, e.g., a compound of formula (IIb) may be treated with a compound of the formula wherein R 5 and R 6 have meanings as defined above, in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base such as sodium or potassium carbonate in an appropriate solvent, e.g., water, dimethoxyethane, acetonitrile, methanol, ethanol or THF, or a mixture of solvents thereof.
  • a palladium catalyst such as tetraki
  • a resulting compound of formula (VIII) may then be converted to a compound of formula (IX) wherein Pg, R 5 and R 6 have meanings as defined above, as described herein for compounds of formula (IV).
  • compounds of formula (X) wherein Pg, X, R 5 and R 6 have meanings as defined herein above may be converted to compounds of formula (IC′) wherein X, R 5 , R 6 , R 7 and R 15 have meanings as defined herein above, or a pharmaceutically acceptable salt thereof, by first coupling a compound of formula (X) with a boronic acid of the formula wherein R 7 and R 15 have meanings as defined herein above, followed by removal of the protecting group under appropriate reaction conditions, e.g., as illustrated herein above.
  • compounds of formula (IC′) wherein R 5 , R 6 , R 7 and R 15 have meanings as defined herein above, and R 1 is —S(O) 0-2 —X, —NR 8 —X, —NR 8 C(O)—X or —NR 8 S(O) 2 —X in which R 8 and X have meanings as defined herein above, may be prepared from compounds of formula (IV) using methods well known in the art.
  • a compound of formula (IV) wherein Pg, R 5 , R 6 , R 7 and R 15 have meanings as defined herein above may be converted to a compound of formula (XIV) or (XV), e.g., by first converting the hydroxyl group to a leaving group (Lg 2 ) such as bromide or iodide to afford a compound of formula (XIII) wherein Pg, R 5 , R 6 , R 7 and R 15 have meanings as defined above and Lg 2 represents a leaving group as described herein above.
  • a leaving group Lg 2
  • Compounds of formulae (XIV) or (XV) may the be converted to compounds of formula (IC′) wherein R 5 , R 6 , R 7 and R 15 have meanings as defined herein above, and R 1 is —S(O) 0-2 —X, —NR 8 —X, —NR 8 C(O)—X or —NR 8 S(O) 2 —X in which R 8 and X have meanings as defined herein above, using methods described herein or using methods well known in the art.
  • protecting groups are to protect the functional groups from undesired reactions with reaction components under the conditions used for carrying out a desired chemical transformation.
  • the need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (hydroxyl group, amino group, etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions.
  • the above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluent, preferably, such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents, respectively and/or inert atmospheres, at low temperatures, room temperature (RT) or elevated temperatures, preferably at or near the boiling point of the solvents used, and at atmospheric or super-atmospheric pressure.
  • diluent preferably, such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents, respectively and/or inert atmospheres, at low temperatures, room temperature (RT) or elevated temperatures, preferably at or near the boiling point of the solvents used, and at atmospheric or super-atmospheric pressure.
  • the invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes.
  • the invention also relates to any novel starting materials, intermediates and processes for their manufacture.
  • the new compounds may be in the form of one of the possible isomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
  • the aforesaid possible isomers or mixtures thereof are within the purview of this invention.
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • the piperidinyl moiety may be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
  • Racemic compounds e.g., those of formula (IV), (IX), (XIV), (XV) and (IC′), may also be resolved by forming covalent diasteromeric derivatives, e.g.
  • esters or amides by condensing an alcohol or a thiol, e.g., those of formula (IV), (IX) or (XIV), or an amine, e.g., those of formula (XV) and (IC′), with a chiral, enantiomerically pure carboxylic acid.
  • the resulting diastereomeric esters or amides can then be separated by crystallization or by chromatography and subsequently hydrolyzed to yield enantiomerically pure compounds of formula (IV), (IX), (XIV), (XV) and (IC′), respectively.
  • Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • Compounds of the invention having basic groups, in particular, the piperidinyl moiety can be converted into acid addition salts, especially pharmaceutically acceptable salts.
  • inorganic acids such as mineral acids, for example, sulfuric acid, a phosphoric or hydrohalic acid
  • organic carboxylic acids such as (C 1 -C 4 )-alkanecarboxylic acids which, for example, are unsubstituted or substituted by halogen, for example, acetic acid, such as saturated or unsaturated dicarboxylic acids, for example, oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylic acids, for example glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example, aspartic or glutamic acid, or with organic sulfonic acids, such as (C 1 -C 4 )-alkylsulfonic acids, for example, methanesulfonic acid; or
  • salts may be converted into salts with pharmaceutically acceptable bases.
  • Such salts include alkali metal salts, like sodium, lithium and potassium salts; alkaline earth metal salts, like calcium and magnesium salts; ammonium salts with organic bases, e.g., trimethylamine salts, diethylamine salts, tris(hydroxymethyl)methylamine salts, dicyclohexylamine salts and N-methyl-D-glucamine salts; salts with amino acids like arginine, lysine and the like. Salts may be formed using conventional methods, advantageously in the presence of an ethereal or alcoholic solvent, such as a lower alkanol.
  • the salts may be precipitated with ethers, e.g., diethyl ether. Resulting salts may be converted into the free compounds by treatment with acids. These or other salts can also be used for purification of the compounds obtained.
  • Prodrug derivatives of any compound of the invention are derivatives of said compounds which following administration release the parent compound in vivo via some chemical or physiological process, e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the parent compound.
  • exemplary prodrug derivatives are, e.g., esters of free carboxylic acids and S-acyl and O-acyl derivatives of thiols, alcohols or phenols, wherein acyl has a meaning as defined herein.
  • ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the ⁇ -(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the ⁇ -(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethyl ester and the like conventionally used in the art.
  • lower alkyl esters e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the ⁇ -(
  • prodrug derivatives In view of the close relationship between the free compounds, the prodrug derivatives and the compounds in the form of their salts, whenever a compound is referred to in this context, a prodrug derivative and a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
  • the compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the compounds of the present invention are inhibitors of renin activity and, thus, may be employed for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.
  • diabetes such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.
  • the present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of a pharmacologically active compound of the instant invention, alone or in combination with one or more pharmaceutically acceptable carriers.
  • compositions according to the present invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, to inhibit renin activity, and for the treatment of conditions associated with renin activity.
  • Such conditions include hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.
  • the pharmacologically active compounds of the invention may be employed in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application.
  • diluents e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;
  • lubricants e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also
  • lubricants e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol
  • binders e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired
  • disintegrants e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or
  • Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, preferably about 1-50%, of the active ingredient.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and pre-determined rate over a prolonged period of time, and means to secure the device to the skin.
  • the present invention provides pharmaceutical compositions as described above for the treatment of conditions mediated by renin activity, preferably, hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.
  • renin activity preferably, hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy
  • compositions may contain a therapeutically effective amount of a compound of the invention as defined above, either alone or in a combination with another therapeutic agent, e.g., each at an effective therapeutic dose as reported in the art.
  • therapeutic agents include:
  • antidiabetic agents such as insulin, insulin derivatives and mimetics; insulin secretagogues such as the sulfonylureas, e.g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; peroxisome proliferator-activated receptor (PPAR) ligands; protein tyrosine phosphatase-1B (PTP-1B) inhibitors such as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors such as SB-517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands such as GW-0791 and AGN-194204; sodium-dependent glucose cotransporter inhibitors such as T-1095; glycogen phosphorylase A inhibitors
  • hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, e.g., lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acid and aspirin;
  • HMG-CoA 3-hydroxy-3-methyl-glutaryl coenzyme A
  • anti-obesity agents such as orlistat
  • anti-hypertensive agents e.g., loop diuretics such as ethacrynic acid, furosemide and torsemide; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na-K-ATPase membrane pump such as digoxin; neutralendopeptidase (NEP) inhibitors; ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril; angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan; ⁇ -a
  • a compound of the present invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation.
  • the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention in combination with a therapeutically effective amount of another therapeutic agent, preferably selected from anti-diabetics, hypolipidemic agents, anti-obesity agents or anti-hypertensive agents, most preferably from antidiabetics, anti-hypertensive agents or hypolipidemic agents as described above.
  • another therapeutic agent preferably selected from anti-diabetics, hypolipidemic agents, anti-obesity agents or anti-hypertensive agents, most preferably from antidiabetics, anti-hypertensive agents or hypolipidemic agents as described above.
  • the present invention further relates to pharmaceutical compositions as described above for use as a medicament.
  • the present invention further relates to use of pharmaceutical compositions or combinations as described above for the preparation of a medicament for the treatment of conditions mediated by renin activity, preferably, hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.
  • renin activity preferably, hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis
  • the present invention also relates to a compound of formula (I) for use as a medicament, to the use of a compound of formula (I) for the preparation of a pharmaceutical composition for the prevention and/or treatment of conditions mediated by renin activity, and to a pharmaceutical composition for use in conditions mediated by renin activity comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier therefor.
  • the present invention further provides a method for the prevention and/or treatment of conditions mediated by renin activity, which comprises administering a therapeutically effective amount of a compound of the present invention.
  • a unit dosage for a mammal of about 50-70 kg may contain between about 1 mg and 1000 mg, advantageously between about 5-600 mg of the active ingredient.
  • the therapeutically effective dosage of active compound is dependent on the species of warm-blooded animal (mammal), the body weight, age and individual condition, on the form of administration, and on the compound involved.
  • the present invention also provides a therapeutic combination, e.g., a kit, kit of parts, e.g., for use in any method as defined herein, comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, to be used concomitantly or in sequence with at least one pharmaceutical composition comprising at least another therapeutic agent, preferably selected from anti-diabetic agents, hypolipidemic agents, anti-obesity agents or anti-hypertensive agents.
  • the kit may comprise instructions for its administration.
  • kits of parts comprising: (i) a pharmaceutical composition of the invention; and (ii) a pharmaceutical composition comprising a compound selected from an anti-diabetic, a hypolipidemic agent, an anti-obesity agent, an anti-hypertensive agent, or a pharmaceutically acceptable salt thereof, in the form of two separate units of the components (i) to (ii).
  • the present invention provides a method as defined above comprising co-administration, e.g., concomitantly or in sequence, of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a second drug substance, said second drug substance being an anti-diabetic, a hypolipidemic agent, an anti-obesity agent or an anti-hypertensive agent, e.g., as indicated above.
  • a compound of the invention is administered to a mammal in need thereof.
  • a compound of the invention is used for the treatment of a disease which responds to modulation of renin activity.
  • the condition associated with renin activity is selected from hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.
  • diabetes such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.
  • the present invention provides a method or use which comprises administering a compound of formula (I) in combination with a therapeutically effective amount of an anti-diabetic agent, a hypolipidemic agent, an anti-obesity agent or an anti-hypertensive agent.
  • the present invention provides a method or use which comprises administering a compound of formula (I) in the form of a pharmaceutical composition as described herein.
  • treatment embraces all the different forms or modes of treatment as known to those of the pertinent art and in particular includes preventive, curative, delay of onset and/or progression, and palliative treatment.
  • the above-cited properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, rabbits, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • Said compounds can be applied in vitro in the form of solutions, e.g., preferably aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution.
  • the dosage in vitro may range between about 10 ⁇ 3 molar and 10 ⁇ 10 molar concentrations.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.001 and 500 mg/kg, preferably between about 0.1 and 100 mg/kg.
  • the compounds of the present invention have enzyme-inhibiting properties. In particular, they inhibit the action of the natural enzyme renin. Renin passes from the kidneys into the blood where it effects the cleavage of angiotensinogen, releasing the decapeptide angiotensin I which is then cleaved in the lungs, the kidneys and other organs to form the octapeptide angiotensin II.
  • the octapeptide increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating from the adrenal glands the sodium-ion-retaining hormone aldosterone, accompanied by an increase in extracellular fluid volume which increase can be attributed to the action of angiotensin II.
  • Inhibitors of the enzymatic activity of renin lead to a reduction in the formation of angiotensin I, and consequently a smaller amount of angiotensin II is produced.
  • the reduced concentration of that active peptide hormone is the direct cause of the hypotensive effect of renin inhibitors.
  • renin inhibitors may be demonstrated inter alia experimentally by means of in vitro tests, the reduction in the formation of angiotensin I being measured in various systems (human plasma, purified human renin together with synthetic or natural renin substrate).
  • An extract of human renin from the kidney (0.5 mGU [milli-Goldblatt units]/mL) is incubated for one h at 37° C. and pH 7.2 in 1M aqueous 2-N-(tris-hydroxymethylmethyl)amino-ethanesulfonic acid buffer solution with 23 ⁇ g/mL of synthetic renin substrate, the tetradecapeptide H-Asp-Arg-Val-Tyr-Ile-His-ProPhe-His-Leu-Leu-Val-Tyr-Ser-OH.
  • the amount of angiotensin I formed is determined by radioimmunoassay.
  • Each of the inhibitors according to the invention is added to the incubation mixture at different concentrations.
  • the IC 50 is defined as the concentration of a particular inhibitor that reduces the formation of angiotensin I by 50%.
  • Recombinant human renin (expressed in Chinese Hamster Ovary cells and purified using standard methods) at 4 nM concentration is incubated with test compound at various concentrations for 1 h at RT in 0.1 M Tris-HCl buffer, pH 7.4, containing 0.05 M NaCl, 0.5 mM EDTA and 0.05% CHAPS.
  • Synthetic peptide substrate Arg-Glu(EDANS)-Ile-His-Pro-Phe-His-Leu-Val-Ile_His_Thr-Lys(DABCYL)-Arg9 is added to a final concentration of 2 ⁇ M and increase in fluorescence is recorded at an excitation wave-length of 340 nm and at an emission wave-length of 485 nm in a microplate spectro-fluorimeter.
  • IC 50 values are calculated from percentage of inhibition of renin activity as a function of test compound concentration (Fluorescence Resonance Energy Transfer, FRET, assay).
  • Recombinant human renin (expressed in Chinese Hamster Ovary cells and purified using standard methods) at 1 nM concentration is incubated with test compound at various concentrations for 1.5 h at 37° C. in 0.1 M Tris/HCl pH 7.4 containing 0.05 M NaCl, 0.5 mM EDTA and 0.025% (w/v) CHAPS.
  • Synthetic peptide substrate Ac-Ile-His-Pro-Phe-His-Leu-Val-lle-His-Asn-Lys-[DY-505-X5] is added to a final concentration of 5 ⁇ M.
  • the enzyme reaction is stopped by adding 6 ⁇ L of 1.0% TFA.
  • the product of the reaction is separated by HPLC and quantified by spectrophotometric measurement at 505 nM wave-length. IC 50 values are calculated from percentage of inhibition of renin activity as a function of test compound concentration.
  • Recombinant human renin (expressed in Chinese Hamster Ovary cells and purified using standard methods) at 3.3 nM concentration, 125I-NVP-AJI891-NX-1 (0.27 ⁇ Ci/mL) and streptavidin-SPA (0.67 mg/mL) beads are incubated with test compound at various concentrations for 2.0 h at RT in 0.1 M Tris/HCl pH 7.4 containing 0.5M NaCl and 0.5% (w/v) Brij35. At the end of the incubation time, the plates are centrifuged (55 g, 60 seconds) and counted in a Wallac MicroBeta reader. IC 50 values are calculated from percentage of displacement of radioligand binding to renin as a function of test compound concentration.
  • renin inhibitors bring about a reduction in blood pressure.
  • Human renin may differ from the renin of other species.
  • primates e.g., marmosets ( Callithrix jacchus ) may be used, because human renin and primate renin are substantially homologous in the enzymatically active region.
  • marmosets Callithrix jacchus
  • test compounds are tested on normotensive marmosets of both sexes having a body weight of approximately 350 g that are conscious, allowed to move freely and in their normal cages.
  • the blood pressure and heart rate are measured via a catheter in the descending aorta and recorded radiometrically.
  • the endogenous release of renin is stimulated by the combination of a 1-week low-salt diet and a single intramuscular injection of furosemide (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid) (5 mg/kg).
  • the test compounds 16 h after the injection of furosemide the test compounds are administered either directly into the femoral artery using an injection cannula or, in the form of a suspension or solution, via an oesophageal tube into the stomach, and their action on the blood pressure and heart rate are evaluated.
  • the compounds of the present invention have hypotensive action at doses of from approximately 0.003 to approximately 1 mg/kg i.v. and at doses of from approximately 0.3 to approximately 100 mg/kg p.o.
  • renin inhibitors may be tested on male normotensive marmosets weighing 250 to 500 g that are conscious, allowed to move freely and in their normal cages.
  • the blood pressure, and heart rate are measured via a catheter placed in the descending aorta and recorded radiometrically.
  • Electrocardiogram are obtained by placing electrodes of transmitter in lead II.
  • the endogenous release of renin is stimulated by two intramuscular injection of furosemide (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid) (10 mg/kg) 43 and 19 hours prior compound application.
  • Test compounds are administered either directly into the femoral artery using an injection cannula or, in the form of a suspension or solution, via an oesophageal tube into the stomach, and their action on the blood pressure, heart rate and ECG are evaluated.
  • compounds of the present invention have hypotensive action at doses of from approximately 0.003 to approximately 0.3 mg/kg i.v. and at doses of from approximately 0.31 to approximately 30 mg/kg p.o.
  • the compounds of the present invention also have the property of regulating, especially reducing, intra-ocular pressure.
  • the extent of the reduction in intra-ocular pressure after administration of a pharmaceutical active ingredient of formula (I) according to the present invention can be determined, for example, in animals, for example rabbits or monkeys. Two typical experimental procedures that illustrate the present invention, but are not limited to in any way, are described hereinafter.
  • the in vivo test on a rabbit of the “Fauve de Bourgogne” type to determine the intra-ocular-pressure-reducing activity of topically applied compositions can be designed, for example, as follows:
  • the intra-ocular pressure (IOP) is measured using an aplanation tonometer both before the experiment and at regular intervals of time.
  • the suitably formulated test compound is applied topically in a precisely defined concentration (e.g. 0.000001-5% by weight) to one eye of the animal in question.
  • the contralateral eye is treated, for example, with physiological saline.
  • the measured values thus obtained are evaluated statistically.
  • the in vivo tests on monkeys of the species Macaca Fascicularis to determine the intra-ocular-pressure-reducing activity of topically applied compositions can be carried out, e.g., as follows:
  • the suitably formulated test compound is applied in a precisely defined concentration (e.g. 0.000001-5% by weight) to one eye of each monkey.
  • the other eye of the monkey is treated correspondingly, for example with physiological saline.
  • the animals are anaesthetised with intramuscular injections of, for example, ketamine.
  • IOP intra-ocular pressure
  • the test is carried out and evaluated in accordance with the rules of “good laboratory practice” (GLP).
  • the compound of Example 1 demonstrates inhibition of renin activity with an IC 50 value of about 70 nM in the FRET assay.
  • the title compound is prepared analogously as described for the title C compound in Example 1 from the title B compound, (3R*,4R*)-3-hydroxy-4-(4′-methoxy-biphenyl-3-yl)-piperidine-1-carboxylic acid t-butyl ester: MS 524.5 [M+H] + ; retention time 8.83 min (HPLC, Nucleosil C18; 5 ⁇ 100% CH 3 CN in H 2 O within 8 min, then 100% CH 3 CN for 2 min).
  • the title compound is prepared analogously as described for the title B compound in Example 1 from the title A compound, 4-(3-bromo-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester: MS 356.2/358.1 [M+H] + ; retention time 6.59 min (HPLC, Nucleosil C18; 5 ⁇ 100% CH 3 CN in H 2 O within 8 min).
  • the title compound is prepared analogously as described for the title C compound in Example 1 from the title B compound, (3R*,4R*)-4-(3-bromo-phenyl)-3-hydroxy-piperidine-1-carboxylic acid t-butyl ester: MS 496.3/498.2 [M+H] + ; retention time 8.87 min (HPLC, Nucleosil C18; 5 ⁇ 100% CH 3 CN in H 2 O within 8 min, then 100% CH 3 CN for 2 min).
  • the aqueous layer is extracted twice with ethyl acetate and the combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the residue is purified by preparative HPLC (Macherey-Nagel 250/4 nucleosil 100-10 C18 column, 20:80 CH 3 CN+0.1% TFA over 11 min, then 100% CH 3 CN+0.1% TFA for 5.5 min, 40 mL/min).
  • To the combined fractions containing the desired product is added 1M aqueous sodium carbonate solution and the acetonitrile is removed under reduced pressure.
  • the resulting aqueous suspension is extracted twice with ethyl acetate.
  • the title compound is prepared analogously as described in Example 31, except that the product is purified by HPLC, and the combined fractions containing the desired product are concentrated under reduced pressure and a solution of the compound in acetonitrile is lyophilized to afford (3R,4R)-4-biphenyl-3-yl-3-[2-(3-methoxy-propoxy)-benzyloxy]-piperidine trifluoroacetic acid: MS 432.2 [M+H]; Rt (HPLC, Nucleosil C18, 10:90-100:0 CH 3 CN/H 2 O+0.1% TFA within 5 min, then 100% CH 3 CN+0.1% TFA): 5.53 min.
  • the title compound is prepared analogously as described in Example 31, except that the product is purified by HPLC, and the combined fractions containing the desired product are concentrated under reduced pressure and a solution of the compound in acetonitrile is lyophilized to afford (3R,4R)-4-biphenyl-3-yl-3-[2-(3-methoxy-propyl)benzyloxy]-piperidine trifluoroacetic acid: MS 416.2 [M+H]; Rt (HPLC, Nucleosil C18, 10:90-100:0 CH 3 CN/H 2 O+0.1% TFA within 5 min, then 100% CH 3 CN+0.1% TFA): 5.56 min.
  • reaction mixture is further stirred for 2 h at room temperature and poured into a saturated NH 4 Cl aqueous solution, the aqueous layer is extracted twice with EtOAc. The combined organic extracts are dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is taken up into ether and the triphenylphosphine oxide precipitate is filtered off through a pad of celite.
  • the filtrate is concentrate and the residual material purified by flash column chromatography on silica gel (hexane/EtOAc 95/5) to afford the title compound (as a mixture Z and E stereoisomers) as a yellow oil: Rt (HPLC, Nucleosil C18, 10:90-100:0 CH 3 CN/H 2 O+0.1% TFA within 5 min, then 100% CH 3 CN+0.1% TFA): 6.30 min.
  • the title compound is prepared analogously as described for the title B compound in Example 45 using (3-methoxy-propyl)-triphenyl-phosphonium bromide and 5-bromo-2-methyl-benzaldehyde (prepared in Example 48; containing 20% of 3-bromo-2-methyl-benzaldehyde): Rt (HPLC, Nucleosil C18, 10:90-100:0 CH 3 CN/H 2 O+0.1% TFA within 5 min, then 100% CH 3 CN+0.1% TFA): 6.60 min.
  • reaction mixture is further stirred for 4 h at room temperature, and wet Na 2 SO 4 is added to the reaction mixture until the evolution of H 2 ceased.
  • the mixture is filtered off and the white solid washed with EtOAc.
  • the filtrate is dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • n-butyl lithium 69 mL, 110 mmol, 1.6 M solution in hexane
  • the resulting solution is treated by the drop wise addition of a THF solution (40 mL) of cyclopropanecarbonyl chloride (10 mL, 110 mmol).
  • the reaction mixture is further stirred at reflux for 1 h, cooled to 0° C. by an ice bath, and slowly hydrolyzed by the addition of water.
  • the aqueous layer is extracted twice with ether and the combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure.

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US10/580,296 2003-11-26 2004-11-25 4-Phenylpiperidine derivatives as renin inhibitors Abandoned US20070078164A1 (en)

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US10/580,296 US20070078164A1 (en) 2003-11-26 2004-11-25 4-Phenylpiperidine derivatives as renin inhibitors
US12/163,038 US7754727B2 (en) 2003-11-26 2008-06-27 4-phenylpiperidine derivatives as renin inhibitors
US12/789,892 US8362040B2 (en) 2003-11-26 2010-05-28 4-phenylpiperidine derivatives as renin inhibitors

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US52537503P 2003-11-26 2003-11-26
PCT/EP2004/013410 WO2005051911A1 (fr) 2003-11-26 2004-11-25 Derives de 4-phenylpiperidine utilises en tant qu'inhibiteurs de la renine
US10/580,296 US20070078164A1 (en) 2003-11-26 2004-11-25 4-Phenylpiperidine derivatives as renin inhibitors

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PT1689712E (pt) * 2003-11-26 2009-11-25 Novartis Ag Derivados de 4-fenilpiperidina como inibidores da renina
ATE462703T1 (de) 2004-08-25 2010-04-15 Actelion Pharmaceuticals Ltd Bicyclononen-derivate als renin-inhibitoren
KR20070101843A (ko) * 2004-10-08 2007-10-17 노파르티스 아게 확장기 기능장애 또는 확장기 심부전의 예방 또는 치료를위한 레닌 억제제의 용도
GB0428526D0 (en) 2004-12-30 2005-02-09 Novartis Ag Organic compounds
EP1707202A1 (fr) * 2005-03-31 2006-10-04 Speedel Experimenta AG Composes organiques
GB0508992D0 (en) * 2005-05-03 2005-06-08 Novartis Ag Organic compounds
BRPI0609890A2 (pt) 2005-05-27 2010-05-04 Actelion Pharmaceuticals Ltd composto, composição farmacêutica, e, uso de um composto
GB0514203D0 (en) * 2005-07-11 2005-08-17 Novartis Ag Organic compounds
PT2420491E (pt) 2005-12-30 2013-10-14 Novartis Ag Compostos de piperidina 3,5-substituída como inibidores de renina
RU2415840C2 (ru) * 2005-12-30 2011-04-10 Новартис Аг 3,5-замещенные пиперидины, как ингибиторы ренина
GB0611696D0 (en) * 2006-06-13 2006-07-26 Novartis Ag Organic compounds
TW200821303A (en) * 2006-08-08 2008-05-16 Speedel Experimenta Ag Organic compounds
WO2008074450A2 (fr) * 2006-12-20 2008-06-26 Nicox S.A. Dérivés nitrés d'inhibiteurs non peptidiques de la rénine
EP1987834A3 (fr) * 2007-02-13 2008-11-19 Speedel Experimenta AG Pipéridines substituées en tant que composants thérapeutiques
EP1958634A3 (fr) * 2007-02-14 2008-09-24 Speedel Experimenta AG Pipéridines substituées en tant que inhibiteurs de la sécrétase beta, cathepsine D, plasmepsin II et/ou protéase du VIH
WO2009000811A1 (fr) 2007-06-25 2008-12-31 Novartis Ag Composés organiques

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PL1689712T3 (pl) 2010-01-29
EP1689712B1 (fr) 2009-08-19
US7754727B2 (en) 2010-07-13
ES2332053T3 (es) 2010-01-25
US20080269255A1 (en) 2008-10-30
EP1689712A1 (fr) 2006-08-16
AU2004293177B2 (en) 2008-10-23
US8362040B2 (en) 2013-01-29
KR20060120146A (ko) 2006-11-24
RU2006122637A (ru) 2008-01-27
DE602004022704D1 (de) 2009-10-01
JP4750712B2 (ja) 2011-08-17
JP2007512282A (ja) 2007-05-17
CN1906163A (zh) 2007-01-31
US20100240679A1 (en) 2010-09-23
PT1689712E (pt) 2009-11-25
ATE440082T1 (de) 2009-09-15
RU2374228C2 (ru) 2009-11-27
WO2005051911A1 (fr) 2005-06-09
CA2546264A1 (fr) 2005-06-09
AU2004293177A1 (en) 2005-06-09

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