IP Library Granted Patent US 7,851,634
Granted Patent B2
US 7,851,634 · App. 10/593,460 · Granted Dec 14, 2010

5-amino 4-hydroxy-7-(1H-indolmethyl)-8-methylnonamide derivatives as renin inhibitors for the treatment of hypertension

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Quick Facts
Patent No.
US 7,851,634
App. No.
10/593,460
Granted
Dec 14, 2010
Kind
B2
Abstract

The application relates to novel alkanamides of the general formula (I) where X is —CH 2 — or >CH—OH; (A) R 1 is e.g. an optionally substituted heterocyclyl radical or an optionally substituted polycyclic, unsaturated hydrocarbon radical where X is hydroxymethylene; R 2 is C 1 -C 6 -alkyl or C 3 -C 6 -cydoalkyl; R 3 are each independently H, C 1 -C 6 -alkyl, C 1-6 -alkoxycarbonyl or C 1 -C 6 -alkanoyl; R 4 is C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 6 -alkenyl or unsubstituted or substituted arylC 1 -C 6 -alkyl; R 5 is C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkanoyloxy C 1 -C 6 -alkyl, C 1 -C 6 -aminoalkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, C 1 -C 6 -dialkylamino-C 1 -C 6 -alkyl, C 1 -C 6 -alkanoylamido-C 1 -C 6 -alkyl, HO(O)C—C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-O—(O)C—C 1 -C 6 -alkyl, H 2 N—C(O)—C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-HN—C(O)—C 1 -C 6 -alkyl, (C 1 ,-C 6 -alkyl) 2 N—C(O)—C 1 -C 6 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, cyano-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, optionally substituted aryl-C o -C 6 -alkyl, optionally substituted C 3 -C 8 -cycloalkyl-C o -C 6 -alkyl or optionally substituted heterocydyl-C o -C 6 -alkyl; to a process for their preparation and to the use of these compounds as medicines, especially as renin inhibitors for the treatment of hypertension.

Claims (10)

1. Compound of the general formula

where

X is —CH 2 —;

R 1 is a radical selected from the group consisting of benzoimidazolyl, di-C 1-6 -alkoxypyrimidinyl, 2- or 5-benzo[b]thienyl, 6- or 7-isoquinolyl, 6- or 7-tetrahydroquinolyl, 6- or 7-tetrahydroisoquinolyl, 6-quinoxalinyl, 6- or 7-quinazolinyl, dihydro-3H-benzo[1,4]oxazinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, 3-oxo-4H-benzo[1,4]oxazinyl, 2-oxobenzooxazolyl, 2-oxo-1,3-dihydroindolyl, 2,3-dihydroindolyl, indazolyl, benzofuranyl, 6- or 7-quinolyl, 6- or 7-isoquinolyl, 6- or 7-tetrahydroquinolyl, oxotetrahydroquinolyl, 6- or 7-tetrahydroisoquinolyl, 6-quinoxalinyl, 6- or 7-quinazolinyl, indolyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazinyl, 2-oxo-2,3-dihydrobenzooxazolyl, 2,3-dihydrobenzothiazinyl, imidazolyl, pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,5-a]pyridinyl and imidazo[1,2-a]pyrimidinyl, each of which is substituted by from one to four radicals selected from hydroxy, halogen, oxo, oxide, carbamoyl, carboxyl, cyano, trifluoromethyl, C 1-6 -alkyl, C 1-6 -alkoxy, hydroxy-C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, C 1-6 -alkoxy-C 1-6 -alkoxy, di-C 1-6 -alkylamino, 2,3-dihydroxypropoxy, 2,3-dihydroxypropoxy-C 1-6 -alkoxy, 2,3-dimethoxypropoxy, methoxybenzyloxy, hydroxybenzyloxy, phenethyloxy, methylenedioxybenzyloxy, dioxolanyl-C 1-6 -alkoxy, cyclopropyl-C 1-6 -alkoxy, pyridylcarbamoyloxy-C 1-6 -alkoxy, 3-morpholino-2-hydroxypropoxy, benzyloxy-C 1-6 -alkoxy, picolyloxy, C 1-6 -alkoxycarbonyl, C 1-6 -alkoxy-C 1-6 -alkoxy-C 1-6 -alkyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylcarbonylamino-C 1-6 -alkyl, C 1-6 -alkylcarbonylamino-C 1-6 -alkoxy, (N—C 1-6 -alkyl)-C 1-6 -alkylcarbonylamino-C 1-6 -alkyl, (N—C 1-6 -alkyl)-C 1-6 -alkylcarbonylamino-C 1-6 -alkoxy, C 3-6 -cycloalkylcarbonylamino-C 1-6 -alkyl, C 3-6 -cycloalkylcarbonylamino-C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, hydroxy-C 1-6 -alkoxy-C 1-6 -alkyl, hydroxy-C 1-6 -alkoxy-C 1-6 -alkoxy, C 1-6 -alkoxycarbonylamino-C 1-6 -alkyl, C 1-6 -alkoxycarbonylamino-C 1-6 -alkoxy, C 1-6 -alkylaminocarbonylamino-C 1-6 -alkyl, C 1-6 -alkylaminocarbonylamino-C 1-6 -alkoxy, C 1-6 -alkylaminocarbonyl-C 1-6 -alkyl, C 1-6 -alkylaminocarbonyl-C 1-6 -alkoxy, C 1-6 -alkylaminocarbonyl-C 1-6 -alkoxy-C 1-6 -alkyl, di-C 1-6 -alkylaminocarbonyl-C 1-6 -alkyl, di-C 1-6 -alkylaminocarbonyl-C 1-6 -alkoxy, C 1-6 -alkylcarbonyloxy-C 1-6 -alkyl, C 1-6 -alkylcarbonyloxy-C 1-6 -alkoxy, cyano-C 1-6 -alkyl, cyano-C 1-6 -alkoxy, 2-oxo-oxazolidinyl-C 1-6 -alkyl, 2-oxooxazolidinyl-C 1-6 -alkoxy, C 1-6 -alkoxycarbonyl-C 1-6 -alkyl, C 1-6 -alkoxycarbonyl-C 1-6 -alkoxy, C 1-6 -alkylsulphonylamino-C 1-6 -alkyl, C 1-6 -alkylsulphonylamino-C 1-6 -alkoxy, (N—C 1-6 -alkyl)-C 1-6 -alkylsulphonylamino-C 1-6 -alkyl, (N—C 1-6 -alkyl)-C 1-6 -alkylsulphonylamino-C 1-6 -alkoxy, C 1-6 -alkylamino-C 1-6 -alkyl, C 1-6 -alkylamino-C 1-6 -alkoxy, di-C 1-6 -alkylamino-C 1-6 -alkyl, di-C 1-6 -alkylamino-C 1-6 -alkoxy, C 1-6 -alkylsulphonyl-C 1-6 -alkyl, C 1-6 -alkylsulphonyl-C 1-6 -alkoxy, carboxy-C 1-6 -alkyl, carboxy-C 1-6 -alkoxy, carboxy-C 1-6 -alkoxy-C 1-6 -alkyl, C 1-6 -alkoxy-C 1-6 -alkyl-carbonyl, acyl-C 1-6 -alkoxy-C 1-6 -alkyl, (N—C 1-6 -alkyl)-C 1-6 -alkoxycarbonylamino, (N-hydroxy)-C 1-6 -alkylaminocarbonyl-C 1-6 -alkyl, (N-hydroxy)-C 1-6 -alkylaminocarbonyl-C 1-6 -alkoxy, (N-hydroxy)aminocarbonyl-C 1-6 -alkyl, (N-hydroxy)amino-carbonyl-C 1-6 -alkoxy, C 1-6 -alkoxy-aminocarbonyl-C 1-6 -alkyl, 6-alkoxyaminocarbonyl-C 1-6 -alkoxy, (N—C 1-6 -alkoxy)-C 1-6 -alkylaminocarbonyl-C 1-6 -alkyl, (N—C 1-6 -alkoxy)-C 1-6 -alkylamino-carbonyl-C 1-6 -alkoxy, (N-acyl)-C 1-6 -alkoxy-C 1-6 -alkylamino, C 1-6 -alkoxy-C 1-6 -alkylcarbamoyl, (N—C 1-6 -alkyl)-C 1-6 -alkoxy-C 1-6 -alkylcarbamoyl, C 1-6 -alkoxy-C 1-6 -alkylcarbonyl, C 1-6 -alkoxy-C 1-6 -alkylcarbonylamino, (N—C 1-6 -alkyl)-C 1-6 -alkoxy-C 1-6 -alkylcarbonylamino, 1-C 1-6 -alkoxy-C 1-6 -alkylimidazol-2-yl, 1-C 1-6 -alkoxy-C 1-6 -alkyltetrazol-5-yl, 5-C 1-6 -alkoxy-C 1-6 -alkyltetrazol-1-yl, 2-C 1-6 -alkoxy-C 1-6 -alkyl-4-oxoimidazol-1-yl, carbamoyl-C 1-6 -alkyl, carbamoyl-C 1-6 -alkoxy, C 1-6 -alkylcarbamoyl, di-C 1-6 -alkylcarbamoyl, C 1-6 -alkylsulphonyl, piperidinoalkyl, piperidinoalkoxy, piperidinoalkoxyalkyl, morpholinoalkyl, morpholinoalkoxy, morpholinoalkoxyalkl, piperazinoalkyl, piperazinoalkoxy, piperazinoalkoxyalkyl, [1,2,4]triazol-1-ylalkyl, [1,2,4]triazol-1-ylalkoxy, [1,2,4]triazol-4-ylalkyl, [1,2,4]triazol-4-ylalkoxy, [1,2,4]oxadiazol-5-ylalkyl, [1,2,4]oxadiazol-5-ylalkoxy, 3-methyl[1,2,4]oxadiazol-5-ylalkyl, 3-methyl[1,2,4]oxadiazol-5-ylalkoxy, 5-methyl[1,2,4]oxadiazol-3-ylalkyl, 5-methyl[1,2,4]oxadiazol-3-ylalkoxy, tetrazol-1-ylalkyl, tetrazol-1-ylalkoxy, tetrazol-2-ylalkyl, tetrazol-2-ylalkoxy, tetrazol-5-ylalkyl, tetrazol-5-ylalkoxy, 5-methyltetrazol-1-ylalkyl, 5-methyltetrazol-1-ylalkoxy, thiazol-4-ylalkyl, thiazol-4-yl-alkoxy, oxazol-4-ylalkyl, oxazol-4-ylalkoxy, 2-oxopyrrolidinylalkyl, 2-oxopyrrolidinylalkoxy, imidazolylalkyl, imidazolylalkoxy, 2-methylimidazolylalkyl, 2-methylimidazolylalkoxy, N-methylpiperazinoalkyl, N-methylpiperazinoalkoxy, N-methylpiperazinoalkoxyalkyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, 4-methylpiperazinyl, morpholinyl, thiomorpholinyl, 2-hydroxymethylpyrrolidinyl, 3-hydroxypyrrolidinyl, 3,4-dihydroxypyrrolidinyl, 3-acetamidomethylpyrrolidinyl, 3-C 1-6 -alkoxy-C 1-6 -alkylpyrrolidinyl, 4-hydroxypiperidinyl, 4-oxopiperidinyl, 3,5-dimethylmorpholinyl, 4,4-dioxothiomorpholinyl, 4-oxothiomorpholinyl, 2,6-dimethylmorpholinyl, 2-oxoimidazolidinyl, 2-oxooxazolidinyl, 2-oxopyrrolidinyl, 2-oxo-[1,3]oxazinyl and 2-oxotetrahydropyrimidinyl;

R 2 is C 1 -C 6 -alkyl;

R 3 is H;

R 4 is C 1 -C 6 -alkyl;

R 5 is C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 2 -C 8 -alkynyl, cyano-C 1 -C 6 -alkyl, optionally substituted C 3 -C 6 -cycloalkyl, C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl, optionally substituted aryl, optionally substituted heterocyclyl-C 0 -C 6 -alkyl which, for C 0 -alkyl, is bonded via a carbon atom or H 2 N—C(O)—C 1 -C 6 -alkyl;

or in which one or more atoms have been replaced by their stable non-radioactive isotopes, or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical preparation comprising, as an active pharmaceutical ingredient, a compound according to claim 1 in free form or as a pharmaceutically acceptable salt, and a pharmaceutically inert excipient.

Assignments (2)
MERGER Recorded Feb 9, 2010
From: SPEEDEL EXPERIMENTA AG
To: NOVARTIS AG
Reel/Frame 023920/0239 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 19, 2006
From: HEROLD, PETER; STUTZ, STEFAN; MAH, ROBERT; TSCHINKE, VINCENZO; STOJANOVIC, ALEKSANDAR; JOTTERAND, NATHALIE; QUIRMBACH, MICHAEL; BEHNKE, DIRK; MARTI, CHRISTIANE
To: SPEEDEL EXPERIMENTA AG
Reel/Frame 018335/0527 →