WO2009106599A2 - Substituted piperidines as therapeutic compounds - Google Patents

Substituted piperidines as therapeutic compounds Download PDF

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WO2009106599A2
WO2009106599A2 PCT/EP2009/052335 EP2009052335W WO2009106599A2 WO 2009106599 A2 WO2009106599 A2 WO 2009106599A2 EP 2009052335 W EP2009052335 W EP 2009052335W WO 2009106599 A2 WO2009106599 A2 WO 2009106599A2
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alkyl
alkoxy
mono
heterocyclyl
alkylated
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PCT/EP2009/052335
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French (fr)
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WO2009106599A3 (en
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Peter Herold
Robert Mah
Stefan Stutz
Vincenzo Tschinke
Isabelle Lyothier
Stjepan Jelakovic
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Novartis Ag
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    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to the use of substituted piperidines as beta-secretase-, cathepsin D-, plasmepsin II- and/or HIV-protease-inhibitors.
  • beta-secretase-, cathepsin D-, plasmepsin II- and/or HlV-protease- inhibition there is still a need for highly potent active ingredients.
  • the improvement of the pharmacokinetic properties is at the forefront. These properties directed towards better bioavailability are, for example, absorption, metabolic stability, solubility or lipophilicity.
  • Alzheimer Disease aspartyl protease Beta-Secretase
  • AD Alzheimer's disease
  • the symptoms of AD include progressive memory loss, language difficulty and ultimately loss of basic neural function and death.
  • the biomarkers in the central nervous system for AD include amyloid plaques, intracellular neurofibrillary tangles and activated microglia. The appearance of these three markers is likely to contribute to the neuronal cell death and memory loss observed in AD.
  • Beta-amyloid is a defining feature of AD and now believed to be a causative precursor in the development of the disease.
  • Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amloidosis of the Dutch-Type (HCHWA-D) and other neurodegenerative disorders.
  • Beta-amyloid plaques are predominantly composed of amyloid beta peptide (A-beta, also sometimes designated betaA4).
  • the A-beta peptide is derived by proteolysis of the beta amyloid precursor protein (APP).
  • Beta-APP is processed by three distinct ordered enzymatic activities.
  • the bulk of beta-APP is processed via alpha-secretase in a non-amyloidogenic pathway.
  • a small fraction of beta-APP is cleaved by beta- secretase activity to generate the membrane-bound C-terminal fragment C99.
  • Gamma-secretase cleaves C99 to generate the amyloidogenic A-beta peptide of 39-42 amino acids.
  • the aspartyl protease activity of beta-secretase has been disclosed using varied nomenclature, including BACE (beta-site APP cleaving enzyme), Asp and memapsin.
  • beta-secretase cleavage of beta-APP as a critical step in the generation of AD is underscored by the observation that human mutations at the beta-secretase cleavage subsites (Swedish mutations) of beta-APP lead to increased A-beta production and early onset familial AD. Furthermore, BACE1 - knockout mice fail to produce A-beta peptide and present a normal phenotype. When crossed with transgenic mice that overexpress APP, the progeny show reduced amounts of A-beta in brain extracts as compared with control animals.
  • Beta-secretase inhibiting compounds as discussed by Thompson et al. (2005) in Curr. Pharm. Des. 11 , 3383-3404 are therefore useful to treat or to prevent diseases that are characterized by amyloid beta deposits or plaques such as AD.
  • the present invention also relates to methods of treating subjects who have, or in preventing subjects from developing a disease or condition selected from the group consisting of AD, for helping prevent or delay the onset of AD, for helping to slow the proression of AD, for treating subjects with mild cognitive impairment (MCI) and preventing or delaying the onset of AD in those who could progress form MCI to AD, for treating Down's syndrome, for treating humans who have HCHWAD, for treating cerebral amyloid angiopathy, and for treating degenerative dementias Alzheimer's Disease aspartyl protease: Cathepsin D
  • Human cathepsin D is an intracellular aspartic peptidase found mainly in lysosomes. It has a number of housekeeping functions, including the degradation of cellular and phagocytosed proteins. The enzymes may be involved in a variety of disease states, including cancer and Alzheimer's disease (AD). Clinical studies have shown that cathepsin D is overexpressed in breast cancer cells and this seems to be associated with an increased risk for metastasis due to enhanced cell growth. Cathepisn D is also thought to be involved in formation of the beta-amyloid peptide in AD. Recently, several genetic association studies linked cathepsin D with amyloid pathology and Alzheimer's disease as described for example by Davidson et al., (2006) in J. Neurol. Neurosurg. Psychiatry 77, 515-517. The availability of selective and potent inhibitors will help to further define the role of cathepsin D in disease and possibly lead to therapeutic agents.
  • Plasmodium falciparum Malaria is considered as one of the most serious infectious diseases in the world, affecting approximately 500 million people. The disease is spread by the anopheles mosquito that is mostly found in tropical regions. The species Plasmodium falciparum is responsible for more than 95% of malaria-related morbidity and mortality. Increasingly, Plasmodium falciparum is becoming resistant to existing therapies such as chloroquine, mefloquine and sulfadoxime/ pyrimethamine. Thus there is an urgent need for new treatments.
  • the parasite In the erythrocytic stage of the parasite's life cycle the parasite invades the red blood cells of its host consuming up to 80% of the hemoglobin as a source of nutrients for growth and development. Hemoglobin degradation takes place in an acidic vacuole of the parasite and many of the current antimalarial drugs appear to disrupt important vacuolar functions.
  • the food vacuole contains aspartic, cysteine and metallo- proteases, which are all considered to play a role in the process of hemoglobin degradation. At least 10 genes encoding aspartic proteases have been identified in the Plasmodium genome. Four of the aspartic proteases have been localized in the - A -
  • plasmepsin I, II, IV and HAP a histo- aspartic protease.
  • Inhibitors of plasmepsin I and Il have shown efficacy in cell and animal models of malaria, indicating that these enzymes may represent targets for drug discovery as described for example by Coombs et al. (2001 ) Trends Parasitol 17, 532-537. Indeed, a non-selective inhibitor of aspartic proteases, pepstatin, inhibits the growth of Plasmodium falciparum in vitro.
  • the present invention relates to the identification of low molecular weight, non- peptidic inhibitors of the Plasmodium falciparum protease plasmepsin Il or other related aspartic proteases to treat and/or to prevent malaria.
  • HIV aspartyl protease HIV-1 peptidase
  • AIDS Acquired immunodeficiency syndrome
  • Gag and Gag-Pol Two polyprotein precursors, Gag and Gag-Pol.
  • the 55-kDa Gag precursor contains the structural proteins and the 160-kDa Gag-Pol polyprotein contains the functional viral enzymes protease, reverse transcriptase, and integrase.
  • Gag and Gag-Pol polyproteins are transported to the plasma membrane where assembly of type-C retroviruses and lentiviruses typically occurs.
  • the viral protease cleaves the Gag and Gag-Pol precursors into the structural and functional proteins required for viral replication.
  • the protease activity within the cytoplasma of infected cells allows for the formation of virions which can be released from the cell in the last stages of budding.
  • the mature HIV-1 protease is an obligatory dimer of identical 11 -kDa subunits, each contributing one of the two catalytic aspartic residues.
  • the cell-derived members of the aspartic protease family are monomehc enzymes with two Asp-Thr- Gly-containing domains.
  • the unique dimeric structure of the retroviral protease is mainly stabilized by an antiparallel beta-sheet formed by the interdigitation of the amino- and carboxyl-terminal beta-strands of each monomer.
  • HIV-1 protease i.e. the dimerization and autocatalytic release from Gag-Pol
  • Inhibition of protease activation causes a severe defect in Gag polyprotein processing and a complete loss of viral infectivity.
  • the viral protease has become a target for HIV therapeutics, resulting in many HIV protease inhibitors reaching clinical trials as reviewed by Rana et al. (1999) in Pharmacotherapy 19, 35-59 and Morse et al., (2006) in Lancet Infect. Dis. 6, 215-225.
  • Most of these drugs are substrate-based inhibitors, whose design has been facilitated by an abundance of crystal structure data for both the native enzyme and enzyme- inhibitor complexes. Additionally, there are now extensive biochemical data detailing both the catalytic mechanism and the molecular basis for substrate selection.
  • the present invention relates to compounds of the general formula
  • R is C2-8-alkenyl, C2-8-alkynyl, Ci-s-alkyl, Co-8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8- alkyl, optionally N-mono- or N,N-di-Ci-8-alkylated or -arylated amino-Ci-s-alkyl, optionally O-Ci-s-alkylated carboxyl-Co- 8 -alkyl, Cs-s-cycloalkyl-Ci-s-alkyl, optionally N-mono- or N,N-di-C3-8-cycloalkyl-Co-8-alkylated or optionally N-mono- or N,N-di- heterocyclyl-Co- 8 -alkylated carbamoyl-Co-s-alkyl, C 3 - 8 -cycloalkyl-C 0 - 8 -alkylcarbonyl- (N-
  • R 1 is aryl or heterocyclyl, each of which is substituted by 1-4 acyl-Ci -8 -alkoxy-Ci-8- alkoxy, acyl-Ci-s-alkoxy-Ci-s-alkyl, (N-acyO-Ci-s-alkoxy-Ci-s-alkylamino, Ci -8 -alkanoyl, Ci-8-alkoxy, Ci-s-alkoxy-Ci-s-alkanoyl, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s- alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, (N-Ci-s-alkoxyJ-Ci-s-alkylaminocarbonyl-Ci-s- alkoxy, (N-Ci-s-alkoxyJ-Ci-s-alkylaminocarbonyl-Ci-
  • X is -AIk-, -0-AIk-, -AIk-O-, -0-AIk-O-, -S-AIk-, -AIk-S-, -AIk-NR 2 -, -NR 2 -Alk-, -C(O)-NR 2 -, -AIk-C(O)-NR 2 -, -C(O)-N R 2 -Alk-, -Alk-C(O)-NR 2 -Alk-, -NR 2 -C(O)-, -Alk-NR 2 -C(O)-, -NR 2 -C(O)-, -NR 2 -C(O)-Alk-, -Alk-NR 2 -C(O)-Alk-, -0AIk-C(O)-NR 2 -, -O-Alk-NR 2 -C(O)-, -S(O) 2 -NR
  • R 2 is hydrogen, Ci -8 -alkyl, Ci-s-alkoxy-Ci-s-alkyl, acyl or aryl-Ci -8 -alkyl; and their pharmaceutically usable salts, prodrugs or compounds, in which one or more atoms have been replaced by their stable, non-radioactive isotopes.
  • Co-alkyl in the above (and hereinafter) mentioned Co- 8 -alkyl groups is a bond or, if located at a terminal position, a hydrogen atom.
  • Co-alkoxy in the above (and hereinafter) mentioned Co-8-alkoxy groups is "-O-" or, if located at a terminal position, an -OH group.
  • Ci -8 -alkyl and -alkoxy radicals are, respectively, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • Ci-s-Alkylene- dioxy radicals are preferably methylenedioxy, ethylenedioxy and propylenedioxy.
  • Examples of Ci-s-alkanoyl radicals are acetyl, propionyl and butyryl.
  • Cycloalkyl is a saturated cyclic hydrocarbon radical having 3-12 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, cyclooctyl, bicyclo[2.2.2]octyl and adamantyl, which may be mono- or polysubstituted.
  • substituents on such cycloalkyl radicals are Ci -8 -alkoxy, Ci -8 -alkyl, Ci -8 -alkyl- carbonyloxy, carbamoyl, carboxyl, cyano, halogen, hydroxyl, oxo, trifluoromethoxy or trifluoromethyl.
  • Ci-s-Alkylene radicals may be linear or branched and are, for example, methylene, ethylene, propylene, 2-methylpropylene, 2-methylbutylene, 2-methylpropyl-2-ene, butyl-2-ene, butyl-3-ene, propyl-2-ene, tetra-, penta- and hexamethylene;
  • C2-8-alkenylene radicals are, for example, vinylene and propenylene;
  • an example of a C2-8-alkynylene radical is ethynylene;
  • acyl radicals are alkanoyl radicals, preferably Ci -8 -alkanoyl radicals, or aroyl radicals such as benzoyl.
  • Aryl denotes mono- or polycyclic aromatic radicals which may be mono- or polysub- stituted, for example phenyl, substituted phenyl, naphthyl or substituted naphthyl.
  • substituents on such aryl radicals are Ci-s-alkyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C2-8-alkenyl, Ci-s-alkylsulphinyl, Ci-s-alkoxy, Ci-S- alkylcarbonyloxy, hydroxyl, halogen, cyano, carbamoyl, carboxyl and Ci-s-alkylene- dioxy, and also optionally halogen-, Ci -8 -alkyl-, Ci -8 -alkoxy- or dihydroxy-Ci -8 -alkyl- aminocarbonyl-substituted phenyl, phenoxy, phenylthio, phenyl-Ci-s-alkyl or
  • substituents on aryl or heterocyclyl radicals are oxide, oxo, Ci-s-alkoxycarbonylphenyl, hydroxy-Ci -8 -alkylphenyl, benzyloxy, pyridyl- carbonylamino-Ci-s-alkyl, C2-8-alkenyloxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s- alkoxy-Ci-s-alkyl, hydroxy-Ci-s-alkoxy, di-Ci-s-alkylamino, 2,3-dihydroxypropoxy, 2,3-dihydroxypropoxy-Ci-s-alkoxy, 2,3-dimethoxypropoxy, methoxybenzyloxy, hydroxybenzyloxy, phenethyloxy, methylenedioxybenzyloxy, dioxolanyl-Ci-s-alkoxy, cyclopropyl-
  • heterocyclyl denotes mono- or bicyclic, saturated and unsaturated heterocyclic radicals having 1 to 4 nitrogen and/or 1 or 2 sulphur or oxygen atoms, which may each be mono- or polysubstituted, especially by (in the case of unsaturated heterocyclyl radicals) alkyl, hydroxyl, alkoxy, nitro or halogen, or by substituents as defined above for aryl radicals, or (in the case of saturated heterocyclyl radicals) may be substituted by alkyl or alkoxy.
  • heterocyclyl radicals are benzimidazolyl, benzo[1 ,3]dioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzo[b]thienyl, quinazolinyl, quinolyl, quinoxalinyl, 2H-chromenyl, carbazolyl, dihydro-2H- benzo[1 ,4]oxazinyl, dihydro-3H-benzo[1 ,4]oxazinyl, dihydro-2H-benzo[1 ,4]thiazinyl, 2,3-dihydroindolyl, dihydro-1 H-pyhdo[2,3-b][1 ,4]oxazinyl, furyl, imidazolyl, imidazo[1 ,2- a]pyridyl, imidazo[1 ,5-a]pyhdyl, indazolyl, indolyl
  • substituted heterocyclyl radicals are 2,2-dimethyl-3-oxo-4H-benzo[1 ,4]oxazinyl, 2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazinyl, 2-aryl-2-methyl-3,4-dihydro-2H- benzo[1 ,4]oxazinyl, 2,2-dimethyl-2H-chromen-6-yl, 2-aryl-2-methyl-2H-chromen-6-yl, 2-oxobenzoimidazolyl, 2-oxodihydrobenzo[d][1 ,3]oxazinyl, 4-oxodihydroimidazolyl, 5-oxo-4H-[1 ,2,4]thazinyl, 3-oxo-4H-benzo[1 ,4]thiazinyl, 1 ,1 ,3-trioxodihydro-2H-1 ⁇ 6 - benzo[1 ,
  • saturated heterocyclyl radicals are azetidinyl, dioxolanyl, dioxanyl, dithiolanyl, dithianyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, morpholinyl, thiomorpholinyl, 2-hydroxymethylpyrrolidinyl, 3-hydroxypyrrolidinyl, 3,4-dihydroxypyrrolidinyl, 4-hydroxypiperidinyl, 4-oxopipehdinyl, 3,5-dimethylmorpholinyl, 4,4-dioxothiomorpholinyl, 4-oxothiomorpholinyl, 2,6-dimethyl- morpholinyl, tetrahydropyranyl, 2-oxoimidazolidinyl, 2-oxooxazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxo[1 ,3]oxaziny
  • bicyclic heterocyclyl radicals are 2-oxabicyclo[4.1.0]heptanyl, 3-oxa- bicyclo[4.1.0]heptanyl, 2-oxabicyclo[3.1.0]hexanyl or 3-oxabicyclo[3.1.0]hexanyl.
  • the aryl, aroyl and heterocyclyl radicals may additionally be substituted by heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkoxyalkyl or heterocyclyl, for example piperidinoalkyl, piperidinoalkoxy, pipehdinoalkoxyalkyl, morpholinoalkyl, morpholinoalkoxy, morpholinoalkoxyalkyl, piperazinoalkyl, piperazinoalkoxy, piperazinoalkoxy, piperazinoalkoxyalkyl, [1 ,2,4]-triazol-1 -ylalkyl, [1 ,2,4]-triazol-1 - ylalkoxy, [1 ,2,4]-thazol-4-ylalkyl, [1 ,2,4]-thazol-4-ylalkoxy, [1 ,2,4]-oxadiazol-5-ylalkyl, [1 ,2,4
  • polyhydroxyalkyl denotes Ci -7 -alkyl radicals which may be substituted by 2-8 hydroxyl groups, for example glyceryl, arabityl, sorbityl, etc.
  • halogen or halo denotes, for example, fluorine, chlorine or bromine, or a radical mono- or polysubstituted by fluorine, chlorine or bromine.
  • the compounds of the formula (I) have at least two asymmetric carbon atoms and may therefore be present in the form of optically pure diastereomers, diastereomer mixtures, diastereomeric racemates, mixtures of diastereomehc racemates or as meso compounds.
  • the invention encompasses all of these forms.
  • Diastereomer mixtures, diastereomeric racemates or mixtures of diastereomeric racemates may be separated by customary methods, for example by column chromatography, thin-layer chromatography, HPLC and the like.
  • Salts are principally pharmaceutically usable salts or non-toxic salts of the compounds of the formula (I).
  • pharmaceutically usable salts encompasses salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like.
  • Salts of compounds with salt-forming groups result principally from the addition of an acid or of a base. If a plurality of salt-forming groups are present, it is also possible for mixed salts or internal salts to be present.
  • Such salts form, for example, from compounds of the formula (I) which contain an acidic functional group, for example a carboxyl group, and are, for example, salts of this functional group with a suitable base, for example non-toxic metal salts of metals of groups Ia, Ib, Ma and Mb of the Periodic Table, for example alkali metal salts, especially lithium, sodium or potassium salts, alkaline earth metal salts, especially magnesium or calcium salts, but also zinc salts and ammonium salts; also included are salts which form with organic amines, such as optionally hydroxy-substituted mono-, di- or thalkylamines, especially with mono-, di- or tri(lower alkyl)amines or with quaternary ammonium bases, for example methyl-, ethyl-, diethyl- or triethyl- amine, mono-, bis- or tris(2-hydroxy(lower alkyl))amines, for example ethanol-, diethanol- or triethanol
  • the compounds of the formula (I) which contain a basic functional group, for example an amino group may form salts with acids, for example with suitable inorganic acids, for example hydrohalic acid, for example hydrochloric acid or hydrobromic acid, sulphuric acid with exchange of one or both protons, phosphoric acid with exchange of one or more protons, for example ortho- or metaphosphoric acid, pyrophosphohc acid with exchange of one or more protons, or with organic carboxylic acids, sulphonic acids or phosphoric acids or N-substituted sulphamic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucahc acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzo
  • Prodrug derivatives of the compounds described in the present context are derivatives thereof which release the original compound by a chemical or physiological process on in vivo administration.
  • a prodrug can be converted to the original compound, for example, on attainment of a physiological pH or by enzymatic conversion.
  • Prodrug derivatives may, for example, be esters of freely available carboxylic acids, S- and O-acyl derivatives of thiols, alcohols or phenols, where the acyl group is as defined in the present context.
  • ester derivatives which are converted to the original carboxylic acid by solvolysis in physiological medium
  • physiological medium for example lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or disubstituted lower alkyl esters, such as lower co-(amino, mono- or dialkylamino, carboxyl, lower alkoxycarbonyl)alkyl esters, or such as lower ⁇ -(alkanoyloxy, alkoxycarbonyl or dialkylaminocarbonyl)alkyl esters; as such, pivaloyloxymethyl esters and similar esters are conventionally used.
  • a particular compound in this invention also includes its prodrug derivative and salt form, where this is possible and appropriate.
  • the definitions mentioned apply within the scope of general chemical principles such as, for example, the usual valencies of atoms.
  • the compounds of the formula (I) also include those compounds in which one or more atoms are replaced by their stable, non-radioactive isotopes; for example, a hydrogen atom by deuterium.
  • Preferred compounds according to the invention are those of the general formula (IA) and the pharmaceutically usable salts thereof
  • a further preferred group of compounds of the formula (I), and particularly preferably of the formula (IA), and the pharmaceutically usable salts thereof, are compounds in which
  • R is C 2- 8-alkenyl, C 2- 8-alkynyl, Ci -8 -alkyl, C 0 -8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8- alkyl, optionally N-mono- or N,N-di-Ci-8-alkylated or -arylated amino-Ci-s-alkyl, optionally O-Ci -8 -alkylated carboxyl-Co-s-alkyl, Cs-s-cycloalkyl-Ci-s-alkyl, optionally N-mono- or N,N-di-C3-8-cycloalkyl-Co-8-alkylated or optionally N-mono- or N,N-di- heterocyclyl-Co- 8 -alkylated carbamoyl-Co- 8 -alkyl, Cs-s-cycloalkyl-Co- ⁇ -alkylcarbonyl- (N-Co
  • R 1 is selected from benzimidazolyl, benzo[1 ,3]dioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzo[b]thienyl, quinazolinyl, quinolyl, quinoxalinyl, 2H-chromenyl, carbazolyl, dihydro-2H-benzo[1 ,4]oxazinyl, dihydro-3H-benzo[1 ,4]oxazinyl, dihydro- 2H-benzo[1 ,4]thiazinyl, 2,3-dihydroindolyl, dihydro-1 H-pyrido[2,3-b][1 ,4]oxazinyl, imidazo[1 ,2-a]pyhdyl, imidazo[1 ,5-a]pyhdyl, indazolyl, indolyl, isobenzofuranyl, iso
  • R 1 is aryl or heterocyclyl, each of which is substituted as specified above; and X is -AIk-, -0-AIk-, -AIk-O-, -0-AIk-O-, -AIk-NR 2 -, -NR 2 -Alk-, -C(O)-NR 2 - or -NR 2 -C(O)- where AIk is Ci-s-alkylene, which may optionally be substituted by halogen; where R 2 is hydrogen or Ci-s-alkyl.
  • a further preferred group of compounds of the formula (I), and particularly preferably of the formula (IA), and the pharmaceutically usable salts thereof, are compounds in which
  • R is Ci-s-alkyl, Co-8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8-alkyl, Cs-s-cycloalkyl-Ci-s- alkyl, optionally N-mono- or N,N-di-C3-8-cycloalkyl-Co-8-alkylated or optionally N-mono- or N,N-di-heterocyclyl-Co-8-alkylated carbamoyl-Co-8-alkyl or Cs-s-cycloalkyl- C 0 - 8 -alkylcarbonyl-(N-Co- 8 -alkyl)amino-Ci- 8 -alkyl or heterocyclylcarbonyl-Co-s-alkyl, each of which is either unsubstituted or substituted by 1-4 Ci-s-alkoxy, Ci-s-alkoxy- Ci-s-alkoxy, Ci-8-alkoxycarbony
  • R is particularly preferably Ci-s-alkyl, Co- 8 -alkylcarbonyl-(N-Co- 8 -alkyl)amino-Ci- 8 -alkyl, Cs-s-cycloalkyl-Ci-s-alkyl, optionally N-mono- or N,N-di-C3-8-cycloalkyl-Co-8-alkylated or optionally N-mono- or N.N-diheterocyclyl-Co- ⁇ -alkylated carbamoyl-Co-8-alkyl, C3-8- cycloalkyl-Co- 8 -alkylcarbonyl-(N-Co- 8 -alkyl)amino-Ci- 8 -alkyl or heterocyclylcarbonyl- Co-8-alkyl, each of which is either unsubstituted or substituted by 1 -4 Ci -8 -alkoxy, Ci -8 - alkoxy-Ci-s-alkoxy
  • R is very particularly preferably Ci-s-alkyl, Co-s-alkylcarbonylamino-Ci-s-alkyl, C 3 - 8 - cycloalkyl-Ci-s-alkyl, optionally N-mono-Cs-s-cycloalkyl-Co-s-alkylated, optionally N-mono-heterocyclyl-Co- ⁇ -alkylated carbamoyl-Co-s-alkyl, Cs-s-cycloalkyl-Co-s- alkylcarbonylamino-Ci-s-alkyl or heterocyclylcarbonyl-Co- 8 -alkyl, each of which is either unsubstituted or substituted by 1-2 heterocyclyl or optionally N-mono- or N.N-di-Ci-Cs-alkylated, N-mono- or N,N-di-arylated or N-mono- or N,N-di-hetero-
  • a further preferred group of compounds of the formula (I), and particularly preferably of the formula (IA), and the pharmaceutically usable salts thereof, are compounds in which
  • R 1 is benzimidazolyl, benzo[1 ,3]dioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzo[b]thienyl, quinazolinyl, quinolyl, quinoxalinyl, 2H-chromenyl, carbazolyl, dihydro-2H-benzo[1 ,4]oxazinyl, dihydro-3H-benzo[1 ,4]oxazinyl, dihydro-2H- benzo[1 ,4]thiazinyl, 2,3-dihydroindolyl, dihydro-1 H-pyrido[2,3-b][1 ,4]oxazinyl, imidazo[1 ,2-a]pyhdyl, imidazo[1 ,5-a]pyhdyl, indazolyl, indolyl, isobenzofuranyl, isoquinolyl
  • R 1 is preferably benzo[1 ,3]dioxolyl, benzofuranyl, benzoimidazolyl, benzooxazolyl, 2H-chromenyl, carbazolyl, dihydro-2H-benzo[1 ,4]oxazinyl, dihydro-3H- benzo[1 ,4]oxazinyl, dihydro-2H-benzo[1 ,4]thiazinyl, indazolyl, indolyl, isobenzo- furanyl, [1 ,5]naphthyridyl, phenyl, phthalazinyl, pyridyl, pyrimidinyl, 1 H-pyrrolo[2,3- b]pyridyl or quinolinyl, each of which is substituted by 1-4 Ci -8 -alkanoyl, Ci -8 -alkoxy, Ci-s-alkoxy-Ci-s-alkanoyl,
  • R 1 is particularly preferably 2H-chromenyl, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl or carbazolyLeach of which is substituted by 1-4 Ci -8 -alkoxy, Ci-s-alkoxy-Ci-s-alkoxy , Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxycarbonylamino- Ci-s-alkoxy, Ci-s-alkoxycarbonylamino-Ci-s-alkyl, Ci-s-alkyl, Co-s-alkylcarbonylamino- Ci-s-alkoxy, Co-s-alkylcarbonylamino-Ci-s-alkyl, halogen, halogen-Ci-s-alkoxy, halogen-Ci-s-alkyl, halogen-aryl or
  • R 1 is very particularly preferably 3,4-dihydro-2H-benzo[1 ,4]oxazinyl substituted by 1 -4 Ci-8-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci -8 - alkoxy-Ci-s-alkyl, Ci-s-alkoxycarbonylamino-Ci-s-alkoxy, Ci -8 -alkoxycarbonylamino- Ci-s-alkyl, Ci -8 -alkyl, Co-s-alkylcarbonylannino-Ci-s-alkoxy, Co-s-alkylcarbonylamino- Ci-s-alkyl, halogen, halogen-Ci-s-alkoxy, halogen-Ci-s-alkyl, halogen-aryl or oxo, where a saturated carbon atom of the hetero
  • a further preferred group of compounds of the formula (I), and particularly preferably of the formula (IA), and the pharmaceutically usable salts thereof, are compounds in which
  • X is -O-Alk- or -O-Alk-O- where AIk is Ci -8 -alkylene.
  • X is particularly preferred -0-AIk-, and very particularly preferred -0-CH 2 -.
  • a further preferred group of compounds of the formula (I), and particularly preferably of the formula (IA), and the pharmaceutically usable salts thereof, are compounds in which
  • R is C 2- 8-alkenyl, C 2- 8-alkynyl, Ci-s-alkyl, Co-8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8- alkyl, optionally N-mono- or N,N-di-Ci-8-alkylated or -arylated amino-Ci-s-alkyl, optionally O-Ci -8 -alkylated carboxyl-Co-s-alkyl, Cs-s-cycloalkyl-Ci-s-alkyl, optionally N-mono- or N,N-di-C3-8-cycloalkyl-Co-8-alkylated or optionally N-mono- or N,N-di- heterocyclyl-Co- 8 -alkylated carbamoyl-Co- 8 -alkyl, Cs-s-cycloalkyl-Co- ⁇ -alkylcarbonyl- (N-Co- 8 -
  • R 1 is 2H-chromenyl, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl or carbazolyl, each of which is substituted by 1 -4 Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy-Ci-s- alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxycarbonylamino-Ci-s-alkoxy, Ci-s-alkoxy- carbonylamino-Ci-s-alkyl, Ci-s-alkyl, Co-s-alkylcarbonylamino-Ci-s-alkoxy, Co- ⁇ - alkylcarbonylamino-Ci-s-alkyl, halogen, halogen-Ci-s-alkoxy, halogen-Ci-s-alkyl, halogen-aryl or
  • X is -0-CH 2 -.
  • a further preferred group of compounds of the formula (I), and particularly preferably of the formula (IA), and the pharmaceutically usable salts thereof, are compounds in which
  • R is C 2- 8-alkenyl, C 2- 8-alkynyl, Ci -8 -alkyl, C 0 -8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8- alkyl, optionally N-mono- or N,N-di-Ci-8-alkylated or -arylated amino-Ci-s-alkyl, optionally O-Ci-s-alkylated carboxyl-Co- 8 -alkyl, Cs-s-cycloalkyl-Ci-s-alkyl, optionally N-mono- or N,N-di-C3-8-cycloalkyl-Co-8-alkylated or optionally N-mono- or N,N-di- heterocyclyl-Co- 8 -alkylated carbamoyl-Co- 8 -alkyl, Cs-s-cycloalkyl-Co- ⁇ -alkylcarbonyl- (N-Co
  • R 1 is 2H-chromenyl, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl or carbazolyl, each of which is substituted by 1 -4 Ci -8 -alkoxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy-Ci-s- alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxycarbonylamino-Ci-s-alkoxy, Ci -8 -alkoxy- carbonylamino-Ci-s-alkyl, Ci-s-alkyl, Co-s-alkylcarbonylamino-Ci-s-alkoxy, Co- 8 -alkyl- carbonylamino-Ci-s-alkyl, halogen, halogen-Ci-s-alkoxy, halogen-Ci-s-alkyl, halogen-
  • X is -0-CH 2 -.
  • a further preferred group of compounds of the formula (I), and particularly preferably of the formula (IA), and the pharmaceutically usable salts thereof, are compounds in which
  • R is Ci- 8 -alkyl, Co-s-alkylcarbonylamino-Ci-s-alkyl, C 3 - 8 -cycloalkyl-Ci -8 -alkyl, optionally N-mono-C3-8-cycloalkyl-Co-8-alkylated, optionally N-mono-heterocyclyl-Co-s-alkylated carbamoyl-Co- 8 -alkyl, Cs-s-cycloalkyl-Co-s-alkylcarbonylamino-Ci-s-alkyl or hetero- cyclylcarbonyl-Co- 8 -alkyl, each of which is either unsubstituted or substituted by 1 -2 heterocyclyl or optionally N-mono- or N.N-di-Ci-Cs-alkylated, N-mono- or N,N-di- arylated or N-mono- or N,N-di-heterocycl
  • R 1 is 2H-chromenyl, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl or carbazolyl, each of which is substituted by 1 -4 Ci -8 -alkoxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy-Ci-s- alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxycarbonylamino-Ci-s-alkoxy, Ci -8 -alkoxy- carbonylamino-Ci-s-alkyl, Ci -8 -alkyl, Co-s-alkylcarbonylamino-Ci-s-alkoxy, C 0- S- alkylcarbonylamino-Ci-s-alkyl, halogen, halogen-Ci -8 -alkoxy, halogen-Ci -8 -alkyl, hal
  • X is -0-CH 2 -.
  • the compounds of the formula (I) or formula (IA) may be prepared in an analogous manner to preparation processes known from the literature.
  • a preferred method of preparing optically pure compounds of the formula (IA) consists in the formation of a pipehdine base structure, for example 6(S)-hydroxymethylpiperidin-3(R)-ol [406945- 58-2], by reacting an aspartic acid derivative with Meldrum's acid and a subsequent diastereoselective ⁇ -hydroxylation according to the exemplary scheme which follows:
  • the compounds of the formula (I) may also be prepared in optically pure form.
  • the separation into antipodes can be effected by methods known per se, either preferably at a synthetically early stage by salt formation with an optically active acid, for example (+)- or (-)-mandelic acid, and separation of the diastereomehc salts by fractional crystallization, or preferably at a rather late stage by dehvatization with a chiral auxiliary unit, for example (+)- or (-)-camphanoyl chloride, and separation of the diastereomeric products by chromatography and/or crystallization and subsequent cleavage of the bond to the chiral auxiliary.
  • the pure diastereomeric salts and derivatives may be analysed by common spectroscopic methods, and X-ray spectroscopy on single crystals constitutes a particularly suitable method.
  • the compounds of formula (I) and (IA), respectively, and their pharmaceutically usable salts reveal inhibitory activities on the enzymes beta-secretase, cathepsin D, plasmepsin Il and/or HIV-protease.
  • inhibitors of beta-secretase cathepsin D, plasmepsin Il and/or HIV protease can be assessed experimentally with following in vitro assays.
  • the protease inhibitory activity of compounds can be tested with an assay kit using the fluorescence resonance energy transfer (FRET) technology and a recombinant i.e. baculovirus expressed enzyme preparation.
  • FRET fluorescence resonance energy transfer
  • the principle of the assay is as follows relies on a measurable energy difference, quantitatively depending on the presence of a peptide sequence.
  • the peptide substrate is synthesized with two terminal fluorophores, a fluorescent donor and quenching acceptor. The distance between these two groups is selected so that upon light excitation, the donor fluorescence energy is significantly quenched by the acceptor through resonance energy transfer.
  • the FRET assay is performed in white polysorp plates.
  • the assay buffer consists of 50 mM sodium acetate pH 5, 392 mM sodium chloride, 12.5% glycerol and 0.1 % BSA.
  • the incubates per well are composed of 160 ⁇ l buffer, 10 ⁇ l inhibitor in DMSO, 10 ⁇ l peptide substrate in DMSO and 20 ⁇ l enzyme-solution.
  • the inhibitors are tested in a concentration range of 1 pM to 1 mM.
  • the fluorescently marked donor and acceptor peptide substrates are generated by solid phase peptide synthesis (Applied Biosystems).
  • the beta-secretase peptide substrate Rh-Glu-Val-Asn-Leu- Asp-Ala-Glu-Phe-Lys-Quencher is obtained from Invitrogen, Carlsbad, CA, USA.
  • the cathepsin D peptide substrate of the sequence DABCYL-Pro-Thr-Glu-Phe-Phe- Arg-Leu-OXL, the plasmepsin peptide substrate of the sequence DABCYL-GI u-Arg- Nle-Phe-Leu-Ser-Phe-Pro-OXL and the HIV protease peptide substrate of the sequence DABCYL-His-Lys-Ala-Arg-Val-Leu-Tyr-Glu-Ala-Nle-Ser-EDANS are all obtained from AnaSpec Inc, San Jose, CA, USA.
  • the recombinantly expressed enzyme preparations are added in various amounts to the assay systems eg the beta-sectrase concentration is 1 unit/ml incubation volume, the cathepsin D concentration is 100 ng/ml, the HIV protease concentration is 500 ng/ml and the plasmepsin Il concentration is 50 ng/ml.
  • the reaction is started upon addition of the enzyme solution. The incubation occurs at 37°C over 30-120 min ie specifically the beta-secretase incubation lasts 60 min, the cathepsin D incubation 120 min, the plasmepsin Il incubation 40 min and the HIV protease incubation 40 min.
  • the reactions are stopped by the addition of 20 ⁇ l of a 1.0 M Tris Base solution.
  • the enzymatic substrate to product conversion is assessed by fluorescence measurements at 460 nm wave length.
  • the compounds of the present invention reveal structure-dependent and enzyme- specific inhibitory activities.
  • the inhibitory activities are measured as IC50 values.
  • the beta-secretase inhibitory activity ranges between 1 pM and 1 mM; the values for cathepsin D range between 1 pM and 1 mM, for plasmepsin Il between 1 pM and 1 mM and for HIV-protease between 1 pM and 1 mM.
  • the compounds of the formula (I) or preferred formula (IA) and the pharmaceutically usable salts thereof may find use as medicines, for example in the form of pharmaceutical preparations.
  • the pharmaceutical preparations may be administered enterally, such as orally, for example in the form of tablets, coated tablets, sugar- coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions, nasally, for example in the form of nasal sprays, rectally, for example in the form of suppositories, or transdermally, for example in the form of ointments or patches.
  • the administration may also be parenteral, such as intramuscular or intravenous, for example in the form of injection solutions.
  • the compounds of the formula (I) and pharmaceutically usable salts thereof may be processed with pharmaceutically inert, inorganic or organic excipients.
  • excipients used for example for tablets, coated tablets and hard gelatine capsules, may be lactose, corn starch, or derivatives thereof, talc, stearic acid or salts thereof etc.
  • Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols, etc.
  • Suitable excipients for preparing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.
  • Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, bile acids, lecithin, etc.
  • Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.
  • the pharmaceutical preparations may additionally also comprise preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavourings, salts for altering the osmotic pressure, buffers, coatings or antioxidants. They may also comprise other therapeutically valuable substances.
  • Subject of the present invention is also the use of the compounds of formula (I) and (IA), respectively, and their pharmaceutically usable salts for the prevention, delay of progression or the treatment of Alzheimer Disease, malaria or HIV infection.
  • Subject of the present invention is also the use of the compounds of formula (I) and (IA), respectively, and their pharmaceutically usable salts for the manufacture of a medication for the prevention, delay of progression or the treatment of Alzheimer Disease, malaria or HIV infection.
  • Subject of the present invention is also the method for the prevention, delay of progression or the treatment of Alzheimer Disease, malaria or HIV infection, whereby a therapeutically effective dose of a compound of the general formula (I) or preferred formula (IA) or a pharmaceutically usable salt thereof is applied.
  • Subject of the present invention is also a pharmaceutical preparation that contains for the inhibition of beta-secretase, cathepsin D, plasmepsin and/or HIV-protease a compound of the general formula (I), or preferred of formula (IA) or a pharmaceutically usable salt thereof as well as commonly used ingredients.
  • Subject of the present invention is also a pharmaceutical preparation for the prevention, delay of progression or treatment of Alzheimer Disease, malaria and HIV infection that contains a compound of the general formula (I), or preferred of formula (IA) or a pharmaceutically usable salt thereof as well as commonly used ingredients.
  • the dose may vary within wide limits and has of course to be adapted to the individual circumstances in each individual case.
  • N- ⁇ (R(or S))-2-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)pipehdin-2-yl]-1- methylethyl ⁇ -2,2-dimethylpropionamide is reacted.
  • the title compound is identified based on the Rf value.
  • the starting materials are prepared as follows: a) N-UR(Or S))-2-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin- 6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-1 -methylethyl)-2,2-dimethyl- propionamide
  • reaction mixture is cooled to room temperature, diluted with tert-butyl methyl ether, filtered through a small amount of silica gel and concentrated by evaporation.
  • the title compound is identified from the residue based on the Rf value by means of flash chromatography (SiO2 60F).
  • the starting materials are prepared as follows: a) 6-r(3R,6S)-6-r2-(2-Methoxyethoxy)-2-methylpropyl1-1 -(toluene-4- sulphonyl)piperidin-3-yloxymethyl1-4-(3-methoxypropyl)-3,4-dihvdro-2H- benzoH ,41oxazine
  • reaction mixture is then admixed with 8.02 mmol of 1 -chloro-2-methoxyethane and 0.11 mmol of tetrabutylammonium iodide and heated to 90 0 C. After 19 hours, the reaction mixture is cooled to room temperature, admixed cautiously with water and extracted with ethyl acetate (2X) - the combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value.
  • reaction mixture is poured onto ice-water, acidified to pH 2.5 with 1 N potassium bisulphate solution and extracted with diethyl ether (2X).
  • the combined organic phases are washed successively with water and 5% sodium hydrogencarbonate solution, dried over sodium sulphate and concentrated by evaporation.
  • the title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value.
  • the title compound is identified based on the Rf value.
  • the starting material is prepared as follows: a) 2-r5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzori ,41oxazin-6-ylnnethoxy1-1 -
  • the starting materials are prepared as follows: a) 3-r(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzo ⁇ ,41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2,2-dimethyl-N- (tetrahvdropyran-4-yl)propionamide
  • reaction mixture is cooled to room temperature and partitioned between ethyl acetate and 4N HCI.
  • the aqueous phase is extracted with ethyl acetate (2X)
  • HMPA hexamethylphosphoramide
  • 6-[(3R,6S)-6-bromomethyl-1 -(toluene-4-sulphonyl)piperidin- 3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1 ,4]oxazine in 2.5 ml of tetrahydrofuran are added dropwise.
  • the reaction mixture is stirred further at -78°C for 30 minutes, at -10 0 C for 30 minutes and at 0 0 C for 3 hours.
  • reaction mixture is quenched at -10 0 C with 1 M HCI until a weakly acidic reaction and then extracted with ethyl acetate (3X).
  • the combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation.
  • the title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a brown oil.
  • the starting materials are prepared as follows: a) 6-Bromomethylspiro[4-(3-methoxypropyl)-4H-benzo[1 ,41oxazin-2,4'- (tetrahydropyran)1-3-one
  • the starting material is prepared as follows: a) [9-(3-Methoxypropyl)-9H-carbazol-2-vHmethanol
  • the starting materials are prepared as follows: a) 3-r(2S,5R)-5-r2-(4-Methoxybutyl)-6-methylpyridin-4-ylmethoxy1-1 -(toluene-4- sulphonyl)piperidin-2-yl1-2,2-dimethyl-N-(tetrahvdropyran-4- yl methyl )propionamide
  • 3-[(2S,5R)-5-[2-(4-methoxybutyl)-6-nnethylpyridin-4- ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2,2-dinnethylpropionic acid and C-(tetrahydropyran-4-yl)methylannine are reacted.
  • the title compound is identified based on the Rf value.
  • Example 17c Analogously to Example 17c (alternative synthesis), 4-[(3R,6S)-6-bromomethyl-1 - (toluene-4-sulphonyl)piperidin-3-yloxymethyl]-2-(4-methoxybutyl)-6-methylpyhdine and methyl isobutyrate are reacted.
  • the title compound is identified based on the Rf value.
  • the title compound is identified based on the Rf value.
  • the starting materials are prepared as follows: a) 1 -Bromo-3-(4-methoxybutyl)-5-methylbenzene
  • the starting material is prepared as follows: a) [4-(3-Methoxypropyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,41oxazin-6-yl1methanol Analogously to Method F, 6-hydroxymethyl-4-(3-methoxypropyl)-2,2-dimethyl-4H- benzo[1 ,4]oxazin-3-one [857281 -72-2] is reacted. The title compound is identified based on the Rf value.
  • the starting materials are prepared as follows: a) 3-r(2S,5R)-5-[4-(3-Methoxypropyl)-2-methyl-2-phenyl-3,4-dihvdro-2H- benzo[1 ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2,2- dimethyl-N-(tetrahvdropyran-4-ylmethyl)propionamide
  • the starting material is prepared as follows: a) Methyl (S)-2-(3-chlorophenyl)-2-hvdroxypropionate
  • the reaction mixture is admixed with 0.40 mmol of methyl (3-chloro- phenyl)oxoacetate [34966-50-2] and then admixed slowly (over 30 hours) with 0.96 mmol of dimethylzinc (1 M in hexane). 12 hours later, the reaction mixture is quenched with 10% aqueous citric acid solution and extracted with ethyl acetate (3X) - the combined organic phases are dried with sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value.
  • the starting materials are prepared as follows: a) (R(or S))-3-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2-methyl-N-(tetrahvdropyran-4- ylmethvDpropionamide
  • the starting materials are prepared as follows: a) (S(or R))-3-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2-methyl-N-(tetrahvdropyran-4- ylmethvDpropionamide
  • the reaction mixture is extracted with dichloromethane (3X), dried over sodium sulphate and concentrated to afford the title compound as a light brown oil.
  • reaction mixture is stirred at -78°C for 1 hour, then at -40 0 C for 18 hours. It is quenched at -40 0 C with saturated aqueous ammonium chloride. Once at room temperature, it is partitioned between dichloromethane and saturated aqueous ammonium chloride. The aqueous phase is re-extracted with dichloromethane (3X). The combined organic extracts are dried over sodium sulphate, concentrated and purified by flash chromatography (SiO2 60F) to afford the title compound as a white solid.
  • Example 53d Starting from methyl 3-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]propionate (Example 53d) using ethyl iodide instead of methyl iodide (in the step analogously to Example 53c).
  • the starting materials are prepared as follows: a) 1 -(2-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxyi-1 -(toluene-4-sulphonyl)piperidin-2-yl1-1 ,1 -dimethylethyl)-3-(tetrahvdro- Pyran-4-yl)urea
  • the reaction mixture is stirred at 0 0 C for one hour and then a solution of 7.96 mmol of sodium azide in 2 ml of water is added at 0 0 C.
  • the reaction solution is stirred at 0 0 C for 45 minutes.
  • the mixture is diluted with water and ethyl acetate - the aqueous phase is washed with water (2X), dried with sodium sulphate and concentrated by evaporation.
  • the residue is taken up in 2 ml of toluene and heated to 115°C for 2 hours.
  • the reaction mixture is cooled to room temperature and concentrated by evaporation.
  • the crude title compound is obtained from the residue.
  • the starting materials are prepared as follows: a) 4-f(2S.5R)-5-f4-(3-Methoxypropyl)-3.4-dihvdrO-2H-benzof1.41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-3,3-dimethyl-1 - (tetrahvdropyran-4-ylamino)butan-2-one
  • a solution of 0.6 mmol of tetrahydropyran-4-ylamine in 5 ml of diethyl ether at room temperature is admixed with a solution of 0.2 mmol of 1 -chloro-4-[(2S,5R)-5-[4-(3- methoxypropyl)-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4- sulphonyl)piperidin-2-yl]-3,3-dimethylbutan-2-one in 5 ml of diethyl ether.
  • the starting materials are prepared as follows: a) N- ⁇ 2-r(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzo ⁇ ,41oxazin-6- ylmethoxyi-1 -(toluene-4-sulphonyl)piperidin-2-yl1-1 ,1 -dimethylethyl)-2-(tetrahvdro- pyran-4-yl)acetamide A solution of 0.511 mmol of tetrahydropyranyl-4-acetic acid [85064-61-5] in 5 ml of dichloromethane is treated with 1.023 mmol of 1 -chloro-N,N-2-thmethylpropenyl- amine.
  • the starting materials are prepared as follows: a) N-UR(Or S))-1 -r(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzo ⁇ ,41oxazin- 6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-ylmethyl1-2-methylpropyl)-2- (tetrahydropyran-4-yl)acetamide
  • reaction mixture is stirred between -15°C and 0 0 C for 3 hours, then at room temperature for 1 hour. It is quenched with saturated aqueous ammonium chloride and extracted with dichloromethane (3X). The combined organic extracts are dried over sodium sulphate, concentrated and purified by flash chromatography (SiO2 60F) to afford the title compounds as colourless oils.
  • the starting materials are prepared as follows: a) N-US(Or R))-2-r(2S.5R)-5-r4-(3-methoxypropyl)-2.2-dimethyl-3.4-dihvdro-2H- benzoH ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-1 -methyl- ethyl)-2-(tetrahvdropyran-4-yl)acetamide
  • Example 1f The title compound is prepared in analogy to the synthesis of Example 1f, starting from 6-chloromethyl-4-(3-methoxypropyl)-2,2-dimethyl-4H-benzo[1 ,4]oxazin-3-one [857281-71 -1].
  • the starting materials are prepared as follows: a) 4-(3-Methoxy-propyl)-2,2-dimethyl-6-r(3R,6S)-6-(2-methyl-2-ri ,2,41triazol-4-yl- propyl)-1 -(toluene-4-sulfonyl)-piperidin-3-yloxymethyl1-3,4-dihvdro-2H- benzoH ,41oxazine
  • the title compound is identified based on the Rf value.
  • Example 105 In analogy to the synthesis of Example 105, the following compound is prepared:
  • the starting materials are prepared as follows: a) (i) 3-r(2S,5R)-5-r4-(3-Methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-yl1-2,2- dimethyl-N-r(S)-1-(tetrahvdro-pyran-4-yl)-ethyl1-propionamide and (ii) 3-r(2S,5R)-5-r4-(3-Methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-yl1-2,2- dimethyl-N-r(R)-1 -(
  • the title compound is identified based on the Rf value.
  • the starting materials are prepared as follows: a) 3-r(2S,5R)-5-r4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-yl1-2,2-dinnethyl- N-((3R,4S)-3-methyl-tetrahvdro-pyran-4-ylmethyl)-propionannide
  • Example 17a 3-[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2- dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)- piperidin-2-yl]-2,2-dimethyl-propionic acid (Example 107b) and C-((3R,4S)-3-methyl- tetrahydro-pyran-4-yl)-methylamine are reacted.
  • the title compound is identified based on the Rf value.
  • the starting materials are prepared as follows: a) 3-r(2S,5R)-5-r4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-yl1-N-((3R,4R)- 3-methoxy-tetrahvdro-pyran-4-ylmethyl)-2,2-dimethyl-propionamide
  • Example 17a 3-[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2- dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)- piperidin-2-yl]-2,2-dimethyl-propionic acid (Example 107b) and C-((3R,4R)-3- methoxy-tetrahydro-pyran-4-yl)-methylamine are reacted.
  • the title compound is identified based on the Rf value.
  • Example 108b Following the procedure for Example 108b, 108c, 108d, 108e and 108f, the title compound is obtained from cis-3-methoxy-tetrahydro-pyran-4-carbonitrile. The title compound is identified based on the Rf value.
  • the starting materials are prepared as follows: a) 1 -r(2S,5R)-5-r4-(3-Methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-ylmethyl1- cvclopropanecarboxylic acid (tetrahvdro-pyran-4-ylmethyl)-amide
  • reaction mixture is stirred at -78°C for 4 hours before the addition of a solution of 6.00 mmol of 6-[(3R,6S)-6-bromomethyl-1 -(toluene-4-sulfonyl)-piperidin-3- yloxymethyl]-4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazine in 10 ml of tetrahydrofuran.
  • the reaction is stirred at -78°C for 1 hour, then allowed to warm to room temperature over 4 hours, and quenched with saturated aqueous ammonium chloride solution.
  • Example 40a Following the proceedure for Example 17d, starting with [4-(3-methoxy-propyl)-2,2- dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-yl]-methanol (Example 40a).
  • N-(4-methoxy-cyclohexylmethyl)-3-[(2S,5R)-5-[4-(3-methoxy- propyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4- sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionamide is reacted.
  • the title compound is identified based on the Rf value.
  • the starting materials are prepared as follows: a) N-(4-methoxy-cvclohexylmethyl)-3-r(2S,5R)-5-r4-(3-methoxy-propyl)-2,2- dimethyl-3,4-dihvdro-2H-benzon ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)- piperidin-2-yl1-2,2-dimethyl-propionamide
  • Example 17a 3-[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2- dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)- piperidin-2-yl]-2,2-dimethyl-propionic acid (Example 107b) and C-(4-methoxy- cyclohexyl)-methylamine are reacted.
  • the title compound is identified based on the Rf value.
  • Example 108b and 108c Following the procedure for Example 108b and 108c, the title compound is obtained from 4-methoxy-cyclohexanecarboxylic acid [73873-59-3]. The title compound is identified based on the Rf value.

Abstract

Use of compounds of the general formula (I) and pharmaceutically acceptable salt thereof, in which R, R1 and X have the definitions illustrated in detail in the description, as beta-secretase, cathepsin D, plasmepsin Il and/or HIV protease inhibitors.

Description

Substituted piperidines as therapeutic compounds
Field of the Invention
The present invention relates to the use of substituted piperidines as beta-secretase-, cathepsin D-, plasmepsin II- and/or HIV-protease-inhibitors.
Background of the Invention
With regard to beta-secretase-, cathepsin D-, plasmepsin II- and/or HlV-protease- inhibition, there is still a need for highly potent active ingredients. In this context, the improvement of the pharmacokinetic properties is at the forefront. These properties directed towards better bioavailability are, for example, absorption, metabolic stability, solubility or lipophilicity.
Alzheimer Disease aspartyl protease: Beta-Secretase
Alzheimer's disease (AD) is a progressive degenerative disease of the brain. The symptoms of AD include progressive memory loss, language difficulty and ultimately loss of basic neural function and death. The biomarkers in the central nervous system for AD include amyloid plaques, intracellular neurofibrillary tangles and activated microglia. The appearance of these three markers is likely to contribute to the neuronal cell death and memory loss observed in AD.
Beta-amyloid is a defining feature of AD and now believed to be a causative precursor in the development of the disease. Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amloidosis of the Dutch-Type (HCHWA-D) and other neurodegenerative disorders.
Beta-amyloid plaques are predominantly composed of amyloid beta peptide (A-beta, also sometimes designated betaA4). The A-beta peptide is derived by proteolysis of the beta amyloid precursor protein (APP). Beta-APP is processed by three distinct ordered enzymatic activities. The bulk of beta-APP is processed via alpha-secretase in a non-amyloidogenic pathway. A small fraction of beta-APP is cleaved by beta- secretase activity to generate the membrane-bound C-terminal fragment C99. Gamma-secretase cleaves C99 to generate the amyloidogenic A-beta peptide of 39-42 amino acids. The aspartyl protease activity of beta-secretase has been disclosed using varied nomenclature, including BACE (beta-site APP cleaving enzyme), Asp and memapsin.
The significance of beta-secretase cleavage of beta-APP as a critical step in the generation of AD is underscored by the observation that human mutations at the beta-secretase cleavage subsites (Swedish mutations) of beta-APP lead to increased A-beta production and early onset familial AD. Furthermore, BACE1 - knockout mice fail to produce A-beta peptide and present a normal phenotype. When crossed with transgenic mice that overexpress APP, the progeny show reduced amounts of A-beta in brain extracts as compared with control animals. This evidence supports the proposal that inhibition of beta-secretase activity and reduction of A-beta peptide deposits in the brain provides a therapeutic strategy for the treatment of AD and other beta amyloid disorders as described by Verdile et al. (2004) in Pharmacol. Res 50, 397-409.
Compounds that are effective inhibitors of beta-secretase may inhibit beta-secretase- mediated cleavage of APP and the production of A-beta peptide. The pharmacological inhibition of A-beta peptide generation may reduce amyloid beta deposits, respectively the formation of plaques. Beta-secretase inhibiting compounds as discussed by Thompson et al. (2005) in Curr. Pharm. Des. 11 , 3383-3404 are therefore useful to treat or to prevent diseases that are characterized by amyloid beta deposits or plaques such as AD.
The present invention also relates to methods of treating subjects who have, or in preventing subjects from developing a disease or condition selected from the group consisting of AD, for helping prevent or delay the onset of AD, for helping to slow the proression of AD, for treating subjects with mild cognitive impairment (MCI) and preventing or delaying the onset of AD in those who could progress form MCI to AD, for treating Down's syndrome, for treating humans who have HCHWAD, for treating cerebral amyloid angiopathy, and for treating degenerative dementias Alzheimer's Disease aspartyl protease: Cathepsin D
Human cathepsin D is an intracellular aspartic peptidase found mainly in lysosomes. It has a number of housekeeping functions, including the degradation of cellular and phagocytosed proteins. The enzymes may be involved in a variety of disease states, including cancer and Alzheimer's disease (AD). Clinical studies have shown that cathepsin D is overexpressed in breast cancer cells and this seems to be associated with an increased risk for metastasis due to enhanced cell growth. Cathepisn D is also thought to be involved in formation of the beta-amyloid peptide in AD. Recently, several genetic association studies linked cathepsin D with amyloid pathology and Alzheimer's disease as described for example by Davidson et al., (2006) in J. Neurol. Neurosurg. Psychiatry 77, 515-517. The availability of selective and potent inhibitors will help to further define the role of cathepsin D in disease and possibly lead to therapeutic agents.
Malaria Aspartyl Protease: Plasmepsin I and Il
Malaria is considered as one of the most serious infectious diseases in the world, affecting approximately 500 million people. The disease is spread by the anopheles mosquito that is mostly found in tropical regions. The species Plasmodium falciparum is responsible for more than 95% of malaria-related morbidity and mortality. Increasingly, Plasmodium falciparum is becoming resistant to existing therapies such as chloroquine, mefloquine and sulfadoxime/ pyrimethamine. Thus there is an urgent need for new treatments.
In the erythrocytic stage of the parasite's life cycle the parasite invades the red blood cells of its host consuming up to 80% of the hemoglobin as a source of nutrients for growth and development. Hemoglobin degradation takes place in an acidic vacuole of the parasite and many of the current antimalarial drugs appear to disrupt important vacuolar functions. The food vacuole contains aspartic, cysteine and metallo- proteases, which are all considered to play a role in the process of hemoglobin degradation. At least 10 genes encoding aspartic proteases have been identified in the Plasmodium genome. Four of the aspartic proteases have been localized in the - A -
acidic food vacuole of the parasite, namely plasmepsin I, II, IV and HAP, a histo- aspartic protease. Inhibitors of plasmepsin I and Il have shown efficacy in cell and animal models of malaria, indicating that these enzymes may represent targets for drug discovery as described for example by Coombs et al. (2001 ) Trends Parasitol 17, 532-537. Indeed, a non-selective inhibitor of aspartic proteases, pepstatin, inhibits the growth of Plasmodium falciparum in vitro. Similar results have been obtained with analogs of pepstatin or with immunodeficiency virus protease inhibitors indicating that inhibition of aspartic proteases interferes with the life cycle of Plasmodium falciparum as noted for example by Andrews et al. (2006) in Antimicrob. Agents Chemother 50, 639-648.
The present invention relates to the identification of low molecular weight, non- peptidic inhibitors of the Plasmodium falciparum protease plasmepsin Il or other related aspartic proteases to treat and/or to prevent malaria.
HIV aspartyl protease: HIV-1 peptidase
First reported in 1981 in a small number of patients, Acquired immunodeficiency syndrome (AIDS) has now become a major epidemic with more than 38 million people infected worldwide, including approximately 1 million in the United States, 580,000 in Western Europe and more than 25 million in Sub-Saharan Africa (http://www.unaids.org). Since AIDS was first clinically identified, scientific and therapeutic progress has been extraordinary. However, AIDS remains out of control, especially in developing countries.
The prognosis of AIDS patients who have full access to current therapies has completely changed since the first cases of AIDS were reported. Today, the median survival for HIV-positive patients receiving treatment exceeds 8 years. The life expectancy for AIDS patients was less than 1 year before AZT was introduced in 1987. This dramatic change is due to the development of effective therapies, to early detection of HIV-positive individuals, and to a sustained effort to analyze and understand viral-resistance mechanisms, which can be overcome by rational drug development and combination therapy. FDA-approved therapies target three steps of the HIV life cycle: reverse transcription, proteolytic maturation and fusion. Triple therapy, commonly referred to as HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART), is now the standard for treatment. It consists of a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor in combination with two nucleoside reverse transcriptase inhibitors.
Translation of human immunodeficiency virus type-1 (HIV-1 ) genomic RNA results in the production of two polyprotein precursors, Gag and Gag-Pol. The 55-kDa Gag precursor contains the structural proteins and the 160-kDa Gag-Pol polyprotein contains the functional viral enzymes protease, reverse transcriptase, and integrase. Gag and Gag-Pol polyproteins are transported to the plasma membrane where assembly of type-C retroviruses and lentiviruses typically occurs. During particle assembly, the viral protease cleaves the Gag and Gag-Pol precursors into the structural and functional proteins required for viral replication. The protease activity within the cytoplasma of infected cells allows for the formation of virions which can be released from the cell in the last stages of budding.
The mature HIV-1 protease is an obligatory dimer of identical 11 -kDa subunits, each contributing one of the two catalytic aspartic residues. In contrast, the cell-derived members of the aspartic protease family are monomehc enzymes with two Asp-Thr- Gly-containing domains. The unique dimeric structure of the retroviral protease is mainly stabilized by an antiparallel beta-sheet formed by the interdigitation of the amino- and carboxyl-terminal beta-strands of each monomer.
The activation of HIV-1 protease i.e. the dimerization and autocatalytic release from Gag-Pol, is a critical step in the viral life cycle. Inhibition of protease activation causes a severe defect in Gag polyprotein processing and a complete loss of viral infectivity. As such, the viral protease has become a target for HIV therapeutics, resulting in many HIV protease inhibitors reaching clinical trials as reviewed by Rana et al. (1999) in Pharmacotherapy 19, 35-59 and Morse et al., (2006) in Lancet Infect. Dis. 6, 215-225. Most of these drugs are substrate-based inhibitors, whose design has been facilitated by an abundance of crystal structure data for both the native enzyme and enzyme- inhibitor complexes. Additionally, there are now extensive biochemical data detailing both the catalytic mechanism and the molecular basis for substrate selection. Detailed Description of the Invention
Firstly, the present invention relates to compounds of the general formula
Figure imgf000007_0001
(I) for the inhibition of beta-secretase, cathepsin D, plasmepsin Il and/or HIV-protease, in which
R is C2-8-alkenyl, C2-8-alkynyl, Ci-s-alkyl, Co-8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8- alkyl, optionally N-mono- or N,N-di-Ci-8-alkylated or -arylated amino-Ci-s-alkyl, optionally O-Ci-s-alkylated carboxyl-Co-8-alkyl, Cs-s-cycloalkyl-Ci-s-alkyl, optionally N-mono- or N,N-di-C3-8-cycloalkyl-Co-8-alkylated or optionally N-mono- or N,N-di- heterocyclyl-Co-8-alkylated carbamoyl-Co-s-alkyl, C3-8-cycloalkyl-C0-8-alkylcarbonyl- (N-C0-8-alkyl)amino-Ci-8-alkyl, arylcarbonyl^N-Co-s-alky^amino-Ci-s-alkyl, optionally N-mono- or N,N-di-Ci-8-alkylated or -arylated sulphamoyl-Co-β-alkyl, Ci-8-alkyl- sulphonyl-Co-8-alkyl or heterocyclylcarbonyl-Co-s-alkyl, each of which is either unsub- stituted or substituted by 1-4 Ci-8-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy , Ci-8-alkoxy- carbonyl-(N-Ci-8-alkyl)amino, Ci-s-alkyl, Ci-s-alkylcarbonyl, Co-s-alkylcarbonyl-(N-Co-s- alkyl)amino, Ci-s-alkylsulphanyl, Ci-s-alkylsulphinyl, Ci-s-alkylsulphonyl, aryl-Co-β- alkoxy, aryl, arylamino, aryl-Co-β-alkylsulphonyl, cyano, Cs-s-cycloalkoxy, halogen, heterocyclyl, heterocyclyl-Co-β-alkoxy, heterocyclyl-Co-β-alkylamino, heterocyclyl- carbonyl, hydroxyl, phosphonyl, optionally N-mono- or N,N-di-Ci-8-alkylated amino, optionally N-mono- or N,N-di-Ci-8-alkylated carbamoyloxy, optionally N-mono- or N,N-di-Ci-8-alkylated sulphamoyl, optionally N-mono-, -di- or -tri-Ci-8-alkylated or heterocyclyl-substituted ureido, optionally N-mono- or N,N-di-Ci-8-alkylated, N-mono- or N,N-di-arylated or N-mono- or N.N-di-heterocyclyl-Co-β-alkylated amino-Co-8- alkylcarbonyl, oxo or trifluoromethyl;
R1 is aryl or heterocyclyl, each of which is substituted by 1-4 acyl-Ci-8-alkoxy-Ci-8- alkoxy, acyl-Ci-s-alkoxy-Ci-s-alkyl, (N-acyO-Ci-s-alkoxy-Ci-s-alkylamino, Ci-8-alkanoyl, Ci-8-alkoxy, Ci-s-alkoxy-Ci-s-alkanoyl, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s- alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, (N-Ci-s-alkoxyJ-Ci-s-alkylaminocarbonyl-Ci-s- alkoxy, (N-Ci-s-alkoxyJ-Ci-s-alkylaminocarbonyl-Ci-s-alkyl, Ci-8-alkoxy-Ci-8-alkyl- carbamoyl, Ci-s-alkoxy-Ci-s-alkylcarbonyl, Ci-s-alkoxy-Ci-s-alkylcarbonylamino, 1 -Ci-s-alkoxy-Ci-s-alkylheterocyclyl, Ci-s-alkoxyaminocarbonyl-Ci-s-alkoxy, Ci-S- alkoxyanninocarbonyl-Ci-8-alkyl, Ci-s-alkoxycarbonyl, Ci-s-alkoxycarbonyl-Ci-s-alkoxy, Ci-s-alkoxycarbonyl-Ci-s-alkyl, Ci-s-alkoxycarbonylannino-Ci-s-alkoxy, Ci-s-alkoxy- carbonylannino-Ci-8-alkyl, Ci-8-alkyl, (N-Ci-s-alkyO-Ci-s-alkoxy-Ci-s-alkylcarbamoyl, (N-Ci-s-alkyO-Ci-s-alkoxy-Ci-s-alkylcarbonylannino, (N-Ci-8-alkyl)-Ci-8-alkoxycarbonyl- amino, (N-Ci-s-alkyO-Ci-s-alkylcarbonylamino-Ci-s-alkoxy, (N-Ci-8-alkyl)-Ci-8-alkyl- carbonylannino-Ci-8-alkyl, (N-Ci-s-alkyO-Ci-s-alkylsulphonylannino-Ci-s-alkoxy, (N-Ci-8- alkyl)-Ci-8-alkylsulphonylamino-Ci-8-alkyl, Ci-s-alkylannidinyl, Ci-s-alkylamino-Ci-s- alkoxy, di-Ci-s-alkylannino-Ci-s-alkoxy, Ci-s-alkylannino-Ci-s-alkyl, di-Ci-s-alkylannino- Ci-s-alkyl, Ci-s-alkylanninocarbonyl-Ci-s-alkoxy, di-Ci-s-alkylaminocarbonyl-Ci-s- alkoxy, Ci-s-alkylaminocarbonyl-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkylaminocarbonyl-Ci-s- alkyl, di-Ci-s-alkylanninocarbonyl-Ci-s-alkyl, Ci-s-alkylaminocarbonylannino-Ci-s- alkoxy, Ci-s-alkylaminocarbonylamino-Ci-s-alkyl, Ci-s-alkylcarbonylannino, Ci-S- alkylcarbonylannino-Ci-8-alkoxy, Ci-s-alkylcarbonylamino-Ci-s-alkyl, Ci-s-alkyl- carbonyloxy-Ci-s-alkoxy, Ci-s-alkylcarbonyloxy-Ci-s-alkyl, Ci-8-alkylsulphonyl, Ci-8- alkylsulphonyl-Ci-s-alkoxy, Ci-s-alkylsulphonyl-Ci-s-alkyl, Ci-s-alkylsulphonylamino- Ci-s-alkoxy, Ci-s-alkylsulphonylamino-Ci-s-alkyl, optionally N-mono- or N,N-di-Ci-8- alkylated amino, aryl-Co-8-alkoxy, aryl-Co-8-alkyl, optionally N-mono- or N,N-di-Ci-8- alkylated carbamoyl-Co-8-alkoxy, optionally N-mono- or N,N-di-Ci-8-alkylated carbamoyl-Co-8-alkyl, carboxy-Ci-8-alkoxy, carboxy-Ci-s-alkoxy-Ci-s-alkyl, carboxy- Ci-s-alkyl, cyano, cyano-Ci-8-alkoxy, cyano-Ci-8-alkyl, Cs-s-cycloalkyl-Ci-s-alkoxy, Cs-s-cycloalkyl-Ci-s-alkyl, C3-8-cycloalkylcarbonylamino-Ci-8-alkoxy, C3-8-cycloalkyl- carbonylamino-Ci-s-alkyl, CN-dimethylhydroxylamino-Ci-s-alkyl, halogen, halogen- Ci-s-alkoxy, halogen-Ci-s-alkyl, halogen-aryl, heterocyclyl-Co-8-alkoxy, heterocyclyl- Co-8-alkyl, heterocyclylcarbonyl, hydroxy-Ci-s-alkoxy-Ci-s-alkoxy, hydroxy-Ci-s-alkoxy- Ci-s-alkyl, hydroxy-Ci-s-alkyl, O-methyloximyl-Ci-s-alkyl, oxide or oxo; where, when R1 is heterocyclyl and contains at least one saturated carbon atom, this heterocyclyl radical may additionally be substituted at a saturated carbon atom by a C2-8-alkylene chain whose two ends are fixed on this saturated carbon atom and thus form a spirocycle, where one CH2 group of the alkylene chain may be replaced by oxygen;
X is -AIk-, -0-AIk-, -AIk-O-, -0-AIk-O-, -S-AIk-, -AIk-S-, -AIk-NR2-, -NR2-Alk-, -C(O)-NR2-, -AIk-C(O)-NR2-, -C(O)-N R2-Alk-, -Alk-C(O)-NR2-Alk-, -NR2-C(O)-, -Alk-NR2-C(O)-, -NR2-C(O)-Alk-, -Alk-NR2-C(O)-Alk-, -0-AIk-C(O)-NR2-, -O-Alk-NR2-C(O)-, -S(O)2-NR2-, -AIk-S(O)2-NR2-, -S(O)2-N R2-Alk-, -Alk-S(O)2-NR2-Alk-, -NR2-S(O)2-, -Alk-NR2-S(O)2-, -NR2-S(O)2-Alk- or -Alk-NR2-S(O)2-Alk-, where AIk is Ci-8-alkylene which may optionally be substituted by halogen; and where
R2 is hydrogen, Ci-8-alkyl, Ci-s-alkoxy-Ci-s-alkyl, acyl or aryl-Ci-8-alkyl; and their pharmaceutically usable salts, prodrugs or compounds, in which one or more atoms have been replaced by their stable, non-radioactive isotopes.
The linkage of the above (and hereinafter) mentioned substituent -X- within the compound of the formula (I) starts from the piperidine ring with the substituent -X- being arranged from left to right when written as indicated above. For example, the fragment "-X-R1" of the compound of the formula (I) with X meaning "-NR2-S(O)2-" is: "-NR2-S(O)2-R1".
The meaning of "Co-alkyl" in the above (and hereinafter) mentioned Co-8-alkyl groups is a bond or, if located at a terminal position, a hydrogen atom.
The meaning of "Co-alkoxy" in the above (and hereinafter) mentioned Co-8-alkoxy groups is "-O-" or, if located at a terminal position, an -OH group.
Examples of Ci-8-alkyl and -alkoxy radicals are, respectively, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. Ci-s-Alkylene- dioxy radicals are preferably methylenedioxy, ethylenedioxy and propylenedioxy. Examples of Ci-s-alkanoyl radicals are acetyl, propionyl and butyryl. Cycloalkyl is a saturated cyclic hydrocarbon radical having 3-12 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, cyclooctyl, bicyclo[2.2.2]octyl and adamantyl, which may be mono- or polysubstituted. Examples of substituents on such cycloalkyl radicals are Ci-8-alkoxy, Ci-8-alkyl, Ci-8-alkyl- carbonyloxy, carbamoyl, carboxyl, cyano, halogen, hydroxyl, oxo, trifluoromethoxy or trifluoromethyl. Ci-s-Alkylene radicals may be linear or branched and are, for example, methylene, ethylene, propylene, 2-methylpropylene, 2-methylbutylene, 2-methylpropyl-2-ene, butyl-2-ene, butyl-3-ene, propyl-2-ene, tetra-, penta- and hexamethylene; C2-8-alkenylene radicals are, for example, vinylene and propenylene; an example of a C2-8-alkynylene radical is ethynylene; acyl radicals are alkanoyl radicals, preferably Ci-8-alkanoyl radicals, or aroyl radicals such as benzoyl.
Aryl denotes mono- or polycyclic aromatic radicals which may be mono- or polysub- stituted, for example phenyl, substituted phenyl, naphthyl or substituted naphthyl. Examples of substituents on such aryl radicals are Ci-s-alkyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C2-8-alkenyl, Ci-s-alkylsulphinyl, Ci-s-alkoxy, Ci-S- alkylcarbonyloxy, hydroxyl, halogen, cyano, carbamoyl, carboxyl and Ci-s-alkylene- dioxy, and also optionally halogen-, Ci-8-alkyl-, Ci-8-alkoxy- or dihydroxy-Ci-8-alkyl- aminocarbonyl-substituted phenyl, phenoxy, phenylthio, phenyl-Ci-s-alkyl or phenyl- Ci-s-alkoxy. Further examples of substituents on aryl or heterocyclyl radicals are oxide, oxo, Ci-s-alkoxycarbonylphenyl, hydroxy-Ci-8-alkylphenyl, benzyloxy, pyridyl- carbonylamino-Ci-s-alkyl, C2-8-alkenyloxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s- alkoxy-Ci-s-alkyl, hydroxy-Ci-s-alkoxy, di-Ci-s-alkylamino, 2,3-dihydroxypropoxy, 2,3-dihydroxypropoxy-Ci-s-alkoxy, 2,3-dimethoxypropoxy, methoxybenzyloxy, hydroxybenzyloxy, phenethyloxy, methylenedioxybenzyloxy, dioxolanyl-Ci-s-alkoxy, cyclopropyl-Ci-8-alkyl, cyclopropyl-Ci-s-alkoxy, hydroxy-Ci-8-alkoxy, carbamoyloxy- Ci-s-alkoxy, pyridylcarbamoyloxy-Ci-s-alkoxy, benzoyloxy-Ci-8-alkoxy, picolyloxy, Ci-8-alkoxycarbonyl, Co-s-alkylcarbonylamino, Co-s-alkylcarbonylamino-Ci-s-alkyl, C0-S- alkylcarbonylamino-Ci-s-alkoxy, (N-Ci-8-alkyl)-Co-8-alkylcarbonylamino-Ci-8-alkyl, (N-Ci-s-alkylJ-Ci-s-alkylcarbonylamino-Ci-s-alkoxy, Cs-s-cycloalkylcarbonylamino-Ci-s- alkyl, Cs-s-cycloalkylcarbonylamino-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkyl, hydroxy-Ci-s- alkyl, hydroxy-Ci-s-alkoxy-Ci-s-alkyl, hydroxy-Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy- carbonylamino-Ci-s-alkyl, Ci-s-alkoxycarbonylamino-Ci-s-alkoxy, Ci-s-alkylamino- carbonylamino-Ci-s-alkyl, Ci-s-alkylaminocarbonylamino-Ci-s-alkoxy, Ci-s-alkyl- aminocarbonyl-Ci-s-alkyl, Ci-s-alkylaminocarbonyl-Ci-s-alkoxy, Ci-s-alkylamino- carbonyl-Ci-s-alkoxy-Ci-s-alkyl, di-Ci-s-alkylaminocarbonyl-Ci-s-alkyl, di-Ci-8-alkyl- anninocarbonyl-Ci-8-alkoxy, Ci-s-alkylcarbonyloxy-Ci-s-alkyl, Ci-8-alkylcarbonyloxy- Ci-s-alkoxy, cyano-Ci-s-alkyl, cyano-Ci-s-alkoxy, 2-oxooxazolidinyl-Ci-8-alkyl, 2-oxo- oxazolidinyl-Ci-s-alkoxy, Ci-s-alkoxycarbonyl-Ci-s-alkyl, Ci-s-alkoxycarbonyl-Ci-s- alkoxy, Ci-s-alkylsulphonylannino-Ci-s-alkyl, Ci-s-alkylsulphonylamino-Ci-s-alkoxy, (N-Ci-s-alkylJ-Ci-s-alkylsulphonylamino-Ci-s-alkyl, (N-Ci-8-alkyl)-Ci-8-alkylsulphonyl- annino-Ci-8-alkoxy, annino-Ci-s-alkyl, annino-Ci-s-alkoxy, Ci-β-alkylamino-C-i-β-alkyl, Ci-s-alkylannino-Ci-s-alkoxy, di-Ci-β-alkylamino-Ci-β-alkyl, di-Ci-s-alkylamino-Ci-s- alkoxy, Ci-β-alkylsulphonyl-Ci-β-alkyI, Ci-s-alkylsulphonyl-Ci-s-alkoxy, carboxy-Ci-8- alkyl, carboxy-Ci-8-alkoxy, carboxy-Ci-β-alkoxy-Ci-β-alkyI, Ci-8-alkoxy-Ci-8-alkyl- carbonyl, acyl-Ci-β-alkoxy-Ci-β-alkyI, (N-Ci-s-alkylJ-Ci-s-alkoxycarbonylamino, (N-hydroxyJ-Ci-e-alkylaminocarbonyl-Ci-e-alkyl, (N-hydroxy)-Ci-8-alkylanninocarbonyl- Ci-s-alkoxy, (N-hydroxy)aminocarbonyl-Ci-8-alkyl, (N-hydroxy)aminocarbonyl-Ci-8- alkoxy, Ci-β-alkoxyaminocarbonyl-Ci-β-alkyl, Ci-s-alkoxyanninocarbonyl-Ci-s-alkoxy, (N-Ci-β-alkoxyJ-Ci-β-alkylaminocarbonyl-Ci-β-alkyl, (N-Ci-8-alkoxy)-Ci-8-alkylannino- carbonyl-Ci-s-alkoxy, (N-acylJ-Ci-β-alkoxy-Ci-β-alkylamino, Ci-8-alkoxy-Ci-8-alkyl- carbamoyl, (N-Ci-β-alkylJ-Ci-β-alkoxy-Ci-β-alkylcarbamoyl, Ci-8-alkoxy-Ci-8-alkyl- carbonyl, Ci-s-alkoxy-Ci-s-alkylcarbonylamino, (N-Ci-β-alkylJ-Ci-β-alkoxy-Ci-β-alkyl- carbonylamino, 1 -Ci-β-alkoxy-Ci-β-alkylimidazol^-yl, 1 -Ci-s-alkoxy-Ci-s-alkyltetrazol- 5-yl, δ-Ci-s-alkoxy-Ci-s-alkyltetrazol-i -yl, 2-Ci-8-alkoxy-Ci-8-alkyl-4-oxoinnidazol-1 -yl, carbamoyl-Ci-8-alkyl, carbannoyl-Ci-s-alkoxy, Ci-β-alkylcarbamoyl, di-Ci-β-alkyl- carbamoyl, Ci-β-alkylsulphonyl, Ci-β-alkylamidinyl, acetamidinyl-Ci-e-alkyl, O-methyl- oxi myl-Ci -8-al ky I , O.N-dimethylhydroxylamino-Ci-β-alkyl, C3-i2-cycloalkyl-Ci-8- alkanoyl, aryl-Ci-8-alkanoyl, heterocyclyl-Ci-e-alkanoyl; and optionally halogen-, Ci-8- alkyl-, Ci-8-alkoxy- or dihydroxy-Ci-s-alkylaminocarbonyl-substituted pyridyl, pyridyl- oxy, pyridylthio, pyridylamino, pyπdyl-Ci-8-alkyl, pyhdyl-Ci-8-alkoxy, pyrimidinyl, pyrimidinyloxy, pyrimidinylthio, pyrimidinylamino, pyrimidinyl-Ci-e-alkyl, pyrimidinyl- Ci-s-alkoxy, thienyl, thienyl-Ci-e-alkyl, thienyl-Ci-s-alkoxy, furyl, furyl-Ci-e-alkyl, furyl- Ci-s-alkoxy.
The expression heterocyclyl denotes mono- or bicyclic, saturated and unsaturated heterocyclic radicals having 1 to 4 nitrogen and/or 1 or 2 sulphur or oxygen atoms, which may each be mono- or polysubstituted, especially by (in the case of unsaturated heterocyclyl radicals) alkyl, hydroxyl, alkoxy, nitro or halogen, or by substituents as defined above for aryl radicals, or (in the case of saturated heterocyclyl radicals) may be substituted by alkyl or alkoxy. Examples of heterocyclyl radicals are benzimidazolyl, benzo[1 ,3]dioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzo[b]thienyl, quinazolinyl, quinolyl, quinoxalinyl, 2H-chromenyl, carbazolyl, dihydro-2H- benzo[1 ,4]oxazinyl, dihydro-3H-benzo[1 ,4]oxazinyl, dihydro-2H-benzo[1 ,4]thiazinyl, 2,3-dihydroindolyl, dihydro-1 H-pyhdo[2,3-b][1 ,4]oxazinyl, furyl, imidazolyl, imidazo[1 ,2- a]pyridyl, imidazo[1 ,5-a]pyhdyl, indazolyl, indolyl, isobenzofuranyl, isoquinolyl, [1 ,5]naphthyridyl, oxazolyl, phthalazinyl, pyranyl, pyrazinyl, pyridyl, pyrimidinyl, 1 H- pyrrolizinyl, 1 H-pyrrolo[2,3-b]pyhdyl, 1 H-pyrrolo[2,3-c]pyhdyl, 1 H-pyrrolo[3,2-b]pyridyl, pyrrolyl, tetrahydroquinolyl, tetrahydroquinoxalinyl, tetrahydroimidazo[1 ,2-a]pyridyl, tetrahydroimidazo[1 ,5-a]pyridyl, tetrahydroisoquinolyl, thiazolyl, thienyl, [1 ,2,3]triazolo[1 ,5-a]pyhdyl, [1 ,2,4]triazolo[4,3-a]pyridyl or triazolyl. Examples of substituted heterocyclyl radicals are 2,2-dimethyl-3-oxo-4H-benzo[1 ,4]oxazinyl, 2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazinyl, 2-aryl-2-methyl-3,4-dihydro-2H- benzo[1 ,4]oxazinyl, 2,2-dimethyl-2H-chromen-6-yl, 2-aryl-2-methyl-2H-chromen-6-yl, 2-oxobenzoimidazolyl, 2-oxodihydrobenzo[d][1 ,3]oxazinyl, 4-oxodihydroimidazolyl, 5-oxo-4H-[1 ,2,4]thazinyl, 3-oxo-4H-benzo[1 ,4]thiazinyl, 1 ,1 ,3-trioxodihydro-2H-1λ6- benzo[1 ,4]thiazinyl, 1-oxopyridyl, 2-oxotetrahydrobenzo[e][1 ,4]diazepinyl, 2-oxodihydro- benzo[e][1 ,4]diazepinyl, 1 -oxo-3H-isobenzofuranyl, 4-oxo-3H-thieno[2,3-d]pyhmidinyl, 3-oxo-4H-benzo[1 ,4]oxazinyl, 1 ,1-dioxodihydro-2H-benzo[1 ,4]thiazinyl, 2-oxo-1 H- pyrido[2,3-b][1 ,4]oxazinyl, 2-oxobenzooxazolyl, 2-oxo-1 ,3-dihydroindolyl, 2-oxodihydro- 1 H-quinazolinyl, nitrobenzothiazolyl, phenyltetrazolyl, phenyloxadiazolyl, phenyl- piperidinyl, phenylpiperazinyl, phenylpyrrolidinyl, thienyloxadiazolyl, furanyloxadiazolyl, benzyloxadiazolyl or phenyloxazolyl. Examples of saturated heterocyclyl radicals are azetidinyl, dioxolanyl, dioxanyl, dithiolanyl, dithianyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, morpholinyl, thiomorpholinyl, 2-hydroxymethylpyrrolidinyl, 3-hydroxypyrrolidinyl, 3,4-dihydroxypyrrolidinyl, 4-hydroxypiperidinyl, 4-oxopipehdinyl, 3,5-dimethylmorpholinyl, 4,4-dioxothiomorpholinyl, 4-oxothiomorpholinyl, 2,6-dimethyl- morpholinyl, tetrahydropyranyl, 2-oxoimidazolidinyl, 2-oxooxazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxo[1 ,3]oxazinyl, 2-oxoazepanyl, 2-oxotetrahydropyrimidinyl and the like. Examples of bicyclic heterocyclyl radicals are 2-oxabicyclo[4.1.0]heptanyl, 3-oxa- bicyclo[4.1.0]heptanyl, 2-oxabicyclo[3.1.0]hexanyl or 3-oxabicyclo[3.1.0]hexanyl.
In the case of R, R1 and R2, the aryl, aroyl and heterocyclyl radicals may additionally be substituted by heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkoxyalkyl or heterocyclyl, for example piperidinoalkyl, piperidinoalkoxy, pipehdinoalkoxyalkyl, morpholinoalkyl, morpholinoalkoxy, morpholinoalkoxyalkyl, piperazinoalkyl, piperazinoalkoxy, piperazinoalkoxyalkyl, [1 ,2,4]-triazol-1 -ylalkyl, [1 ,2,4]-triazol-1 - ylalkoxy, [1 ,2,4]-thazol-4-ylalkyl, [1 ,2,4]-thazol-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-ylalkoxy, oxazol-4-ylalkyl, oxazol-4-ylalkoxy, 2-oxopyrrol id inyl al kyl , 2-oxopyrrolidinylalkoxy, imidazolylalkyl, imidazolylalkoxy, 2-methylimidazolylalkyl, 2-methylimidazolylalkoxy or N-methylpiperazinoalkyl, N-methylpiperazinoalkoxy, N-methylpiperazinoalkoxyalkyl, and also alkylaminoalkyl, alkylaminoalkoxy, alkylaminoalkoxyalkyl, mono- and polyhydroxyalkyl, -alkoxy, -alkoxyalkyl and -alkoxyalkoxy, carbamoylalkyloxy, Ci-s-alkoxy, amino-Ci-s-alkoxy, hydroxy-Ci-8-alkoxy, dioxolanyl, dioxanyl, dithiolanyl, dithianyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, 4-methylpiperazinyl, morpholinyl, thiomorpholinyl, 2-hydroxymethylpyrrolidinyl, 3-hydroxypyrrolidinyl, 3,4-dihydroxypyrrolidinyl, 3-acetamidomethylpyrrolidinyl, 3-Ci-8-alkoxy-Ci-8-alkylpyrrolidinyl, 4-hydroxy- piperidinyl, 4-oxopiperidinyl, 3,5-dimethylmorpholinyl, 4,4-dioxothiomorpholinyl, 4-oxothiomorpholinyl, 2,6-dimethylmorpholinyl, 2-oxoimidazolidinyl, 2-oxooxa- zolidinyl, 2-oxopyrrol id inyl, 2-oxo-[1 ,3]oxazinyl, 2-oxotetrahydropyhmidinyl and the like, or by the -O-CH2CH(OH)CH2NRx radical, where NRx is a mono- or di-Ci-8- alkylamino, piperidino, morpholino, piperazino or N-methylpiperazino radical.
The expression polyhydroxyalkyl denotes Ci-7-alkyl radicals which may be substituted by 2-8 hydroxyl groups, for example glyceryl, arabityl, sorbityl, etc. The expression halogen or halo denotes, for example, fluorine, chlorine or bromine, or a radical mono- or polysubstituted by fluorine, chlorine or bromine.
The compounds of the formula (I) have at least two asymmetric carbon atoms and may therefore be present in the form of optically pure diastereomers, diastereomer mixtures, diastereomeric racemates, mixtures of diastereomehc racemates or as meso compounds. The invention encompasses all of these forms. Diastereomer mixtures, diastereomeric racemates or mixtures of diastereomeric racemates may be separated by customary methods, for example by column chromatography, thin-layer chromatography, HPLC and the like.
Salts are principally pharmaceutically usable salts or non-toxic salts of the compounds of the formula (I). The expression "pharmaceutically usable salts" encompasses salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like.
For the purposes of isolation and purification, pharmaceutically unsuitable salts may also find use.
Salts of compounds with salt-forming groups result principally from the addition of an acid or of a base. If a plurality of salt-forming groups are present, it is also possible for mixed salts or internal salts to be present.
Such salts form, for example, from compounds of the formula (I) which contain an acidic functional group, for example a carboxyl group, and are, for example, salts of this functional group with a suitable base, for example non-toxic metal salts of metals of groups Ia, Ib, Ma and Mb of the Periodic Table, for example alkali metal salts, especially lithium, sodium or potassium salts, alkaline earth metal salts, especially magnesium or calcium salts, but also zinc salts and ammonium salts; also included are salts which form with organic amines, such as optionally hydroxy-substituted mono-, di- or thalkylamines, especially with mono-, di- or tri(lower alkyl)amines or with quaternary ammonium bases, for example methyl-, ethyl-, diethyl- or triethyl- amine, mono-, bis- or tris(2-hydroxy(lower alkyl))amines, for example ethanol-, diethanol- or triethanolamine, tris(hydroxymethyl)methylamine or 2-hydroxy-tert- butylamine, N,N-di(lower alkyl)-N-hydroxy(lower alkyl))amines, for example N1N- dimethyl-N-(2-hydroxyethyl)amine or N-methyl-D-glucamine, or quaternary ammonium hydroxides, for example tetrabutylammonium hydroxide. The compounds of the formula (I) which contain a basic functional group, for example an amino group, may form salts with acids, for example with suitable inorganic acids, for example hydrohalic acid, for example hydrochloric acid or hydrobromic acid, sulphuric acid with exchange of one or both protons, phosphoric acid with exchange of one or more protons, for example ortho- or metaphosphoric acid, pyrophosphohc acid with exchange of one or more protons, or with organic carboxylic acids, sulphonic acids or phosphoric acids or N-substituted sulphamic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucahc acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, pamoic acid, nicotinic acid, isonicotinic acid, and also amino acids, for example the above- mentioned alpha-amino acids, but also methanesulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid, ethane-1 ,2-disulphonic acid, benzenesulphonic acid, 4-methylbenzenesulphonic acid, naphthol-2-benzenesulphonic acid, 2- or 3- phosphoglycerate, glucose-6-phosphate, N-cyclohexylsulphamic acid (with formation of the cyclamates) or with other organic acidic compounds, for example ascorbic acid. Compounds of the formula (I) which have acidic and basic functional groups may also form internal salts.
Prodrug derivatives of the compounds described in the present context are derivatives thereof which release the original compound by a chemical or physiological process on in vivo administration. A prodrug can be converted to the original compound, for example, on attainment of a physiological pH or by enzymatic conversion. Prodrug derivatives may, for example, be esters of freely available carboxylic acids, S- and O-acyl derivatives of thiols, alcohols or phenols, where the acyl group is as defined in the present context. Preference is given to pharmaceutically usable ester derivatives which are converted to the original carboxylic acid by solvolysis in physiological medium, for example lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or disubstituted lower alkyl esters, such as lower co-(amino, mono- or dialkylamino, carboxyl, lower alkoxycarbonyl)alkyl esters, or such as lower α-(alkanoyloxy, alkoxycarbonyl or dialkylaminocarbonyl)alkyl esters; as such, pivaloyloxymethyl esters and similar esters are conventionally used.
Because of the close relationship between a free compound, a prodrug derivative and a salt compound, a particular compound in this invention also includes its prodrug derivative and salt form, where this is possible and appropriate. The definitions mentioned apply within the scope of general chemical principles such as, for example, the usual valencies of atoms.
The compounds of the formula (I) also include those compounds in which one or more atoms are replaced by their stable, non-radioactive isotopes; for example, a hydrogen atom by deuterium.
Preferred compounds according to the invention are those of the general formula (IA) and the pharmaceutically usable salts thereof
Figure imgf000016_0001
(IA) in which R, R1 and X are each as defined above for the compounds of the formula (I).
A further preferred group of compounds of the formula (I), and particularly preferably of the formula (IA), and the pharmaceutically usable salts thereof, are compounds in which
R is C2-8-alkenyl, C2-8-alkynyl, Ci-8-alkyl, C0-8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8- alkyl, optionally N-mono- or N,N-di-Ci-8-alkylated or -arylated amino-Ci-s-alkyl, optionally O-Ci-8-alkylated carboxyl-Co-s-alkyl, Cs-s-cycloalkyl-Ci-s-alkyl, optionally N-mono- or N,N-di-C3-8-cycloalkyl-Co-8-alkylated or optionally N-mono- or N,N-di- heterocyclyl-Co-8-alkylated carbamoyl-Co-8-alkyl, Cs-s-cycloalkyl-Co-β-alkylcarbonyl- (N-Co-8-alkyl)amino-Ci-8-alkyl, arylcarbonyl^N-Co-s-alkylJamino-Ci-s-alkyl, optionally N-mono- or N,N-di-Ci-8-alkylated or -arylated sulphamoyl-Co-8-alkyl, Ci-s-alkyl- sulphonyl-Co-8-alkyl or heterocyclylcarbonyl-Co-8-alkyl, each of which is either un- substituted or substituted by 1 -4 Ci-8-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-8-alkoxy- carbonyl-(N-Ci-8-alkyl)amino, Ci-8-alkyl, Ci-8-alkylcarbonyl, C0-8-alkylcarbonyl-(N-C0-8- alkyl)amino, Ci-8-alkylsulphanyl, Ci-8-alkylsulphinyl, Ci-8-alkylsulphonyl, aryl-C0-8- alkoxy, aryl, arylamino, aryl-C0-8-alkylsulphonyl, cyano, C3-8-cycloalkoxy, halogen, heterocyclyl, heterocyclyl-Co-8-alkoxy, heterocyclyl-Co-s-alkylamino, heterocyclyl- carbonyl, hydroxyl, phosphonyl, optionally N-mono- or N,N-di-Ci-8-alkylated amino, optionally N-mono- or N,N-di-Ci-8-alkylated carbamoyloxy, optionally N-mono- or N,N-di-Ci-8-alkylated sulphamoyl, optionally N-mono-, -di- or -tri-Ci-s-alkylated or heterocyclyl-substituted ureido, optionally N-mono- or N,N-di-Ci-8-alkylated, N-mono- or N,N-di-arylated or N-mono- or N.N-di-heterocyclyl-Co-β-alkylated amino-Co-8- alkylcarbonyl, oxo or trifluoromethyl; and
R1 is selected from benzimidazolyl, benzo[1 ,3]dioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzo[b]thienyl, quinazolinyl, quinolyl, quinoxalinyl, 2H-chromenyl, carbazolyl, dihydro-2H-benzo[1 ,4]oxazinyl, dihydro-3H-benzo[1 ,4]oxazinyl, dihydro- 2H-benzo[1 ,4]thiazinyl, 2,3-dihydroindolyl, dihydro-1 H-pyrido[2,3-b][1 ,4]oxazinyl, imidazo[1 ,2-a]pyhdyl, imidazo[1 ,5-a]pyhdyl, indazolyl, indolyl, isobenzofuranyl, isoquinolyl, [1 ,5]naphthyhdyl, phenyl, phthalazinyl, pyridyl, pyhmidinyl, 1 H-pyrrolo[2,3-b]pyhdyl, 1 H-pyrrolo[2,3-c]pyhdyl, 1 H-pyrrolo[3,2-b]pyridyl, tetrahydro- quinolyl, tetrahydroquinoxalinyl, tetrahydroimidazo[1 ,2-a]pyridyl, tetrahydro- imidazo[1 ,5-a]pyhdyl, tetrahydroisoquinolyl, [1 ,2,3]thazolo[1 ,5-a]pyhdyl and [1 ,2,4]triazolo[4,3-a]pyridyl, each of which is substituted by 1 -4 acyl-Ci-8-alkoxy-Ci-8- alkoxy, acyl-Ci-s-alkoxy-Ci-s-alkyl, (N-acyO-Ci-s-alkoxy-Ci-s-alkylamino, Ci-8-alkanoyl, Ci-8-alkoxy, Ci-s-alkoxy-Ci-s-alkanoyl, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s- alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, (N-Ci-s-alkoxyJ-Ci-s-alkylaminocarbonyl-Ci-s- alkoxy, (N-Ci-s-alkoxyJ-Ci-s-alkylaminocarbonyl-Ci-s-alkyl, Ci-8-alkoxy-Ci-8-alkyl- carbamoyl, Ci-s-alkoxy-Ci-s-alkylcarbonyl, Ci-s-alkoxy-Ci-s-alkylcarbonylamino, 1 -Ci-s-alkoxy-Ci-s-alkylheterocyclyl, Ci-s-alkoxyaminocarbonyl-Ci-s-alkoxy, Ci-8- alkoxyanninocarbonyl-Ci-8-alkyl, Ci-8-alkoxycarbonyl, Ci-s-alkoxycarbonyl-Ci-s-alkoxy, Ci-s-alkoxycarbonyl-Ci-s-alkyl, Ci-s-alkoxycarbonylannino-Ci-s-alkoxy, Ci-s-alkoxy- carbonylamino-Ci-8-alkyl, Ci-s-alkyl, (N-Ci-s-alkylJ-Ci-s-alkoxy-Ci-s-alkylcarbamoyl, (N-Ci-s-alkylJ-Ci-s-alkoxy-Ci-s-alkylcarbonylannino, (N-Ci-8-alkyl)-Ci-8-alkoxycarbonyl- amino, (N-Ci-s-alkylJ-Ci-s-alkylcarbonylamino-Ci-s-alkoxy, (N-Ci-s-alkyl)-Ci-8-alkyl- carbonylannino-Ci-8-alkyl, (N-Ci-s-alkyO-Ci-s-alkylsulphonylamino-Ci-s-alkoxy, (N-Ci-8- alkyO-Ci-s-alkylsulphonylannino-Ci-s-alkyl, Ci-8-alkylamidinyl, Ci-s-alkylamino-Ci-s- alkoxy, di-Ci-s-alkylannino-Ci-s-alkoxy, Ci-s-alkylannino-Ci-s-alkyl, di-Ci-s-alkylannino- Ci-s-alkyl, Ci-s-alkylanninocarbonyl-Ci-s-alkoxy, di-Ci-s-alkylaminocarbonyl-Ci-s- alkoxy, Ci-s-alkylanninocarbonyl-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkylaminocarbonyl-Ci-s- alkyl, di-Ci-s-alkylaminocarbonyl-Ci-s-alkyl, Ci-s-alkylaminocarbonylannino-Ci-s- alkoxy, Ci-s-alkylanninocarbonylannino-Ci-s-alkyl, Ci-s-alkylcarbonylannino, Ci-S- alkylcarbonylannino-Ci-8-alkoxy, Ci-s-alkylcarbonylannino-Ci-s-alkyl, Ci-s-alkyl- carbonyloxy-Ci-s-alkoxy, Ci-s-alkylcarbonyloxy-Ci-s-alkyl, Ci-8-alkylsulphonyl, Ci-8- alkylsulphonyl-Ci-s-alkoxy, Ci-s-alkylsulphonyl-Ci-s-alkyl, Ci-8-alkylsulphonylannino- Ci-s-alkoxy, Ci-s-alkylsulphonylannino-Ci-s-alkyl, optionally N-mono- or N,N-di-Ci-8- alkylated amino, aryl-Co-s-alkoxy, aryl-Co-s-alkyl, optionally N-mono- or N,N-di-Ci-8- alkylated carbamoyl-Co-8-alkoxy, optionally N-mono- or N,N-di-Ci-8-alkylated carbamoyl-Co-8-alkyl, carboxy-Ci-s-alkoxy, carboxy-Ci-s-alkoxy-Ci-s-alkyl, carboxy- Ci-s-alkyl, cyano, cyano-Ci-s-alkoxy, cyano-Ci-s-alkyl, Cs-s-cycloalkyl-Ci-s-alkoxy, Cs-s-cycloalkyl-Ci-s-alkyl, Cs-s-cycloalkylcarbonylamino-Ci-s-alkoxy, C3-8-cycloalkyl- carbonylamino-Ci-s-alkyl, CN-dimethylhydroxylamino-Ci-s-alkyl, halogen, halogen- Ci-s-alkoxy, halogen-Ci-8-alkyl, halogen-aryl, heterocyclyl-Co-s-alkoxy, heterocyclyl- Co-8-alkyl, heterocyclylcarbonyl, hydroxy-Ci-s-alkoxy-Ci-s-alkoxy, hydroxy-Ci-8-alkoxy- Ci-s-alkyl, hydroxy-Ci-8-alkyl, O-methyloximyl-Ci-8-alkyl, oxide or oxo, where, when R1 is heterocyclyl and contains at least one saturated carbon atom, this heterocyclyl radical may additionally be substituted on a saturated carbon atom by a C2-8-alkylene chain whose two ends are fixed on this saturated carbon atom and thus form a spirocycle, where one CH2 group of the alkylene chain may be replaced by oxygen. A further preferred group of compounds of the formula (I), more preferably of the formula (IA), and the pharmaceutically usable salts thereof, is that of compounds in which
R1 is aryl or heterocyclyl, each of which is substituted as specified above; and X is -AIk-, -0-AIk-, -AIk-O-, -0-AIk-O-, -AIk-NR2-, -NR2-Alk-, -C(O)-NR2- or -NR2-C(O)- where AIk is Ci-s-alkylene, which may optionally be substituted by halogen; where R2 is hydrogen or Ci-s-alkyl.
A further preferred group of compounds of the formula (I), and particularly preferably of the formula (IA), and the pharmaceutically usable salts thereof, are compounds in which
R is Ci-s-alkyl, Co-8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8-alkyl, Cs-s-cycloalkyl-Ci-s- alkyl, optionally N-mono- or N,N-di-C3-8-cycloalkyl-Co-8-alkylated or optionally N-mono- or N,N-di-heterocyclyl-Co-8-alkylated carbamoyl-Co-8-alkyl or Cs-s-cycloalkyl- C0-8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8-alkyl or heterocyclylcarbonyl-Co-s-alkyl, each of which is either unsubstituted or substituted by 1-4 Ci-s-alkoxy, Ci-s-alkoxy- Ci-s-alkoxy, Ci-8-alkoxycarbonyl-(N-Ci-8-alkyl)amino, Ci-8-alkyl, Ci-8-alkylcarbonyl, Co-8-alkylcarbonyl-(N-C0-8-alkyl)amino, Ci-8-alkylsulphanyl, Ci-8-alkylsulphinyl, Ci-8- alkylsulphonyl, aryl-Co-8-alkoxy, aryl, arylamino, aryl-Co-8-alkylsulphonyl, cyano, C3-8- cycloalkoxy, halogen, heterocyclyl, heterocyclyl-Co-8-alkoxy, heterocyclyl-Co-β-alkyl- amino, heterocyclylcarbonyl, hydroxyl, phosphonyl, optionally N-mono- or N,N-di- Ci-s-alkylated amino, optionally N-mono- or N,N-di-Ci-8-alkylated carbamoyloxy, optionally N-mono- or N,N-di-Ci-8-alkylated sulphamoyl, optionally N-mono-, -di- or -tri-Ci-s-alkylated or heterocyclyl-substituted ureido, optionally N-mono- or N,N-di- Ci-s-alkylated, N-mono- or N,N-di-arylated or N-mono- or N,N-di-heterocyclyl-Co-8- alkylated amino-Co-8-alkylcarbonyl, oxo or trifluoromethyl.
R is particularly preferably Ci-s-alkyl, Co-8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8-alkyl, Cs-s-cycloalkyl-Ci-s-alkyl, optionally N-mono- or N,N-di-C3-8-cycloalkyl-Co-8-alkylated or optionally N-mono- or N.N-diheterocyclyl-Co-β-alkylated carbamoyl-Co-8-alkyl, C3-8- cycloalkyl-Co-8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8-alkyl or heterocyclylcarbonyl- Co-8-alkyl, each of which is either unsubstituted or substituted by 1 -4 Ci-8-alkoxy, Ci-8- alkoxy-Ci-s-alkoxy, Ci-8-alkoxycarbonyl-(N-Ci-8-alkyl)annino, Ci-8-alkyl, Ci-8-alkyl- carbonyl, C0-8-alkylcarbonyl-(N-C0-8-alkyl)annino, Ci-8-alkylsulphonyl, aryl-Co-s-alkoxy, aryl, arylamino, cyano, Cs-s-cycloalkoxy, halogen, heterocyclyl, heterocyclyl-Co-8- alkoxy, heterocyclyl-Co-β-alkylamino, heterocyclylcarbonyl, hydroxyl, optionally N-mono- or N,N-di-Ci-8-alkylated amino, optionally N-mono- or N,N-di-Ci-8-alkylated carbamoyloxy, optionally N-mono- or N,N-di-Ci-8-alkylated sulphamoyl, optionally N-mono-, di-, or tri-Ci-8-alkylated or heterocyclyl substituted ureido, optionally N-mono- or N,N-di-Ci-8-alkylated, N-mono- or N,N-diarylated or N-mono- or N.N-diheterocyclyl-Co-β-alkylated amino-Co-8-alkylcarbonyl, oxo or trifluoromethyl.
R is very particularly preferably Ci-s-alkyl, Co-s-alkylcarbonylamino-Ci-s-alkyl, C3-8- cycloalkyl-Ci-s-alkyl, optionally N-mono-Cs-s-cycloalkyl-Co-s-alkylated, optionally N-mono-heterocyclyl-Co-β-alkylated carbamoyl-Co-s-alkyl, Cs-s-cycloalkyl-Co-s- alkylcarbonylamino-Ci-s-alkyl or heterocyclylcarbonyl-Co-8-alkyl, each of which is either unsubstituted or substituted by 1-2 heterocyclyl or optionally N-mono- or N.N-di-Ci-Cs-alkylated, N-mono- or N,N-di-arylated or N-mono- or N,N-di-hetero- cyclyl-Co-8-alkylated carbamoyl, wherein the heterocyclyl is particularly preferably a saturated heterocyclyl preferaby selected from the group comprising tetrahydro- pyranyl, morpholinyl, piperidinyl, tetrahydrofuranyl, 3-oxa-bicyclo[3.1.0]hexanyl and 6-oxa-spiro[2.5]octanyl which heterocyclyl substituents may be further substituted.
A further preferred group of compounds of the formula (I), and particularly preferably of the formula (IA), and the pharmaceutically usable salts thereof, are compounds in which
R1 is benzimidazolyl, benzo[1 ,3]dioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzo[b]thienyl, quinazolinyl, quinolyl, quinoxalinyl, 2H-chromenyl, carbazolyl, dihydro-2H-benzo[1 ,4]oxazinyl, dihydro-3H-benzo[1 ,4]oxazinyl, dihydro-2H- benzo[1 ,4]thiazinyl, 2,3-dihydroindolyl, dihydro-1 H-pyrido[2,3-b][1 ,4]oxazinyl, imidazo[1 ,2-a]pyhdyl, imidazo[1 ,5-a]pyhdyl, indazolyl, indolyl, isobenzofuranyl, isoquinolyl, [1 ,5]naphthyhdyl, phenyl, phthalazinyl, pyridyl, pyrimidinyl, 1 H- pyrrolo[2,3-b]pyhdyl, 1 H-pyrrolo[2,3-c]pyhdyl, 1 H-pyrrolo[3,2-b]pyridyl, tetrahydro- quinolyl, tetrahydroquinoxalinyl, tetrahydroimidazo[1 ,2-a]pyridyl, tetrahydro- imidazo[1 ,5-a]pyridyl, tetrahydroisoquinolyl, [1 ,2,3]triazolo[1 ,5-a]pyridyl or [1 ,2,4]triazolo[4,3-a]pyridyl, each of which is substituted by 1 -4 Ci-8-alkanoyl, Ci-8- alkoxy, Ci-s-alkoxy-Ci-s-alkanoyl, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy- Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxycarbonylannino-Ci-s-alkoxy, Ci-s-alkoxy- carbonylamino-Ci-8-alkyl, Ci-s-alkyl, Co-β-alkylcarbonylamino-Ci-s-alkoxy, Co-8-alkyl- carbonylannino-Ci-8-alkyl, aryl-Co-8-alkoxy, aryl-Co-8-alkyl, cyano, cyano-Ci-s-alkoxy, cyano-Ci-8-alkyl, halogen, halogen-Ci-8-alkoxy, halogen-Ci-8-alkyl, halogen-aryl, heterocyclyl-Co-8-alkoxy, heterocyclyl-Co-s-alkyl, oxide or oxo, where, when R1 is heterocyclyl and contains at least one saturated carbon atom, this heterocyclyl radical may additionally be substituted on a saturated carbon atom by a C2-8-alkylene chain whose two ends are fixed on this saturated carbon atom and thus form a spirocycle, where one CH2 group of the alkylene chain may be replaced by oxygen.
R1 is preferably benzo[1 ,3]dioxolyl, benzofuranyl, benzoimidazolyl, benzooxazolyl, 2H-chromenyl, carbazolyl, dihydro-2H-benzo[1 ,4]oxazinyl, dihydro-3H- benzo[1 ,4]oxazinyl, dihydro-2H-benzo[1 ,4]thiazinyl, indazolyl, indolyl, isobenzo- furanyl, [1 ,5]naphthyridyl, phenyl, phthalazinyl, pyridyl, pyrimidinyl, 1 H-pyrrolo[2,3- b]pyridyl or quinolinyl, each of which is substituted by 1-4 Ci-8-alkanoyl, Ci-8-alkoxy, Ci-s-alkoxy-Ci-s-alkanoyl, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxycarbonylamino-Ci-s-alkoxy, Ci-8-alkoxycarbonyl- amino-Ci-s-alkyl, Ci-8-alkyl, Co-s-alkylcarbonylamino-Ci-s-alkoxy, C0-8-alkylcarbonyl- amino-Ci-s-alkyl, aryl-Co-8-alkoxy, aryl-Co-8-alkyl, cyano, cyano-Ci-s-alkoxy, cyano- Ci-s-alkyl, halogen, halogen-Ci-s-alkoxy, halogen-Ci-s-alkyl, halogen-aryl, hetero- cyclyl-Co-8-alkoxy, heterocyclyl-Co-s-alkyl, oxide or oxo, where, when R1 is heterocyclyl and contains at least one saturated carbon atom, this heterocyclyl radical may additionally be substituted on a saturated carbon atom by a C2-8-alkylene chain whose two ends are fixed on this saturated carbon atom and thus form a spirocycle, where one CH2 group of the alkylene chain may be replaced by oxygen. R1 is particularly preferably 2H-chromenyl, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl or carbazolyLeach of which is substituted by 1-4 Ci-8-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy , Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxycarbonylamino- Ci-s-alkoxy, Ci-s-alkoxycarbonylamino-Ci-s-alkyl, Ci-s-alkyl, Co-s-alkylcarbonylamino- Ci-s-alkoxy, Co-s-alkylcarbonylamino-Ci-s-alkyl, halogen, halogen-Ci-s-alkoxy, halogen-Ci-s-alkyl, halogen-aryl or oxo, where a saturated carbon atom of the heterocyclyl radical may additionally be substituted on the saturated carbon atom by a C2-8-alkylene chain whose two ends are fixed on this saturated carbon atom and thus form a spirocycle, where one CH2 group of the alkylene chain may be replaced by oxygen.
R1 is very particularly preferably 3,4-dihydro-2H-benzo[1 ,4]oxazinyl substituted by 1 -4 Ci-8-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci-8- alkoxy-Ci-s-alkyl, Ci-s-alkoxycarbonylamino-Ci-s-alkoxy, Ci-8-alkoxycarbonylamino- Ci-s-alkyl, Ci-8-alkyl, Co-s-alkylcarbonylannino-Ci-s-alkoxy, Co-s-alkylcarbonylamino- Ci-s-alkyl, halogen, halogen-Ci-s-alkoxy, halogen-Ci-s-alkyl, halogen-aryl or oxo, where a saturated carbon atom of the heterocyclyl radical may additionally be substituted on the saturated carbon atom by a C2-8-alkylene chain whose two ends are fixed on this saturated carbon atom and thus form a spirocycle, where one CH2 group of the alkylene chain may be replaced by oxygen.
A further preferred group of compounds of the formula (I), and particularly preferably of the formula (IA), and the pharmaceutically usable salts thereof, are compounds in which
X is -O-Alk- or -O-Alk-O- where AIk is Ci-8-alkylene.
X is particularly preferred -0-AIk-, and very particularly preferred -0-CH2-.
A further preferred group of compounds of the formula (I), and particularly preferably of the formula (IA), and the pharmaceutically usable salts thereof, are compounds in which
R is C2-8-alkenyl, C2-8-alkynyl, Ci-s-alkyl, Co-8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8- alkyl, optionally N-mono- or N,N-di-Ci-8-alkylated or -arylated amino-Ci-s-alkyl, optionally O-Ci-8-alkylated carboxyl-Co-s-alkyl, Cs-s-cycloalkyl-Ci-s-alkyl, optionally N-mono- or N,N-di-C3-8-cycloalkyl-Co-8-alkylated or optionally N-mono- or N,N-di- heterocyclyl-Co-8-alkylated carbamoyl-Co-8-alkyl, Cs-s-cycloalkyl-Co-β-alkylcarbonyl- (N-Co-8-alkyl)amino-Ci-8-alkyl, arylcarbonyl^N-Co-s-alkylJamino-Ci-s-alkyl, optionally N-mono- or N,N-di-Ci-8-alkylated or -arylated sulphamoyl-Co-8-alkyl, Ci-s-alkyl- sulphonyl-Co-8-alkyl or heterocyclylcarbonyl-Co-8-alkyl, each of which is either un- substituted or substituted by 1 -4 Ci-8-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-8-alkoxy- carbonyl-(N-Ci-8-alkyl)amino, Ci-8-alkyl, Ci-8-alkylcarbonyl, C0-8-alkylcarbonyl-(N-C0-8- alkyl)amino, Ci-8-alkylsulphanyl, Ci-8-alkylsulphinyl, Ci-8-alkylsulphonyl, aryl-C0-8- alkoxy, aryl, arylamino, aryl-C0-8-alkylsulphonyl, cyano, C3-8-cycloalkoxy, halogen, heterocyclyl, heterocyclyl-Co-8-alkoxy, heterocyclyl-Co-s-alkylamino, heterocyclyl- carbonyl, hydroxyl, phosphonyl, optionally N-mono- or N,N-di-Ci-8-alkylated amino, optionally N-mono- or N,N-di-Ci-8-alkylated carbamoyloxy, optionally N-mono- or N,N-di-Ci-8-alkylated sulphamoyl, optionally N-mono-, -di- or -tri-Ci-s-alkylated or heterocyclyl-substituted ureido, optionally N-mono- or N,N-di-Ci-8-alkylated, N-mono- or N,N-di-arylated or N-mono- or N.N-di-heterocyclyl-Co-β-alkylated amino-Co-8- alkylcarbonyl, oxo or thfluoromethyl, wherein the heterocyclyl is particularly preferably a saturated heterocyclyl preferaby selected from the group comprising tetrahydropyranyl, morpholinyl, piperidinyl, tetrahydrofuranyl, 3-oxa- bicyclo[3.1.0]hexanyl and 6-oxa-spiro[2.5]octanyl which heterocyclyl substituents may be further substituted;
R1 is 2H-chromenyl, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl or carbazolyl, each of which is substituted by 1 -4 Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy-Ci-s- alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxycarbonylamino-Ci-s-alkoxy, Ci-s-alkoxy- carbonylamino-Ci-s-alkyl, Ci-s-alkyl, Co-s-alkylcarbonylamino-Ci-s-alkoxy, Co-β- alkylcarbonylamino-Ci-s-alkyl, halogen, halogen-Ci-s-alkoxy, halogen-Ci-s-alkyl, halogen-aryl or oxo, where a saturated carbon atom of the heterocyclyl radical may additionally be substituted on the saturated carbon atom by a C2-8-alkylene chain whose two ends are fixed on this saturated carbon atom and thus form a spirocycle, where one CH2 group of the alkylene chain may be replaced by oxygen and
X is -0-CH2-. A further preferred group of compounds of the formula (I), and particularly preferably of the formula (IA), and the pharmaceutically usable salts thereof, are compounds in which
R is C2-8-alkenyl, C2-8-alkynyl, Ci-8-alkyl, C0-8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8- alkyl, optionally N-mono- or N,N-di-Ci-8-alkylated or -arylated amino-Ci-s-alkyl, optionally O-Ci-s-alkylated carboxyl-Co-8-alkyl, Cs-s-cycloalkyl-Ci-s-alkyl, optionally N-mono- or N,N-di-C3-8-cycloalkyl-Co-8-alkylated or optionally N-mono- or N,N-di- heterocyclyl-Co-8-alkylated carbamoyl-Co-8-alkyl, Cs-s-cycloalkyl-Co-β-alkylcarbonyl- (N-Co-8-alkyl)amino-Ci-8-alkyl, arylcarbonyl^N-Co-β-alkylJamino-Ci-s-alkyl, optionally N-mono- or N,N-di-Ci-8-alkylated or -arylated sulphamoyl-Co-β-alkyl, Ci-8-alkyl- sulphonyl-Co-8-alkyl or heterocyclylcarbonyl-Co-s-alkyl, each of which is either unsubstituted or substituted by 1-4 Ci-8-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy , Ci-8-alkoxy- carbonyl-(N-Ci-8-alkyl)amino, Ci-8-alkyl, Ci-8-alkylcarbonyl, Co-s-alkylcarbonyl-(N-Co-s- alkyl)amino, Ci-s-alkylsulphanyl, Ci-s-alkylsulphinyl, Ci-s-alkylsulphonyl, aryl-Co-s- alkoxy, aryl, arylamino, aryl-Co-s-alkylsulphonyl, cyano, Cs-s-cycloalkoxy, halogen, heterocyclyl, heterocyclyl-Co-8-alkoxy, heterocyclyl-Co-s-alkylamino, heterocyclyl- carbonyl, hydroxyl, phosphonyl, optionally N-mono- or N,N-di-Ci-8-alkylated amino, optionally N-mono- or N,N-di-Ci-8-alkylated carbamoyloxy, optionally N-mono- or N,N-di-Ci-8-alkylated sulphamoyl, optionally N-mono-, -di- or -th-Ci-8-alkylated or heterocyclyl-substituted ureido, optionally N-mono- or N,N-di-Ci-8-alkylated, N-mono- or N,N-di-arylated or N-mono- or N.N-di-heterocyclyl-Co-s-alkylated amino-Co-8-alkyl- carbonyl, oxo or trifluoromethyl;
R1 is 2H-chromenyl, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl or carbazolyl, each of which is substituted by 1 -4 Ci-8-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy-Ci-s- alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxycarbonylamino-Ci-s-alkoxy, Ci-8-alkoxy- carbonylamino-Ci-s-alkyl, Ci-s-alkyl, Co-s-alkylcarbonylamino-Ci-s-alkoxy, Co-8-alkyl- carbonylamino-Ci-s-alkyl, halogen, halogen-Ci-s-alkoxy, halogen-Ci-s-alkyl, halogen- aryl or oxo, where a saturated carbon atom of the heterocyclyl radical may additionally be substituted on the saturated carbon atom by a C2-8-alkylene chain whose two ends are fixed on this saturated carbon atom and thus form a spirocycle, where one CH2 group of the alkylene chain may be replaced by oxygen and
X is -0-CH2-.
A further preferred group of compounds of the formula (I), and particularly preferably of the formula (IA), and the pharmaceutically usable salts thereof, are compounds in which
R is Ci-8-alkyl, Co-s-alkylcarbonylamino-Ci-s-alkyl, C3-8-cycloalkyl-Ci-8-alkyl, optionally N-mono-C3-8-cycloalkyl-Co-8-alkylated, optionally N-mono-heterocyclyl-Co-s-alkylated carbamoyl-Co-8-alkyl, Cs-s-cycloalkyl-Co-s-alkylcarbonylamino-Ci-s-alkyl or hetero- cyclylcarbonyl-Co-8-alkyl, each of which is either unsubstituted or substituted by 1 -2 heterocyclyl or optionally N-mono- or N.N-di-Ci-Cs-alkylated, N-mono- or N,N-di- arylated or N-mono- or N,N-di-heterocyclyl-Co-8-alkylated carbamoyl, wherein the heterocyclyl is particularly preferably a saturated heterocyclyl preferaby selected from the group comprising tetrahydropyranyl, morpholinyl, piperidinyl, tetrahydrofuranyl, 3- oxa-bicyclo[3.1.0]hexanyl and 6-oxa-spiro[2.5]octanyl which heterocyclyl substituents may be further substituted;
R1 is 2H-chromenyl, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl or carbazolyl, each of which is substituted by 1 -4 Ci-8-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy-Ci-s- alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxycarbonylamino-Ci-s-alkoxy, Ci-8-alkoxy- carbonylamino-Ci-s-alkyl, Ci-8-alkyl, Co-s-alkylcarbonylamino-Ci-s-alkoxy, C0-S- alkylcarbonylamino-Ci-s-alkyl, halogen, halogen-Ci-8-alkoxy, halogen-Ci-8-alkyl, halogen-aryl or oxo, where a saturated carbon atom of the heterocyclyl radical may additionally be substituted on the saturated carbon atom by a C2-8-alkylene chain whose two ends are fixed on this saturated carbon atom and thus form a spirocycle, where one CH2 group of the alkylene chain may be replaced by oxygen and
X is -0-CH2-.
The abovementioned compound groups should not be regarded as closed, but rather it is possible in a sensible manner, for example to replace general by more specific definitions by exchanging parts of these compound groups with one another or with the definitions given above or omitting them. In case a range is indicated, for example 1 -4, both endpoints are comprised in the range. The preferences apply equally also to the use of the compounds of the formulae (I) and (IA), and to the pharmaceutical products comprising the compounds of the formula (I) or (IA).
The compounds of the formula (I) or formula (IA) may be prepared in an analogous manner to preparation processes known from the literature. A preferred method of preparing optically pure compounds of the formula (IA) consists in the formation of a pipehdine base structure, for example 6(S)-hydroxymethylpiperidin-3(R)-ol [406945- 58-2], by reacting an aspartic acid derivative with Meldrum's acid and a subsequent diastereoselective α-hydroxylation according to the exemplary scheme which follows:
Figure imgf000026_0001
[406945-58-2] a) Meldrum's acid, EDC, DMAP, CH2CI2; b) NaBH4, CH2CI2/AcOH (10:1 ); c) toluene, reflux; d) LiHMDS, (+)-(10-camphorsulphonyl)oxaziridine; e) HCI/dioxane; f) LAH, reflux
Further details and alternative preparation processes are specified in J. Org. Chem.
67 (2002), 8440-8449 and Lieb. Ann./Recueil (1997), 1267-1272, and literature cited there.
Details of the specific preparation variants can be taken from the examples.
The compounds of the formula (I) may also be prepared in optically pure form. The separation into antipodes can be effected by methods known per se, either preferably at a synthetically early stage by salt formation with an optically active acid, for example (+)- or (-)-mandelic acid, and separation of the diastereomehc salts by fractional crystallization, or preferably at a rather late stage by dehvatization with a chiral auxiliary unit, for example (+)- or (-)-camphanoyl chloride, and separation of the diastereomeric products by chromatography and/or crystallization and subsequent cleavage of the bond to the chiral auxiliary. To determine the absolute configuration of the pipehdine present, the pure diastereomeric salts and derivatives may be analysed by common spectroscopic methods, and X-ray spectroscopy on single crystals constitutes a particularly suitable method.
The compounds of formula (I) and (IA), respectively, and their pharmaceutically usable salts reveal inhibitory activities on the enzymes beta-secretase, cathepsin D, plasmepsin Il and/or HIV-protease.
The activitiy of inhibitors of beta-secretase, cathepsin D, plasmepsin Il and/or HIV protease can be assessed experimentally with following in vitro assays.
The protease inhibitory activity of compounds can be tested with an assay kit using the fluorescence resonance energy transfer (FRET) technology and a recombinant i.e. baculovirus expressed enzyme preparation. The FRET is used to monitor the cleavage of the peptide substrate. The principle of the assay is as follows relies on a measurable energy difference, quantitatively depending on the presence of a peptide sequence. The peptide substrate is synthesized with two terminal fluorophores, a fluorescent donor and quenching acceptor. The distance between these two groups is selected so that upon light excitation, the donor fluorescence energy is significantly quenched by the acceptor through resonance energy transfer. Upon cleavage by the protease, the fluorophore is separated from the quenching group, restoring the fluorescence yield of the donor. Thus a weakly fluorescent peptide substrate becomes highly fluorescent upon enzymatic cleavage; the increase in fluorescence is linearly related to the rate of proteolysis. The FRET assay is performed in white polysorp plates. The assay buffer consists of 50 mM sodium acetate pH 5, 392 mM sodium chloride, 12.5% glycerol and 0.1 % BSA. The incubates per well are composed of 160 μl buffer, 10 μl inhibitor in DMSO, 10 μl peptide substrate in DMSO and 20 μl enzyme-solution. The inhibitors are tested in a concentration range of 1 pM to 1 mM. The fluorescently marked donor and acceptor peptide substrates are generated by solid phase peptide synthesis (Applied Biosystems). The beta-secretase peptide substrate Rh-Glu-Val-Asn-Leu- Asp-Ala-Glu-Phe-Lys-Quencher is obtained from Invitrogen, Carlsbad, CA, USA. The cathepsin D peptide substrate of the sequence DABCYL-Pro-Thr-Glu-Phe-Phe- Arg-Leu-OXL, the plasmepsin peptide substrate of the sequence DABCYL-GI u-Arg- Nle-Phe-Leu-Ser-Phe-Pro-OXL and the HIV protease peptide substrate of the sequence DABCYL-His-Lys-Ala-Arg-Val-Leu-Tyr-Glu-Ala-Nle-Ser-EDANS are all obtained from AnaSpec Inc, San Jose, CA, USA. The recombinantly expressed enzyme preparations are added in various amounts to the assay systems eg the beta-sectrase concentration is 1 unit/ml incubation volume, the cathepsin D concentration is 100 ng/ml, the HIV protease concentration is 500 ng/ml and the plasmepsin Il concentration is 50 ng/ml. The reaction is started upon addition of the enzyme solution. The incubation occurs at 37°C over 30-120 min ie specifically the beta-secretase incubation lasts 60 min, the cathepsin D incubation 120 min, the plasmepsin Il incubation 40 min and the HIV protease incubation 40 min. The reactions are stopped by the addition of 20 μl of a 1.0 M Tris Base solution. The enzymatic substrate to product conversion is assessed by fluorescence measurements at 460 nm wave length.
In vitro enzyme inhibitory activities
The compounds of the present invention reveal structure-dependent and enzyme- specific inhibitory activities. The inhibitory activities are measured as IC50 values. Thus the beta-secretase inhibitory activity ranges between 1 pM and 1 mM; the values for cathepsin D range between 1 pM and 1 mM, for plasmepsin Il between 1 pM and 1 mM and for HIV-protease between 1 pM and 1 mM.
The compounds of the formula (I) or preferred formula (IA) and the pharmaceutically usable salts thereof may find use as medicines, for example in the form of pharmaceutical preparations. The pharmaceutical preparations may be administered enterally, such as orally, for example in the form of tablets, coated tablets, sugar- coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions, nasally, for example in the form of nasal sprays, rectally, for example in the form of suppositories, or transdermally, for example in the form of ointments or patches. The administration may also be parenteral, such as intramuscular or intravenous, for example in the form of injection solutions.
To prepare tablets, coated tablets, sugar-coated tablets and hard gelatine capsules, the compounds of the formula (I) and pharmaceutically usable salts thereof may be processed with pharmaceutically inert, inorganic or organic excipients. Such excipients used, for example for tablets, coated tablets and hard gelatine capsules, may be lactose, corn starch, or derivatives thereof, talc, stearic acid or salts thereof etc.
Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols, etc.
Suitable excipients for preparing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.
Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, bile acids, lecithin, etc.
Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.
The pharmaceutical preparations may additionally also comprise preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavourings, salts for altering the osmotic pressure, buffers, coatings or antioxidants. They may also comprise other therapeutically valuable substances. Subject of the present invention is also the use of the compounds of formula (I) and (IA), respectively, and their pharmaceutically usable salts for the prevention, delay of progression or the treatment of Alzheimer Disease, malaria or HIV infection.
Subject of the present invention is also the use of the compounds of formula (I) and (IA), respectively, and their pharmaceutically usable salts for the manufacture of a medication for the prevention, delay of progression or the treatment of Alzheimer Disease, malaria or HIV infection.
Subject of the present invention is also the method for the prevention, delay of progression or the treatment of Alzheimer Disease, malaria or HIV infection, whereby a therapeutically effective dose of a compound of the general formula (I) or preferred formula (IA) or a pharmaceutically usable salt thereof is applied.
Subject of the present invention is also a pharmaceutical preparation that contains for the inhibition of beta-secretase, cathepsin D, plasmepsin and/or HIV-protease a compound of the general formula (I), or preferred of formula (IA) or a pharmaceutically usable salt thereof as well as commonly used ingredients.
Subject of the present invention is also a pharmaceutical preparation for the prevention, delay of progression or treatment of Alzheimer Disease, malaria and HIV infection that contains a compound of the general formula (I), or preferred of formula (IA) or a pharmaceutically usable salt thereof as well as commonly used ingredients.
The dose may vary within wide limits and has of course to be adapted to the individual circumstances in each individual case. In general, for oral administration, a daily dose of about 3 mg to about 3 g, preferably about 10 mg to about 1 g, for example about 300 mg, per adult (70 kg), divided into preferably 1-3 individual doses which may, for example, be of equal size, may be appropriate, although the upper limit specified may also be exceeded if this should be found to be appropriate; typically, children receive a lower dose according to their age and body weight. Examples
The examples which follow illustrate the present invention. All temperatures are reported in degrees Celsius, pressures in mbar. Unless stated otherwise, the reactions take place at room temperature. The abbreviation "Rf = xx (A)" means, for example, that the Rf value xx is determined in the solvent system A. The ratio of solvents relative to one another is always reported in parts by volume. Chemical names for end products and intermediates were generated with the aid of the program AutoNom 2000 (automatic nomenclature). The absolute configuration of all compounds is given. In cases where the stereochemical assignment could not be determined with certainty, the opposite configuration of the stereocenter is given in parenthesis.
HPLC gradients:
A) on Hypersil BDS C-18 (5 μm); column: 4 x 125 mm
I 90% water*/10% acetonitrile* to 0% water*/100% acetonitrile* in 5 minutes + 2.5 minutes (1.5 ml/min)
II 95% water75% acetonitrile* to 0% water7100% acetonitrile* in 40 minutes (0.8 ml/min)
* contains 0.1 % trifluoroacetic acid
B) on Supelco Discovery HS C18 (3 μm) (#569250-11); column: 4.6 x 50 mm
III 90% water*/10% acetonitrile* to 10% water*/90% acetonitrile* in 5 minutes, then to 1 % water*/99% acetonitrile* in 1 minute (2.2 ml/min)
* contains 0.05% trifluoroacetic acid
The following abbreviations are used:
Rf ratio of distance travelled by a substance to separation of the eluent front from the start point in thin-layer chromatography Rt retention time of a substance in HPLC (in minutes) m.p. melting point (temperature) General Method A: (N-Tos deprotection)
0.44 mmol of sodium dihydrogenphosphate and 0.90 mmol of sodium amalgam (10% Na) are added successively at room temperature to a solution of 0.09 mmol of "tosylamide" in 10 ml of methanol. The reaction mixture is left to stir for 2-18 hours, diluted with water and extracted with ethyl acetate. The organic phase is removed and washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
General Method B: (amide coupling I)
5.0 mmol of triethylamine and 1.2 mmol of thpropylphosphonic anhydride [68957-94-8] (50% in ethyl acetate) are added at room temperature to a solution of 1.0 mmol of "acid" and 1.2 mmol of "amine" in 20 ml of dichloromethane. The reaction mixture is stirred at room temperature for 1-3 hours and then diluted with dichloromethane, and washed with 1 M HCI and finally with brine. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
General Method C: (nitrile hydrolysis)
A suspension of 3.5 mmol of "nitrile" in 55 ml of ethanol and 55 ml of 2M NaOH is stirred at 800C for 21 hours. Subsequently, the mixture is concentrated and the residue is adjusted to pH 2-3 with 1 M HCI. The mixture is extracted with ethyl acetate (2X). The residue is diluted with dichloromethane, and washed with 1 M HCI and finally with brine. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained from the residue.
General Method D: (substitution of mesylate by nitrile)
A solution of 0.5 mmol of "mesylate" and 5.5 mmol of sodium cyanide in 3 ml of dimethyl sulphoxide is stirred at 600C for 20 hours. Subsequently, the mixture is diluted with ethyl acetate and washed with brine. The aqueous phase is extracted with ethyl acetate (2X). The combined organic phases are dried with sodium sulphate and concentrated by evaporation. The crude title compound is obtained from the residue. General Method E: (alcohol mesylation)
5 mmol of triethylamine and 2 mmol of methanesulphonyl chloride are added gradually at 00C to a solution of 1 mmol of "alcohol" in 10 ml of dichloromethane. The mixture is stirred at 00C for one hour, diluted with dichloromethane and washed with 1 M HCI. The organic phase is dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained from the residue.
General Method F (lactam reduction with BH3)
2-4 mmol of a solution of borane-tetrahydrofuran complex (1 M in tetrahydrofuran) are added at room temperature to a solution of 1.0 mmol of "lactam" in 800 ml of tetrahydrofuran. The reaction mixture is heated to 500C for 2-8 hours, admixed with 10 ml of methanol and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
General Method G: (Q-TIPS deprotection)
300 mmol of tetrabutylammonium fluoride (1 M in tetrahydrofuran) are added to a solution of 160 mmol of "TIPS ether" in 1 I of tetrahydrofuran. The mixture is stirred at room temperature for 18 hours, and the reaction mixture is diluted with brine and extracted with tert-butyl methyl ether (2X). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
General Method H: (alcohol-halomethylaryl coupling)
A solution of 235 mmol of "alcohol", 235 mmol of "halomethylaryl" and 282 mmol of tetrabutylammonium iodide in 800 ml of N,N-dimethylformamide is stirred at room temperature for 15 minutes. 239 mmol of sodium hydride (60% dispersion in oil) are added in portions, then the mixture is stirred at room temperature for 3 hours. Ice- water is added and the mixture is extracted with dichloromethane (2X). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F). General Method I: (Q-TIPS protection)
1.185 mol of imidazole and 261 mmol of thisopropylsilyl chloride are added to a solution of 238 mmol of "alcohol" in 1.7 I of N,N-dimethylformamide. The mixture is stirred at room temperature for 18 hours. Subsequently, the mixture is concentrated and the residue is admixed with 1 M HCI and water. The mixture is extracted with tert- butyl methyl ether (2X). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
General Method J: (N-tosylation)
12.43 mmol of 4-toluenesulphonyl chloride are added to a mixture of 11.3 mmol of "amine" in 200 ml of ethyl acetate and 200 ml of 2M Na2CO3 solution. The reaction mixture is stirred at room temperature for 17 hours. The phases are separated and the aqueous phase is extracted with ethyl acetate (2X). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
General Method K: (bromination)
60 mmol of bromotrimethylsilane are slowly added dropwise at 20-250C to a solution of 40 mmol of "benzyl alcohol" in 125 ml of chloroform. After the addition, the reaction mixture is concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
General Method L: (acid reduction with BH3)
9.4 mmol of a solution of borane-tetrahydrofuran complex (1 M in tetrahydrofuran) are added at room temperature to a solution of 4.7 mmol of "acid" in 50 ml of tetrahydrofuran. The reaction mixture is heated to 500C for 17 hours, admixed with 10 ml of methanol and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
General Method M: (alcohol alkylation)
239 mmol of sodium hydride (60% dispersion in oil) are added in portions at room temperature to a solution of 235 mmol of "alcohol" in 800 ml of N,N-dimethyl- formannide; the mixture is stirred at room temperature for 1 hour. Subsequently, 235 mmol of "haloalkyl" and, if appropriate, 47 mmol of tetrabutylammonium iodide are added and the mixture is stirred at room temperature for a further 3 hours. Ice- water is added and the mixture is extracted with dichloromethane (2X). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
General Method N: (amide coupling II)
98 mmol of thethylamine and 21.6 mmol of "acid chloride" are added to a solution of 19.6 mmol of "amine" in 300 ml of dichloromethane. The reaction mixture is stirred at room temperature for 1 hour and diluted with water and dichloromethane. The organic phase is dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
General Method O: (azide reduction)
0.3 mmol of Pd/C (10%) is added to a solution of 26.2 mmol of "azide" in 1.5 I of methanol. The mixture is hydrogenated up to complete conversion under a hydrogen atmosphere at standard pressure, then the mixture is filtered from the catalyst and concentrated by evaporation. The crude title compound is obtained from the residue.
General Method P: (substitution of mesylate by azide) A solution of 0.5 mmol of "mesylate" and 5.5 mmol of sodium azide in 5 ml of dimethyl sulphoxide is stirred at room temperature for 20 hours. Subsequently, the mixture is diluted with water and tert-butyl methyl ether and washed with brine. The aqueous phase is extracted with tert-butyl methyl ether (2X). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained from the residue.
General Method Q: (amide alkylation)
246 mmol of sodium hydride (60% dispersion in oil) are added in portions at room temperature to a solution of 123 mmol of "primary amide" in 1 I of N,N-dimethyl- formamide; the mixture is stirred at room temperature for 1 hour. Subsequently,
1.59 mol of "haloalkyl" are added and the mixture is stirred at room temperature for a further 3 hours. 1 M NaHCO3 is added and the mixture is extracted with tert-butyl methyl ether (2X). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
General Method R: (Substitution of mesylate by alkoxide)
28 mmol of sodium hydride (60% dispersion in oil) and 56 mmol of 3-methoxyphenol [150-19-6] are added at room temperature to a solution of 14 mmol of "mesylate" in 500 ml of N,N-dimethylformamide; the mixture is stirred at 900C for 8 hours. Subsequently, the mixture is cooled to room temperature. Water is added and the mixture is extracted with ethyl acetate/tetrahydrofuran (10:1 ) (3X). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
General Method S: (carbonyl reduction with BH3)
2 mmol of a solution of borane-tetrahydrofuran complex (1 M in tetrahydrofuran) are added at room temperature to a solution of 1.0 mmol of "carbonyl" in 10 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 2 hours, admixed with 10 ml of methanol and concentrated. The two diastereomeric title compounds are obtained from the residue by means of flash chromatography (SiO2 60F).
General Method T: (alkylmagnesium halide addition to the Weinreb amide) 1.705 mmol of a solution of "alkylmagnesium halide" are added at 00C to a solution of 0.34 mmol of "Weinreb amide" in 3 ml of tetrahydrofuran. The reaction mixture is stirred at 00C for 1.5 hours, quenched with 1 M KHSO4 and extracted with tert-butyl methyl ether (2X). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
General Method U: (Substitution of mesylate by thiolate) A solution of 0.5 mmol of "mesylate" and 2 mmol of "sodium thiolate" in 5 ml of dimethyl sulphoxide is stirred at 700C for 20 hours. The mixture is diluted with dichloromethane and 1 M NaHCO3 and the phases are separated. The aqueous phase is extracted with dichloromethane (2X). The combined organic phases are dried with sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
General Method V: (reductive amination)
A solution of 1.57 mmol of "ketone", 3.14 mmol of "amine", 4.71 mmol of sodium cyanoborohydhde and 1.57 mmol of acetic acid in 50 ml of ethanol is stirred at room temperature for 19 hours. The mixture is diluted with dichloromethane and 1 M NaOH, and the phases are separated. The aqueous phase is extracted with dichloromethane (2X). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained from the residue.
General Method W: (aryl halide formylation)
19.19 mmol of butyllithium (1.6M in hexane) are added at -78°C to a solution of 17.445 mmol of "aryl halide" in 50 ml of tetrahydrofuran. The reaction mixture is stirred at -78°C for 30 minutes and quenched with 34.89 mmol of N,N-dimethyl- formamide. The mixture is stirred at -78°C for a further one hour, and the reaction is stopped at this temperature by adding 1 M HCI. The mixture is warmed to room temperature, neutralized with 1 M NaOH and extracted with tert-butyl methyl ether (3X). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
General Method X: (dimethylcarbamic acid coupling)
8.7 mmol of sodium hydride (60% dispersion in oil) are added in portions at room temperature to a solution of 1.45 mmol of "alcohol" in 10 ml of tetrahydrofuran; the mixture is stirred at room temperature for 30 minutes. Subsequently, 5.08 mmol of dimethylcarbamoyl chloride are added and the mixture is stirred at room temperature for a further 3 hours. Ice-water is added and the mixture is extracted with dichloromethane (2X). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F). General Method Y: (chlorination)
The solution of 40 mmol of "benzyl alcohol" in 6.40 ml of pyridine and 100 ml of dichloromethane is added dropwise slowly at 0-50C to the precooled solution of 7.65 ml of thionyl chloride in 20 ml of dichloromethane. The reaction mixture is stirred at 00C and then at room temperature for one hour each and then poured into 200 ml of ice-water. The mixture is extracted with dichloromethane (2x200 ml). The organic phases are washed successively with 1 M aqueous sodium hydrogencarbonate solution (2x200 ml) and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
Example 1
N-((R(or S))-2-((2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxyipiperidin-2-yl)-1 -methylethyl)-2,2-dimethylpropionamide Analogously to Method A, N-{(R(or S))-2-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)pipehdin-2-yl]-1- methylethyl}-2,2-dimethylpropionamide is reacted. The title compound is identified based on the Rf value.
The starting materials are prepared as follows: a) N-UR(Or S))-2-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin- 6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-1 -methylethyl)-2,2-dimethyl- propionamide
Analogously to Method N, (R(or S))-2-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro- 2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-1 -methyl- ethylamine and 2,2-dimethylpropionyl chloride are reacted. The title compound is identified based on the Rf value.
b) (R(or S))-2-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-1 -methylethylamine Analogously to Method O, 6-[(3R,6S)-6-((R(or S))-2-azidopropyl)-1 -(toluene-4- sulphonyl)piperidin-3-yloxynnethyl]-4-(3-nnethoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazine is reacted. The title compound is identified based on the Rf value.
c) 6-r(3R,6S)-6-((R(or S))-2-Azidopropyl)-1 -(toluene-4-sulphonyl)piperidin-3- yloxyιinethyl1-4-(3-nnethoxypropyl)-3,4-dihvdro-2H-benzori ,41oxazine
A solution of 2.11 mmol of (S(or R))-2-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro- 2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)pipehdin-2-yl]-1 -methyl- ethyl methanesulphonate in 5 ml of 1 ,3-dimethyltetrahydropyrimidin-2-one (DMPU) is admixed with 21.1 mmol of sodium azide, and then the reaction mixture is heated to 800C. After 4 hours, the reaction mixture is cooled to room temperature, diluted with tert-butyl methyl ether, filtered through a small amount of silica gel and concentrated by evaporation. The title compound is identified from the residue based on the Rf value by means of flash chromatography (SiO2 60F).
d) (S(or R))-2-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-1 -methylethyl methanesulphonate
Analogously to Method E, (S(or R))-1 -[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro- 2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]propan-2-ol is reacted. The title compound is identified based on the Rf value.
e) (i) (R(or S))-1 -r(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-
6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-ylipropan-2-ol and (ii) (S(or R))-1-r(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-
6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-ylipropan-2-ol A solution of 2.76 mmol of [(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]acetaldehyde in 15 ml of tetrahydrofuran at 00C is admixed with 5.52 mmol of methylmagnesium bromide (3M in diethyl ether) and then the reaction mixture is warmed to room temperature. After 1 hour, the reaction mixture is poured onto 1 N potassium bisulphate solution and extracted with ethyl acetate (3X) - the combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compounds are identified from the residue based on the Rf values by means of flash chromatography (SiO2 60F).
f) r(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6-ylmethoxy1- 1 -(toluene-4-sulphonyl)piperidin-2-yl1acetaldehvde
8.60 mmol of diisobutylaluminium hydride (1 M in dichloromethane) is added dropwise at -300C to a solution of 5.06 mmol of [(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro- 2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]acetonitrile in 100 ml of dichloromethane. After 2 hours, the reaction mixture is quenched with 1 N HCI. The organic phase is extracted with water - the aqueous phases are each extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained from the residue as a brown resin. Rt = 4.76 (gradient I).
g) r(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6-ylmethoxy1- 1 -(toluene-4-sulphonyl)piperidin-2-yl1acetonitrile
Analogously to Method D, 10.6 mmol of (2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro- 2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl methyl methanesulphonate are reacted. The title compound is obtained as a yellow oil. Rf = 0.38 (2:1 EtOAc-heptane); Rt = 4.85 (gradient I).
h) (2S.5R)-5-f4-(3-Methoxypropyl)-3.4-dihvdrO-2H-benzof1.41oxazin-6-ylmethoxy1-1 -
(toluene-4-sulphonyl)piperidin-2-ylmethyl methanesulphonate Analogously to Method E, 9.91 mmol of [(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro- 2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]methanol are reacted. The crude title compound is obtained as a brown oil. Rf = 0.13 (1 :1 EtOAc- heptane); Rt = 4.83 (gradient I).
i) r(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6-ylmethoxy1-
1 -(toluene-4-sulphonyl)piperidin-2-yl1methanol
Analogously to Method G, 6.66 mmol of 4-(3-methoxypropyl)-6-[(3R,6S)-1 -(toluene- 4-sulphonyl)-6-triisopropylsilanyloxymethylpiperidin-3-yloxymethyl]-3,4-dihydro-2H- benzo[1 ,4]oxazine are reacted. The title compound is obtained as a yellowish oil. Rf = 0.35 (EtOAc); Rt = 4.42 (gradient I).
j) 4-(3-Methoxypropyl)-6-r(3R,6S)-1 -(toluene-4-sulphonyl)-6-thisopropylsilanyloxy- methylpiperidin-3-yloxymethyl1-3,4-dihvdro-2H-benzoπ ,41oxazine Analogously to Method F, 6.73 mmol of 4-(3-methoxypropyl)-6-[(3R,6S)-1 -(toluene-4- sulphonyl)-6-triisopropylsilanyloxymethylpiperidin-3-yloxynnethyl]-4H- benzo[1 ,4]oxazin-3-one are reacted. The crude title compound is obtained as a yellowish oil. Rf = 0.25 (1 :3 EtOAc-heptane); Rt = 6.30 (gradient I).
k) 4-(3-Methoxypropyl)-6-[(3R,6S)-1 -(toluene-4-sulphonyl)-6-triisopropylsilanyloxy- methylpiperidin-3-yloxymethvH-4H-benzo[1 ,41oxazin-3-one Analogously to Method H, 11 mmol of (3R,6S)-1 -(toluene-4-sulphonyl)-6-thiso- propylsilanyloxymethylpiperidin-3-ol and 11 mmol of 6-chloromethyl-4-(3- methoxypropyl)-4H-benzo[1 ,4]oxazin-3-one [857272-02-7] are reacted. The title compound is obtained as a yellow oil. Rf = 0.25 (1 :3 EtOAc-heptane); Rt = 6.84 (gradient I).
I) (3R,6S)-1-(Toluene-4-sulphonyl)-6-thisopropylsilanyloxymethylpiperidin-3-ol A solution of 0.018 mol of (3R,6S)-6-hydroxymethyl-1 -(toluene-4-sulphonyl)piperidin- 3-ol in 85 ml of N,N-dimethylformamide at room temperature is admixed with 0.09 mol of imidazole and 0.02 mol of triisopropylsilyl chloride. Further triisopropylsilyl chloride (1.8, 9 and 4.5 mmol) is added after 20, 23 and 39 hours. After a total of 42 hours, the reaction mixture is diluted with water and extracted with tert-butyl methyl ether (2X). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a yellow-orange oil. Rt = 5.70 (gradient III).
m) (3R,6S)-6-Hvdroxymethyl-1 -(toluene-4-sulphonyl)piperidin-3-ol An aqueous solution (28.5 ml) comprising approx. 6 mmol of (3R,6S)-6-hydroxy- methylpiperidin-3-ol from the preceding stage is brought to pH 8 with 0.5 ml of cone. HCI and then 39.6 mmol of sodium carbonate are added. A solution of 9 mmol of p-toluenesulphonyl chloride in 30 ml of tetrahydrofuran is added dropwise at room temperature and then the triphasic mixture is heated to 700C. Further p-toluene- sulphonyl chloride (3 mmol) is added after 16 and 18 hours. After a total of 22 hours, the reaction mixture is cooled to 400C and concentrated by evaporation. The aqueous residue is extracted with ethyl acetate (2X) - the combined organic phases are washed successively with 10% sodium carbonate solution (2X) and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a brown oil. Rf = 0.60 (dichloromethane-methanol = 4:1 + 1 % of 25% cone, ammonia); Rt = 1.82 (gradient III).
n) (3R,6S)-6-Hvdroxymethylpiperidin-3-ol
2.5 mmol of lithium aluminium hydride are suspended in tetrahydrofuran and a solution of 1.0 mmol of benzyl (2S,5R)-5-hydroxy-6-oxopiperidine-2-carboxylate in tetrahydrofuran is added dropwise at 66°C. After the addition has ended, the mixture is stirred at 66°C for another 2 hours. The suspension is cooled to 00C, quenched with water and acidified with 3N HCI. The tetrahydrofuran is removed on a rotary evaporator. The yellow suspension is taken up in ethyl acetate and the organic phase is washed with 2N HCI. The combined water phases are brought to pH >11 with 30% NaOH, the resulting suspension is filtered and the precipitate is washed with water. The yellow solution comprising the crude title compound is used directly in the next stage. Rf = 0.20 (dichloromethane-methanol = 4:1 + 1 % of 25% cone, ammonia).
o) Benzyl (2S,5R)-5-hvdroxy-6-oxopiperidine-2-carboxylate A solution of 0.017 mol of benzyl tert-butyl (2S,5R)-5-hydroxy-6-oxopiperidine-1 ,2- dicarboxylate [480460-75-1] in 48 ml of dichloromethane at room temperature is admixed with 12 ml of trifluoroacetic acid and the reaction mixture is stirred overnight. The reaction mixture is added dropwise to saturated sodium hydrogencarbonate solution and then extracted with dichloromethane (2X). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a white- yellow crystalline solid. Rf = 0.50 (EtOAc); Rt = 3.17 (gradient III). The following compound is prepared in an analogous manner by the process described in Example 1 :
2 N-((S(or R))-2-{(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H- benzo[1 ,41oxazin-6-ylmethoxyipiperidin-2-yl)-1 -methyl -ethyl )-2, 2- dimethylpropionamide
Starting from (R(or S))-1 -[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]propan-2-ol
(Example 1 e(i)).
Example 15
6-{(3R,6S)-6-r2-(2-Methoxyethoxy)-2-methylpropylipiperidin-3-yloxymethyl)-4-(3- methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazine
Analogously to Method A, 6-[(3R,6S)-6-[2-(2-methoxyethoxy)-2-methylpropyl]-1-
(toluene-4-sulphonyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazine is reacted. The title compound is identified based on the Rf value.
The starting materials are prepared as follows: a) 6-r(3R,6S)-6-r2-(2-Methoxyethoxy)-2-methylpropyl1-1 -(toluene-4- sulphonyl)piperidin-3-yloxymethyl1-4-(3-methoxypropyl)-3,4-dihvdro-2H- benzoH ,41oxazine
A solution of 0.54 mmol of 1 -[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2-methylpropan- 2-ol in 2 ml of N,N-dimethylformamide at room temperature is admixed with 2.68 mmol of sodium hydride (60% dispersion in oil) and the reaction mixture is stirred for 1 hour. The reaction mixture is then admixed with 8.02 mmol of 1 -chloro-2-methoxyethane and 0.11 mmol of tetrabutylammonium iodide and heated to 900C. After 19 hours, the reaction mixture is cooled to room temperature, admixed cautiously with water and extracted with ethyl acetate (2X) - the combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value. b) 1 -r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-vπ-2-methylpropan-2-ol
A solution of 2.45 mmol of 1 -[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]propan-2-one in 10 ml of tetrahydrofuran at room temperature is admixed with 2.45 mmol of methyl- magnesium chloride (3M in tetrahydrofuran). After 4 hours, the reaction mixture is poured onto 1 N potassium bisulphate solution and extracted with ethyl acetate (2X) - the combined organic phases are dried with sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value.
c) 1 -r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-ylipropan-2-one
A solution of 5.0 mmol of (S,R)-1 -[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]propan-2-ol (Example 1 e(i,ii)) in 10 ml of dimethyl sulphoxide and 50 ml of dichloromethane at 00C is admixed with 25.0 mmol of triethylamine and 16.5 mmol of pyhdine-sulphur trioxide complex (in portions over 5 minutes) and then warmed slowly to room temperature. After 3 hours, the reaction mixture is poured onto ice-water, acidified to pH 2.5 with 1 N potassium bisulphate solution and extracted with diethyl ether (2X). The combined organic phases are washed successively with water and 5% sodium hydrogencarbonate solution, dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value.
Example 16
2-{(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6- ylmethoxyipiperidin-2-yl)-1 ,1 -dimethylethyl dimethylcarbamate Analogously to Method A, 2-[5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-1 ,1 - dimethylethyl dimethylcarbamate is reacted. The title compound is identified based on the Rf value. The starting material is prepared as follows: a) 2-r5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzori ,41oxazin-6-ylnnethoxy1-1 -
(toluene-4-sulphonyl)piperidin-2-yl1-1 ,1-dimethylethyl dimethylcarbamate A solution of 0.51 mmol of 1 -[5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2- methylpropan-2-ol (Example 15b) in 3 ml of tetrahydrofuran at room temperature is admixed with 2.05 mmol of potassium hydride (60% dispersion in oil), and the reaction mixture is stirred for 1 hour. 5.13 mmol of dimethylcarbamoyl chloride are added, and the reaction mixture is stirred further at room temperature overnight. After 19 hours, the reaction mixture is cooled to 00C, quenched cautiously with ethanol, diluted with water and extracted with ethyl acetate (2X). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value.
Example 17
3-((2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N-(tetrahvdropyran-4-yl)propionamide Analogously to Method A, 0.013 mmol of 3-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2,2- dimethyl-N-(tetrahydropyran-4-yl)propionamide is reacted. The title compound is obtained as a yellow oil. Rf = 0.10 (200:20:1 dichloromethane-methanol-25% cone, ammonia); Rt = 3.38 (gradient I).
The starting materials are prepared as follows: a) 3-r(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2,2-dimethyl-N- (tetrahvdropyran-4-yl)propionamide
A solution of 0.016 mmol of 3-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2,2-dimethyl- propionic acid in 2 ml of dichloromethane at room temperature is admixed with 0.032 mmol of (1 -chloro-2-methylpropenyl)dimethylamine, stirred for 1.5 hours and then admixed with 0.080 mmol of tetrahydropyran-4-ylamine. After 1 hour, the reaction mixture is diluted with water and extracted with dichloromethane (3X) - the combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a yellow oil. Rf = 0.20 (2:1 EtOAc- heptane); Rt = 4.74 (gradient I).
b) 3-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2,2-dimethylpropionic acid
A solution of 0.037 mmol of methyl 3-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro- 2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2,2- dimethylpropionate in 1.5 ml of methanol and 1.5 ml of tetrahydrofuran at room temperature is admixed with 2 ml of 4N NaOH and then heated to 600C. After
4 hours, the reaction mixture is cooled to room temperature and partitioned between ethyl acetate and 4N HCI. The aqueous phase is extracted with ethyl acetate (2X)
- the combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a yellow oil. Rf = 0.30 (EtOAc); Rt = 4.84 (gradient I).
c) Methyl 3-f(2S.5R)-5-f4-(3-methoxypropyl)-3.4-dihvdrO-2H-benzof1.41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2,2-dimethylpropionate
A solution of 0.64 mmol of methyl (R,S)-3-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2- methylpropionate (Example 53c) in 20 ml of tetrahydrofuran at -78°C is admixed with 0.80 mmol of a lithium diisopropylamide solution (0.5M in tetrahydrofuran) within
5 minutes, stirred for 1.5 hours and then admixed with 2.96 mmol of methyl iodide. After 2 hours, the reaction mixture is quenched with 0.5M HCI and extracted with dichloromethane (2X) - the combined organic phases are washed with water (2X), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a brown oil. Rf = 0.34 (1 :1 EtOAc-heptane); Rt = 5.47 (gradient I).
Alternative synthesis for methyl 3-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2,2-dimethyl- propionate (Example 17c):
A solution of 4.52 mmol of methyl isobutyrate in 2.5 ml of tetrahydrorfuran at -78°C is admixed with 4.52 mmol of a lithium diisopropylamide solution (0.5M in cyclohexane) and stirred for 30 minutes. 9.04 mmol of hexamethylphosphoramide (HMPA) and a solution of 1.13 mmol of 6-[(3R,6S)-6-bromomethyl-1 -(toluene-4-sulphonyl)piperidin- 3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1 ,4]oxazine in 2.5 ml of tetrahydrofuran are added dropwise. The reaction mixture is stirred further at -78°C for 30 minutes, at -100C for 30 minutes and at 00C for 3 hours. The reaction mixture is quenched at -100C with 1 M HCI until a weakly acidic reaction and then extracted with ethyl acetate (3X). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a brown oil.
d) 6-r(3R,6S)-6-Bromomethyl-1 -(toluene-4-sulphonyl)piperidin-3-yloxymethyl1-4-(3- methoxypropyl)-3,4-dihvdro-2H-benzo[1 ,41oxazine
A mixture of 1.75 mmol of (2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-ylmethyl methanesulphonate (Example 1 h) and 17.5 mmol of lithium bromide in 6 ml of N1N- dimethylformamide is stirred overnight at 65°C. Further lithium bromide (17.5 mmol) is added after 16 hours. After a total of 19 hours, the reaction mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate (3X). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a yellow oil. Rf = 0.45 (1 :1 EtOAc-heptane); Rt = 5.42 (gradient I). Alternative synthesis for 3-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)pipeπdin-2-yl]-2,2-dimethyl- propionic acid methyl ester (Example 17c)
Analogously to Method H, 6.77 mmol of 3-[(2S,5R)-5-hydroxy-1 -(toluene-4- sulphonyl)piperidin-2-yl]-2,2-dimethylpropionic acid methyl ester and 7.10 mmol of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1 ,4]oxazin-3-one [857272-02-7] are reacted. The title compound is obtained as a yellow oil. Rf = 0.40 (2:1 EtOAc- heptane); Rt = 5.14 (gradient I).
e) 3-r(2S,5R)-5-Hvdroxy-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2,2-dimethylpropionic acid methyl ester
A solution of 11.03 mmol of 3-[(2S,5R)-5-(4-methoxybenzyloxy)-1-(toluene-4- sulphonyl)piperidin-2-yl]-2,2-dimethylpropionic acid methyl ester is dissolved in 100 ml of methanol. 1.03 mmol of Pd/C (10%) are added under argon. The reaction system is purged 3 times with hydrogen, and the reaction mixture is stirred under an atmosphere of hydrogen for 16 hours, then filtered through Hyflo, washing with methanol. The filtrate is concentrated under reduced pressure and purified by flash chromatography (SiO2 60F), to afford the title compound as a colourless oil. Rf = 0.38 (EtOAc-heptane 2:1 ); Rt = 4.07 (gradient I).
f) 3-r(2S,5R)-5-(4-Methoxybenzyloxy)-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2,2- dimethylpropionic acid methyl ester
A solution of 44.20 mmol of potassium tert-butoxide and 2.21 mmol of 18-crown-6 is dissolved in 200 ml of dry tetrahydrofuran and cooled to -78°C. A solution of 11.05 mmol of 3-[(2S,5R)-5-(4-methoxybenzyloxy)-1 -(toluene-4-sulphonyl)piperidin- 2-yl]-propionic acid methyl ester in 50 ml of dry tetrahydrofuran is added dropwise. The reaction mixture is stirred at -78°C for 1 hour, 44.20 mmol of iodomethane are then added and the reaction mixture is stirred for another 1.5 hours, then quenched with 0.2N HCI. The reaction mixture is allowed to reach room temperature, diluted with 0.2N HCI, extracted with dichloromethane (3X). The combined organic extracts are dried over sodium sulphate and concentrated to afford the crude product as a colourless oil. Rf = 0.60 (EtOAc-heptane 2:1 ); Rt = 5.43 (gradient I). g) 3-[(2S,5R)-5-(4-Methoxybenzyloxy)-1 -(toluene-4-sulphonyl)piperidin-2-vπ- propionic acid methyl ester
28.48 mmol of sodium borohydride are slowly added to a solution of 14.24 mmol of (E)-3-[(2S,5R)-5-(4-methoxybenzyloxy)-1 -(toluene-4-sulphonyl)piperidin-2-yl]acrylic acid methyl ester and 1.424 mmol of nickel chloride hexahydrate in 500 ml of methanol, at 00C. The reaction mixture is stirred for 1 hour, then filtered through Hyflo, washing with methanol. The filtrate is concentrated under reduced pressure, and purified by flash chromatography (SiO2 60F) to afford the title compound as a colourless oil. Rf = 0.36 (EtOAc-heptane); Rt = 5.03 (gradient I).
h) (E)-3-r(2S,5R)-5-(4-Methoxybenzyloxy)-1 -(toluene-4-sulphonyl)piperidin-2-yl1- acrylic acid methyl ester
A suspension of 21.07 mmol of sodium hydride (60% in oil) in 200 ml of tetrahydro- furan is cooled to 00C and treated with a solution of 22.47 mmol of trimethyl phosphonoacetate in 40 ml of tetrahydrofuran. The reaction mixture is stirred at 00C for 30 minutes, before the addition of 14.044 mmol of (2S,5R)-5-(4-methoxy- benzyloxy)-1 -(toluene-4-sulphonyl)pipehdine-2-carbaldehyde in 40 ml of tetrahydrofuran. After 1 hour, the reaction mixture is quenched with 0.5N HCI, extracted with dichloromethane (3X), dried over sodium sulphate and concentrated under reduced pressure to afford the crude product as a yellow oil. Rf = 0.57 (EtOAc-heptane 2:1 ); Rt = 5.01 (gradient I).
i) (2S,5R)-5-(4-Methoxybenzyloxy)-1-(toluene-4-sulphonyl)piperidine-2- carbaldehvde
A solution of 20.844 mmol of oxalyl chloride in 100 ml of dichloromethane at -78°C is treated with 41.69 mmol of N,N-dimethyl sulphoxide. The reaction mixture is stirred at -78°C for 45 minutes, a solution of 13.90 mmol of [(2S,5R)-5-(4-methoxybenzyloxy)- 1 -(toluene-4-sulphonyl)piperidin-2-yl]methanol in 30 ml of dichloromethane is then added dropwise, and the reaction mixture is stirred for another hour at -78°C. 97.27 mmol of thethylamine are then added, the reaction mixture is allowed to reach room temperature over 30 minutes, poured onto 0.5N HCI, extracted with dichloromethane (3X), dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a beige sticky solid. Rf = 0.57 (EtOAc-heptane 2:1 ); Rt = 4.78 (gradient I).
h) r(2S,5R)-5-(4-Methoxybenzyloxy)-1-(toluene-4-sulphonyl)piperidin-2-yl1methanol Following Method G, 21.123 mmol of (2S,5R)-5-(4-methoxy-benzyloxy)-1 -(toluene-4- sulphonyl)-2-triisopropylsilanyloxymethylpipehdine are reacted with 25.35 mmol of tetrabutylammonium fluoride to afford the title compound as a yellow oil. Rf = 0.13 (EtOAc-heptane 1 :1 ); Rt = 4.34 (gradient I).
i) (2S,5R)-5-(4-Methoxybenzyloxy)-1-(toluene-4-sulphonyl)-2- trusopropylsilanyloxymethylpiperidine
Following Method H, 25.13 mmol of (3R,6S)-1-(toluene-4-sulphonyl)-6-thisopropyl- silanyloxymethylpiperidin-3-ol (Example 11) are reacted with 27.643 mmol of 4-methoxybenzyl chloride to afford the title compound as an orange oil. Rf = 0.60 (EtOAc-heptane 1 :1 ); Rt = 7.01 (gradient I).
The following compounds are prepared in an analogous manner by the process described in Example 17:
18 3-{(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6- ylmethoxyipiperidin-2-yl)-2,2-dimethyl-1 -morpholin-4-ylpropan-1 -one
19 3-{(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6- ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N-(tetrahvdropyran-4-ylmethyl)- propionamide
20 3-{(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6- ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N-(S)-1-piperidin-3- ylmethylpropionamide
21 3-{(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6- ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N-(R)-1-piperidin-3- ylmethylpropionamide 3-((2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N-(R)-1-piperidin-2- ylmethylpropionannide
3-{(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6- ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N-(S)-1-piperidin-2- ylmethylpropionannide
3-{(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6- ylmethoxyipiperidin-2-yl)-2,2,N-trimethylpropionamide
N-Cvclopropylmethyl-3-{(2S,5R)-5-r4-(3-methoxypropyl)-3,4-dihvdro-2H- benzoπ ,41oxazin-6-ylnnethoxyipipeπdin-2-yl)-2,2-dinnethylpropionannide
N-(2-Carbamoyl-2-methylpropyl)-3-{(2S,5R)-5-r4-(3-methoxypropyl)-3,4- dihvdro-2H-benzoπ ,41oxazin-6-ylnnethoxyipipeπdin-2-yl)-2,2- dimethylpropionamide
3-{(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6- ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N-r(1 S,5R,6S)-1 -(3-oxa- bicvclo[3.1.01hex-6-yl)methvHpropionannide
3,4-dihvdro-2H-Benzori ,41oxazin-6-ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N- (1 R,5S,6R)-3-oxa-bicvclo[3.1.OIhex-6-ylpropionannide
3-{(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6- ylmethoxyipipeπdin-2-yl)-2,2-dinnethyl-N-r(S)-1 -(tetrahvdrofuran-2-yl)ιinethyl1- propionamide
N-(4-Methoxycvclohexyl)-3-{(2S,5R)-5-r4-(3-methoxypropyl)-3,4-dihvdro-2H- benzoπ ,41oxazin-6-ylnnethoxyipipeπdin-2-yl)-2,2-dinnethylpropionannide
N-((R)-2-Hvdroxy-3-methoxypropyl)-3-{(2S,5R)-5-r4-(3-methoxypropyl)-3,4- dihvdro-2H-benzoπ ,41oxazin-6-ylnnethoxyipipeπdin-2-yl)-2,2- dimethylpropionamide 32 3-((2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxyipipeπdin-2-yl)-2,2-dinnethyl-N-(2-ιinorpholin-4-ylethyl)-propionannide
33 3-((2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N-[(S)-1 -(6-oxaspiro[2.51oct-1 - vDmethylipropionannide
34 3-((2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N-[(R)-1 -(6-oxaspiro[2.51oct-1 - vDmethylipropionannide
94 3-{(2S,5R)-5-rspiror(4-(3-Methoxypropyl)-3-oxo-3,4-dihvdro-2H- benzori ,41oxazine)-2,4'-(tetrahvdropyran)1-6-ylnnethoxyipipeπdin-2-yl)-2,2- dimethyl-N-(tetrahvdropyran-4-ylnnethyl)propionannide and_
95 3-{(2S,5R)-5-rspiror(4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazine)- 2,4'-(tetrahydropyran)1-6-ylnnethoxyipiperidin-2-yl)-2,2-dinnethyl-N-(tetrahvdro- pyran-4-ylnnethyl)propionannide
Figure imgf000052_0001
Starting from 6-bromomethylspiro[4-(3-methoxypropyl)-4H-benzo[1 ,4]oxazin-2,4'-(tetra- hydropyran)]-3-one.
The starting materials are prepared as follows: a) 6-Bromomethylspiro[4-(3-methoxypropyl)-4H-benzo[1 ,41oxazin-2,4'- (tetrahydropyran)1-3-one
Figure imgf000052_0002
A solution of 2.086 mmol of spiro[4-(3-methoxypropyl)-6-nnethyl-4H- benzo[1 ,4]oxazine]-2,4'-(tetrahydropyran)]-3-one in 20 ml of carbon tetrachloride is heated at 700C and treated with 3.338 mmol of N-bromosuccinimide, 0.073 mmol of 2,2'-azobis(2-methylpropionitrile) and 0.052 mmol of benzoyl peroxide. The reaction mixture is stirred at 800C for 60 hours, then cooled to 0°C, filtered through Hyflo, and concentrated under reduced pressure. Purification by flash chromatography (SiO2 60F) affords the title compound as a colourless oil. Rf = 0.33 (EtOAc-heptane 1 :1 ); Rt = 4.38 (gradient I).
b) Spiro[4-(3-Methoxypropyl)-6-methyl-4H-benzo[1 ,41oxazine1-2,4'- (tetrahvdropyran)1-3-one
Figure imgf000053_0001
A solution of 6.72 mmol of 6-methylspiro[4H-benzo[1 ,4]oxazin-2,4'-(tetrahydro- pyran)]-3-one in 80 ml of acetonitrile is treated with 13.44 mmol of 1 -chloro-3- methoxypropane [36215-07-3], 37.03 mmol of potassium fluoride on alox and 0.134 mmol of potassium iodide. The reaction mixture is stirred for 18 hours, cooled to room temperature and filtered through Hyflo. Purification by flash chromatography (SiO2 60F) affords the title compound as a colourless oil. Rf = 0.47 (EtOAc-heptane 1 :1 ); Rt = 4.29 (gradient I).
c) 6-Methylspiro[4H-benzo[1 ,41oxazine-2,4'-(tetrahvdropyran)1-3-one
Figure imgf000053_0002
A solution of 19.39 mmol of 4-(4-methyl-2-nitrophenoxy)tetrahydropyran-4-carboxylic acid in 60 ml of acetic acid and 6 ml of water at 500C is treated with 110.55 mmol of iron powder. The reaction mixture is stirred at 50°C for 18 hours, cooled to room temperature and filtered through Hyflo. The filter cake is washed with dichloro- methane and water. The phases are separated, the aqueous phase is re-extracted 3X with dichloromethane. The combined organic extracts are dried over sodium sulphate and concentrated under reduced pressure. Purification by flash chromato- graphy (SiO2 60F) affords the title compound as a white solid. Rf = 0.38 (EtOAc- heptane 1 :1 ); Rt = 3.52 (gradient I).
d) 4-(4-Methyl-2-nitrophenoxy)tetrahvdropyran-4-carboxylic acid To a solution of 19.39 mmol of 4-methyl-2-nitrophenol in 70 ml of tetrahydrofuran is added 165 mmol of powdered NaOH and the reaction mixture is stirred at room temperature for 15 minutes. 175 mmol of tetrahydro-4H-pyran-4-one are added, and the mixture is cooled to 00C. 78 mmol of chloroform are added dropwise, and the reaction mixture is stirred at 00C for 1 hour, then at room temperature for 18 hours. The reaction mixture is partitioned between water and dichloromethane. The aqueous phase is re-extracted with dichloromethane (3X). The aqueous phase is acidified with 4M HCI, then extracted 3X with dichloromethane. These organic extracts are dried over sodium sulphate, and concentrated to afford the crude title compound as a brown oil. Rf = 0.15 (EtOAc-heptane 1 :1 ).
96 3-{(2S,5R)-5-r4-(3-Methoxypropyl)-2-spirocvclopropyl-3-oxo-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N-(tetrahvdropyran- 4-yl methyl )propionamide and
97 3-{(2S,5R)-5-r4-(3-Methoxypropyl)-2-spirocvclopropyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N-(tetrahvdropyran- 4-yl methyl )propionamide
Figure imgf000054_0001
Starting from 6-hydroxymethyl-4-(3-methoxypropyl)-2-spirocyclopropyl-4H- benzo[1 ,4]oxazin-3-one. The starting materials are prepared as follows: a) G-Hydroxynnethyl^-O-nnethoxypropyD^-spirocvclopropyl^H- benzoH ,41oxazin-3-one
Figure imgf000055_0001
A solution of 4.236 mmol of 4-(3-methoxypropyl)-2-spirocyclopropyl-3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazine-6-carboxylic acid in 10 ml of tetrahydrofuran is treated with 4.871 mmol of triethylamine and cooled to 00C. 4.66 mmol of ethyl chloroformate is added dropwise and the reaction mixture is stirred for 1.5 hours at 00C. The mixture is then diluted with dichloromethane, and washed with cold 0.5N HCI. The aqueous layer is re-extracted with dichloromethane (2X), the combined organic layers are dried over sodium sulphate, and concentrated under reduced pressure. This intermediate is re-dissolved in tetrahydrofuran (10 ml, including washings), and added dropwise to a solution of 10.6 mmol of sodium borohydhde in 4 ml of water at 0°C. Once the addition is completed, the reaction mixture is warmed to room temperature, and stirred for 2 hours. The reaction mixture is cautiously acidified with 1 N HCI, and extracted with tert-butyl methyl ether. The organic extracts are washed with 1 N NaOH and brine, dried over sodium sulphate and concentrated. This affords the title compound as a colourless oil. Rf = 0.15 (EtOAc-heptane 2:1 ); Rt = 3.22 (gradient I).
b) 4-(3-Methoxypropyl)-2-spirocvclopropyl-3-oxo-3,4-dihvdro-2H-benzoπ ,41oxazine- 6-carboxylic acid
Figure imgf000055_0002
Following the procedure for Example 17b, 4.389 mmol of 4-(3-methoxypropyl)-2- spirocyclopropyl-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazine-6-carboxylic acid methyl ester are reacted. The title compound is isolated as a white solid. Rf = 0.10 (EtOAc- heptane 1 :1 ); Rt = 3.48 (gradient I).
c) 4-(3-Methoxypropyl)-2-spirocvclopropyl-3-oxo-3,4-dihvdro-2H-benzoπ ,41oxazine- 6-carboxylic acid methyl ester
Figure imgf000056_0001
Following the procedure for Example 94b, 10.76 mmol of 2-spirocyclopropyl-3-oxo- 3,4-dihydro-2H-benzo[1 ,4]oxazine-6-carboxylic acid methyl ester are reacted to afford the title compound as a colourless oil. Rf = 0.45 (EtOAc-heptane 1 :1 ); Rt = 4.30 (gradient I).
d) 2-Spirocvclopropyl-3-oxo-3,4-dihvdro-2H-benzoπ ,41oxazine-6-carboxylic acid methyl ester
Figure imgf000056_0002
Following the procedure for Example 94c, 11.22 mmol of 4-(1 -methoxycarbonylcyclo- propoxy)-3-nitrobenzoic acid methyl ester are reacted to afford the title compound as a pale yellow solid. Rf = 0.45 (EtOAc-heptane 1 :1 ); Rt = 3.56 (gradient I).
e) 4-(1 -Methoxycarbonylcvclopropoxy)-3-nitrobenzoic acid methyl ester
To a suspension of 20.81 mmol of sodium hydride in 10 ml of dry N,N-dimethyl- formamide at 00C is added a solution of 17.34 mmol of methyl 1 -hydroxy-1 - cyclopropane carboxylate in 10 ml of dry N,N-dimethylformamide. The reaction mixture is stirred at 00C for 1 hour, before the addition of 27.74 mmol of methyl 4-fluoro-3-nitrobenzoate. The reaction mixture is stirred at 00C for 1 hour, then at room temperature for 3 hours, poured onto saturated aqueous ammonium chloride, extracted with tert-butyl methyl ether (3X), dried over sodium sulphate and concentrated. Purification by flash chromatography (SiO2 60F) affords the title compound as a thick yellow oil. Rf = 0.48 (EtOAc-heptane 1 :1 ); Rt = 4.18 (gradient I).
98 3-{(2S,5R)-5-r9-(3-Methoxypropyl)-9H-carbazol-2-ylmethoxyipiperidin-2-yl)-
2,2-dimethyl-N-(tetrahvdropyran-4-ylmethyl)propionamide Starting from [9-(3-methoxypropyl)-9H-carbazol-2-yl]methanol.
The starting material is prepared as follows: a) [9-(3-Methoxypropyl)-9H-carbazol-2-vHmethanol
A solution of 8.307 mmol of 9-(3-methoxypropyl)-9H-carbazole-2-carboxylic acid methyl ester [925930-95-6] in 65 ml of tetrahydrofuran is cooled to 00C and treated over 1 hour with 83.07 mmol of lithium aluminium hydride. The reaction is then stirred at room temperature for 2 hours, quenched cautiously with 6 ml of water, followed by 2 ml of 2N NaOH and 20 ml of water. The resulting solution is stirred at room temperature for 18 hours, filtered through Hyflo, and concentrated under reduced pressure. Purification by flash chromatography (SiO2 60F) affords the title compound as a yellow oil. Rf = 0.43 (EtOAc); Rt = 4.18 (gradient I).
Example 35
3-{(2S,5R)-5-r2-(4-Methoxybutyl)-6-methylpyridin-4-ylmethoxyipiperidin-2-yl)-2,2- dimethyl-N-(tetrahvdropyran-4-ylmethyl)propionamide
Analogously to Method A, 3-[(2S,5R)-5-[2-(4-methoxybutyl)-6-methylpyridin-4- ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2,2-dimethyl-N-(tetrahydropyran-4- ylmethyl)propionamide is reacted. The title compound is identified based on the
Rf value.
The starting materials are prepared as follows: a) 3-r(2S,5R)-5-r2-(4-Methoxybutyl)-6-methylpyridin-4-ylmethoxy1-1 -(toluene-4- sulphonyl)piperidin-2-yl1-2,2-dimethyl-N-(tetrahvdropyran-4- yl methyl )propionamide Analogously to Example 23a, 3-[(2S,5R)-5-[2-(4-methoxybutyl)-6-nnethylpyridin-4- ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2,2-dinnethylpropionic acid and C-(tetrahydropyran-4-yl)methylannine are reacted. The title compound is identified based on the Rf value.
b) 3-r(2S,5R)-5-r2-(4-Methoxybutyl)-6-methylpyridin-4-ylmethoxy1-1 -(toluene-4- sulphonyl)piperidin-2-vH-2,2-dimethylpropionic acid
Analogously to Example 17b, methyl 3-[(2S,5R)-5-[2-(4-methoxybutyl)-6-methyl- pyridin-4-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2,2-dimethylpropionate is reacted. The title compound is identified based on the Rf value.
c) Methyl 3-f(2S.5R)-5-f2-(4-methoxybutyl)-6-methylpyridin-4-ylmethoxy1-1 -(toluene- 4-sulphonyl)piperidin-2-vH-2,2-dimethylpropionate
Analogously to Example 17c (alternative synthesis), 4-[(3R,6S)-6-bromomethyl-1 - (toluene-4-sulphonyl)piperidin-3-yloxymethyl]-2-(4-methoxybutyl)-6-methylpyhdine and methyl isobutyrate are reacted. The title compound is identified based on the Rf value.
d) 4-r(3R,6S)-6-Bromomethyl-1 -(toluene-4-sulphonyl)piperidin-3-yloxymethyl1-2-(4- methoxybutyl)-6-methylpyridine
Analogously to Example 17d, (2S,5R)-5-[2-(4-methoxybutyl)-6-methylpyridin-4- ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-ylmethyl methanesulphonate is reacted. The title compound is identified based on the Rf value.
e) (2S,5R)-5-r2-(4-Methoxybutyl)-6-methylpyridin-4-ylmethoxy1-1 -(toluene-4- sulphonyl)piperidin-2-ylmethyl methanesulphonate
Analogously to Method E, [(2S,5R)-5-[2-(4-methoxybutyl)-6-methylpyhdin-4- ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]methanol is reacted. The title compound is identified based on the Rf value.
f) f(2S.5R)-5-f2-(4-Methoxybutyl)-6-methylpyridin-4-ylmethoxy1-1 -(toluene-4- sulphonyl)piperidin-2-yl1methanol Analogously to Method G, 2-(4-methoxybutyl)-6-methyl-4-[(3R,6S)-1 -(toluene-4- sulphonyl)-6-tπisopropylsilanyloxynnethylpipeπdin-3-yloxynnethyl]pyπdine is reacted. The title compound is identified based on the Rf value.
g) 2-(4-Methoxybutyl)-6-methyl-4-[(3R,6S)-1-(toluene-4-sulphonyl)-6- triisopropylsilanyloxymethylpiperidin-3-yloxymethvnpyridine Analogously to Method H, (3R,6S)-1 -(toluene-4-sulphonyl)-6-triisopropylsilanyloxy- methylpipehdin-3-ol (Example 11) and 4-bromomethyl-2-(4-methoxybutyl)-6-methyl- pyhdine are reacted. The title compound is identified based on the Rf value.
h) 4-Bromomethyl-2-(4-methoxybutyl)-6-methylpyhdine
Analogously to Method K, [2-(4-methoxybutyl)-6-methylpyridin-4-yl]methanol is reacted. The title compound is identified based on the Rf value.
i) [2-(4-Methoxybutyl)-6-methylpyhdin-4-vHmethanol
Analogously to Method S, 2-(4-methoxybutyl)-6-methylpyridine-4-carbaldehyde is reacted. The title compound is identified based on the Rf value.
j) 2-(4-Methoxybutyl)-6-methylpyhdine-4-carbaldehvde
Analogously to Method W, 4-bromo-2-(4-methoxybutyl)-6-methylpyridine is reacted.
The title compound is identified based on the Rf value.
k) 4-Bromo-2-(4-methoxybutyl)-6-methylpyhdine
A solution of 0.208 mmol of 4-bromo-2-(4-methoxybut-1 -ynyl)-6-methylpyhdine in 1 ml of tetrahydrofuran is admixed with 0.208 mmol of triethylamine and 0.008 mmol of platinum oxide hydrate and hydrogenated under a hydrogen atmosphere at standard pressure for 4 hours. The mixture is filtered from the catalyst; the filtercake is washed with tetrahydrofuran. The clear solution is washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value.
I) 4-Bromo-2-(4-methoxybut-1 -vnyl)-6-methylpyridine
1.2 mmol of diisopropylamine and 1.1 mmol of 4-methoxybutyne [158878-83-2] are added to a mixture of 1 mmol of 2,4-dibromo-6-methylpyridine [79055-52-0], 0.07 mmol of copper(l) iodide and 0.07 mmol of bis(triphenylphosphine)palladiunn chloride in 3.6 ml of dioxane. The mixture is stirred at room temperature for 1.5 hours and diluted with water. The mixture is extracted with tert-butyl methyl ether (3X) - the combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value.
The following compounds are prepared in an analogous manner by the process described in Example 35:
36 3-{(2S,5R)-5-r3-(4-Methoxybutyl)-5-methylbenzyloxyipiperidin-2-yl)-2,2- dimethyl-N-(tetrahvdropyran-4-ylmethyl)propionamide Starting from 1 -bromo-3-(4-methoxybutyl)-5-methylbenzene.
The starting materials are prepared as follows: a) 1 -Bromo-3-(4-methoxybutyl)-5-methylbenzene
A solution of 0.208 mmol of 1 -bromo-3-((E,Z)-4-methoxybut-1 -enyl)-5-methylbenzene in 1 ml of ethanol is admixed with 0.008 mmol of palladium on carbon (10%) and hydrogenated under a hydrogen atmosphere at standard pressure for 2 hours. The mixture is filtered from the catalyst, and the filtercake is washed with ethanol and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value.
b) 1 -Bromo-3-((E,Z)-4-methoxybut-1 -envD-5-methylbenzene
3.45 mmol of sodium bis(trimethylsilyl)amide are added at 00C to a suspension of 3.45 mmol of (3-methoxypropyl)triphenylphosphonium bromide [111088-69-8] in 7.5 ml of tetrahydrofuran. The solution is stirred at 00C for 30 minutes and 2.3 mmol of 3-bromo-5-methylbenzaldehyde [1611-92-3] are added. The reaction mixture is warmed to room temperature over 30 minutes and diluted with tert-butyl methyl ether. The mixture is washed with 1 M sodium hydrogencarbonate solution (2X), dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value. 37 3-{(2S,5R)-5-r4-Methoxy-3-(3-methoxypropoxy)benzyloxylpiperidin-2-yl)-2,2- dimethyl-N-(tetrahvdropyran-4-ylnnethyl)propionannide
Starting from 4-bromomethyl-1 -methoxy-2-(3-nnethoxypropoxy)benzene [172900-73-1].
38 3-{(2S,5R)-5-r4-(3-Methoxypropyl)-2,2-dimethyl-2H-chromen-6-ylmethoxy1- piperidin-2-yl)-2,2-dimethyl-N-(tetrahvdropyran-4-ylmethyl)propionamide
Starting from 6-chloromethyl-4-(3-methoxypropyl-2,2-dimethyl-2H-chromene.
The starting materials are prepared as follows: a) 6-Chloromethyl-4-(3-methoxypropyl)-2,2-dimethyl-2H-chromene
1.720 ml of 1 -chloro-N,N-2-thmethylpropenylamine are added dropwise at room temperature to a solution of 0.225 g of [4-(3-methoxypropyl)-2,2-dimethyl-2H- chromen-6-yl]methanol in 5 ml of dichloromethane. The reaction solution is stirred at room temperature for 60 minutes and then concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) and used immediately in the next stage.
b) r4-(3-Methoxypropyl)-2,2-dimethyl-2H-chromen-6-yl1methanol
A solution of 5.200 g of 4-(3-methoxypropyl)-2,2-dimethyl-2H-chromene-6-carbal- dehyde in 60 ml of dry tetrahydrofuran is admixed at 00C with 0.294 g of lithium borohydhde in portions. The reaction mixture is stirred at 00C for 1 hour and then admixed with 5 ml of methanol and 50 ml of water, and extracted with tert-butyl methyl ether (3X). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf = 0.28 (1 :1 EtOAc-heptane); Rt = 4.79 (gradient I).
c) 4-(3-Methoxypropyl)-2,2-dimethyl-2H-chromene-6-carbaldehvde
A solution of 7.500 g of 6-[1 ,3]dioxolan-2-yl-4-(3-methoxypropyl)-2,2-dimethyl- chroman-4-ol in 100 ml of methanol is admixed with 0.56O g of p-toluenesulphonic acid monohydrate. The reaction solution is heated to reflux over 1 hour and then stirred at room temperature over 16 hours. The reaction solution is concentrated by evaporation and the title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf = 0.28 (1 :2 EtOAc-heptane); Rt = 4.73 (gradient I).
d) 6-ri ,31Dioxolan-2-yl-4-(3-methoxypropyl)-2,2-dimethylchroman-4-ol A solution of 5.700 g of 6-[1 ,3]dioxolan-2-yl-2,2-dimethylchroman-4-one [221301 -35- 5] in 60 ml of tetrahydrofuran is admixed with 36 ml of 3-methoxypropylmagnesium chloride solution [14202-12-1] (approx. 1.84M in tetrahydrofuran). The reaction mixture is stirred at room temperature for 30 minutes, quenched with saturated aqueous sodium carbonate solution and extracted with tert-butyl methyl ether (3X). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The crude product is obtained as a yellowish oil and used in the next stage without further purification. Rt = 5.66 (gradient I).
39 3-{(2S,5R)-5-r4-(3-Methoxypropyl)-2,2-dimethyl-3-oxo-3,4-dihvdro-2H- benzo[1 ,41oxazin-6-ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N-(tetrahvdropyran- 4-yl methyl )propionamide
Starting from 6-hydroxymethyl-4-(3-methoxypropyl)-2,2-dimethyl-4H- benzo[1 ,4]oxazin-3-one [857281 -71 -1].
40 3-{(2S,5R)-5-[4-(3-Methoxypropyl)-2,2-dimethyl-3,4-dihvdro-2H- benzo[1 ,41oxazin-6-ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N-(tetrahvdropyran- 4-yl methyl )propionamide
Starting from [4-(3-methoxypropyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6- yl]methanol.
The starting material is prepared as follows: a) [4-(3-Methoxypropyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,41oxazin-6-yl1methanol Analogously to Method F, 6-hydroxymethyl-4-(3-methoxypropyl)-2,2-dimethyl-4H- benzo[1 ,4]oxazin-3-one [857281 -72-2] is reacted. The title compound is identified based on the Rf value.
41 3-{(2S,5R)-5-r4-(3-Methoxypropyl)-2,2-dimethyl-3-oxo-3,4-dihvdro-2H- benzo[1 ,41oxazin-6-ylmethoxyipiperidin-2-yl)-2,2,N-trimethylpropionamide Starting from 6-hydroxymethyl-4-(3-methoxypropyl)-2,2-dimethyl-4H- benzo[1 ,4]oxazin-3-one [857281 -71 -1].
42 3-{(2S,5R)-5-r4-Fluoro-3-(3-methoxypropoxy)benzyloxylpiperidin-2-yl)-2,2- dimethyl-N-(tetrahvdropyran-4-ylnnethyl)propionannide
Starting from 4-chloromethyl-1 -fluoro-2-(3-methoxypropoxy)benzene [857272-79-8].
43 3-{(2S,5R)-5-r3-(3-Methoxypropoxy)-4-methylbenzyloxyipiperidin-2-yl)-2,2- dimethyl-N-(tetrahvdropyran-4-ylmethyl)propionamide
Starting from 4-chloromethyl-2-(3-methoxypropoxy)-1 -methylbenzene [857272-46-9].
Example 44
3-{(2S,5R)-5-r4-(3-Methoxypropyl)-2-methyl-2-phenyl-3,4-dihvdro-2H- benzo[1 ,41oxazin-6-ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N-(tetrahvdropyran-4- ylmethvDpropionamide
Analogously to Method A, 3-[(2S,5R)-5-[4-(3-methoxypropyl)-2-methyl-2-phenyl-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2,2- dimethyl-N-(tetrahydropyran-4-ylmethyl)propionamide is reacted. The title compound is identified based on the Rf value.
The starting materials are prepared as follows: a) 3-r(2S,5R)-5-[4-(3-Methoxypropyl)-2-methyl-2-phenyl-3,4-dihvdro-2H- benzo[1 ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2,2- dimethyl-N-(tetrahvdropyran-4-ylmethyl)propionamide
Analogously to Example 17a, 3-[(2S,5R)-5-[4-(3-methoxypropyl)-2-methyl-2-phenyl- 3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]- 2,2-dimethylpropionic acid and C-(tetrahydropyran-4-yl)methylamine are reacted. The title compound is identified based on the Rf value.
b) 3-r(2S,5R)-5-[4-(3-Methoxypropyl)-2-methyl-2-phenyl-3,4-dihvdro-2H- benzo[1 ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2,2- dimethylpropionic acid Analogously to Example 17b, methyl 3-[(2S,5R)-5-[4-(3-methoxypropyl)-2-methyl-2- phenyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4- sulphonyl)piperidin-2-yl]-2,2-dimethylpropionate is reacted. The title compound is identified based on the Rf value.
c) Methyl 3-r(2S,5R)-5-r4-(3-methoxypropyl)-2-methyl-2-phenyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2,2- dimethylpropionate
Analogously to Method F, methyl 3-[(2S,5R)-5-[4-(3-methoxypropyl)-2-methyl-3-oxo- 2-phenyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4- sulphonyl)piperidin-2-yl]-2,2-dimethylpropionate is reacted. The title compound is identified based on the Rf value.
d) Methyl 3-r(2S,5R)-5-r4-(3-methoxypropyl)-2-methyl-3-oxo-2-phenyl-3,4-dihvdro- 2H-benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2,2- dimethylpropionate
Analogously to Method H, methyl 3-[(2S,5R)-5-hydroxy-1 -(toluene-4- sulphonyl)piperidin-2-yl]-2,2-dimethylpropionate and 6-bromomethyl-4-(3-methoxy- propyl)-2-methyl-2-phenyl-4H-benzo[1 ,4]oxazin-3-one are reacted. The title compound is identified based on the Rf value.
e) 6-Bromomethyl-4-(3-methoxypropyl)-2-methyl-2-phenyl-4H-benzoπ ,41oxazin-3-one A solution of 4.4 mmol of 4-(3-methoxypropyl)-2,6-dimethyl-2-phenyl-4H- benzo[1 ,4]oxazin-3-one in 50 ml of carbon tetrachloride at 700C is admixed with 4.4 mmol of N-bromosuccinimide. The reaction mixture is heated to 900C and then admixed with 0.09 mmol of 2,2'-azobis(2-methylpropionithle) and 0.09 mmol of dibenzoyl peroxide. After 2 hours, the reaction mixture is cooled to room temperature, clarified by filtration and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value.
f) 4-(3-Methoxypropyl)-2,6-dimethyl-2-phenyl-4H-benzoπ ,41oxazin-3-one
A suspension of 7.22 mmol of 2,6-dimethyl-2-phenyl-4H-benzo[1 ,4]oxazin-3-one, 14.45 mmol of i -chloro-3-methoxypropane, 7.23 g of potassium fluoride on aluminiunn oxide and 0.14 mmol of potassium iodide in 150 ml of acetonitrile is stirred at reflux over 72 hours. The reaction mixture is cooled and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value.
g) 2,6-Dimethyl-2-phenyl-4H-benzo[1 ,41oxazin-3-one
A solution of 6.27 mmol of methyl 2-(4-methyl-2-nitrophenoxy)-2-phenylpropionate in 26 ml of acetic acid and 1.5 ml of water is admixed at 500C with 36 mmol of iron powder in portions. After 4 hours, the reaction mixture is cooled to room temperature and clarified by filtration, and the filtrate is washed with brine (3X). The organic phase is dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value.
h) Methyl 2-(4-methyl-2-nitrophenoxy)-2-phenylpropionate
A solution of 24.14 mmol of 4-methyl-2-nitrophenol [119-33-5] in 25 ml of acetonitrile at room temperature is admixed with 36.22 mmol of caesium carbonate and a solution of methyl 2-bromo-2-phenylpropionate [84892-13-7] in 10 ml of acetonitrile. After reflux for 24 hours, the reaction mixture is cooled to room temperature and clarified by filtration, and the filtrate is concentrated by evaporation. The residue is dissolved in ethyl acetate and washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value.
The following compounds are prepared in an analogous manner by the process described in Example 44:
45 3-{(2S,5R)-5-r2-(3-Chlorophenyl)-4-(3-methoxypropyl)-2-methyl-3,4-dihvdro- 2H-benzo[1 ,41oxazin-6-ylmethoxyipipehdin-2-yl)-2,2-dimethyl-N-(tetrahvdro- Pyran-4-ylmethyl)propionamide
Starting from ethyl 2-(3-chlorophenyl)-2-hydroxypropionate [198287-11 -5]. 46 3-{(2S,5R)-5-r2-(3-Fluorophenyl)-4-(3-methoxypropyl)-2-methyl-3,4-dihvdro- 2H-benzoπ ,41oxazin-6-ylnnethoxyipipeπdin-2-yl)-2,2-dinnethyl-N-(tetrahvdro- pyran-4-ylnnethyl)propionannide
Starting from ethyl (3-fluorophenyl)oxoacetate [110193-59-4].
47 3-{(2S,5R)-5-[2-(3,5-Difluorophenyl)-4-(3-methoxypropyl)-2-methyl-3,4- dihvdro-2H-benzori ,41oxazin-6-ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N- (tetrahvdropyran-4-ylmethyl)propionamide
Starting from ethyl (3,5-difluorophenyl)oxoacetate [208259-57-8].
48 3-{(2S,5R)-5-[(S)-4-(3-Methoxypropyl)-2-methyl-2-phenyl-3,4-dihvdro-2H- benzo[1 ,41oxazin-6-ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N-(tetrahvdropyran- 4-yl methyl )propionamide
Starting from methyl (S)-2-hydroxy-2-phenylpropionate [13448-80-1].
49 3-{(2S,5R)-5-[(S)-2-(3-Chlorophenyl)-4-(3-methoxypropyl)-2-methyl-3,4- dihvdro-2H-benzo[1 ,41oxazin-6-ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N- (tetrahvdropyran-4-ylmethyl)propionamide
Starting from methyl (S)-2-(3-chlorophenyl)-2-hydroxypropionate.
The starting material is prepared as follows: a) Methyl (S)-2-(3-chlorophenyl)-2-hvdroxypropionate
A solution of 0.04 mmol of (3S,5S)-1-benzyl-5-(hydroxydiphenylmethyl)-pyrrolidin-3- ol [648424-86-6] in 1 ml of toluene at room temperature is admixed with 0.036 mmol of dimethylzinc (1 M in hexane), stirred for 30 minutes, admixed with isopropanol (8.25 μl in 0.1 ml of toluene), stirred for a further 30 minutes and then cooled to -200C. The reaction mixture is admixed with 0.40 mmol of methyl (3-chloro- phenyl)oxoacetate [34966-50-2] and then admixed slowly (over 30 hours) with 0.96 mmol of dimethylzinc (1 M in hexane). 12 hours later, the reaction mixture is quenched with 10% aqueous citric acid solution and extracted with ethyl acetate (3X) - the combined organic phases are dried with sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value. 50 3-{(2S,5R)-5-r(S)-2-(3-Fluorophenyl)-4-(3-methoxypropyl)-2-methyl-3,4- dihvdro-2H-benzo[1 Λ1oxazin-6-ylmethoxy]piperidin-2-yl)-2,2-dimethyl-N- (tetrahvdropyran-4-ylnnethyl)propionannide
Starting from methyl (S)-2-(3-fluorophenyl)-2-hydroxypropionate, which is prepared analogously to Example 49a from methyl (3-fluorophenyl)oxoacetate [185030-42-6].
51 3-{(2S,5R)-5-r(S)-2-(3,5-Difluorophenyl)-4-(3-methoxypropyl)-2-methyl-3,4- dihvdro-2H-benzori ,41oxazin-6-ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N- (tetrahvdropyran-4-ylmethyl)propionamide
Starting from methyl (S)-2-(3,5-difluorophenyl)-2-hydroxypropionate, which is prepared analogously to Example 49a from methyl (3,5-difluorophenyl)oxoacetate [259739-92-9].
52 (S)-3-{(2S,5R)-5-[(S)-4-(3-Methoxypropyl)-2-methyl-3-oxo-2-phenyl-3,4- dihvdro-2H-benzo[1 ,41oxazin-6-ylmethoxyipiperidin-2-yl)-2,2-dimethyl-N- (tetrahvdropyran-4-ylmethyl)propionamide
Analogously to Example 48, omitting step c.
113 3-{(2S,5R)-5-r(S)-4-(3-Methoxy-propyl)-2-methyl-2-pyhdin-4-yl-3,4-dihvdro-2H- benzo[1 ,41oxazin-6-ylmethoxy1-piperidin-2-yl)-2,2-dimethyl-N-(tetrahvdro- pyran-4-ylmethyl)-propionamide
Starting from (S)-2-hydroxy-2-pyhdin-4-yl-propionic acid ethyl ester, synthesized in analogy to Example 49a using oxo-pyridin-4-yl-acetic acid ethyl ester [156093-78-6].
114 3-{(2S,5R)-5-r(S)-4-(3-Methoxy-propyl)-2-methyl-2-(tetrahvdro-pyran-4-yl)-3,4- dihvdro-2H-benzo[1 ,41oxazin-6-ylmethoxy1-piperidin-2-yl)-2,2-dimethyl-N- (tetrahvdro-pyran-4-ylmethyl)-propionamide
Starting from (S)-2-hydroxy-2-(tetrahydro-pyran-4-yl)-propionic acid ethyl ester, synthesized in analogy to Example 49a using oxo-(tetrahydro-pyran-4-yl)-acetic acid ethyl ester [861160-58-9]. 115 3-{(2S,5R)-5-r(R)-2-Methoxymethyl-4-(3-methoxy-propyl)-2-methyl-3,4- dihvdro-2H-benzo[1 Λ1oxazin-6-ylmethoxy1-piperidin-2-yl)-2,2-dimethyl-N- (tetrahvdro-pyran-4-ylnnethyl)-propionannide
Starting from (S)-2-hydroxy-3-methoxy-2-methyl-propionic acid methyl ester, synthesized in analogy to Example 49a using 3-methoxy-2-oxo-propionic acid methyl ester [89364-44-3].
Example 53
(R(or S))-3-((2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxyipiperidin-2-yl)-2-methyl-N-(tetrahvdropyran-4-ylmethyl)propionamide Following Method A, 0.436 mmol of (R(or S))-3-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2- methyl-N-(tetrahydropyran-4-ylmethyl)propionamide is reacted. The title compound is obtained as a yellow resin. Rf = 0.27 (dichloromethane-methanol-conc ammonia 200:20:1 ); Rt = 11.75 (gradient II).
The starting materials are prepared as follows: a) (R(or S))-3-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2-methyl-N-(tetrahvdropyran-4- ylmethvDpropionamide
Following Method B, 0.865 mmol of (R(or S))-3-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2- methylpropionic acid is reacted. The title compound is obtained as a yellow resin. Rf = 0.19 (EtOAc); Rt = 19.05 (gradient II).
b) (R(or S))-3-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2-methylpropionic acid
A solution of 0.81 mmol of methyl (R,S)-3-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2- methylpropionate in 10 ml of methanol at room temperature is admixed with 10 ml of an aqueous sodium hydroxide solution (2M) and the mixture is heated to 65°C. After 3 hours, the reaction mixture is cooled to room temperature and the methanol is concentrated by evaporation - the residue is acidified to pH 2 with 4N HCI and extracted with ethyl acetate (3X). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue as a brown resin. Rt = 19.60 (gradient II).
c) Methyl (R,S)-3-r(2S,5R)-5-r4-(3-methoxypropyl)-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2- methylpropionate
A solution of 0.89 mmol of methyl 3-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]propionate in 20 ml of tetrahydrofuran at -78°C is admixed over 10 minutes with sodium bis(tri- methylsilyl)amide (1 M in tetrahydrofuran). After one hour, the reaction mixture is admixed with 2.05 mmol of iodomethane at -78°C. After one hour, the reaction mixture is quenched with 0.5N HCI at -78°C, warmed to room temperature and extracted with dichloromethane (2X) - the combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a yellow resin. Rf = 0.40 (2:1 EtOAc-heptane); Rt = 5.32 (gradient I).
d) Methyl 3-f(2S.5R)-5-f4-(3-methoxypropyl)-3.4-dihvdrO-2H-benzof1.41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-ylipropionate
A solution of 2.38 mmol of 3-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]propionic acid in 40 ml of methanol at 00C is admixed slowly with 22.8 mmol of thmethylsilyldiazo- methane (2M in hexane). Further thmethylsilyldiazomethane (4 mmol) is added after 2, 16 and 18 hours within 15 minutes in each case. After a total of 20 hours, the reaction mixture is quenched with magnesium sulphate heptahydrate, stirred for one hour and filtered, and the filtrate is concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a yellowish oil. Rf = 0.33 (2:1 EtOAc-heptane); Rt = 5.13 (gradient I).
e) 3-r(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-ylipropionic acid Analogously to Method C, 2.79 mmol of 3-[(2R,5R)-5-[4-(3-methoxypropyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)pipendin-2-yl]- propionitrile are reacted. The title compound is obtained as a brown resin. Rf = 0.37 (10:1 dichloromethane-methanol); Rt = 4.54 (gradient I).
f) 3-r(2R.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-ylipropionitrile
Analogously to Method D, 2.73 mmol of 2-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]ethyl methanesulphonate are reacted. The title compound is obtained as an orange-brown oil. Rf = 0.12 (1 :1 EtOAc-heptane); Rt = 4.94 (gradient I).
g) 2-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1ethyl methanesulphonate
Analogously to Method E, 2.72 mmol of 2-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]- ethanol are reacted. The title compound is obtained as a brown oil. Rf = 0.21 (2:1 EtOAc-heptane); Rt = 4.91 (gradient I).
h) 2-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1ethanol Analogously to Example 1f, 4.63 mmol of [(2S,5R)-5-[4-(3-methoxypropyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)pipehdin-2-yl]- acetaldehyde (Example 1f) are reacted. The title compound is obtained as a yellow resin. Rf = 0.37 (EtOAc); Rt = 4.54 (gradient I).
Example 54
(S(or R))-3-((2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxyipiperidin-2-yl)-2-methyl-N-(tetrahvdropyran-4-ylmethyl)propionamide Analogously to Method A, 0.066 mmol of (S(or R))-3-[(2S,5R)-5-[4-(3-methoxy- propyl)-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4- sulphonyl)piperidin-2-yl]-2-methyl-N-(tetrahydropyran-4-ylmethyl)propionamide is reacted. The title compound is obtained as a yellow oil. Rf = 0.25 (200:20:1 dichloromethane-nnethanol-25% cone, ammonia); Rt = 3.13 (gradient I).
The starting materials are prepared as follows: a) (S(or R))-3-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2-methyl-N-(tetrahvdropyran-4- ylmethvDpropionamide
Analogously to Example 17a, 0.087 mmol of (S(or R))-3-[(2S,5R)-5-[4-(3-methoxy- propyl)-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4- sulphonyl)piperidin-2-yl]-2-methylpropionic acid is reacted. The title compound is obtained as a yellow oil. Rf = 0.13 (EtOAc); Rt = 4.65 (gradient I).
b) (S(or R))-3-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2-methylpropionic acid
To a solution of 0.069 mmol of (S)-4-benzyl-3-{(S(or R))-3-[(2S,5R)-5-[4-(3- methoxypropyl)-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4- sulphonyl)piperidin-2-yl]-2-methylpropionyl}oxazolidin-2-one in 4 ml of tetrahydro- furan and 0.5 ml of water at 00C is added 0.152 mmol of lithium hydroxide, followed by 0.3 ml of 30% hydrogen peroxide. The reaction mixture is stirred at 00C for 2 hours, then quenched with 10 ml of saturated aqueous sodium thiosulphate, and stirred at room temperature for 30 minutes. 0.1 N HCI is added till pH = 2. The reaction mixture is extracted with dichloromethane (3X), dried over sodium sulphate and concentrated to afford the title compound as a light brown oil. Rf = 0.12 (EtOAc- heptane 2:1 ); Rt = 4.66 (gradient I).
c) (S)-4-Benzyl-3-{(S(or R))-3-r(2S,5R)-5-r4-(3-methoxypropyl)-3,4-dihvdro-2H- benzo[1 ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-2- methylpropionylk>xazolidin-2-one
Following Method F, 0.468 mmol of 6-[(3R,6S)-6-[(S(or R))-3-((S)-4-benzyl-2-oxo- oxazolidin-3-yl)-2-methyl-3-oxopropyl]-1-(toluene-4-sulphonyl)piperidin-3-yloxy- methyl]-4-(3-methoxypropyl)-4H-benzo[1 ,4]oxazin-3-one is reacted. The title compound is obtained as a white solid. Rf = 0.45 (EtOAc-heptane 2:1 ); Rt = 5.79 (gradient I). d) 6-r(3R,6S)-6-r(S(or R))-3-((S)-4-Benzyl-2-oxooxazolidin-3-yl)-2-methyl-3-oxo- propyl1-1-(toluene-4-sulphonyl)pipeπdin-3-yloxynnethyl1-4-(3-nnethoxypropyl)-4H- benzoH ,41oxazin-3-one
A solution of 0.799 mmol of (S)-4-benzyl-3-{(S(or R))-3-[(2S,5R)-5-hydroxy-1 - (toluene-4-sulphonyl)piperidin-2-yl]-2-nnethylpropionyl}oxazolidin-2-one and 0.959 mmol of 2,2,2-trichloroacetimidic acid 4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethyl ester in 10 ml of dichloromethane at 00C is treated with 0.040 mmol of scandium triflate and stirred at 00C for 2 hours. The reaction mixture is then diluted with 30 ml of dichloromethane and washed with 30 ml of water. The aqueous layer is re-extracted with dichloromethane (2X20 ml). The combined organic extracts are washed with brine, dried over sodium sulphate and concentrated. The crude product is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow solid. Rf = 0.42 (EtOAc-heptane 2:1 ); Rt = 5.49 (gradient I).
e) (S)-4-Benzyl-3-{(S(or R))-3-r(2S,5R)-5-hvdroxy-1 -(toluene-4-sulphonyl)piperidin- 2-vH-2-methylpropionylk>xazolidin-2-one
A solution of 1.128 mmol of (S)-4-benzyl-3-{(S(or R))-3-[(2S,5R)-5-(4-methoxy- benzyloxy)-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2-methylpropionyl}oxazolidin-2-one and 0.113 mmol of 5% palladium on charcoal in 3 ml of methanol and 2 ml of tetra- hydrofuran is hydrogenated at atmospheric pressure for 18 h. The reaction mixture is then filtered through Hyflo, concentrated and purified by flash chromatography (SiO2 60F) to afford the title compound as a beige solid. Rf = 0.31 (EtOAc-heptane 2:1 ); Rt = 4.64 (gradient I).
f) (S)-4-Benzyl-3-{(S(or R))-3-r(2S,5R)-5-(4-methoxybenzyloxy)-1 -(toluene-4- sulphonyl)piperidin-2-vH-2-methylpropionylk>xazolidin-2-one
To a solution of 2.241 mmol of (S)-4-benzyl-3-{3-[(2S,5R)-5-(4-methoxybenzyloxy)-1 - (toluene-4-sulphonyl)piperidin-2-yl]propionyl}oxazolidin-2-one in 14 ml of tetrahydro- furan at -78°C is added 2.689 mmol of lithium diisopropylamide. The reaction mixture is stirred at -78°C for 45 minutes, then at -400C for 20 minutes. The mixture is cooled again to -78°C for 10 minutes, before the addition of 11.205 mmol of methyl iodide. The reaction mixture is stirred at -78°C for 1 hour, then at -400C for 18 hours. It is quenched at -400C with saturated aqueous ammonium chloride. Once at room temperature, it is partitioned between dichloromethane and saturated aqueous ammonium chloride. The aqueous phase is re-extracted with dichloromethane (3X). The combined organic extracts are dried over sodium sulphate, concentrated and purified by flash chromatography (SiO2 60F) to afford the title compound as a white solid. Rf = 0.55 (EtOAc-heptane); Rt = 5.74 (gradient I).
g) (S)-4-Benzyl-3-{3-r(2S,5R)-5-(4-methoxybenzyloxy)-1 -(toluene-4- sulphonyl)piperidin-2-ylipropionyl)oxazolidin-2-one
A solution of 5.541 mmol of 3-[(2S,5R)-5-(4-methoxybenzyloxy)-1-(toluene-4- sulphonyl)piperidin-2-yl]propionic acid and 6.095 mmol of thethylamine in 20 ml of diethyl ether and 3 ml of dichloromethane is cooled to -78°C. 5.541 mmol of pivaloyl chloride are added, the reaction mixture is stirred at -78°C for 5 minutes, then at 00C for 1 hour, then cooled again to -78°C. In the meantime, 6.649 mmol of (S)-benzyl-2- oxazolidinone are dissolved in 20 ml of tetrahydrofuran and cooled to -78°C. 6.372 mmol of n-butyllithium (1.6M in hexane) are added dropwise, and the mixture is stirred at -78°C for 45 minutes. The solution of the mixed anhydride previously mentioned is transferred via cannula, washing with 5 ml of tetrahydrofuran. The reaction mixture is stirred at -78°C for 1 h, then transferred in an ice-bath and stirred for 1.5 hours, then at room temperature for 0.5 h. It is quenched with 1 N ammonium chloride, extracted with dichloromethane (4X), dried over sodium sulphate, and concentrated. Purification by flash chromatography (SiO2 60F) affords the title compound as a white solid. Rf = 0.51 (EtOAc-heptane 2:1 ); Rt = 5.26 (gradient I).
h) 3-r(2S,5R)-5-(4-Methoxybenzyloxy)-1 -(toluene-4-sulphonyl)piperidin-2-yl1- propionic acid
Following Example 17b, 4.116 mmol of 3-[(2S,5R)-5-(4-methoxybenzyloxy)-1 - (toluene-4-sulphonyl)piperidin-2-yl]propionic acid methyl ester (Example 23g) are reacted. The title compound is obtained as a colourless sticky oil. Rf = 0.24 (EtOAc- heptane 2.1 ); Rt = 4.48 (gradient I).
i) 2,2,2-Thchloroacetimidic acid 4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H- benzoH ,41oxazin-6-ylmethyl ester To a solution of 3.98 mmol of 6-hydroxymethyl-4-(3-methoxypropyl)-4H- benzo[1 ,4]oxazin-3-one [857272-03-8] in 15 ml of dichloromethane at 00C is added 15 ml of 50% aqueous KOH, followed by 0.199 mmol of tetrabutylammonium hydrogen sulphate, and 4.776 mmol of thchloroacetonithle. The reaction mixture is stirred vigorously at 00C for 1 hour, then at room temperature for 1 hour. It is then extracted with dichloromethane (3X). The combined organic extracts are dried over sodium sulphate, and concentrated, to afford the title compound as a yellow gum. Rf = 0.50 (EtOAc-heptane 1 :1 ).
The following compounds are prepared in an analogous manner by the processes described in Examples 53 and 54:
56 (S(or R))-3-((2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin- 6-ylmethoxyipiperidin-2-yl)-2-methyl-N-(tetrahvdropyran-4-yl)propionamide
59 (R(or S))-N-(2-Carbamoyl-2-methylpropyl)-3-{(2S,5R)-5-r4-(3-methoxypropyl)- 3,4-dihvdro-2H-benzori ,41oxazin-6-ylmethoxyipiperidin-2-yl)-2-methyl- propionamide
62 (S(or R))-3-{(2S,5R)-5-r4-(3-Methoxypropyl)-3-oxo-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxyipiperidin-2-yl)-2-methyl-N-(tetrahvdropyran-4- yl methyl )propionamide
63 (R(or S))-3-{(2S,5R)-5-r2-(3-Chlorophenyl)-4-(3-methoxypropyl)-2-methyl-3,4- dihvdro-2H-benzori ,41oxazin-6-ylmethoxyipiperidin-2-yl)-2-methyl-N- (tetrahvdropyran-4-ylmethyl)propionamide
Starting from ethyl 2-(3-chlorophenyl)-2-hydroxypropionate [198287-11 -5].
64 (R(or S))-3-{(2S,5R)-5-[2-(3-Fluorophenyl)-4-(3-methoxypropyl)-2-methyl-3,4- dihvdro-2H-benzo[1 ,41oxazin-6-ylmethoxyipiperidin-2-yl)-2-methyl-N- (tetrahvdropyran-4-ylmethyl)propionamide
Starting from ethyl (3-fluorophenyl)oxoacetate [110193-59-4]. 68 (S(or R))-3-{(2S,5R)-5-r2-(3,5-Difluorophenyl)-4-(3-methoxypropyl)-2-methyl- 3Λ-dihvdro-2H-benzo[1 Λ1oxazin-6-ylmethoxy]piperidin-2-yl)-2-methyl-N- (tetrahvdropyran-4-ylnnethyl)propionannide
Starting from ethyl (3,5-difluorophenyl)oxoacetate [208259-57-8].
79 (R(or S))-3-{(2S,5R)-5-r4-Methoxy-3-(3-methoxypropoxy)benzyloxyipiperidin- 2-yl)-2-methyl-N-(tetrahvdropyran-4-ylmethyl)propionamide
Starting from 4-bromomethyl-1 -methoxy-2-(3-methoxypropoxy)benzene [172900-73-1].
80 (R(or S))-2-((2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin- 6-ylmethoxyipiperidin-2-ylmethyl)-N-(tetrahvdropyran-4-ylmethyl)butyramide
Starting from methyl 3-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]propionate (Example 53d) using ethyl iodide instead of methyl iodide (in the step analogously to Example 53c).
Example 84
1 -(2-{(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzo[1 ,41oxazin-6- ylmethoxyipiperidin-2-yl)-1 ,1 -dimethylethyl)-3-(tetrahvdropyran-4-yl)urea Analogously to Method A, 1 -{2-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-1 ,1 -dimethyl- ethyl}-3-(tetrahydropyran-4-yl)urea is reacted. The title compound is identified based on the Rf value.
The starting materials are prepared as follows: a) 1 -(2-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxyi-1 -(toluene-4-sulphonyl)piperidin-2-yl1-1 ,1 -dimethylethyl)-3-(tetrahvdro- Pyran-4-yl)urea
A solution of 0.221 mmol of 6-[(3R,6S)-6-(2-isocyanato-2-methylpropyl)-1 -(toluene-4- sulphonyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazine and 2.21 mmol of 4-aminotetrahydropyran in 1 ml of tetrahydro- furan is stirred at room temperature for 2 hours. The reaction mixture is concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value.
b) 6-r(3R,6S)-6-(2-lsocvanato-2-methylpropyl)-1 -(toluene-4-sulphonyl)piperidin-3- yloxymethyl1-4-(3-methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazine A solution of 0.398 mmol of 3-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2,2-dimethyl- propionic acid (Example 17b) and 0.995 mmol of triethylamine in 4 ml of tetrahydro- furan is cooled to 00C and 0.796 mmol of ethyl chloroformate is added. The reaction mixture is stirred at 00C for one hour and then a solution of 7.96 mmol of sodium azide in 2 ml of water is added at 00C. The reaction solution is stirred at 00C for 45 minutes. The mixture is diluted with water and ethyl acetate - the aqueous phase is washed with water (2X), dried with sodium sulphate and concentrated by evaporation. The residue is taken up in 2 ml of toluene and heated to 115°C for 2 hours. The reaction mixture is cooled to room temperature and concentrated by evaporation. The crude title compound is obtained from the residue.
Example 87
4-((2S.5R)-5-f4-(3-Methoxypropyl)-3.4-dihvdrO-2H-benzof1.41oxazin-6- ylmethoxyipiperidin-2-yl)-3,3-dimethyl-1 -(tetrahvdropyran-4-ylamino)butan-2-one Analogously to Method A, 4-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-3,3-dimethyl-1 - (tetrahydropyran-4-ylamino)butan-2-one is reacted. The title compound is identified based on the Rf value.
The starting materials are prepared as follows: a) 4-f(2S.5R)-5-f4-(3-Methoxypropyl)-3.4-dihvdrO-2H-benzof1.41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-3,3-dimethyl-1 - (tetrahvdropyran-4-ylamino)butan-2-one
A solution of 0.6 mmol of tetrahydropyran-4-ylamine in 5 ml of diethyl ether at room temperature is admixed with a solution of 0.2 mmol of 1 -chloro-4-[(2S,5R)-5-[4-(3- methoxypropyl)-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4- sulphonyl)piperidin-2-yl]-3,3-dimethylbutan-2-one in 5 ml of diethyl ether. After 8 hours, the reaction mixture is admixed with 15% NaOH - the organic phase is washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value.
b) 1 -Chloro-4-r(2S,5R)-5-r4-(3-methoxypropyl)-3,4-dihvdro-2H-benzon ,41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-3,3-dimethylbutan-2-one A solution of 2.24 mmol of chloroiodomethane in 20 ml of tetrahydrofuran and 20 ml of diethyl ether at -1000C is admixed with 1.12 mmol of n-butyllithium (1.6M in hexane). After one hour, 0.32 mmol of methyl 3-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro- 2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-2,2-dimethyl- propionate (Example 17c) is added. The reaction mixture is heated to -78°C over one hour, poured into brine and extracted with tert-butyl methyl ether (3X) - the combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on the Rf value.
Example 88
N-(2-{(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6- ylmethoxyipiperidin-2-yl)-1 ,1 -dimethylethyl)-2-(tetrahvdropyran-4-yl)acetamide Following Method A, 0.163 mmol of N-{2-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-1 ,1 - dimethylethyl}-2-(tetrahydropyran-4-yl)acetamide is reacted to afford the title compound as a yellow resin. Rf = 0.17 (dichloromethane-methanol-conc. ammonia); Rt = 3.34 (gradient I).
The starting materials are prepared as follows: a) N-{2-r(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6- ylmethoxyi-1 -(toluene-4-sulphonyl)piperidin-2-yl1-1 ,1 -dimethylethyl)-2-(tetrahvdro- pyran-4-yl)acetamide A solution of 0.511 mmol of tetrahydropyranyl-4-acetic acid [85064-61-5] in 5 ml of dichloromethane is treated with 1.023 mmol of 1 -chloro-N,N-2-thmethylpropenyl- amine. The reaction mixture is stirred at room temperature for 1.5 hours. In a second flask, a solution of 0.341 mmol of 2-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-1 ,1 -dimethyl- ethylamine in 10 ml of dichloromethane are treated with 1.023 mmol of thethylamine, and cooled to 00C. The solution of acid chloride is added dropwise to this second flask, and the reaction mixture is stirred at room temperature for 2 hours. Water is added, and the aqueous phase is extracted with dichloromethane (3X). The combined organic extracts are dried over sodium sulphate, concentrated and purified by flash chromatography (SiO2 60F) to afford the title compound as a dark yellow resin. Rf = 0.20 (dichloromethane-methanol-conc ammonia); Rt = 4.94 (gradient I).
b) 2-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxyi-1 -(toluene-4-sulphonyl)piperidin-2-yl1-1 ,1 -dimethylethylamine
A solution of 1.383 mmol of {2-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-1 ,1 -dimethyl- ethyljcarbamic acid benzyl ester and 0.138 mmol of palladium on charcoal in 20 ml of methanol is hydrogenated at atmospheric pressure and room temperature for 2 hours. The reaction mixture is then filtered through Hyflo, and concentrated under reduced pressure, to afford the title compound as a yellow resin. Rf = 0.17 (dichloromethane-methanol-conc ammonia); Rt = 4.22 (gradient I).
c) (2-r(2S.5R)-5-r4-(3-Methoxypropyl)-3.4-dihvdro-2H-benzori .41oxazin-6- ylmethoxyi-1 -(toluene-4-sulphonyl)piperidin-2-yl1-1 ,1 -dimethylethyllcarbamic acid benzyl ester
A mixture of 1.484 mmol of 6-[(3R,6S)-6-(2-isocyanato-2-methylpropyl)-1 -(toluene-4- sulphonyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazine (Example 84a) and 29.68 mmol of benzyl alcohol is stirred at 1200C for 2 hours then cooled to room temperature. Purification by flash chromatography (SiO2 60F) affords the title compound as a yellow resin. Rf = 0.27 (EtOAc- heptane 1 :1 ); Rt = 5.71 (gradient I). Example 89
N-((R(or S))-1 -{(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6- ylmethoxyipiperidin-2-ylmethyl)-2-methylpropyl)-2-(tetrahvdropyran-4-yl)acetamide Following Method A, 0.066 mmol of N-{(R(or S))-1 -[(2S,5R)-5-[4-(3-methoxypropyl)- 3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)pipendin-2- ylmethyl]-2-nnethylpropyl}-2-(tetrahydropyran-4-yl)acetannide is reacted to afford the title compound as a yellow oil. Rf = 0.27 (dichloromethane-methanol cone ammonia 200:20:1 ); Rt = 3.26 (gradient I).
The starting materials are prepared as follows: a) N-UR(Or S))-1 -r(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin- 6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-ylmethyl1-2-methylpropyl)-2- (tetrahydropyran-4-yl)acetamide
Following the procedure for Example 88a, 0.393 mmol of (R(or S))-1 -[(2S,5R)-5-[4- (3-methoxypropyl)-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4- sulphonyl)piperidin-2-ylmethyl]-2-methylpropylamine is reacted. The title compound is obtained as a yellow oil. Rf = 0.46 (dichloromethane-methanol-conc ammonia 200:20:1 ); Rt = 4.77 (gradient I).
b) (R(or S))-1 -r(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-6- ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-ylmethyl1-2-methylpropylamine
Following Method O, 0.393 mmol of 6-[(3R,6S)-6-((R(or S))-2-azido-3-methylbutyl)-1 - (toluene-4-sulphonyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazine is reacted to afford the title compound as a brown oil. Rf = 0.60 (EtOAc); Rt = 4.29 (gradient I).
c) 6-r(3R,6S)-6-((R(or S))-2-Azido-3-methylbutyl)-1 -(toluene-4-sulphonyl)piperidin-3- yloxymethyl1-4-(3-methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazine
A solution of 0.412 mmol of methanesulphonic acid (S(or R))-1 -[(2S,5R)-5-[4-(3- methoxypropyl)-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4- sulphonyl)piperidin-2-ylmethyl]-2-methylpropyl ester and 2.06 mmol of sodium azide is stirred at 800C for 18 hours. The reaction mixture is cooled to room temperature, diluted with water, extracted with tert-butyl methyl ether (3X). The combined organic extracts are washed with water, then brine, dried over sodium sulphate, and concentrated. The crude product is obtained as a brown oil. Rf = 0.47 (EtOAc- heptane 2.1 ); Rt = 5.95 (gradient I).
d) Methanesulphonic acid (S(or R))-1 -r(2S,5R)-5-r4-(3-methoxypropyl)-3,4-dihvdro- 2H-benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-ylmethyl1-2- methylpropyl ester
Following Method E, 0.412 mmol of (S(or R))-1 -[(2S,5R)-5-[4-(3-methoxypropyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-3- methylbutan-2-ol is reacted to afford the title compound as a brown oil. Rf = 0.40 (EtOAc-heptane 2:1 ); Rt = 5.27 (gradient I).
e) (i) (S(or R))-1 -r(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-
6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-3-methylbutan-2-ol and (ii) (R(or S))-1-r(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzoπ ,41oxazin-
6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-3-methylbutan-2-ol To a solution of 1.56 mmol of [(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]acetaldehyde (1f) in 10 ml of dry tetrahydrofuran at -15°C is added 3.12 mmol of isopropyl- magnesium chloride. The reaction mixture is stirred between -15°C and 00C for 3 hours, then at room temperature for 1 hour. It is quenched with saturated aqueous ammonium chloride and extracted with dichloromethane (3X). The combined organic extracts are dried over sodium sulphate, concentrated and purified by flash chromatography (SiO2 60F) to afford the title compounds as colourless oils. Rf = 0.24 and 0.20 (EtOAc-heptane 1 :1 ); Rt = 5.34 and 5.20 (gradient I).
In analogy to Examples 89 and 40, the following compounds are synthesized:
100 N-((R(or S))-1 -{(2S,5R)-5-r4-(3-Methoxypropyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxyipiperidin-2-ylmethyl)-2-methylpropyl)-2- (tetrahvdropyran-4-yl)acetamide 102 4-Methoxycvclohexanecarboxylic acid ((R(or S))-1 -U2S,5R)-5-[4-(3- methoxypropyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,41oxazin-6- ylmethoxyipiperidin-2-ylmethyl)-2-methylpropyl)amide
Example 99
N-((S(or R))-2-{(2S,5R)-5-r4-(3-Methoxypropyl)-2,2-dimethyl-3,4-dihvdro-2H- benzoπ ,41oxazin-6-ylnnethoxyipipeπdin-2-yl)-1 -ιinethylethyl)-2-(tetrahvdropyran-4- vDacetamide
Following Method A, N-{(S(or R))-2-[(2S,5R)-5-[4-(3-methoxypropyl)-2,2-dimethyl-
3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)pipendin-2-yl]-
1 -methylethyl}-2-(tetrahydropyran-4-yl)-acetannide is reacted. The title compound is identified based on the Rf value.
The starting materials are prepared as follows: a) N-US(Or R))-2-r(2S.5R)-5-r4-(3-methoxypropyl)-2.2-dimethyl-3.4-dihvdro-2H- benzoH ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-1 -methyl- ethyl)-2-(tetrahvdropyran-4-yl)acetamide
Following the procedure for Example 88a, (S(or R))-2-[(2S,5R)-5-[4-(3-methoxy- propyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4- sulphonyl)piperidin-2-yl]-1 -methylethylamine is reacted. The title compound is identified based on the Rf value.
b) (S(or R))-2-r(2S,5R)-5-r4-(3-Methoxypropyl)-2,2-dimethyl-3,4-dihvdro-2H- benzoH ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-1 -methyl- ethylamine
Following Method O, 6-[(3R,6S)-6-((S(or R))-2-azidopropyl)-1 -(toluene-4- sulphonyl)piperidin-3-yloxymethyl]-4-(3-methoxypropyl)-2,2-dimethyl-3,4-dihydro-2H- benzo[1 ,4]oxazine is reacted. The title compound is identified based on the Rf value.
c) 6-f(3R.6S)-6-((S(or R))-2-azidopropyl)-1-(toluene-4-sulphonyl)piperidin-3- yloxymethyl1-4-(3-methoxypropyl)-2,2-dimethyl-3,4-dihvdro-2H-benzo[1 ,41oxazine Following the procedure for Example 89c, methanesulphonic acid (R(or S))-2- [(2S,5R)-5-[4-(3-methoxypropyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6- ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-1 -methylethyl ester is reacted. The title compound is identified based on the Rf value.
d) Methanesulphonic acid (R(or S))-2-r(2S,5R)-5-r4-(3-methoxypropyl)-2,2-dimethyl- 3,4-dihvdro-2H-benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin- 2-yl1-1 -methylethyl ester
Following Method E, (R(or S))-1-[(2S,5R)-5-[4-(3-methoxypropyl)-2,2-dimethyl-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2- yl]propan-2-ol is reacted. The title compound is identified based on the Rf value.
e) (i) (R(or S))-1-r(2S,5R)-5-r4-(3-methoxypropyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-ylipropan-2-ol and (ii) (S(or R))-1 -r(2S,5R)-5-r4-(3-methoxypropyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-ylipropan-2-ol Following the procedure for Example 89e, [(2S,5R)-5-[4-(3-methoxypropyl)-2,2- dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4- sulphonyl)piperidin-2-yl]acetaldehyde is reacted with methylmagnesium bromide. The title compounds are identified based on the Rf values.
f) r(2S,5R)-5-r4-(3-methoxypropyl)-2,2-dimethyl-3,4-dihvdro-2H-benzoπ ,41oxazin- 6-ylmethoxy1-1 -(toluene-4-sulphonyl)piperidin-2-yl1-acetaldehvde
The title compound is prepared in analogy to the synthesis of Example 1f, starting from 6-chloromethyl-4-(3-methoxypropyl)-2,2-dimethyl-4H-benzo[1 ,4]oxazin-3-one [857281-71 -1].
In analogy to the synthesis of Example 99, the following compound is prepared:
101 4-Methoxycvclohexanecarboxylic acid ((S(or R))-2-{(2S,5R)-5-[4-(3-methoxy- propyl)-2,2-dimethyl-3,4-dihvdro-2H-benzori ,41oxazin-6-ylmethoxyipiperidin-2- yl)-1 -methylethvDamide 104 Tetrahvdro-pyran-4-carboxylic acid ((S(or R))-2-{(2S,5R)-5-r4-(3-methoxy- propyl)-2,2-dimethyl-3,4-dihvdro-2H-benzo[1 Λ1oxazin-6-ylmethoxy]-piperidin- 2-yl)-1 -methyl -ethyl )-amide
Example 103
4-(3-Methoxy-propyl)-2,2-dimethyl-6-r(3R,6S)-6-(2-methyl-2-ri ,2,41triazol-4-yl-propyl)- pipeπdin-3-yloxymethyl1-3,4-dihvdro-2H-benzoπ ,41oxazine
Following general Method A, 4-(3-methoxy-propyl)-2,2-dimethyl-6-[(3R,6S)-6-(2- methyl-2-[1 ,2,4]thazol-4-yl-propyl)-1-(toluene-4-sulfonyl)-piperidin-3-yloxymethyl]-3,4- dihydro-2H-benzo[1 ,4]oxazine is reacted. The title compound is identified based on the Rf value.
The starting materials are prepared as follows: a) 4-(3-Methoxy-propyl)-2,2-dimethyl-6-r(3R,6S)-6-(2-methyl-2-ri ,2,41triazol-4-yl- propyl)-1 -(toluene-4-sulfonyl)-piperidin-3-yloxymethyl1-3,4-dihvdro-2H- benzoH ,41oxazine
A solution of 0.70 mmol of 4H-[1 ,2,4]thazole in 1 ml N,N-dimethylformamide is treated at room temperature with 0.70 mmol of sodium hydride (60% dispersion in oil) and stirred for 30 minutes. A solution of 0.14 mmol of methanesulfonic acid 2-[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6- ylmethoxy]-1 -(toluene-4-sulfonyl)-piperidin-2-yl]-1 ,1 -dimethyl-ethyl ester in 1 ml N1N- dimethylformamide is added and the reaction mixture is warmed at 400C. After 24 hours,, the reaction mixture is cooled to room temperature, diluted with water, and extracted with ethyl acetate (3x). The combined organic extracts are dried with sodium sulfate, and concentrated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.
b) Methanesulfonic acid 2-r(2S,5R)-5-r4-(3-methoxy-propyl)-2,2-dimethyl-3,4- dihvdro-2H-benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-yl1- 1 ,1 -dimethyl-ethyl ester Following general Method E, 1 -[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2-dimethyl-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)-pipendin-2-yl]-2- methyl-propan-2-ol is reacted. The title compound is identified based on the Rf value.
c) 1 -f(2S.5R)-5-f4-(3-methoxy-prOPyl)-2.2-dimethyl-3.4-dihvdrO-2H-benzof1.41oxazin- 6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-yl1-2-methyl-propan-2-ol
Following the procedure for Example 15b, 1 -[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2- dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)- piperidin-2-yl]-propan-2-one is reacted. The title compound is identified based on the Rf value.
d) 1 -r(2S,5R)-5-r4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-yl1-propan-2-one
Following the procedure for Example 15c, (S,R)-1 -[(2S,5R)-5-[4-(3-methoxy-propyl)- 2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)- piperidin-2-yl]-propan-2-ol (Example 99e) is reacted. The title compound is identified based on the Rf value.
Example 105
(S(or R))-2-Methoxy-3-{(2S,5R)-5-r4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-piperidin-2-yl)-N-(tetrahvdro-pyran-4-ylmethyl)- propionamide
Following general Method A, (S(or R))-2-methoxy-3-[(2S,5R)-5-[4-(3-methoxy- propyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4- sulfonyl)-piperidin-2-yl]-N-(tetrahydro-pyran-4-ylmethyl)-propionamide is reacted.
The title compound is identified based on the Rf value.
The starting materials are prepared as follows: a) (S(or R))-2-Methoxy-3-r(2S,5R)-5-r4-(3-methoxy-propyl)-2,2-dimethyl-3,4- dihvdro-2H-benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-yl1- N-(tetrahvdro-pyran-4-ylmethyl)-propionamide Following the procedure for Example 17a, (S(or R))-2-methoxy-3-[(2S,5R)-5-[4-(3- methoxy-propyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 - (toluene-4-sulfonyl)-piperidin-2-yl]-propionic acid is reacted. The title compound is identified based on the Rf value.
b) (S(or R))-2-Methoxy-3-r(2S,5R)-5-r4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzoH ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-yl1-propionic acid
Following the procedure for Example 54b, (S)-4-benzyl-3-{(S(or R))-2-methoxy-3- [(2S,5R)-5-[4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6- ylmethoxy]-1 -(toluene-4-sulfonyl)-piperidin-2-yl]-propionyl}-oxazolidin-2-one is reacted. The title compound is identified based on the Rf value.
c) (S)-4-Benzyl-3-{(S(or R))-2-methoxy-3-r(2S,5R)-5-r4-(3-methoxy-propyl)-2,2- dimethyl-3,4-dihvdro-2H-benzon ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)- piperidin-2-yl1-propionyl)-oxazolidin-2-one
Following the procedure for Example 54c, 6-[(3R,6S)-6-[(S(or R))-3-((S)-4-Benzyl-2- oxo-oxazolidin-3-yl)-2-methoxy-3-oxo-propyl]-1 -(toluene-4-sulfonyl)-piperidin-3- yloxymethyl]-4-(3-methoxy-propyl)-2,2-dimethyl-4H-benzo[1 ,4]oxazin-3-one is reacted. The title compound is identified based on the Rf value.
d) 6-r(3R,6S)-6-r(S(or R))-3-((S)-4-Benzyl-2-oxo-oxazolidin-3-yl)-2-methoxy-3-oxo- propyl1-1-(toluene-4-sulfonyl)-piperidin-3-yloxymethyl1-4-(3-methoxy-propyl)-2,2- dimethyl-4H-benzo[1 ,41oxazin-3-one
Following the procedure for Example 54d, (S)-4-Benzyl-3-{(S)-3-[(2S,5R)-5-hydroxy- 1 -(toluene-4-sulfonyl)-piperidin-2-yl]-2-methoxy-propionyl}-oxazolidin-2-one and 2,2,2-trichloro-acetimidic acid 4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro- 2H-benzo[1 ,4]oxazin-6-ylmethyl ester are reacted. The title compound is identified based on the Rf value.
e) (S)-4-Benzyl-3-{(S)-3-r(2S,5R)-5-hvdroxy-1 -(toluene-4-sulfonyl)-piperidin-2-yll-2- methoxy-propionyl)-oxazolidin-2-one
Following the procedure for Example 54e, (S)-4-benzyl-3-{(S)-2-methoxy-3-[(2S,5R)- 5-(4-methoxy-benzyloxy)-1 -(toluene-4-sulfonyl)-piperidin-2-yl]-propionyl}-oxazolidin- 2-one is reacted. The title compound is identified based on the Rf value. f) (S)-4-Benzyl-3-{(S)-2-methoxy-3-r(2S,5R)-5-(4-methoxy-benzyloxy)-1 -(toluene-4- sulfonyl)-pipeπdin-2-yl1-propionyl)-oxazolidin-2-one
To a solution of 0.2 mmol of (S)-4-benzyl-3-{(S)-2-hydroxy-3-[(2S,5R)-5-(4-methoxy- benzyloxy)-1 -(toluene-4-sulfonyl)-piperidin-2-yl]-propionyl}-oxazolidin-2-one in 10 ml of dry dichloromethane is added sequentially at 00C 4 A molecular sieves (500 mg), N,N,N',N'-tetramethyl-naphthalene-1 ,8-diamine (2 mmol) and trimethyloxonium tetrafluoroborate (1.8 mmol). After stirring at room temperature for 3 hours, the reaction is quenched by adding water (20 ml). The layers are separated and the aqueous phase is extracted with tert butyl-methyl ether (3x). The combined organic solutions are washed with saturated, aqueous copper sulfate (2x) and brine, dried with sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.
g) (S)-4-Benzyl-3-{(S)-2-hvdroxy-3-r(2S,5R)-5-(4-methoxy-benzyloxy)-1-(toluene-4- sulfonyl)-piperidin-2-yl1-propionyl)-oxazolidin-2-one
A solution of 0.25 mmol of (S)-4-benzyl-3-{3-[(2S,5R)-5-(4-methoxy-benzyloxy)-1- (toluene-4-sulfonyl)-piperidin-2-yl]-propionyl}-oxazolidin-2-one (Example 54g) in 15 ml of tetrahydrofuran at -78°C is treated with 0.30 mmol of sodium bis(trimethyl- silyl)amide. The reaction mixture is stirred at -78°C for 30 minutes, then at -400C for 15 minutes, before being cooled again to -78°C. A solution of 0.33 mmol of 3-phenyl- 2-(phenylsulfonyl)-1 ,2-oxazihdine [63160-13-4] in 5 ml of tetrahydrofuran is added, the reaction mixture is stirred at -78°C for 2 hours, then quenched with 100 ml of saturated aqueous ammonium chloride solution. Once at room temperature, the reaction mixture is extracted with tert butyl-methyl ether (3x). The combined organic extracts are washed with brine, with sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.
h) 2,2,2-Thchloro-acetimidic acid 4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4- dihvdro-2H-benzo[1 ,41oxazin-6-ylmethyl ester Following the procedure for Example 54j, 6-hydroxymethyl-4-(3-methoxy-propyl)-2,2- dimethyl-4H-benzo[1 ,4]oxazin-3-one [857281 -72-2] is reacted. The title compound is identified based on the Rf value.
In analogy to the synthesis of Example 105, the following compound is prepared:
106 (R(or S))-2-Methoxy-3-{(2S,5R)-5-r4-(3-methoxy-propyl)-2,2-dimethyl-3,4- dihvdro-2H-benzori ,41oxazin-6-ylmethoxy1-piperidin-2-yl)-N-(tetrahvdro-pyran- 4-yl methyl )-propionamide
Example 107
3-((2S.5R)-5-f4-(3-Methoxy-propyl)-2.2-dimethyl-3.4-dihvdrO-2H-benzof1.41oxazin-6- ylmethoxy1-piperidin-2-yl)-2,2-dimethyl-N-r(S)-1 -(tetrahvdro-pyran-4-yl)-ethyl1- propionamide
Following general Method A, 3-[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2-dimethyl-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)-piperidin-2-yl]-2,2- dimethyl-N-[(S)-1-(tetrahydro-pyran-4-yl)-ethyl]-propionamide is reacted. The title compound is identified based on the Rf value.
The starting materials are prepared as follows: a) (i) 3-r(2S,5R)-5-r4-(3-Methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-yl1-2,2- dimethyl-N-r(S)-1-(tetrahvdro-pyran-4-yl)-ethyl1-propionamide and (ii) 3-r(2S,5R)-5-r4-(3-Methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-yl1-2,2- dimethyl-N-r(R)-1 -(tetrahvdro-pyran-4-yl)-ethyl1-propionamide Following the procedure for Example 17a, 3-[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2- dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)- piperidin-2-yl]-2,2-dimethyl-propionic acid and 1 -(tetrahydro-pyran-4-yl)-ethylamine [854697-78-2] are reacted. The title compound is identified based on the Rf value. b) 3-r(2S,5R)-5-r4-(3-Methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzoπ ,41oxazin-6-ylnnethoxy1-1 -(toluene-4-sulfonyl)-pipeπdin-2-yl1-2,2-dinnethyl- propionic acid
Following the procedure for Example 17b, 3-[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2- dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)- piperidin-2-yl]-2,2-dimethyl-propionic acid methyl ester is reacted. The title compound is isolated as a pale violet resin. Rf = 0.31 (EtOAc); Rt = 5.28 (gradient I).
c) 3-r(2S,5R)-5-r4-(3-Methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-pipehdin-2-yl1-2,2-dimethyl- propionic acid methyl ester
Following general Method F, 3-[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo- 3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)-piperidin-2-yl]- 2,2-dimethyl-propionic acid methyl ester is reacted. The title compound is isolated as a yellow oil. Rf = 0.53 (EtOAc-heptane 1 :1 ); Rt = 5.79 (gradient I).
d) 3-r(2S,5R)-5-r4-(3-Methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-yl1-2,2-dimethyl- propionic acid methyl ester
Following general Method H, 3-[(2S,5R)-5-hydroxy-1 -(toluene-4-sulfonyl)-piperidin-2- yl]-2,2-dimethyl-propionic acid methyl ester (Example 17e) and 6-chloromethyl-4-(3- methoxy-propyl)-2,2-dimethyl-4H-benzo[1 ,4]oxazin-3-one [857281-71 -1] are reacted. The title compound is isolated as a colourless oil. Rf = 0.52 (EtOAc-heptane 3:1 ); Rt = 5.48 (gradient I).
Example 108
3-((2S.5R)-5-f4-(3-Methoxy-propyl)-2.2-dimethyl-3.4-dihvdrO-2H-benzof1.41oxazin-6- ylmethoxy1-piperidin-2-yl)-2,2-dimethyl-N-((3R,4S)-3-methyl-tetrahvdro-pyran-4- yl methyl )-propionamide
Following general Method A, 3-[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2-dimethyl-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)-piperidin-2-yl]-2,2- dimethyl-N-((3R,4S)-3-methyl-tetrahydro-pyran-4-ylmethyl)-propionamide is reacted.
The title compound is identified based on the Rf value. The starting materials are prepared as follows: a) 3-r(2S,5R)-5-r4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-yl1-2,2-dinnethyl- N-((3R,4S)-3-methyl-tetrahvdro-pyran-4-ylmethyl)-propionannide
Following the procedure for Example 17a, 3-[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2- dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)- piperidin-2-yl]-2,2-dimethyl-propionic acid (Example 107b) and C-((3R,4S)-3-methyl- tetrahydro-pyran-4-yl)-methylamine are reacted. The title compound is identified based on the Rf value.
b) C-((3R,4S)-3-Methyl-tetrahvdro-pyran-4-yl)-methylamine
A solution of 3.1 mmol of (3S,4R)-3-methyl-tetrahydro-pyran-4-carboxylic acid amide in 20 ml of dry tetrahydrofuran at 00C under argon is treated with 12.4 mmol of lithium aluminium hydride. The reaction mixture is stirred at room temperature for 16 hours. It is then quenched with 2 ml of water, followed by 4 ml of 3N NaOH. The mixture is filtered through hyflow. The filtrate is diluted with water, extracted with tert butyl- methyl ether (3X). The combined organic extracts are washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.
c) (3S,4R)-3-methyl-tetrahvdro-pyran-4-carboxylic acid amide
A solution of 3.5 mmol of (3S,4R)-3-methyl-tetrahydro-pyran-4-carboxylic acid and 3.5 mmol of N,N'-carbonyldiimidazole in 10 ml of dry ethyl acetate is stirred under argon at room temperature for 4 hours. It is then quenched with 10 ml of ammonium- hydroxide and the reaction mixture is stirred for further 17 hours. The phases are separated. The organic layer is washed with water (2x), dried with sodium sulfate, and concentrated under reduced pressure. The title compound is identified based on the Rf value. d) (3S,4R)-3-methyl-tetrahvdro-pyran-4-carboxylic acid
Following the procedure for Example 54b, (R)-4-benzyl-3-((3S,4R)-3-methyl- tetrahydro-pyran-4-carbonyl)-oxazolidin-2-one is reacted. The title compound is identified based on the Rf value.
e) (i) (R)-4-Benzyl-3-((3S,4R)-3-methyl-tetrahvdro-pyran-4-carbonyl)-oxazolidin-2-one and
(ii) (R)-4-Benzyl-3-((3R,4S)-3-methyl-tetrahvdro-pyran-4-carbonyl)-oxazolidin-2-one Following the procedure for Example 54g, cis-S-methyl-tetrahydro-pyran^-carboxylic acid and (R)-4-benzyl-oxazolidin-2-one are reacted. The title compounds are identified based on the Rf values.
f) cis S-methyl-tetrahydro-pyran^-carboxylic acid
A solution of 9.8 mmol of cis-S-methyl-tetrahydro-pyran^-carbonitrile in 50 ml of acetic acid and 10 ml of concentrated HCI is stirred at 800C for 3 hours, then cooled to room temperature and concentrated under reduced pressure. The residue is partitioned between water and ethyl acetate. The water phase is re-extracted with ethyl acetate. (3x). The combined organic extracts are dried with sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.
g) cis-3-Methyl-tetrahvdro-pyran-4-carbonitrile
To a solution of 10.5 mmol of methanesulfonic acid 3-methyl-tetrahydro-pyran-4-yl ester in 70 ml of acetonithle is added 21 mmol of tetrabutylammonium cyanide. The reaction mixture is stirred at 800C for 5 hours, then cooled to room temperature, diluted with 400 ml of water, and extracted with ethyl acetate (4x). The combined organic extracts are dried with sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.
h) Methanesulfonic acid cis-3-methyl-tetrahvdro-pyran-4-yl ester A solution of 10.5 mmol of (3R,4S)-3-methyl-tetrahydro-pyran-4-ol [3174-64-9] in 80 ml of dichloromethane is cooled to 0°C and treated with 14.7 mmol of triethyl- amine and 11.3 mmol of methanesulfonyl chloride. The reaction mixture is stirred for 3 hours, letting the temperature warm slowly to room temperature. Water is added, and the reaction mixture is extracted with dichloromethane (3x). The combined organic extracts are dried with sodium sulfate, and concentrated under reduced pressure. The crude title compound is identified based on the Rf value.
Example 109
3-((2S.5R)-5-f4-(3-Methoxy-propyl)-2.2-dimethyl-3.4-dihvdrO-2H-benzof1.41oxazin-6- ylmethoxy1-piperidin-2-yl)-N-((3R,4R)-3-methoxy-tetrahvdro-pyran-4-ylmethyl)-2,2- dimethyl-propionamide
Following Method A, 3-[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)-piperidin-2-yl]-N-((3R,4R)-3- methoxy-tetrahydro-pyran-4-ylmethyl)-2,2-dimethyl-propionamide is reacted. The title compound is identified based on the Rf value.
The starting materials are prepared as follows: a) 3-r(2S,5R)-5-r4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-yl1-N-((3R,4R)- 3-methoxy-tetrahvdro-pyran-4-ylmethyl)-2,2-dimethyl-propionamide
Following the procedure for Example 17a, 3-[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2- dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)- piperidin-2-yl]-2,2-dimethyl-propionic acid (Example 107b) and C-((3R,4R)-3- methoxy-tetrahydro-pyran-4-yl)-methylamine are reacted. The title compound is identified based on the Rf value.
b) C-((3R,4R)-3-Methoxy-tetrahvdro-pyran-4-yl)-methylamine
Following the procedure for Example 108b, 108c, 108d, 108e and 108f, the title compound is obtained from cis-3-methoxy-tetrahydro-pyran-4-carbonitrile. The title compound is identified based on the Rf value.
c) cis-S-Methoxy-tetrahydro-pyran^-carbonitrile
A solution of 8.2 mmol of cis-S-hydroxy-tetrahydro-pyran^-carbonithle (Tetrahedron, 1994, 50 (4), 1261 ) in 65 ml of tetrahydrofuran is cooled to -78°C and treated with 9.02 mmol of n-butyllithium (0.6M in hexane). The reaction mixture is stirred at -78°C for 45 minutes, before the addition of 16.4 mmol of trifluoro-methanesulfonic acid methyl ester. The reaction mixture is allowed to warm to -400C and stirred at this temperature for 4 hours, before being quenched with saturated aqueous ammonuim chloride solution. The mixture is warmed to room temperature, extracted with tert butyl-methyl ether (3x). The combined organic extracts are dried with sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.
Example 110
1 -((2S.5R)-5-f4-(3-Methoxy-propyl)-2.2-dimethyl-3.4-dihvdrO-2H-benzof1.41oxazin-6- ylmethoxy1-piperidin-2-ylmethyl)-cvclopropanecarboxylic acid (tetrahvdro-pyran-4- ylmethvD-amide
Following Method A, 1-[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)-piperidin-2-ylmethyl]- cyclopropanecarboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide is reacted. The title compound is identified based on the Rf value.
The starting materials are prepared as follows: a) 1 -r(2S,5R)-5-r4-(3-Methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-ylmethyl1- cvclopropanecarboxylic acid (tetrahvdro-pyran-4-ylmethyl)-amide
Following the procedure for Example 17a, 1 -[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2- dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)- piperidin-2-ylmethyl]-cyclopropanecarboxylic acid is reacted. The title compound is identified based on the Rf value.
b) 1 -r(2S,5R)-5-r4-(3-Methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-ylmethyl1- cvclopropanecarboxylic acid
A solution of 2.61 mmol of 1 -[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2-dimethyl-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)-piperidin-2- ylmethyl]-cyclopropanecarboxylic acid tert-butyl ester in 20 ml of dichloromathane is treated at 00C with 13.05 mmol of trifluoroacetic acid. The reaction mixture is stirred at room temperature for 5 hours, then diluted with water and extracted with dichloromathane (3x). The combined organic extracts are dried with sodium sulfate, and concentrated under reduced pressure. The crude title compound is identified based on the Rf value.
c) 1 -r(2S,5R)-5-r4-(3-Methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-ylmethyl1- cvclopropanecarboxylic acid tert-butyl ester
A solution of 5.00 mmol of cyclopropanecarboxylic acid tert-butyl ester [87661 -20-9] in 50 ml of tetrahydrofuran at -78°C is treated with 5.5 mmol of lithium diisopropyl- amine. The reaction mixture is stirred at -78°C for 4 hours before the addition of a solution of 6.00 mmol of 6-[(3R,6S)-6-bromomethyl-1 -(toluene-4-sulfonyl)-piperidin-3- yloxymethyl]-4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazine in 10 ml of tetrahydrofuran. The reaction is stirred at -78°C for 1 hour, then allowed to warm to room temperature over 4 hours, and quenched with saturated aqueous ammonium chloride solution. The mixture is extracted with tert butyl-methyl ether (3x), the combined organic extracts are dried with sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.
d) 6-r(3R,6S)-6-Bromomethyl-1 -(toluene-4-sulfonyl)-piperidin-3-yloxymethyl1-4-(3- methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H-benzo[1 ,41oxazine
Following the proceedure for Example 17d, starting with [4-(3-methoxy-propyl)-2,2- dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-yl]-methanol (Example 40a).
Example 111
N-(4-Methoxy-cvclohexylmethyl)-3-{(2S,5R)-5-r4-(3-methoxy-propyl)-2,2-dimethyl-3,4- dihvdro-2H-benzori ,41oxazin-6-ylmethoxy1-piperidin-2-yl)-2,2-dimethyl-propionamide Following Method A, N-(4-methoxy-cyclohexylmethyl)-3-[(2S,5R)-5-[4-(3-methoxy- propyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4- sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionamide is reacted. The title compound is identified based on the Rf value.
The starting materials are prepared as follows: a) N-(4-methoxy-cvclohexylmethyl)-3-r(2S,5R)-5-r4-(3-methoxy-propyl)-2,2- dimethyl-3,4-dihvdro-2H-benzon ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)- piperidin-2-yl1-2,2-dimethyl-propionamide
Following the procedure for Example 17a, 3-[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2- dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)- piperidin-2-yl]-2,2-dimethyl-propionic acid (Example 107b) and C-(4-methoxy- cyclohexyl)-methylamine are reacted. The title compound is identified based on the Rf value.
b) C-(4-Methoxy-cvclohexyl)-methylamine
Following the procedure for Example 108b and 108c, the title compound is obtained from 4-methoxy-cyclohexanecarboxylic acid [73873-59-3]. The title compound is identified based on the Rf value.
Example 112
4-Methoxy-cvclohexanecarboxylic acid ((S(or R))-1-{(2S,5R)-5-r4-(3-methoxy-propyl)-
2,2-dimethyl-3,4-dihvdro-2H-benzori ,41oxazin-6-ylmethoxy1-piperidin-2-ylmethyl)- propyD-amide
Following Method A, 4-methoxy-cyclohexanecarboxylic acid {(S(or R))-1 -[(2S,5R)-5-
[4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -
(toluene-4-sulfonyl)-piperidin-2-ylmethyl]-propyl}-amide is reacted. The title compound is identified based on the Rf value.
The starting materials are prepared as follows: a) 4-Methoxy-cvclohexanecarboxylic acid {(S(or R))-1-r(2S,5R)-5-[4-(3-methoxy- propyl)-2,2-dimethyl-3,4-dihvdro-2H-benzoπ ,41oxazin-6-ylmethoxy1-1 -(toluene-4- sulfonyl)-piperidin-2-ylmethyl1-propyl)-amide Following the procedure for Example 88a, (S(or R))-1 -[(2S,5R)-5-[4-(3-methoxy- propyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4- sulfonyl)-piperidin-2-ylmethyl]-propylamine and trans-4-methoxycyclohexane- carboxylic acid [73873-61 -7] are reacted. The title compound is identified based on the Rf value.
b) (S(or R))-1-r(2S,5R)-5-r4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-ylmethyl1- propylamine
Following Method O, 6-[(3R,6S)-6-((S(or R))-2-azido-butyl)-1-(toluene-4-sulfonyl)- piperidin-3-yloxymethyl]-4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihydro-2H- benzo[1 ,4]oxazine is reacted. The title compound is identified based on the Rf value.
c) 6-[(3R,6S)-6-((S(or R))-2-Azido-butyl)-1 -(toluene-4-sulfonyl)-piperidin-3- yloxymethyl1-4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzo[1 ,41oxazine
Following the procedure for Example 89c, methanesulfonic acid (R(or S))-1 -[(2S,5R)- 5-[4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]- 1 -(toluene-4-sulfonyl)-piperidin-2-ylmethyl]-propyl ester is reacted. The title compound is identified based on the Rf value.
d) Methanesulfonic acid (R(or S))-1 -r(2S,5R)-5-r4-(3-methoxy-propyl)-2,2-dimethyl- 3,4-dihvdro-2H-benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2- ylmethyli-propyl ester
Following Method E, (R(or S))-1-[(2S,5R)-5-[4-(3-methoxy-propyl)-2,2-dimethyl-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)-piperidin-2-yl]- butan-2-ol is reacted. The title compound is identified based on the Rf value.
e) (i) (R(or S))-1-r(2S,5R)-5-r4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-yl1-butan-2-ol and
(ii) (S(or R))-1 -r(2S,5R)-5-r4-(3-methoxy-propyl)-2,2-dimethyl-3,4-dihvdro-2H- benzori ,41oxazin-6-ylmethoxy1-1 -(toluene-4-sulfonyl)-piperidin-2-yl1-butan-2-ol Following the procedure for Example 89e, [(2S,5R)-5-[4-(3-methoxy-propyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulfonyl)-piperidin-2-yl]- acetaldehyde (Example 1f) and ethylmagnesium bromide are reacted. The title compounds are identified based on the Rf values.
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001

Claims

Claims
1. A compound of formula
Figure imgf000100_0001
(I) for the inhibition of beta-secretase, cathepsin D, plasmepsin Il and/or HIV-protease, in which
R is C2-8-alkenyl, C2-8-alkynyl, Ci-8-alkyl, C0-8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8- alkyl, optionally N-mono- or N,N-di-Ci-8-alkylated or -arylated amino-Ci-s-alkyl, optionally O-Ci-8-alkylated carboxyl-Co-s-alkyl, Cs-s-cycloalkyl-Ci-s-alkyl, optionally N-mono- or N,N-di-C3-8-cycloalkyl-Co-8-alkylated or optionally N-mono- or N,N-di- heterocyclyl-Co-8-alkylated carbamoyl-Co-8-alkyl, C3-8-cycloalkyl-Co-8-alkylcarbonyl-(N- Co-8-alkyl)amino-Ci-8-alkyl, arylcarbonyl-(N-Co-8-alkyl)amino-Ci-8-alkyl, optionally N-mono- or N,N-di-Ci-8-alkylated or -arylated sulphamoyl-Co-8-alkyl, Ci-s-alkyl- sulphonyl-Co-8-alkyl or heterocyclylcarbonyl-Co-8-alkyl, each of which is either unsub- stituted or substituted by 1-4 Ci-8-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-8-alkoxy- carbonyl-(N-Ci-8-alkyl)amino, Ci-8-alkyl, Ci-8-alkylcarbonyl, C0-8-alkylcarbonyl-(N-C0-8- alkyl)amino, Ci-8-alkylsulphanyl, Ci-8-alkylsulphinyl, Ci-8-alkylsulphonyl, aryl-C0-8- alkoxy, aryl, arylamino, aryl-Co-s-alkylsulphonyl, cyano, C3-8-cycloalkoxy, halogen, heterocyclyl, heterocyclyl-Co-8-alkoxy, heterocyclyl-Co-β-alkylamino, heterocyclyl- carbonyl, hydroxyl, phosphonyl, optionally N-mono- or N,N-di-Ci-8-alkylated amino, optionally N-mono- or N,N-di-Ci-8-alkylated carbamoyloxy, optionally N-mono- or N,N-di-Ci-8-alkylated sulphamoyl, optionally N-mono-, -di- or -tri-Ci-s-alkylated or heterocyclyl-substituted ureido, optionally N-mono- or N,N-di-Ci-8-alkylated, N-mono- or N,N-di-arylated or N-mono- or N.N-di-heterocyclyl-Co-β-alkylated amino-Co-8- alkylcarbonyl, oxo or trifluoromethyl;
R1 is aryl or heterocyclyl, each of which is substituted by 1-4 acyl-Ci-s-alkoxy-Ci-s- alkoxy, acyl-Ci-s-alkoxy-Ci-s-alkyl, (N-acyO-Ci-s-alkoxy-Ci-s-alkylamino, Ci-8-alkanoyl, Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkanoyl, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s- alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, (N-Ci-s-alkoxyJ-Ci-s-alkylaminocarbonyl-Ci-s- alkoxy, (N-Ci-s-alkoxyJ-Ci-s-alkylaminocarbonyl-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl- carbamoyl, Ci-s-alkoxy-Ci-s-alkylcarbonyl, Ci-s-alkoxy-Ci-s-alkylcarbonylamino, 1 -Ci-s-alkoxy-Ci-s-alkylheterocyclyl, Ci-s-alkoxyanninocarbonyl-Ci-s-alkoxy, Ci-S- alkoxyanninocarbonyl-Ci-8-alkyl, Ci-s-alkoxycarbonyl, Ci-s-alkoxycarbonyl-Ci-s-alkoxy, Ci-s-alkoxycarbonyl-Ci-s-alkyl, Ci-s-alkoxycarbonylamino-Ci-s-alkoxy, Ci-8-alkoxy- carbonylannino-Ci-8-alkyl, Ci-8-alkyl, (N-Ci-s-alkyO-Ci-s-alkoxy-Ci-s-alkylcarbannoyl, (N-Ci-s-alkyO-Ci-s-alkoxy-Ci-s-alkylcarbonylannino, (N-Ci-8-alkyl)-Ci-8-alkoxycarbonyl- amino, (N-Ci-s-alkyO-Ci-s-alkylcarbonylannino-Ci-s-alkoxy, (N-Ci-8-alkyl)-Ci-8-alkyl- carbonylamino-Ci-8-alkyl, (N-Ci-s-alkylJ-Ci-s-alkylsulphonylannino-Ci-s-alkoxy, (N-Ci-S- alkyl)-Ci-8-alkylsulphonylamino-Ci-8-alkyl, Ci-s-alkylannidinyl, Ci-s-alkylamino-Ci-s- alkoxy, di-Ci-s-alkylannino-Ci-s-alkoxy, Ci-s-alkylannino-Ci-s-alkyl, di-Ci-s-alkylannino- Ci-s-alkyl, Ci-s-alkylanninocarbonyl-Ci-s-alkoxy, di-Ci-s-alkylaminocarbonyl-Ci-s- alkoxy, Ci-s-alkylanninocarbonyl-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkylaminocarbonyl-Ci-s- alkyl, di-Ci-s-alkylanninocarbonyl-Ci-s-alkyl, Ci-s-alkylaminocarbonylannino-Ci-s- alkoxy, Ci-s-alkylaminocarbonylamino-Ci-s-alkyl, Ci-s-alkylcarbonylannino, Ci-S- alkylcarbonylannino-Ci-8-alkoxy, Ci-s-alkylcarbonylannino-Ci-s-alkyl, Ci-s-alkyl- carbonyloxy-Ci-s-alkoxy, Ci-s-alkylcarbonyloxy-Ci-s-alkyl, Ci-s-alkylsulphonyl, Ci-S- alkylsulphonyl-Ci-8-alkoxy, Ci-s-alkylsulphonyl-Ci-s-alkyl, Ci-s-alkylsulphonylamino- Ci-s-alkoxy, Ci-s-alkylsulphonylannino-Ci-s-alkyl, optionally N-mono- or N,N-di-Ci-8- alkylated amino, aryl-Co-8-alkoxy, aryl-Co-8-alkyl, optionally N-mono- or N,N-di-Ci-8- alkylated carbamoyl-Co-8-alkoxy, optionally N-mono- or N,N-di-Ci-8-alkylated carbamoyl-Co-8-alkyl, carboxy-Ci-8-alkoxy, carboxy-Ci-s-alkoxy-Ci-s-alkyl, carboxy- Ci-s-alkyl, cyano, cyano-Ci-8-alkoxy, cyano-Ci-8-alkyl, Cs-s-cycloalkyl-Ci-s-alkoxy, Cs-s-cycloalkyl-Ci-s-alkyl, C3-8-cycloalkylcarbonylamino-Ci-8-alkoxy, C3-8-cycloalkyl- carbonylamino-Ci-s-alkyl, CN-dimethylhydroxylamino-Ci-s-alkyl, halogen, halogen- Ci-s-alkoxy, halogen-Ci-s-alkyl, halogen-aryl, heterocyclyl-Co-8-alkoxy, heterocyclyl- Co-8-alkyl, heterocyclylcarbonyl, hydroxy-Ci-s-alkoxy-Ci-s-alkoxy, hydroxy-Ci-s-alkoxy- Ci-s-alkyl, hydroxy-Ci-s-alkyl, O-methyloximyl-Ci-s-alkyl, oxide or oxo; where, when R1 is heterocyclyl and contains at least one saturated carbon atom, this heterocyclyl radical may additionally be substituted at a saturated carbon atom by a C2-8-alkylene chain whose two ends are fixed on this saturated carbon atom and thus form a spirocycle, where one CH2 group of the alkylene chain may be replaced by oxygen;
X is -AIk-, -0-AIk-, -AIk-O-, -0-AIk-O-, -S-AIk-, -AIk-S-, -AIk-NR2-, -NR2-Alk-, -C(O)- NR2-, -AIk-C(O)-NR2-, -C(O)-N R2-Alk-, -Alk-C(O)-NR2-Alk-, -NR2-C(O)-, -AIk-NR2- C(O)-, -NR2-C(O)-Alk-, -Alk-NR2-C(O)-Alk-, -0-AIk-C(O)-NR2-, -O-Alk-NR2-C(O)-, -S(O)2-NR2-, -AIk-S(O)2-NR2-, -S(O)2-N R2-Alk-, -Alk-S(O)2-NR2-Alk-, -NR2-S(O)2-, -Alk-NR2-S(O)2-, -NR2-S(O)2-Alk- or -Alk-NR2-S(O)2-Alk-, where AIk is Ci-8-alkylene which may optionally be substituted by halogen; and where
R2 is hydrogen, Ci-8-alkyl, Ci-s-alkoxy-Ci-s-alkyl, acyl or aryl-Ci-8-alkyl; or its pharmaceutically usable salt, prodrug or compound, in which one or more atoms have been replaced by their stable, non-radioactive isotopes.
2. A compound according to claim 1 of formula
Figure imgf000102_0001
(IA)
or a pharmaceutically usable salt thereof, in which R, R1 and X are each as defined for the compound of the formula (I) according to Claim 1.
3. A comound according to claim 1 or 2, wherein
R is Ci-8-alkyl, C0-8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8-alkyl, C3-8-cycloalkyl-Ci-8- alkyl, optionally N-mono- or N,N-di-C3-8-cycloalkyl-C0-8-alkylated or optionally N-mono- or N.N-di-heterocyclyl-Co-s-alkylated carbamoyl-Co-s-alkyl or C3-8-cycloalkyl- Co-8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8-alkyl or heterocyclylcarbonyl-Co-8-alkyl, each of which is either unsubstituted or substituted by 1-4 Ci-s-alkoxy, Ci-s-alkoxy- Ci-s-alkoxy, Ci-8-alkoxycarbonyl-(N-Ci-8-alkyl)amino, Ci-s-alkyl, Ci-s-alkylcarbonyl, Co-δ-alkylcarbonyl^N-Co-δ-alkylJamino, Ci-s-alkylsulphanyl, Ci-s-alkylsulphinyl, Ci-S- alkylsulphonyl, aryl-Co-s-alkoxy, aryl, arylamino, aryl-C-o-β-alkylsulphonyl, cyano, C3-S- cycloalkoxy, halogen, heterocyclyl, heterocyclyl-Co-s-alkoxy, heterocyclyl-Co-s-alkyl- amino, heterocyclylcarbonyl, hydroxyl, phosphonyl, optionally N-mono- or N,N-di- Ci-s-alkylated amino, optionally N-mono- or N,N-di-Ci-8-alkylated carbamoyloxy, optionally N-mono- or N,N-di-Ci-8-alkylated sulphamoyl, optionally N-mono-, -di- or -tri-Ci-s-alkylated or heterocyclyl-substituted ureido, optionally N-mono- or N,N-di- Ci-s-alkylated, N-mono- or N,N-di-arylated or N-mono- or N,N-di-heterocyclyl-Co-8- alkylated amino-Co-8-alkylcarbonyl, oxo or trifluoromethyl.
4. A compound according to any one of claims 1 to 3, wherein R1 is benzimidazolyl, benzo[1 ,3]dioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzo[b]thienyl, quinazolinyl, quinolyl, quinoxalinyl, 2H-chromenyl, carbazolyl, dihydro-2H-benzo[1 ,4]oxazinyl, dihydro-3H-benzo[1 ,4]oxazinyl, dihydro-2H- benzo[1 ,4]thiazinyl, 2,3-dihydroindolyl, dihydro-1 H-pyrido[2,3-b][1 ,4]oxazinyl, imidazo[1 ,2-a]pyhdyl, imidazo[1 ,5-a]pyhdyl, indazolyl, indolyl, isobenzofuranyl, isoquinolyl, [1 ,5]naphthyridyl, phenyl, phthalazinyl, pyridyl, pyrimidinyl, 1 H- pyrrolo[2,3-b]pyhdyl, 1 H-pyrrolo[2,3-c]pyhdyl, 1 H-pyrrolo[3,2-b]pyridyl, tetrahydro- quinolyl, tetrahydroquinoxalinyl, tetrahydroimidazo[1 ,2-a]pyridyl, tetrahydro- imidazo[1 ,5-a]pyhdyl, tetrahydroisoquinolyl, [1 ,2,3]thazolo[1 ,5-a]pyridyl or [1 ,2,4]triazolo[4,3-a]pyridyl, each of which is substituted by 1 -4 Ci-8-alkanoyl, Ci-8- alkoxy, Ci-s-alkoxy-Ci-s-alkanoyl, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy- Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxycarbonylamino-Ci-s-alkoxy, Ci-8-alkoxy- carbonylamino-Ci-s-alkyl, Ci-s-alkyl, Co-s-alkylcarbonylamino-Ci-s-alkoxy, Co-β- alkylcarbonylamino-Ci-s-alkyl, aryl-Co-8-alkoxy, aryl-Co-8-alkyl, cyano, cyano-Ci-s- alkoxy, cyano-Ci-s-alkyl, halogen, halogen-d-s-alkoxy, halogen-d-s-alkyl, halogen- aryl, heterocyclyl-Co-s-alkoxy, heterocyclyl-Co-s-alkyl, oxide or oxo, where, when R1 is heterocyclyl and contains at least one saturated carbon atom, this heterocyclyl radical may additionally be substituted on a saturated carbon atom by a C2-8-alkylene chain whose two ends are fixed on this saturated carbon atom and thus form a spirocycle, where one CH2 group of the alkylene chain may be replaced by oxygen.
5. A compound according to any one of claims 1 to 4, wherein
R is C2-8-alkenyl, C2-8-alkynyl, Ci-s-alkyl, Co-8-alkylcarbonyl-(N-Co-8-alkyl)amino-Ci-8- alkyl, optionally N-mono- or N,N-di-Ci-8-alkylated or -arylated amino-Ci-s-alkyl, optionally O-Ci-8-alkylated carboxyl-Co-s-alkyl, Cs-s-cycloalkyl-Ci-s-alkyl, optionally N-mono- or N,N-di-C3-8-cycloalkyl-Co-8-alkylated or optionally N-mono- or N,N-di- heterocyclyl-Co-8-alkylated carbamoyl-Co-s-alkyl, C3-8-cycloalkyl-C0-8-alkylcarbonyl-(N- Co-8-alkyl)amino-Ci-8-alkyl, arylcarbonyl-(N-Co-8-alkyl)amino-Ci-8-alkyl, optionally N-mono- or N,N-di-Ci-8-alkylated or -arylated sulphamoyl-Co-8-alkyl, Ci-s-alkyl- sulphonyl-Co-8-alkyl or heterocyclylcarbonyl-Co-8-alkyl, each of which is either unsub- stituted or substituted by 1-4 Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy- carbonyl-(N-Ci-8-alkyl)amino, Ci-8-alkyl, Ci-8-alkylcarbonyl, C0-8-alkylcarbonyl-(N-C0-8- alkyl)amino, Ci-8-alkylsulphanyl, Ci-8-alkylsulphinyl, Ci-8-alkylsulphonyl, aryl-C0-8- alkoxy, aryl, arylamino, aryl-Co-β-alkylsulphonyl, cyano, C3-8-cycloalkoxy, halogen, heterocyclyl, heterocyclyl-Co-s-alkoxy, heterocyclyl-Co-s-alkylamino, hetero- cyclylcarbonyl, hydroxyl, phosphonyl, optionally N-mono- or N,N-di-Ci-8-alkylated amino, optionally N-mono- or N,N-di-Ci-8-alkylated carbamoyloxy, optionally N-mono- or N,N-di-Ci-8-alkylated sulphamoyl, optionally N-mono-, -di- or -tri-Ci-s-alkylated or heterocyclyl-substituted ureido, optionally N-mono- or N,N-di-Ci-8-alkylated, N-mono- or N,N-di-arylated or N-mono- or N.N-di-heterocyclyl-Co-β-alkylated amino-Co-8- alkylcarbonyl, oxo or trifluoromethyl;
R1 is 2H-chromenyl, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl or carbazolyl, each of which is substituted by 1 -4 Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy-Ci-s- alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxycarbonylamino-Ci-s-alkoxy, Ci-8-alkoxy- carbonylamino-Ci-s-alkyl, Ci-8-alkyl, Co-s-alkylcarbonylamino-Ci-s-alkoxy, C0-S- alkylcarbonylamino-Ci-s-alkyl, halogen, halogen-Ci-8-alkoxy, halogen-Ci-8-alkyl, halogen-aryl or oxo, where a saturated carbon atom of the heterocyclyl radical may additionally be substituted on the saturated carbon atom by a C2-8-alkylene chain whose two ends are fixed on this saturated carbon atom and thus form a spirocycle, where one CH2 group of the alkylene chain may be replaced by oxygen and
X is -0-CH2-.
6. A compound according to any one of claims 1 to 5, wherein
R is Ci-8-alkyl, Co-s-alkylcarbonylamino-Ci-s-alkyl, Cs-s-cycloalkyl-Ci-s-alkyl, optionally N-mono-C3-8-cycloalkyl-Co-8-alkylated, optionally N-mono-heterocyclyl-Co-s-alkylated carbamoyl-Co-8-alkyl, Cs-s-cycloalkyl-Co-s-alkylcarbonylamino-Ci-s-alkyl or hetero- cyclylcarbonyl-Co-8-alkyl, each of which is either unsubstituted or substituted by 1 -2 heterocyclyl or optionally N-mono- or N.N-di-Ci-Cs-alkylated, N-mono- or N,N-di- arylated or N-mono- or N,N-di-heterocyclyl-Co-8-alkylated carbamoyl, wherein the heterocyclyl is particularly preferably a saturated heterocyclyl preferaby selected from the group comprising tetrahydropyranyl, morpholinyl, piperidinyl, tetrahydrofuranyl, 3-oxa-bicyclo[3.1.0]hexanyl and 6-oxa-spiro[2.5]octanyl which heterocyclyl sub- stituents may be further substituted;
R1 is 2H-chromenyl, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl or carbazolyl, each of which is substituted by 1 -4 Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy-Ci-s- alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxycarbonylamino-Ci-s-alkoxy, Ci-8-alkoxy- carbonylamino-Ci-s-alkyl, Ci-8-alkyl, Co-s-alkylcarbonylamino-Ci-s-alkoxy, C0-S- alkylcarbonylamino-Ci-s-alkyl, halogen, halogen-Ci-8-alkoxy, halogen-Ci-8-alkyl, halogen-aryl or oxo, where a saturated carbon atom of the heterocyclyl radical may additionally be substituted on the saturated carbon atom by a C2-8-alkylene chain whose two ends are fixed on this saturated carbon atom and thus form a spirocycle, where one CH2 group of the alkylene chain may be replaced by oxygen; and
X is -0-CH2-.
7. A compound of the general formula (I) or (IA), or a pharmaceutically usable salt thereof, according to any one of claims 1 to 6 for the prevention, delay of progression or treatment of Alzheimer Disease, malaria or HIV infection.
8. A pharmaceutical preparation for the prevention, delay of progression or treatment of Alzheimer disease, malaria or HIV infection, whereby said preparation contains a compound of the general formula (I) or (IA), or a pharmaceutically usable salt thereof, according to any one of claims 1 to 6, as well as commonly used ingredients.
PCT/EP2009/052335 2008-02-29 2009-02-27 Substituted piperidines as therapeutic compounds WO2009106599A2 (en)

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WO2012068560A2 (en) * 2010-11-18 2012-05-24 Jenrin Discovery 4-quinolinemethanols as anti-malarial agents
WO2012068560A3 (en) * 2010-11-18 2013-08-15 Jenrin Discovery 4-quinolinemethanols as anti-malarial agents
US8716265B2 (en) 2010-11-18 2014-05-06 Jenrin Discovery, Inc. 4-quinolinemethanols as anti-malarial agents
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
WO2015009731A3 (en) * 2013-07-15 2015-03-19 The Regents Of The University Of California Azacyclic constrained analogs of fty720
US10077236B2 (en) 2013-07-15 2018-09-18 The Regents Of The University Of California Azacyclic constrained analogs of FTY720
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10995068B2 (en) 2015-09-24 2021-05-04 The Regents Of The University Of California Synthetic sphingolipid-like molecules, drugs, methods of their synthesis and methods of treatment
US11479530B2 (en) 2015-09-24 2022-10-25 The Regents Of The University Of California Synthetic sphingolipid-like molecules, drugs, methods of their synthesis and methods of treatment
WO2021130731A1 (en) 2019-12-27 2021-07-01 Lupin Limited Substituted tricyclic compounds

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