WO2004009549A2 - Piperidines utiles pour traiter des maladies du systeme nerveux central - Google Patents

Piperidines utiles pour traiter des maladies du systeme nerveux central Download PDF

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WO2004009549A2
WO2004009549A2 PCT/EP2003/007298 EP0307298W WO2004009549A2 WO 2004009549 A2 WO2004009549 A2 WO 2004009549A2 EP 0307298 W EP0307298 W EP 0307298W WO 2004009549 A2 WO2004009549 A2 WO 2004009549A2
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mixtures
lower alkyl
aryl
heteroaryl
diastereomers
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PCT/EP2003/007298
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WO2004009549A3 (fr
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Christoph Boss
Daniel Bur
Walter Fischli
Francois Jenck
Thomas Weller
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Actelion Pharmaceuticals Ltd
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Publication of WO2004009549A3 publication Critical patent/WO2004009549A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a 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
    • C07D405/02—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
    • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to substituted amino-aza-cycloalkane derivatives of the general formula I. Parts of these compounds summarized by general formula I have been described in WO 02/24649 as inhibitors of plasmepsin II, useful as antimalarial medicines. It has now surprisingly been found that a substantial number of said compounds are ⁇ -secretase inhibitors useful for prevention or treatment of diseases related to the formation and aggregation of amyloid- ⁇ -peptides (A ⁇ ). More particularly, the compounds and compositions are useful for treating or preventing Alzheimer's disease, other age-associated dementias as well as related A ⁇ dependent diseases (e.g. ⁇ amyloid angiopathy, Down's syndrome or inclusion body myositis). The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of general formula I and especially their use as inhibitors of the transmembrane bound aspartic protease BACE1 or other related aspartic proteases.
  • the World Health Organization emphasized the importance of mental disorders in the World Health Report 2001 [2] by giving a comprehensive analysis of the world's fastest growing disease group.
  • AD Alzheimer's disease
  • the therapeutic situation has improved with respect to treatment of symptoms such as depression, sleeplessness or agitation but no treatment is available being able to halt progression or even cure Alzheimer's disease.
  • AD Alzheimer's disease
  • APP amyloid precursor protein
  • AD Alzheimer's disease
  • a ⁇ is a major component of neuritic plaques in AD brains and increasing evidence supports that A ⁇ neurotoxicity and fibrillar assembly are key pathogenic features of AD. Smaller numbers of neurotoxic lesions in a more restricted anatomical distribution are found in the brains of most aged humans who do not display clinical AD.
  • amyloid deposits and vascular amyloid angiopathy also characterize individuals with Down's syndrome (trisomy 21), hereditary cerebral hemorrhage of the Dutch type and other neurodegenerative disorders.
  • a ⁇ is generated from APP which is a ubiquitously expressed type I protein with a large N-terminal domain, a single transmembrane domain and a short cytoplasmic domain coded by a gene located on human chromosome 21 (Price et al., Annu Rev Neurosci 21: 479-505, 1998; Selkoe, Trends Cell Biol 8: 447-453, 1998). APP can undergo several proteolytic events near and within its membrane domain.
  • a proteolytic activity named ⁇ -secretase initially cleaves APP to form two products: a secreted peptide named APPs ⁇ and the membrane bound C99 fragment of APP.
  • C99 is the substrate of a second proteolytic activity called ⁇ -secretase, which cleaves at position 711 (40) or 713 (42) to form A ⁇ 1-40 and A ⁇ 1-42 .
  • ⁇ -secretase a second proteolytic activity
  • cleavage of APP by ⁇ -secretase within the amyloid domain results in the release of the large soluble fragment, APPs ⁇ , and generation of a lOkDa membrane anchored C- terminal fragment, C83.
  • APP The processing of APP is similar to that of other proteins that undergo regulated intramembrane proteolysis such as Notch (Niwa et al., Cell 99: 691-702, 1999; Mumm et al., Dev Biol 228: 151-165, 2000) to generate fragments which play a role as transcription factors.
  • Notch Nawa et al., Cell 99: 691-702, 1999; Mumm et al., Dev Biol 228: 151-165, 2000
  • a ⁇ naturally arises in the endoplasmatic reticulum, the Golgi apparatus or the endosomal-lysosomal system and most is secreted as A ⁇ 1-40 or A ⁇ 1-42 (5-10%).
  • intracellular aggregates of A ⁇ also accumulate in brains of AD patients, Down's syndrome patients and aging monkeys. This precedes the appearance of neurofibrillary tangles and senile plaques in the hippocampus and entorhinal cortex of affected
  • BACE1 ⁇ -site APP cleaving enzyme
  • memapsin-2 memapsin-2
  • Asp2 memapsin-2
  • BACE1 is a membrane- bound aspartic protease with all the known functional properties and characteristics of ⁇ - secretase. It is a 501 amino acid sequence peptide most closely related to the pepsin aspartic protease family.
  • Two aspartic protease active-site motifs with the sequence DTGS (residues 93-96) and DSGT (289-292) are present, mutation of either aspartic acid abolishes the catalytic acitivity of the enzyme.
  • BACE1 has a single predicted C-terminal transmembrane domain (455-480) with a luminal active site. This is the correct topological orientation for APP cleavage.
  • Six cysteins are present in the catalytic domain to form three intramolecular disulfide bonds. The number of dislufide bridges is identical to other aspartic proteases such as pepsin. While the bond spanning between Cys330-380 appears conserved, the positions of two cysteine bridges (Cys278-443, Cys 216-420) are quite different when compared to pepsin, without changing the shape of the catalytic domain. Most cell types produce A ⁇ , indicating broad expression of ⁇ -secretase.
  • BACE2 a second homologous aspartyl protease named BACE2 was found to have ⁇ -secretase activity in vitro and is expressed at low levels in most peripheral organs, although not significantly in the brain.
  • BACEl protein expression with antisense oligonucleotides suppresses APPs ⁇ production in cells transfected with APPsw 2 .
  • overexpression of BACEl in cells leads to an increase of ⁇ -secretase activity: levels of C99 and APPs ⁇ are increased several-fold compared to untransfected cells.
  • mice In mice, expressing huBACEl in addition to human APP wild-type or carrying the Swedish mutation, the induction of APP processing results in increased brain levels of ⁇ -amyloid peptides A ⁇ 1-40 and A ⁇ 1-42 at steady state.
  • BACE knock-out mice are fully viable. A ⁇ production is significantly decreased in the brain of these animals, even when the BACE null mutation is introduced in transgenic mice overexpressing APP (Luo et al., Nature Neurosci. 4:231-232, 2001). However, no deleterious side-effects due to the loss of BACEl function was observed in these animals.
  • the healthy phenotype of BACEl knockouts gives ⁇ -secretase significant therapeutic potential although, as with ⁇ -secretase, substrates other than APP may exist.
  • the positive results from the knockout mice suggest that a potential mechanism-based toxicity might not be a major issue for BACEl specific inhibitors.
  • the present invention relates to the identification of novel as well as partially structurally known, low molecular weight non-peptidic inhibitors of BACEl of the general formula I (exhibiting a different binding mode to the protein compared to substrate derived inhibitors) to treat and/or prevent Alzheimer's Disease and other CNS -disorders associated with amyloid deposition in the brain.
  • the compounds of general formula I were tested against BACEl, plasmepsin II, plasmepsin IN, human cathepsin D, human cathepsin E, human renin and HIN-protease.
  • the proteolytic activity of human BACEl (Sinha, S., et al. (1999), Nature 402:537-540) was determined in a FRET-based assay, with a peptide-substrate whose sequence corresponds to the cleavage site of ⁇ -secretase in the Swedish variant of the amyloid precursor protein.
  • Commercial source of the BACEl -assay PanVera Corporation Madison WI 53719 USA (www.panvera.com)
  • the present invention relates to pharmaceutical compositions for treatment, prevention or delaying the onset of central nervous system disorders comprising substituted piperidines of the general formula I, wherein the substituent is attached either to position 3 or position 4 of the central piperidine-ring:
  • R 1 represents lower alkyl; lower alkenyl-lower alkyl; lower alkynyl-lower alkyl; cycloalkyl; cycloalkenyl-lower alkyl; heterocyclyl; aryl; heteroaryl;
  • R 2 represents cycloalkyl; cycloalkenyl; heterocyclyl; aryl; heteroaryl;
  • R represents lower alkyl; cycloalkyl; cycloalkenyl; heterocyclyl; aryl; heteroaryl;
  • A represents -(CH 2 ) m -;
  • n represents the whole numbers 1, 2 or 3;
  • k, p and q represent the whole numbers 0, 1, 2, 3 or 4 and may be the same or different;
  • f represents the whole numbers 1, 2, 3 or 4;
  • g represents the whole numbers 2,3 or 4;
  • lower means straight and branched chain groups with one to seven carbon atoms, preferably 1 to 4 carbon atoms which may optionally be substituted with hydroxy or lower alkoxy.
  • lower alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert.-butyl, n-pentyl, n-hexyl, n-heptyl and the like.
  • lower alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy; iso-butoxy, sec.-butoxy and tert.-butoxy and the like.
  • lower alkynyl groups are ethinyl, propynyl, butynyl, pentynyl, hexynyl and the like which may be optionally substituted by hydroxy or lower alkoxy.
  • lower alkynyloxy groups are 3-methoxy-prop-l-ynyl and the like.
  • Lower alkylendioxy- groups as substituents of aromatic rings onto two adjacent carbon atoms are preferably methylen-dioxy and ethylen-dioxy.
  • Lower alkylen-oxy groups as substituents of aromatic rings onto two adjacent carbon atoms are preferably ethylen-oxy and propylen-oxy.
  • Examples of lower alkanoyl-groups are acetyl, n-propanoyl and n-butanoyl.
  • cycloalkyl alone or in combination, means a saturated cyclic hydrocarbon ring system with 3 to 6 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl which may be mono- or di- substituted with lower alkyl; lower alkoxy; aryl- lower alkoxy; heteroaryl-lower alkoxy; aryl-lower alkyl-amino; heteroaryl-lower alkyl- amino; lower alkyl-amino; bis-(lower alkyl)-amino; aryl-lower alkoxy-lower alkyl; heteroaryl-lower alkoxy-lower alkyl; aryl-lower alkyl-amino-lower alkyl; heteroaryl-lower alkyl-amino-lower alkyl; aryl-sulfonyl-amino-lower alkyl; heteroaryl-sulf
  • cycloalkenyl alone or in combination, means an unsaturated cyclic hydrocarbon ring system with 5 to 7 carbon atoms, e.g. cyclopentenyl, cyclohexenyl and cycloheptenyl which may be substituted with lower alkyl groups or lower alkoxy groups.
  • heterocyclyl alone or in combination, means a saturated or unsaturated (but not aromatic) five-, six- or seven-membered ring containing one or two heteroatoms chosen from nitrogen, oxygen or sulfur which may be the same or different and which rings may be substituted with lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower alkoxy; aryl-lower alkoxy-lower alkyl; aryl-oxy; heteroaryl-lower alkoxy; heteroaryl-lower alkoxy-lower alkyl; heteroaryl-oxy; amino; bis-(lower alkyl)-amino; alkanoyl-amino; halogen; hydroxy; hydroxy-lower alkyl; lower alkoxy; phenoxy.
  • rings are morpholinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, pyrrolidinyl, tetrahydrofuranyl, dihydropyrrolyl, imidazolidinyl, dihydropyrazolyl, pyrazolidinyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and the like, and substituted derivatives of such type rings with substituents as outlined hereinbefore.
  • heteroaryl alone or in combination, means six-membered aromatic rings containing one to four nitrogen atoms; benzofused six-membered aromatic rings containing one to three nitrogen atoms; five-membered aromatic rings containing one oxygen, one nitrogen or one sulfur atom and benzo-fused derivatives thereof; five-musined aromatic rings containing two nitrogen atoms and benzo-fused derivatives thereof; five membered aromatic rings containig one oxygen and one nitrogen atom and benzo-fused derivatives thereof; five termed aromatic rings containing one sulfur and one nitrogen atom and benzo fused derivatives thereof; five membered aromatic rings containing three nitrogen atoms and benzo fused derivatives thereof or the tetrazolyl ring; examples of such rings are furanyl, thienyl, pyrrolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl, thiazinyl, pyrazo
  • aryl alone or in combination, means six membered aromatic rings and condensed systems like naphthyl or indenyl and the like, whereby such ring systems may be mono-, di- or tri-substituted with cycloalkyl; heterocyclyl; aryl; heteroaryl; aryloxy; aryl- lower alkoxy; heteroaryl-lower alkoxy; lower alkyl; lower alkenyl; lower alkynyl; lower alkenylen; lower alkyl-carbonyl; aryl-carbonyl; heteroaryl-carbonyl; cycloalkyl-carbonyl; heterocyclyl-carbonyl; amino; lower alkyl-amino; aryl-amino; heteroaryl-amino; bis-(lower- alkyl)-amino; bis-aryl-amino; lower alkanoyl-amino; aryl-carbonyl-amino; heteroaryl- carbonyl; amino
  • halogen means fluorine; chlorine; bromine and iodine but fluorine, chlorine and bromine are preferred.
  • R 5 represents lower alkyl; hydroxy-lower alkyl; aryl; aryl-lower alkyl; heteroaryl; heteroaryl-lower alkyl; heterocyclyl; heterocyclyl-lower alkyl; cycloalkyl; cycloalkyl-lower alkyl;
  • R 6 represents lower alkyl; lower alkynyl; aryl; heteroaryl; heterocyclyl; aryl-amino; heteroaryl-amino; cycloalkyl-amino; aryl-lower alkyl-amino; heteroaryl-lower alkyl-amino; heterocyclyl-lower alkyl-amino; cycloalkyl-lower alkyl amino; aryloxy; heteroaryloxy; cyloalkyloxy; aryl-lower alkyloxy; heteroaryl-lower alkyloxy; heterocyclyl-lower alkyloxy; cycloalkyl-lower alkyloxy; cycloalkyl-lower alkyloxy;
  • R 7 represents aryl; heteroaryl; heterocyclyl; cycloalkyl; aryl-amino; heteroaryl-amino; cycloalkyl-amino; aryl-lower alkyl-amino; heteroaryl-lower alkyl-amino; heterocyclyl-lower alkyl-amino; cycloalkyl-lower alkyl amino; aryl-oxy; heteroaryl-oxy; aryl-lower alkyl-oxy; heteroaryl-lower alkyl-oxy;
  • salts encompasses either salts with inorganic acids or organic acids like hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, methylsulfonic acid, p-toluolsulfonic acid and the like or in case the compound of formula I is acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and the like.
  • the compounds of general formula I can be transformed to suitable produrgs like carboxylic acid esters, phosphonic acid esters, sulfuric acid esters, acetales, ketales, phenyl carbamates, amino acid amides, Mannich bases, Schiff bases, oximes, enolesters, oxazolidines, thiazolidines and the like if necessary and advantageous. All forms of produrgs leading to an active component comprised in general formula I are included in the present invention.
  • the compounds of the general formula I can contain one or more asymmetric carbon atoms and may be prepared in form of optically pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates and mixtures of diastereomeric racemates and the meso-form.
  • the compounds of general formula I may also contain one or more partially or fully substituted carbon-carbon double bond(s), which may be Z- or E-substituted.
  • the present invention encompasses all these forms. Mixtures may be separated in a manner known per se, i.e. by column chromatography, thin layer chromatography, HPLC, crystallization and the like.
  • the compounds of the general formula I and their pharmaceutically acceptable salts may be used as therapeutics e.g. in form of pharmaceutical compositions. They may especially be used in prevention or treatment of CNS-disorders related to amyloid- ⁇ -peptide-deposition in the brain, like Alzheimer's disease, Down's Syndrome, Inclusion Body Myositis and other age-associated dementias as well as other amyloid- ⁇ -peptide-dependent diseases.
  • These compositions may be administered in enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions or suspensions, in nasal form like sprays or rectally in form of suppositories.
  • These compounds may also be administered in intramuscular, parenteral or intraveneous form, e.g. in form of injectable solutions.
  • compositions may contain the compounds of general formula I as well as their pharmaceutically acceptable salts in combination with inorganic and/or organic excipients which are usual in the pharmaceutical industry like lactose, maize or derivatives thereof, talcum, stearinic acid or salts of these materials.
  • vegetable oils, waxes, fats, liquid or half-liquid polyols and the like may be used.
  • solutions and sirups e.g. water, polyols saccharose, glucose and the like are used.
  • injectables are prepared by using e.g. water, polyols, alcohols, glycerin, vegetable oils, lecithin, liposomes and the like.
  • Suppositories are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats), liquid or half-liquid polyols and the like.
  • compositions may contain in addition preservatives, stability improving substances, viscosity improving or regulating substances, solubility improving substances, sweeteners, dyes, taste improving compounds, salts to change the osmotic pressure, buffer, anti-oxidants and the like.
  • the compounds of general formula I may also be used in combination with one or more other therapeutically useful substances e. g. with other medicaments used for the treatment of symptoms of Alzheimer's disease such as acetylcholine esterase inhibitors, medicaments for the treatment of depression, agitation or sleeplessness, with other medicaments/substances which halt or retard the formation of amyloid-plaques in the brain such as other BACEl -inhibitors or ⁇ -secretase-inhibitors, with antioxidants such as vitamin E, with LDL lowering agents such as HMG-CoA-reductase inhibitors and the like.
  • other medicaments used for the treatment of symptoms of Alzheimer's disease such as acetylcholine esterase inhibitors, medicaments for the treatment of depression, agitation or sleeplessness, with other medicaments/substances which halt or retard the formation of amyloid-plaques in the brain such as other BACEl -inhibitors or ⁇ -secretase-inhibitors, with antioxidants such as vitamin E
  • the dosage may vary within wide limits but should be adapted to the specific situation.
  • the dosage given in oral form should daily be between about 1 mg and about 3 g, preferably between about 10 mg and about 1 g, especially preferred between 5 mg and 300 mg, per adult with a body weight of about 70 kg.
  • the dosage should be administered preferably in 1 to 3 doses per day, which are of equal weight. As usual, children should receive lower doses which are adapted to body weight and age.
  • a group of preferred compounds for incorporation into pharmaceutical compositions for treatment, prevention or delaying the onset of central nervous system disorders are compounds of the formula II:
  • R 1 , R 2 , R 3 , X, Z and A are as defined in general formula I above
  • Another group of preferred compounds for incorporation into pharmaceutical compositions for treatment, prevention or delaying the onset of central nervous system disorders are compounds of the formula III:
  • R 1 , R 2 , Z and A are as defined in general formula I above
  • R 11 represents lower alkyl; lower alkyloxy; cycloalkyl; cycloalkyl-lower alkyloxy;
  • Another group of preferred compounds for incorporation into pharmaceutical compositions for treatment, prevention or delaying the onset of central nervous system disorders are compounds of the formula IV:
  • R 1 , R 2 A and Z are as defined in general formula I above, and wherein
  • R 12 represents lower alkyl; lower alkyloxy; lower alkyloxy-lower alkyloxy; aryl; heteroaryl; heterocyclyl;
  • Another group of preferred compounds for incorporation into pharmaceutical compositions for treatment, prevention or delaying the onset of central nervous system disorders are compounds of the formula V:
  • R 1 , R 3 , X and Z are as defined in general formula I above and
  • M represents -O-; -CH 2 -
  • R ,13 represents hydrogen; lower alkyl; lower alkenyl; lower alkynyl; cycloalkyl; cycloalkyl- lower alkyl; aryl; aryl-lower alkyl; heteroaryl; heteroaryl-lower alkyl;
  • Another group of preferred compounds for incorporation into pharmaceutical compositions for treatment, prevention or delaying the onset of central nervous system disorders are compounds of the formula VI:
  • R 1 , R 3 , X, and Z are as defined in general formula I
  • M represents -O-; -CH 2 -; or can be absent;
  • R ,14 represents hydrogen; lower alkyl; aryl; aryl-lower alkyl; heteroaryl; heteroaryl-lower alkyl; cycloalkyl; cycloalkyl-lower alkyl; and in case M is absent, R 14 can also represent heterocyclyl;
  • Another group of preferred compounds for incorporation into pharmaceutical compositions for treatment, prevention or delaying the onset of central nervous system disorders are compounds of the formula VII:
  • R , ⁇ , R , A and Z are as defined in general formula I above
  • R represents hydrogen; lower alkyl; lower alkenyl; lower alkynyl; cycloalkyl; cycloalkyl- lower alkyl; aryl; aryl-lower alkyl; heteroaryl; heteroaryl-lower alkyl; and in case W represents a bond, R can also represent heterocyclyl; cyano; trifluoromethyl; trifluoromethoxy;
  • W represents a bond; -O-; -NH-; -N(R ⁇ )-; whereby in the group -N(R ⁇ )- the substituent R 11 is as defined in formula III above, and W may be attached to the benzene-ring either in position 2a or 3a or 4a;
  • Another group of preferred compounds for incorporation into pharmaceutical compositions for treatment, prevention or delaying the onset of central nervous system disorders are compounds of the formula VIII:
  • R 1 , R 2 , A and Z are as defined in general formula I above;
  • R 16 represents lower alkyl; lower alkenyl; lower alkynyl; cycloalkyl; cycloalkyl-lower alkyl; aryl; aryl-lower alkyl; heteroaryl; heteroaryl-lower alkyl; heterocyclyl-lower alkyl;
  • Another group of preferred compounds for incorporation into pharmaceutical compositions for treatment, prevention or delaying the onset of central nervous system disorders are compounds of the formula IX:
  • R , ⁇ , R , X and Z are as defined in general formula I above;
  • U represents aryl; heteroaryl;
  • Q represents aryl; heteroaryl; cycloalkyl; heterocyclyl; alkynyl;
  • the compounds of the formulae II to IX are incorporated into pharmaceutical compositions for the treatment, prevention or delaying the onset of central nervous system disorders together with inert carrier material.
  • the invention also relates to novel compounds of the formula XI:
  • R 1 , R 2 , R 3 , X, Z and A are as defined in general formula I above
  • the compounds of the general formula I of the present invention may be prepared according to the procedures and general sequences of reactions outlined below, wherein R 1 , R 2 , R 3 , A, X and Z are as defined in general formula I above (for simplicity and clarity reasons, only parts of the synthetic possibilities which lead to compounds of formulae I-XI are described). For general methods of certain steps see also pages 37-40 and WO 02/24649.
  • the carboxylic acid chlorides ⁇ R 3 -(CO)-Cl ⁇ may be obtained in situ from the corresponding carboxylic acid as described in the literature (i. e.: Devos, A.; Remion, J.; Frisque-Hesbain, A.-M.; Colens,A.; Ghosez, L., J. Chem. Soc, Chem. Commun. 1979, 1180).
  • the urea derivatives 4 are obtained by reaction of the amines 2 in dichloromethane, with one equivalent isocyanate.
  • the N-Boc protected 4-amino-piperidine 7 (Scheme 2) can be prepared in a two step procedure starting by reacting 4-hydroxy-N-Boc-piperidine with methanesulfonylchloride in an inert solvent like DCM in the presence of a base like TEA to generate 4-mesyloxy-N- Boc-piperidine.
  • the mesyloxy group is substituted with sodium azide followed by reduction of the azide functionality to the amino group to give 7.
  • the amine 7 is transfo ⁇ ned to the secondary amine 8 via the typical procedure for the reductive amination described above.
  • the synthesis of compounds 9, 10, 11 and 12 can also be performed via the typical procedures described above.
  • Boc-deprotection is achieved either with hydrochloric acid in a solvent like diethylether or dioxane or with TFA in DCM.
  • the second reductive amination step of the derivatives 13, 14, 15 and 16 to the fully derivatized final compounds 17, 18, 19 and 20 can be performed according to the typical procedure described above (see also: A. F. Abdel-Magid et al; J. Org. Chem.; 1996, 61, 3849 - 3862; K. A. Nommeh et al; J. Chem. Soc. Perkin Trans. 1; 1998, 2527 - 2531; B. J. Lavey et al; J. Org. Chem.; 1996, 61, 7633 - 7636.).
  • Compounds 8 / 22 were subsequently acylated by either acid chlorides, carboxylic acids (+ activation reagent like PyBOP or l-chloro-N,N,2-trimethylpropenylamine[Acros Organics 30027-0050]) for the preparation of derivatives 9 / 23, or sulfonyl chlorides for the preparation of derivatives 11 / 25, in solvents like DCM, chloroform or 1,2-dichloroethane at rt or slightly elevated temperatures in the presence of a base like Hunig's base, TEA or NMO. Reactions usually run for 4 to 24 h followed by aqueous work up with saturated sodium carbonate solution. The combined organic extracts were dried and the solvents were evaporated.
  • acid chlorides carboxylic acids (+ activation reagent like PyBOP or l-chloro-N,N,2-trimethylpropenylamine[Acros Organics 30027-0050]
  • sulfonyl chlorides for the preparation of derivative
  • the reaction was performed by first stirring the ketone and the amine in titanium(IV) isopropoxide at rt for 4 to 8 h followed by addition of methanol and sodium borohydride. The reaction was usually complete within 1 h and aqueous work up was performed by addition of saturated sodium carbonate solution, filtration and extraction with DCM. The combined organic layers were dried and evaporated in vacuo. The products were purified by column chromatography on silica gel with an appropriate solvent mixture depending on the polarity of the products or by recrystallization [J. G. Schunbucher et al; Tetrahedron Lett; 1998, 39, 8207; Ahmed F. Abdel-Magid et al; J. Org.
  • Boc-deprotection on the intermediates 9 / 23, 10 / 24, 12 / 26 and 11 / 25 was achieved by addition of a 4 M solution of hydrogen chloride in dioxane to a solution of the respective Boc-protected intermediate in dioxane at rt.
  • the reaction was usually finished within 1 to 3 h.
  • the solvent was evaporated and the amine hydrohloride intermediates were dried at HV [P. J. Kocienski, Protecting Groups, Thieme, 1994; T. W. Greene, P. G. M. Wuts; Protective Groups in Organic Synthesis, John Wiley & sons; 1991.].
  • the final compounds e.g. 17, 18, 19, 20 or 31, 32, 33 and 34
  • the reactions were performed as described before for the preparation of 10 / 24.
  • the amine and the aldehyde (1.5 eq.) (which are used as starting materials, are known compounds or the synthesis is described in the Reference Examples), are mixed in anhydrous methanol and refluxed for 4 h. The mixture is cooled to rt and then treated with sodium borohydride (1.5 eq.) and again stirred for 2 h at reflux temperature. The reaction mixture is concentrated in vacuo and water is slowly added followed by extraction with DCM (3x). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude compound is purified by column chromatography on silica gel by an appropriate mixture of EtOAc / hexane containing 1% TEA or by recrystallization from a suitable solvent. Typical procedure B) for the acylation (with acid chlorides or sulfonylchlorides):
  • the arylchloride, the boronic acid (1.5 eq) and potassium phosphate (K3PO4; 3 eq)) were added subsequently to dioxane (5 ml / mmol arylchloride). While heating to 100°C, nitrogen is bubbled through the mixture. Then a solution of 2'-(dimethylamino)-2-biphenylyl- palladium(II)-chloride dinorbomylphosphine-complex (from Solvias or Fluka 36037; 0.01 eq)) was added to the hot reaction mixture and stirring was continued for 6 to 18 h. The reaction mixture is cooled to rt, water is added and the product extracted with EtOAc. The combined organic layers were dried with magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography (EtO Ac/heptane gradient).
  • biaryl-, heteroaryl-aryl-, aryl-heteroaryl- and heterobiaryl- substituents can be prepared according to Typical Procedures H) and I) or according to methods described in [WO 02/24649 or A. F. Littke and G. C. Fu; Angew. Chem.; 1998, 110, 3586 and references cited there].
  • Referential Example 1 only gives an illustrative overview of such substituents and does not limit the invention towards the structures depicted above.
  • For the preparation of the biaryl-carboxylic acids see also [Y. Gong and H. W. Pauls; Synlett, 2000, 829.]
  • Example 2 Example 3, Example 4 and Example 5 were prepared from Intermediate 3 by reaction with iso-valeraldehyde, furane-2-carboxaldehyde, furane-3-carboxaldehyde and acetophenone, respectively according to Typical Procedure D) (Example 2, Example 3, Example 4) and according to Typical Procedure E) (Example 5).
  • Example 7 Example 8, Example 9 and Example 10 were prepared from Intermediate 6 by reaction with thiophene-2-carboxaldehyde, iso-valeraldehyde cyclohexane-carboxaldehyde and 4-fluoro-benzaldehyde, respectively according to Typical Procedure D).
  • Example 70 and 71 were prepared according to the Typical Procedures described on pages 35-39.
  • Example 71 was subsequently used in Suzuki-reactions with aryl-boronic acids according to Typical Procedure H) (p. 38) to prepare Examples 72, 73 and 74.
  • Charts 17 to 20 were prepared according to the synthetic pathway described in Scheme 4 by changing certain starting materials in order to obtain the structural variations depicted in Charts 17 to 20.

Abstract

L'invention concerne des composés consistant en des dérivés substitués chiraux ou achiraux de 3- ou 4-aminopipéridine représentés par la formule (I). Elle concerne également des aspects associés, y compris des procédés servant à préparer ces composés, des compositions pharmaceutiques contenant un ou plusieurs composés représentés par la formule (I) et, en particulier, leur utilisation en tant qu'inhibiteurs de β-sécrétases.
PCT/EP2003/007298 2002-07-18 2003-07-08 Piperidines utiles pour traiter des maladies du systeme nerveux central WO2004009549A2 (fr)

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CN112480066A (zh) * 2020-11-27 2021-03-12 太原理工大学 一种席夫碱类多功能荧光探针及其制备方法和应用
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