US20120053197A1 - Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation - Google Patents

Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation Download PDF

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US20120053197A1
US20120053197A1 US13/029,690 US201113029690A US2012053197A1 US 20120053197 A1 US20120053197 A1 US 20120053197A1 US 201113029690 A US201113029690 A US 201113029690A US 2012053197 A1 US2012053197 A1 US 2012053197A1
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dimethyl
isopropyl
tetrahydro
spiro
tert
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Inventor
Holger Wagner
Daniela Berta
Klaus Fuchs
Riccardo Giovannini
Dieter Wolfgang Hamprecht
Ingo Konetzki
Ruediger Streicher
Thomas Trieselmann
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Boehringer Ingelheim International GmbH
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Assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH reassignment BOEHRINGER INGELHEIM INTERNATIONAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KONETZKI, INGO, TRIESELMANN, THOMAS, FUCHS, KLAUS, GIOVANNINI, RICCARDO, HAMPRECHT, DIETER WOLFGANG, STREICHER, RUEDIGER, BERTA, DANIELA, WAGNER, HOLGER
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • the present invention relates to 1,3,6,7,8,9-hexahydro-furo[3,4-c]quinoline derivatives having the following chemical scaffold which is structurally defined by the formula I
  • the invention further relates to pharmaceutical compositions containing one or more compounds according to the invention as well as the use of the compounds according to the invention as medicaments, particularly for preparing pharmaceutical compositions for the treatment and/or prevention of cardiometabolic or cardiovascular disorders.
  • the invention relates to processes for preparing the compounds and pharmaceutical compositions according to the invention.
  • the invention relates to compounds and pharmaceutical compositions according to the invention for use in methods of inhibiting CETP as well as of treating and/or preventing cardiovascular or related disorders.
  • CETP cholesterol ester transfer protein
  • the aim of the present invention is to find new compounds particularly those which have valuable pharmacological properties, especially those which are active with regard to the enzyme CETP, such as e.g. 1,3,6,7,8,9-hexahydro-furo[3,4-c]quinoline derivatives.
  • a further aim of the present invention is to discover 1,3,6,7,8,9-hexahydro-furo[3,4-c]quinoline derivatives which have an inhibitory effect on the enzyme CETP in vitro and/or in vivo and possess suitable pharmacological and pharmacokinetic properties to use them as medicaments.
  • a further aim of the present invention is to provide new pharmaceutical compositions which are suitable for the prevention and/or treatment of cardiometabolic or cardiovascular disorders, particularly hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hypercholesterolemia and atherosclerosis.
  • cardiometabolic or cardiovascular disorders particularly hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hypercholesterolemia and atherosclerosis.
  • the present invention relates to compounds which are structurally defined by the formula I
  • the compounds of formula I according to the invention and the pharmaceutically acceptable salts thereof have valuable pharmacological properties, particularly an inhibitory effect on the enzyme cholesteryl ester transfer protein (CETP).
  • CETP cholesteryl ester transfer protein
  • the present invention also relates to the pharmaceutically acceptable salts of the compounds of formula I according to the invention with inorganic or organic acids.
  • This invention also relates to pharmaceutical compositions, comprising at least one compound of formula I according to the invention or a pharmaceutically acceptable salt thereof, optionally together with one or more inert carriers and/or diluents.
  • compositions comprising or made of (e.g. by combining or mixing of) at least one compound according to the invention (including a pharmaceutically acceptable salt thereof), and one or more excipients, carriers and/or diluents.
  • This invention also relates to the use of at least one compound of formula I according to the invention or one of the pharmaceutically acceptable salts thereof for preparing a pharmaceutical composition which is suitable for the treatment and/or prevention of diseases, disorders or conditions which can be influenced by inhibiting the enzyme cholesteryl ester transfer protein (CETP), such as e.g. those cardiometabolic or cardiovascular disorders mentioned herein.
  • CETP cholesteryl ester transfer protein
  • This invention also relates to the use of at least one compound of formula I according to the invention or one of the pharmaceutically acceptable salts thereof for preparing a pharmaceutical composition which is suitable for the treatment and/or prevention of cardiovascular and related disorders, such as e.g. hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hypercholesterolemia or atherosclerosis.
  • cardiovascular and related disorders such as e.g. hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hypercholesterolemia or atherosclerosis.
  • This invention also relates to the use of at least one compound of formula I according to the invention or one of the pharmaceutically acceptable salts thereof for preparing a pharmaceutical composition for inhibiting the enzyme cholesteryl ester transfer protein (CETP).
  • CETP cholesteryl ester transfer protein
  • This invention also relates to a compound according to the present invention which is suitable for use in therapy and/or prophylaxis, e.g. for the treatment and/or prevention of diseases or conditions which can be influenced by inhibiting the enzyme cholesteryl ester transfer protein (CETP), e.g. cardiovascular and related disorders, such as e.g. any of those diseases, disorders and conditions mentioned herein.
  • CETP cholesteryl ester transfer protein
  • This invention also relates to a compound according to the present invention which is suitable for inhibiting the enzyme cholesteryl ester transfer protein (CETP).
  • CETP cholesteryl ester transfer protein
  • the invention further relates to a process for preparing a pharmaceutical composition according to the invention, comprising incorporating a compound of formula I according to the invention or one of the pharmaceutically acceptable salts thereof in one or more inert carriers and/or diluents preferably by a non-chemical method.
  • the present invention also relates to a method for treating and/or preventing a disease or condition which can be influenced by inhibiting the enzyme cholesteryl ester transfer protein (CETP), e.g. a cardiovascular or related disorder, such as e.g. any of those diseases and conditions mentioned herein, in a mammalian (particularly human) patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound of formula I according to the invention or one of the pharmaceutically acceptable salts thereof.
  • CETP cholesteryl ester transfer protein
  • the present invention also relates to a pharmaceutical compound or composition according to this invention for use in a method of treating and/or preventing a condition which can be influenced by inhibiting the enzyme cholesteryl ester transfer protein (CETP), e.g. a cardiovascular or related disorder, such as e.g. any of those diseases and conditions mentioned herein, said method comprising administration of said compound or composition, optionally alone or in combination (such as e.g. separately, sequentially, simultaneously, concurrently or chronologically staggered) with one or more other therapeutic agents, such as e.g. selected from those mentioned herein.
  • CETP cholesteryl ester transfer protein
  • the present invention also relates to processes and intermediates for preparing the compounds of general formula I according to the invention (see processes a, b, c and d in general synthesis section).
  • R 3 and R 4 are defined as hereinbefore and hereinafter, R a denotes independently methyl or ethyl and R 8 denotes hydrogen.
  • Each a i , b i , c i , d i , e i , f i represents a characterized, individual embodiment of the corresponding substituent as described above.
  • preferred individual embodiments of the compounds of formula I according to the invention are fully characterized by the term (a i b i c i d i e i f i ), wherein for each index i an individual figure is given and i ranges from 1 to the highest number given above; index 0 for each letter refers to the individual embodiment given at the outset of the part “Object of the invention”.
  • Indices i vary independently from each other. All individual embodiments described by the term in parantheses with full permutation of the indices i, including i equals 0, referring to the definitions above, shall be comprised by the present invention.
  • Table 1 shows, exemplarily and in the order of increasing preference from the first line to the last line, such embodiments E-1 to E-12 of the compounds according to the invention that are considered preferred. This means that embodiment E-12, represented by the entries in the last row of Table 1, is the most preferred embodiment.
  • variables R 1 -R 8 are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • This embodiment also includes compounds of formula I*, wherein the variables R 1 -R 8 are selected from above definitions a) (a 1 ) to f) (f 3 ), their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • this embodiment refers to compounds of formula I* as defined by the embodiment E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11 or E-12 in Table 1, and the salts thereof.
  • variables R 1 -R 8 are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • This embodiment also includes compounds of formula I**, wherein the variables R 1 -R 8 are selected from above definitions a) (a 1 ) to f) (f 3 ), their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • this embodiment refers to compounds of formula I** as defined by the embodiment E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11 or E-12 in Table 1, and the salts thereof.
  • variables R 1 -R 8 are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • This embodiment also includes compounds of formula I***, wherein the variables R 1 -R 8 are selected from above definitions a) (a 1 ) to f) (f 3 ), their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • this embodiment refers to compounds of formula I*** as defined by the embodiment E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11 or E-12 in Table 1, and the salts thereof.
  • variables R 1 -R 8 are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • This embodiment also includes compounds of formula I****, wherein the variables R 1 -R 8 are selected from above definitions a) (a 1 ) to f) (f 3 ), their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • this embodiment refers to compounds of formula I**** as defined by the embodiment E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11 or E-12 in Table 1, and the salts thereof.
  • This embodiment also includes compounds of formula I*****, wherein the variables R 1 -R 8 are selected from above definitions a) (a 1 ) to f) (f 3 ), their tautomers, their stereoisomers, mixtures thereof, and the salts thereof.
  • this embodiment refers to compounds of formula I***** as defined by the embodiment E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11 or E-12 in Table 1, and the salts thereof.
  • the invention further includes all mixtures of the stereoisomers mentioned herein independent of the ratio, including the racemates.
  • a particularly preferred compound according to the invention is a compound selected from the group consisting of:
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
  • n may have a value of 1 to 6, denotes a saturated, branched or unbranched aliphatic, acyclic hydrocarbon group having 1 to n C atoms.
  • groups may include, without being limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.
  • 2-nC-alkenyl alone or as part of another group, wherein n may have a value of 2 to 4, denotes an unsaturated, branched or unbranched aliphatic, acyclic hydrocarbon group having 2 to n C atoms and at least one C ⁇ C double bond.
  • groups may include, without being limited to, ethenyl, prop-1-en-1-yl, prop-1-en-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-2-yl, etc.
  • halogen within the meaning of the present invention refers to fluorine, chlorine, bromine and iodine, of which fluorine, chlorine and bromine are more worthy to be mentioned.
  • 1-nC-alkoxy denotes a 1-nC-alkyl-O— group, wherein 1-nC-alkyl is as hereinbefore defined.
  • groups may include, without being limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n-hexoxy, iso-hexoxy, etc.
  • 1-nC-alkoxy-1-nC-alkyl means a 1-nC-alkyl group as defined herein which is substituted by a 1-nC-alkoxy group as defined herein.
  • cyano-1-nC-alkyl means a 1-nC-alkyl group as defined herein which is substituted by a cyano group.
  • hydroxy-1-nC-alkyl means a 1-nC-alkyl group as defined herein which is substituted by a hydroxy group.
  • aryl group as mentioned herein, alone or as part of another group refers to a carbocyclic, mono- or fused bicyclic (fully or partially) aromatic ring system having the indicated numbers of ring members.
  • Representative 6- or 10-membered mono- or fused bicyclic aryl groups include, without being limited to, phenyl and naphthyl.
  • a heteroaryl group as mentioned herein, alone or as part of another group, refers to a heterocyclic, mono- or fused bicyclic (fully or partially) heteroaromatic ring system having the indicated numbers of ring members and containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur.
  • Representative 5-membered monocyclic heteroaryl groups include, without being limited to, thiophenyl (thienyl), furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, and oxadiazolyl,
  • 6-membered monocyclic heteroaryl groups include, without being limited to, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl.
  • Representative 9-membered fused bicyclic groups groups include, without being limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzpyrazolyl (indazolyl), benzthiazolyl, benzoxazolyl, benzisothiazolyl, and benzisooxazolyl.
  • Representative 10-membered fused bicyclic heteroaryl groups include, without being limited to, quinolyl, isoquinolyl, and quinazolyl.
  • thiophenyl, thiazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and naphthyl are more worthy to be mentioned.
  • 3-nC-cycloalkyl alone or as part of another group, wherein n may have a value of 4 to 7, denotes a saturated, monocyclic, aliphatic hydrocarbon ring group having 3 to n ring C atoms.
  • groups may include, without being limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are more worthy to be mentioned.
  • 3-nC-cycloalkane alone or as part of another group, wherein n may have a value of 4 to 7, denotes a saturated, monocyclic, aliphatic hydrocarbon ring having 3 to n ring C atoms.
  • examples of such rings may include, without being limited to, a cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane ring, of which cyclopropane, cyclobutane, cyclopentane and cyclohexane are more worthy to be mentioned.
  • 1-nC-alkyl-3-nC-cycloalkyl means a 3-nC-cycloalkyl group as defined herein which is substituted by a 1-nC-alkyl group as defined herein.
  • cyano-3-nC-cycloalkyl means a 3-nC-cycloalkyl group as defined herein which is substituted by a cyano group.
  • Completely or partially fluorine-substituted 1-nC-alkyl is, for example difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoro-1-ethyl or 1,1,1,3,3,3-hexafluorisopropyl, of which trifluoromethyl is to be emphasized.
  • partially fluorine-substituted 1-nC-alkyl stands for predominantly fluorine-substituted 1-nC-alkyl. “Predominantly” in this connection means that more than half of the hydrogen atoms of the 1-nC-alkyl groups are replaced by fluorine atoms.
  • Completely or partially fluorine-substituted 1-nC-alkoxy is, for example difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy or 1,1,1,3,3,3-hexafluorisopropoxy.
  • partially fluorine-substituted 1-nC-alkoxy stands for predominantly fluorine-substituted 1-nC-alkoxy. “Predominantly” in this connection means that more than half of the hydrogen atoms of the 1-nC-alkoxy groups are replaced by fluorine atoms.
  • heterocyclic groups mentioned herein include all the possible isomeric forms thereof, e.g. tautomers and/or positional isomers thereof.
  • pyridyl includes pyridine-2-yl, pyridine-3-yl and pyridine-4-yl.
  • carbocyclic groups which are substituted as mentioned herein may be substituted by their given substituents or parent molecular groups at any possible position.
  • heterocyclic groups mentioned herein may be substituted by their given substituents or parent molecular groups, unless otherwise noted, at any possible position, such as e.g. at any substitutable ring carbon or ring nitrogen atom.
  • rings containing quaternizable amino- or imino-type ring nitrogen atoms may be preferably not quaternized on these amino- or imino-type ring nitrogen atoms.
  • the last named subgroup is the radical attachment point, for example, the substituent “1-nC-alkoxy-1-nC-alkyl” means a 1-nC-alkoxy group which is bound to a 1-nC-alkyl group, the latter of which is bound to the core or to the group to which the substituent is attached.
  • All atoms/elements, including atoms that are part of a group, described herein comprise all stable isotopic forms of the respective element. For instance, whenever hydrogen is mentioned, either explicitly or as part of a group such as methyl, this includes hydrogen and deuterium as stable isotopic forms of the element hydrogen.
  • R 1 to R 8 , R 7′ , PG, R a , R b , R 9 to R 11 are defined as above and below.
  • the substituents R 9 , R 10 and/or R 11 can be attached in the ortho, meta or para position with respect to the binding position in which the aryl ring is bonded to the scaffold ring system, whereby emphasis is given to the attachment in the meta or in the para position.
  • Salts of the compounds of formula I according to the present invention include—depending upon their nature—all acid addition salts and all salts with bases, especially all pharmaceutically acceptable acid addition salts and salts with bases. Particular mention may be made of the physiologically tolerable salts with inorganic or organic acids or bases customarily used in pharmacy.
  • the salts include water-insoluble and, particularly, water-soluble salts.
  • Inorganic acids suitable for forming pharmaceutically or physiologically acceptable acid addition salts include, by way of example and not limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and the like.
  • Organic acids suitable for forming pharmaceutically or physiologically acceptable acid addition salts include, by way of example and not limitation, citric acid, maleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid, methanesulfonic acid, and the like.
  • pharmaceutically or physiologically acceptable acid addition salts with inorganic or organic acids include, by way of example and not limitation, hydrochlorides, hydrobromides, phosphates, sulfates, citrates, maleates, fumarates, succinates, lactates, tartrates, methanesulfonates (mesylates), and the like.
  • Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds of formula I or their pharmaceutically acceptable salts, are also included.
  • the compounds of the present invention contain at least two asymmetrically substituted carbon atoms, and may be isolated as pure diastereomers or diastereomeric mixtures in optically active or racemic forms.
  • the compounds of formula I are chiral compounds having chiral centers at least in positions 3 and 9, as well as, depending on the meanings of R 3 and R 4 , in position 7, depending on the meanings of R 8 , in position 6 and, depending on the meanings of R 6 and R 7 , in position 1.
  • the invention contemplates all conceivable stereoisomers, particularly the diastereomers and enantiomers mentioned herein, e.g. in substantially pure form, in enriched form (e.g. substantially free of any or all other undesired diastereomers and/or enantiomers) and/or in any mixing ratio, including the racemic forms, as well as the salts thereof.
  • substantially pure stereoisomers can be obtained according to synthetic principles customary to the skilled person, e.g. by separation of corresponding mixtures, by using stereochemically pure starting materials and/or by stereoselective synthesis.
  • optically active forms such as by resolution of racemic forms or by synthesis, e.g. from optically active starting materials and/or by using chiral reagents.
  • Enantiomerically pure compounds of this invention can be prepared via asymmetric synthesis, for example by preparation and separation of appropriate diastereoisomeric compounds/intermediates which can be separated by known methods (e.g. by chromatographic separation or (fractional) crystallization from a suitable solvent), and/or by using chiral reaction components (e.g. chiral reagents, chiral catalysts, chiral ligands, chiral synthons, chiral building blocks, or the like).
  • chiral reaction components e.g. chiral reagents, chiral catalysts, chiral ligands, chiral synthons, chiral building blocks, or the like.
  • the biological properties of the new compounds may be investigated as follows:
  • CETP inhibitory activity of compounds of the present invention can be determined in a fluorometric assay puchased from Roar Biomedical, Inc. (New York, N.Y., USA).
  • the compounds of the present invention inhibit CETP-dependent cholesterol ester transfer from HDL to LDL as described here.
  • Recombinant human CETP was partially purified from medium conditioned by CETP expressing CHO cells. In a 384 well format 2.5 ⁇ l of compound solution in DMSO was combined with 2 ⁇ l of donor solution, 2 ⁇ l of acceptor solution and 0.8 ⁇ l of recombinant human CETP solution in a total volume of 100 ⁇ l with assay buffer and incubated for 3 hours at 37° C. The fluorescence intensity was measured at excitation wavelength of 485 nm and emission wavelength of 535 nm. IC 50 values are calculated from dose effect curves from compound concentrations between 1 nM and 30 ⁇ M.
  • the compounds of general formula I according to the invention for example have IC 50 values below 10000 nM, preferably below 2000 nM, more preferably below 400 nM and most preferably below 100 nM.
  • the IC 50 values of the examples compiled in the experimental part are provided in the following Table 2.
  • the compounds of formula I and their physiologically tolerable salts according to the present invention have valuable pharmacological properties which make them commercially applicable.
  • these compounds can act as inhibitors of CETP and are expected to be commercially applicable in the therapy of diseases responsive to the inhibition of CETP, such as e.g. any of those diseases mentioned herein.
  • the compounds of general formula I according to the invention and the corresponding pharmaceutically acceptable salts thereof are theoretically suitable for the treatment and/or prevention of all those conditions or diseases which may be affected by the inhibition of the cholesterol ester transfer protein (CETP) activity.
  • compounds according to the invention are particularly suitable for the treatment and/or prevention of cardiovascular and related disorders, in particular atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbeta-lipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, prevention of diabetes, insulin resistance, obesity or endotoxemia.
  • the compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral, parenteral or topical administration. They may be administered in any of the generally accepted modes of administration available in the art, e.g., perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally (including intravenously), e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils.
  • oral and intravenous delivery are preferred.
  • compositions such as e.g. diluents, carriers, binders, disintegrants, surfactants, lubricants, vehicles, auxiliaries, adjuvants and/or further additives which are known to be suitable for preparing pharmaceutical compositions, on account of his/her expert knowledge.
  • excipients such as e.g. diluents, carriers, binders, disintegrants, surfactants, lubricants, vehicles, auxiliaries, adjuvants and/or further additives which are known to be suitable for preparing pharmaceutical compositions, on account of his/her expert knowledge.
  • any excipients known to be appropriate for pharmaceutical compositions come into consideration.
  • examples thereof include, but are not limited to, diluents, fillers, binders, disintegrants, lubricants, glidants, solvents, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants, preservatives, stabilizers, carriers, thickeners, complexing agents, buffers, pH regulators (e.g. to obtain neutral, alkaline or acidic formulations), permeation promoters, polymers, coating agents, propellants, tonicity adjusting agents, surfactants, colorants, flavorings, sweeteners and dyes.
  • diluents fillers, binders, disintegrants, lubricants, glidants, solvents, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants, preservatives, stabilizers, carriers, thickeners,
  • suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials.
  • lactose, starches (e.g. corn starch) or derivatives thereof, talc, silica, polyvinylpyrrolidones, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules.
  • Suitable carrier materials for soft gelatine capsules are, e.g., vegetable oils, waxes, fats and semi-solid and liquid polyols.
  • Suitable carrier materials for the production of solutions and syrups are, e.g., water, polyols, sucrose, invert sugar and the like.
  • Suitable carrier materials for injection or infusion solutions are, e.g., water, alcohols, polyols, glycerol and vegetable oils.
  • Suitable carrier materials for suppositories are, e.g., natural or hardened oils, waxes, fats and semi-liquid or liquid polyols or polyethylene glycols.
  • Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
  • excipients, carriers and/or diluents of a type appropriate to the desired pharmaceutical composition, formulation or preparation and the desired mode of administration are used.
  • compositions according to this invention can be prepared by processes which are known per se and familiar to the person skilled in the art, e.g. by incorporating the described compounds of formula I or their pharmaceutically acceptable salts (optionally combined with other active substances) optionally together with one or more conventional carriers (e.g. solid or liquid carriers) and/or diluents, e.g.
  • conventional carriers e.g. solid or liquid carriers
  • diluents e.g.
  • the dosage of the compounds of the invention can vary within wide limits depending on the compound which is to be administered, the nature and gravity of the disease to be treated or prevented, the age and the individual condition of the patient and the mode and frequency of administration, and will, of course, be fitted to the individual requirements in each particular case.
  • the dosage may be from 0.1 ng/ml to 10 mg/ml, preferably 1 ng/ml to 10 mg/ml, by intravenous route, and 0.1 to 2000 mg, preferably 1 to 100 mg, by oral route, in each case administered 1 to 4 times a day.
  • the dosage may be convenient to administer the daily dosage in several dosage units.
  • the compounds according to the invention may also be used in conjunction with other active substances, particularly for the treatment and/or prevention of the diseases, disorders and conditions mentioned above.
  • active substances which are suitable for such a combination include for example those which potentiate the therapeutic effect of a cholesterol ester transfer protein (CETP) inhibitor according to the invention with respect to one of the indications mentioned and/or which allow the dosage of a cholesterol ester transfer protein (CETP) inhibitor according to the invention to be reduced.
  • CETP cholesterol ester transfer protein
  • Lipid modulating agents comprise HMG CoA reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and the derivatives thereof, PPAR ( ⁇ , ⁇ or ⁇ / ⁇ ) agonists or modulators, ACAT inhibitors (e.g. avasimibe), MTP inhibitors, squalene cyclase and squalene synthase inhibitors, LXR agonists or modulators, bile acid-binding substances such (e.g. cholestyramine), cholesterol absorption inhibitors (e.g. ezetimibe), niacin, PCSK9 inhibitors, bile acid reuptake inhibitors and lipase inhibitors.
  • HMG CoA reductase inhibitors e.g. simvastatin, atorvastatin
  • fibrates e.g. bezafibrate
  • therapeutic agents which are suitable for such a combination include one or more antidiabetic agents as for example metformin, alpha-glucosidase inhibitors (e.g. acarbose, voglibose), PPAR ( ⁇ , ⁇ or ⁇ / ⁇ ) agonists or modulators, DPP-IV inhibitors (e.g. Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, Linagliptin), SGLT 2 inhibitors (e.g. dapagliflozin, sergliflozin), GLP-1 or GLP-1 analogues (e.g.
  • antidiabetic agents as for example metformin, alpha-glucosidase inhibitors (e.g. acarbose, voglibose), PPAR ( ⁇ , ⁇ or ⁇ / ⁇ ) agonists or modulators, DPP-IV inhibitors (e.g. Sitagliptin, Vild
  • exenatide liraglutide
  • insulin or insulin analogues e.g. sulphonylureas (e.g. glibenclamide, tolbutamide, glimepiride), thiazolidinediones (e.g.
  • nateglinide rosiglitazone, pioglitazone
  • 11- ⁇ -HSD inhibitors glucose-6-phosphatase inhibitors, fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glucagon receptor antagonists, inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase and glucokinase activators.
  • antiobesity agents including for example sibutramine, tetrahydrolipostatin, leptin, leptin mimetics, antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or ⁇ 3-agonists such as SB-418790 or AD-9677 and agonists of the 5HT2c receptor.
  • drugs for influencing high blood pressure or chronic heart failure such as e.g. A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, ⁇ -blockers, Ca-antagonists, centrally acting antihypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable.
  • angiotensin II receptor antagonists examples include candesartan cilexetil, potassium losartan, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701, etc.
  • Angiotensin II receptor antagonists are preferably used for the treatment or prevention of high blood pressure and complications of diabetes, often combined with a diuretic such as hydrochlorothiazide.
  • the therapeutic agents mentioned herein above as combination partners of the compounds according to this invention are meant to include pharmaceutically acceptable derivatives thereof, such as e.g. their pharmaceutically acceptable salts.
  • pharmaceutically acceptable derivatives thereof such as e.g. their pharmaceutically acceptable salts.
  • the person skilled in the art is aware on the base of his/her expert knowledge of the kind, total daily dosage(s) and administration form(s) of the additional therapeutic agent(s) coadministered. Said total daily dosage(s) can vary within a wide range.
  • the dosage for the combination partners mentioned above is 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dose.
  • the compounds according to this invention may be administered in combination therapy separately, sequentially, simultaneously, concurrently or chronologically staggered with one or more further active substances, such as e.g. any of the therapeutic agents mentioned herein above as a combination partner.
  • the present invention further relates to a combination comprising a first active ingredient, which is at least one compound according to this invention, and a second active ingredient, which is at least one of the active substances described above as a combination partner, for separate, sequential, simultaneous, concurrent or chronologically staggered use in therapy, particularly for treatment and/or prevention of cardiovascular or related disorders, such as e.g. any of those mentioned herein.
  • this invention relates to the use of a compound according to this invention combined with at least one of the active substances described above as a combination partner, for preparing a pharmaceutical composition which is suitable for the treatment or prevention of diseases or conditions which may be affected by the inhibition of the cholesterol ester transfer protein (CETP) activity, particularly cardiometabolic and/or cardiovascular disorders, more particularly one of the diseases, disorders or conditions listed above.
  • CETP cholesterol ester transfer protein
  • this invention relates to a pharmaceutical composition which comprises a compound according to the invention and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.
  • combination may be present as a fixed combination, a non-fixed combination, a free combination or a kit-of-parts.
  • a “fixed combination” is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity.
  • a “fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration.
  • Another example of a “fixed combination” is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.
  • kits-of-parts is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit.
  • a “kit-of-parts” is a combination wherein the said first active ingredient and the said second active ingredient are present separately.
  • the components of the kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • the first and second active ingredient of a kit-of-parts according to this invention may be provided as separate formulations (i.e. independently of one another), which are subsequently brought together for simultaneous, concurrent, sequential, separate or chronologically staggered use in combination therapy; or packaged and presented together as separate components of a combination pack for simultaneous, concurrent, sequential, separate or chronologically staggered use in combination therapy.
  • the type of pharmaceutical formulation of the first and second active ingredient of a kit-of-parts according to this invention can be similar, i.e. both ingredients are formulated in separate tablets or capsules, or can be different, i.e. suited for different administration forms, such as e.g. one active ingredient is formulated as tablet or capsule and the other is formulated for e.g. intravenous administration.
  • the amounts of the first and second active ingredients of the combinations, compositions or kits according to this invention may together comprise a therapeutically effective amount, particularly for the treatment and/or prevention of the diseases, disorders and conditions mentioned above.
  • the compounds according to the invention may be obtained using methods of synthesis known in principle.
  • the compounds are obtained by the following methods according to the invention which are described in more detail hereinafter.
  • First step is the condensation of triester of formula II, wherein each R a denotes independently methyl or ethyl (preferably all R a are identical) with enaminoketones of formula III.
  • This reaction is usually carried out neat at temperatures between 150° C. and 250° C., and yields the bicyclic dihydroxypyridines of formula IV.
  • Compounds of formula V can be converted in compounds of formula VI by installing the R 2 group via a carbon-carbon-coupling reaction, preferably either by a Negishi reaction or by a Suzuki reaction.
  • Negishi reaction compounds of formula V are reacted with suitable (cyclo)alkyl-zinc-halogenide reagents or (cyclo)alkenyl-zinc-halogenide reagents of formula R 2 —ZnX, wherein X is a halogen (e.g. chlorine) in a suitable solvent such as e.g. toluene, tetrahydrofurane, 1,4-dioxane or diethylether in the presence of a suitable catalyst such as e.g.
  • a suitable solvent such as e.g. toluene, tetrahydrofurane, 1,4-dioxane or diethylether
  • a suitable catalyst such as e.g.
  • a palladium source like e.g. palladium diacetate or tris-(dibenzylideneacetone)-dipalladium-(0) and a suitable ligand like e.g.
  • tri-tert.-butylphosphine tri-cyclohexylphosphine, di-adamantan-1-yl-butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-thisopropyl-1,1′-biphenyl or 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl, at temperatures between 40° C. and 180° C., but preferably between 70° C. and 130° C.
  • the (cyclo)alkyl-zinc-halogenide reagents or (cyclo)alkenyl-zinc-halogenide reagents can optionally be prepared by transmetalation of corresponding (cyclo)alkyl-magnesium-halogenide reagents or (cyclo)alkenyl-magnesium-halogenide reagents, e.g. with zinc chloride in diethylether, tetrahydrofurane or 1,4-dioxane.
  • the Suzuki reaction is performed by reacting compounds of formula V with a suitable R 2 -borone reagent, such as e.g. (cyclo)alkyl-boronic acids, (cyclo)alkenyl-boronic acids, (cyclo)alkyl-boronic acid-esters, (cyclo)alkenyl-boronic acid-esters, potassium (cyclo)alkyl-trifluoroborates or potassium (cyclo)alkenyltrifluoroborates.
  • a suitable solvent such as e.g.
  • a suitable base such as e.g. aqueous sodium carbonate, aqueous potassium carbonate, aqueous caesium carbonate, silver carbonate, caesium fluoride, triethylamine or N,N-diisopropyl-N-ethyl-amine and in the presence of a suitable catalyst such as e.g.
  • a palladium source like e.g. palladium diacetate or tris-(dibenzylideneacetone)-dipalladium-(0) and a suitable ligand like e.g.
  • tri-tert.-butylphosphine tri-cyclohexylphosphine, di-adamantan-1-yl-butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-thisopropyl-1,1′-biphenyl or 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl, at temperatures between 0° C. and 180° C., but preferably between room temperature and 120° C.
  • reaction is proceeded by a reduction of the double bond.
  • a suitable catalyst such as e.g. palladium on charcoal or palladiumhydroxide on charcoal
  • a suitable solvent such as e.g. methanol, ethanol, ethylacetate, tetrahydrofurane or 1,4-dioxane but preferably methanol, at temperatures between ⁇ 20° C. and 100° C. but preferably between 0° C. and 80° C.
  • 1-3C-perfluoroalkyl reagent such as e.g. 1-3C-perfluoroalkyl-iodide, 1-3C-perfluoroalkyl-trimethylsilane, potassium 1-3C-perfluoroalkyl-carboxylate or methyl 2,2-difluoro-2-(fluorosulfonyl)-acetate
  • a suitable solvent such as e.g. N,N-dimethylformamide, N-methylpyrrolidone or dimethylsulfoxide
  • a suitable catalyst such as e.g.
  • Transformation of compounds of formula VI wherein R b denotes hydroxyl in compounds of formula VI wherein R b denotes chlorine is done by reacting with phosphoroxychloride and catalytic amounts of N,N-dimethylformamide, at temperatures between 50° C. and 150° C. but preferably between 70° C. and 120° C.
  • Reaction of compounds of formula VI wherein R b denotes iodine with a suitable hydride donating reagent such as e.g. borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex, borane-dimethylaniline-complex, borane-diethylaniline-complex, sodium borohydride, lithium borohydride, lithium aluminium hydride in a suitable solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between ⁇ 78° C. and 100° C., but preferably between ⁇ 50° C.
  • a suitable hydride donating reagent such as e.g. borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex, borane-dimethylaniline-complex, borane-dieth
  • alkylation reaction of compounds of formula VI wherein R b denotes iodine with a suitable alkyl metal compound such as e.g. 1-4C-dialkylzinc-, 1-4C-alkylmagnesium halogenide-, or 1-4C-alkyllithium-reagent, particularly 1-2C-dialkylzinc-, 1-2C-alkylmagnesium halogenide-, or 1-2C-alkyllithium-reagent, in a suitable solvent such as e.g.
  • n-hexane, cyclohexane, toluene, diethylether, tetrahydrofurane or 1,4-dioxane optionally in the presence of a chiral ligand as for example (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, ( ⁇ )-3-exo-dimethylamino-isoborneol, (+)-3-exo-dimethylamino-isoborneol or ligands as described in J.
  • a chiral ligand as for example (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-methyl-3
  • the alcohol group in compounds of formula VII can be temporarily protected with a suitable protecting group, e.g. as a tert.-butyldimethylsilylether by the reaction with tert.-butyldimethylsilylchloride in a suitable solvent such as e.g. N,N-dimethylformamide or acetonitrile in the presence of imidazole, at temperatures between ⁇ 20° C. and 120° C., but preferably between 0° C. and 80° C., to give the protected derivatives of formula VIII, in which PG stands for this suitable protecting group.
  • a suitable protecting group e.g. as a tert.-butyldimethylsilylether by the reaction with tert.-butyldimethylsilylchloride in a suitable solvent such as e.g. N,N-dimethylformamide or acetonitrile in the presence of imidazole, at temperatures between ⁇ 20° C. and 120° C.,
  • This protection can also be carried out by reacting compounds of formula VII with tert.-butyldimethylsilyl-trifluormethansulfonate in the presence of a suitable base such as e.g. pyridine or 2,6-lutidine in a suitable solvent such as e.g. dichloromethane, diethylether, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between ⁇ 50° C. and 100° C. but preferably between ⁇ 30° C. and 50° C.
  • any other suitable protecting group as described e.g. in “ Protective Groups in Organic Synthesis”, 2 nd edition, Greene T. W., Wuts P. G. M.; Wiley-Interscience: New York, 1991 or in “ Protective Groups ”, Kocienski P. J.; Thieme: New York, 1994 can be used.
  • the esters of formula VIII can be converted to the aldehydes of formula IX, e.g. by a two step sequence.
  • First step is the reduction to the alcohol with a suitable reducing agent, such as e.g. diisobutylamuminium hydride or lithiumaluminiumhydride in an aprotic solvent such as e.g. dichloromethane, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between ⁇ 78° C. and 100° C., but preferably between ⁇ 30° C. and 50° C.
  • Second step is the oxidation of the alcohol to the aldehyde, which can be carried out with Dess-Martin-Periodinan ( J.
  • dichloromethane tetrahydrofurane, 1,4-dioxane, benzene or toluene but preferably in toluene optionally as a mixture with water, at temperatures between ⁇ 30° C. and 80° C. but preferably between 0° C. and 40° C.
  • Aldehydes of formula IX are transformed to the alcohols of formula X by reaction with a suitable R 1 -metal reagent, such as e.g. R 1 -magnesium halogenide- or R 1 -lithium-reagent, in an aprotic solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between ⁇ 78° C. and 80° C., but preferably between ⁇ 50° C. and 40° C.
  • a suitable R 1 -metal reagent such as e.g. R 1 -magnesium halogenide- or R 1 -lithium-reagent
  • an aprotic solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene
  • aquous sodium carbonate aquous potassium carbonate, aquous caesium carbonate, silver carbonate, caesium fluoride, triethylamine or N,N-diisopropyl-N-ethyl-amine but preferably caesium fluoride and in the presence of a suitable catalyst such as e.g.
  • a suitable palladium source such as e.g. palladium diacetate or tris-(dibenzylideneacetone)-dipalladium-(0)
  • a suitable ligand such as e.g.
  • tri-tert.-butylphosphine tri-cyclohexylphosphine, di-adamantan-1-yl-butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl or 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl, at temperatures between 0° C. and 180° C., but preferably between room temperature and 120° C., gives compounds of formula XI.
  • These compounds of formula XII are reduced to the compounds of formula XIII with a suitable reducing agent, such as e.g. tris-trimethylsilylsilane or tributyltin hydride in the presence of a suitable radical starter such as e.g. azo-bis-isobutyronitrile or dibenzoylperoxide in a suitable solvent such as e.g. carbontetrachloride, benzene or toluene, at temperatures between 80° C. and 150° C.
  • a suitable reducing agent such as e.g. tris-trimethylsilylsilane or tributyltin hydride
  • a suitable radical starter such as e.g. azo-bis-isobutyronitrile or dibenzoylperoxide
  • a suitable solvent such as e.g. carbontetrachloride, benzene or toluene
  • a suitable solvent such as e.g. methanol, ethanol, tetrahydrofurane or 1,4-dioxane but preferably methanol.
  • This reaction may be carried out in the presence of a suitable base such as e.g. triethylamine or N,N-diisopropyl-N-ethyl-amine, at temperatures between ⁇ 20° C. and 100° C. but preferably between 0° C. and 80° C.
  • Elimination of hydroiodic acid or hydrobromic acid in compounds of formula XII delivers compounds of formula XIII which contain a double bond. This elimination is performed by reaction with a suitable base such as e.g. triethylamine, N,N-diisopropyl-N-ethyl-amine, sodium methanolate, sodium ethanolate, sodium tert.-butylate, potassium tert.-butylate, lithium diisopropylamide or lithium hexamethyldisilazide in a suitable solvent such as e.g.
  • a suitable base such as e.g. triethylamine, N,N-diisopropyl-N-ethyl-amine, sodium methanolate, sodium ethanolate, sodium tert.-butylate, potassium tert.-butylate, lithium diisopropylamide or lithium hexamethyldisilazide
  • a suitable solvent such as e.g.
  • methanole, ethanole, tert.-butanole, tetrahydrofurane or 1,4-dioxane at temperatures between ⁇ 20° C. and 150° C., preferably between 0° C. and 100° C.
  • any other protecting group introduced before can be cleaved by suitable methods as described in the literature e.g. in “ Protective Groups in Organic Synthesis”, 2 nd edition, Greene T. W., Wuts P. G. M.; Wiley-Interscience: New York, 1991 or in “ Protective Groups ”, Kocienski P. J.; Thieme: New York, 1994.
  • First step is the formation of N-oxides of formula XV.
  • This reaction is performed by treating compounds of formula XIV with a suitable oxidizing reagent, such as e.g. meta-chlor-perbenzoic acid (MCPBA), in a suitable solvent such as e.g. dichloromethane, 1,2-dichloroethane, chloroform or tetrachloromethane, at temperatures between ⁇ 10° C. and 60° C.
  • MCPBA meta-chlor-perbenzoic acid
  • a suitable solvent such as e.g. dichloromethane, 1,2-dichloroethane, chloroform or tetrachloromethane
  • Compounds of formula XV are then reacted with acetic acid anhydride or propionic acid anhydride at temperatures between 90° C. and 180° C. to deliver compounds of formula XIII, wherein R 8 denotes acetoxy or propionyloxy.
  • compounds of formula VIII can be prepared according to the invention related process c) shown in scheme 3, wherein R a , R 2 , R 3 , R 4 and R 5 are defined as described before and R 8 denotes hydrogen, starting from compounds of formula V, wherein R b denotes chlorine.
  • compounds of formula V wherein R b denotes chlorine, are converted into compounds of formula XVI by reacting with a suitable iodination reagent such as e.g. sodium iodide and acetylchloride in a suitable solvent such as e.g. acetonitrile, N,N-dimethylformamide, 1,4-dioxane or tetrahydrofurane but preferably in acetonitrile, at temperatures between 0° C. and 100° C. but preferably between room temperature and 80° C.
  • a suitable iodination reagent such as e.g. sodium iodide and acetylchloride
  • a suitable solvent such as e.g. acetonitrile, N,N-dimethylformamide, 1,4-dioxane or tetrahydrofurane but preferably in acetonitrile
  • a suitable hydride donating reagent such as e.g. borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex, borane-dimethylaniline-complex, borane-diethylaniline-complex, sodium borohydride, lithium borohydride, lithium aluminium hydride in a suitable solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between ⁇ 78° C. and 100° C., but preferably between ⁇ 50° C.
  • a suitable solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene
  • alkylation reaction of compounds of formula XVI wherein R b denotes iodine with a suitable alkyl metal compound such as e.g. 1-4C-dialkylzinc-, 1-4C-alkylmagnesium halogenide-, or 1-4C-alkyllithium-reagent, particularly 1-2C-dialkylzinc-, 1-2C-alkylmagnesium halogenide-, or 1-2C-alkyllithium-reagent, in a suitable solvent such as e.g.
  • n-hexane, cyclohexane, toluene, diethylether, tetrahydrofurane or 1,4-dioxane optionally in the presence of a chiral ligand as for example (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, ( ⁇ )-3-exo-dimethylamino-isoborneol, (+)-3-exo-dimethylamino-isoborneol or ligands as described in J.
  • a chiral ligand as for example (R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, (R)-1-methyl-3
  • the alcohol group in compounds of formula XVII can be temporarily protected with a suitable protecting group, e.g. as a tert.-butyldimethylsilylether by the reaction with tert.-butyldimethylsilylchloride in a suitable solvent such as e.g. N,N-dimethylformamide or acetonitrile in the presence of imidazole, at temperatures between ⁇ 20° C. and 120° C., but preferably between 0° C. and 80° C., to give the protected derivatives of formula XVIII, in which PG stands for this suitable protecting group.
  • a suitable protecting group e.g. as a tert.-butyldimethylsilylether by the reaction with tert.-butyldimethylsilylchloride in a suitable solvent such as e.g. N,N-dimethylformamide or acetonitrile in the presence of imidazole, at temperatures between ⁇ 20° C.
  • This protection can also be carried out by reacting compounds of formula XVII with tert.-butyldimethylsilyl-trifluormethansulfonate in the presence of a suitable base such as e.g. pyridine or 2,6-lutidine in a suitable solvent such as e.g. dichloromethane, diethylether, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between ⁇ 50° C. and 100° C. but preferably between ⁇ 30° C. and 50° C.
  • any other suitable protecting group as described e.g. in “ Protective Groups in Organic Synthesis”, 2 nd edition, Greene T. W., Wuts P. G. M.; Wiley-Interscience: New York, 1991 or in “ Protective Groups ”, Kocienski P. J.; Thieme: New York, 1994 can be used.
  • a suitable solvent such as e.g. toluene, tetrahydrofurane, 1,4-dioxane or diethylether
  • a suitable catalyst such as e.g.
  • tri-tert.-butylphosphine tri-cyclohexylphosphine, di-adamantan-1-yl-butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl or 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl, at temperatures between 40° C. and 180° C., but preferably between 70° C. and 130° C., delivers compounds of formula VIII.
  • the (cyclo)alkyl-zinc-halogenide reagents may optionally be prepared by transmetalation of corresponding (cyclo)alkyl-magnesium-halogenide reagents, e.g. with zinc chloride in diethylether, tetrahydrofurane or 1,4-dioxane.
  • toluene N,N-dimethylformamide, acetonitrile, 1,4-dioxane or tetrahydrofurane or mixtures of toluene and tetrahydrofurane in the presence of a suitable base such as e.g aquous sodium carbonate, aquous potassium carbonate, aquous caesium carbonate, silver carbonate, caesium fluoride, triethylamine or N,N-diisopropyl-N-ethyl-amine but preferably caesium fluoride and in the presence of a suitable catalyst such as e.g.
  • a suitable base such as e.g aquous sodium carbonate, aquous potassium carbonate, aquous caesium carbonate, silver carbonate, caesium fluoride, triethylamine or N,N-diisopropyl-N-ethyl-amine but preferably caesium fluoride
  • a suitable palladium source such as e.g. palladium diacetate or tris-(dibenzylideneacetone)-dipalladium-(0)
  • a suitable ligand such as e.g.
  • tri-tert.-butylphosphine tri-cyclohexylphosphine, di-adamantan-1-yl-butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl or 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl, at temperatures between 0° C. and 180° C., but preferably between room temperature and 120° C., gives compounds of formula XIX.
  • a suitable hydride donating reagent such as e.g. borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex, borane-dimethylaniline-complex, borane-diethylaniline-complex, sodium borohydride, lithium borohydride, lithium aluminium hydride in a suitable solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between ⁇ 78° C. and 100° C., but preferably between ⁇ 50° C.
  • a suitable solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene
  • a chiral ligand such as e.g. (1R,2S)-(+)-cis-1-Amino-2-indanol, (1S,2R)-(+)-cis-1-Amino-2-indanol, (R)-1-Methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole or (S)-1-Methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole gives the alcohols of formula XX, wherein R 5 denotes hydrogen.
  • alkylation reaction of compounds of formula XIX with a suitable alkyl metal compound such as e.g. 1-4C-dialkylzinc-, 1-4C-alkylmagnesium halogenide-, or 1-4C-alkyllithium-reagent, particularly 1-2C-dialkylzinc-, 1-2C-alkylmagnesium halogenide-, or 1-2C-alkyllithium-reagent, in a suitable solvent such as e.g.
  • the alcohol group in compounds of formula XX can be temporarily protected with a suitable protecting group, e.g. as a tert.-butyldimethylsilylether by the reaction with tert.-butyldimethylsilylchloride in a solvent such as e.g. dimethylformamide or acetonitrile in the presence of imidazole, at temperatures between ⁇ 20° C. and 120° C., but preferably between 0° C. and 80° C., to give the protected derivatives of formula XXI, in which PG stands for this suitable protecting group.
  • a suitable protecting group e.g. as a tert.-butyldimethylsilylether by the reaction with tert.-butyldimethylsilylchloride in a solvent such as e.g. dimethylformamide or acetonitrile in the presence of imidazole, at temperatures between ⁇ 20° C. and 120° C., but preferably between 0°
  • This protection can also be carried out by reacting compounds of formula XX with tert.-butyldimethylsilyl-trifluormethansulfonat in the presence of a base such as e.g. pyridine or 2,6-lutidine in a solvent such as e.g. dichloromethane, diethylether, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between ⁇ 50° C. and 100° C. but preferably between ⁇ 30° C. and 50° C.
  • any other suitable protecting group as described e.g. in “ Protective Groups in Organic Synthesis”, 2 nd edition, Greene T. W., Wuts P. G. M.; Wiley-Interscience: New York, 1991 or in “ Protective Groups ”, Kocienski P. J.; Thieme: New York, 1994 can be used.
  • the esters of formula XXI can be converted to the aldehydes of formula XXII e.g. by a two step sequence.
  • First step is the reduction to the alcohol with a suitable reducing agent, such as e.g. diisobutylamuminium hydride of lithiumaluminiumhydride in an aprotic solvent such as e.g. dichloromethane, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between ⁇ 78° C. and 100° C., but preferably between ⁇ 30° C. and 50° C.
  • a suitable reducing agent such as e.g. diisobutylamuminium hydride of lithiumaluminiumhydride in an aprotic solvent such as e.g. dichloromethane, tetrahydrofurane, 1,4-dioxane or toluene
  • Second step is the oxidation of the alcohol to the aldehyde which can be carried out with Dess-Martin-Periodinan ( J. Chem. Soc. 1983, 48, 4156), by Swern oxidation ( J. Org. Chem.
  • Aldehydes of formula XXII are transformed to the alcohols of formula XI by reaction with a suitable R 1 -metal reagent, such as e.g. R 1 -magnesium halogenide- or R 1 -lithium-reagent, in an aprotic solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene, at temperatures between ⁇ 78° C. and 80° C., but preferably between ⁇ 50° C. and 40° C.
  • a suitable R 1 -metal reagent such as e.g. R 1 -magnesium halogenide- or R 1 -lithium-reagent
  • an aprotic solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene
  • aromatic hydroxy groups can be converted into aromatic sulfonyloxy groups such as methylsulfonyloxy, tosylsulfonyloxy or trifluoromethylsulfonyloxy.
  • This transformation is performed by reacting compounds with aromatic hydroxy group with a sulfonyl anhydride, sulfonylchloride or sulfonylimide in a solvent such as e.g. dichloromethane, 1,2-dichloroethane, diethylether, tetrahydrofurane, 1,4-dioxane, acetonitrile or toluene at temperatures between ⁇ 78° C.
  • a solvent such as e.g. dichloromethane, 1,2-dichloroethane, diethylether, tetrahydrofurane, 1,4-dioxane, acetonitrile or toluene at temperatures between ⁇ 78° C.
  • a base such as e.g. triethylamine, N,N-diisopropyl-N-ethyl-amine, pyridine or 2,6-lutidine
  • a base such as e.g. triethylamine, N,N-diisopropyl-N-ethyl-amine, pyridine or 2,6-lutidine
  • an acylation catalyst as 4-dimethylamino-pyridine (DMAP).
  • aromatic sulfonyloxy groups can be further transformed into alkenyl groups or optionally substituted cyclopropyl groups by reacting the compounds with aromatic sulfonyloxy groups with potassium alkenyltrifluoroborates, alkenyl-boronic acids, alkenyl-boronic acid pinacol esters, optionally substituted cyclopropyl-boronic acids or optionally substituted cyclopropyl-boronic acid pinacol esters in toluene, N,N-dimethylformamide, isopropanol, acetonitrile, 1,4-dioxane or tetrahydrofurane or mixtures of toluene and tetrahydrofurane in the presence of a base as such as e.g.
  • aquous sodium carbonate aquous potassium carbonate, aquous caesium carbonate, silver carbonate, caesium fluoride, triethylamine or N,N-diisopropyl-N-ethyl-amine and in the presence of a catalyst such as e.g.
  • a palladium source such as e.g. palladium diacetate or tris-(dibenzylideneacetone)-dipalladium-(0) and a suitable ligand like e.g.
  • tri-tert.-butylphosphine tri-cyclohexylphosphine, di-adamantan-1-yl-butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-thisopropyl-1,1′-biphenyl or 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl at temperatures between 0° C. and 180° C., but preferably between room temperature and 120° C.
  • Alkenyl groups can be transformed into an optionally substituted cyclopropyl group by a Simmons-Smith reaction.
  • This reaction is performed by reacting with bromo-iodo-methane or diiodomethane and diethylzinc, optionally in the presence of trifluoroacetic acid, in a solvent such as e.g. dichloromethane, 1,2-dichloroethane, diethylether, tetrahydrofurane, 1,4-dioxane or toluene at temperatures between ⁇ 50° C. and 80° C., but preferably between ⁇ 10° C. and room temperature.
  • a solvent such as e.g. dichloromethane, 1,2-dichloroethane, diethylether, tetrahydrofurane, 1,4-dioxane or toluene
  • Alkoxycarbonyl groups can be transformed into dialkylmethanol groups. This transformation is performed by reacting with an alkyllithium reagent or with an alkyl-Grignard reagent in a solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane or toluene at temperatures between ⁇ 50° C. and 80° C., but preferably between ⁇ 20° C. and room temperature. Alternatively alkoxycarbonyl groups, can be transformed into compounds hydroxymethyl groups. This transformation is performed by reacting with a reducing reagent such as e.g.
  • Hydroxy groups can be further transformed into alkoxy groups by alkylation. This transformation is performed by reacting with an alkylating agent such as e.g. an alkyl halogenide, methanesulfonic acid-alkyl-ester, p-toluenesulfonic acid-alkyl-ester or trifluoromethanesulfonic acid-alkyl-ester in the presence of a base such as e.g.
  • an alkylating agent such as e.g. an alkyl halogenide, methanesulfonic acid-alkyl-ester, p-toluenesulfonic acid-alkyl-ester or trifluoromethanesulfonic acid-alkyl-ester in the presence of a base such as e.g.
  • a solvent such as e.g. diethylether, tetrahydrofurane, 1,4-dioxane, N,N-dimethylformamide, acetonitrile or toluene at temperatures between ⁇ 50° C. and 80° C., but preferably between ⁇ 20° C. and 50° C.
  • any reactive groups present such as carboxy-, carbonyl-, hydroxy-, amino-, alkylamino- or imino-groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
  • a protecting group for a carboxy group may be the methyl-, ethyl-, tert.-butyl- or benzyl-group.
  • a protecting group for a carbonyl group may be an acetal or ketal like the 1,3-dioxolane- or the 1,3-dioxane-group.
  • a protecting group for a hydroxy group may be a trimethylsilyl-, tert.-butyldimethylsilyl-, acetyl-, trityl-, benzyl- or tetrahydropyranyl-group.
  • Protecting groups for an amino, alkylamino or imino group may be, for example, a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.
  • the cleavage of a carboxymethyl- or a carboxyethyl-group can for example be carried out hydrolytically in an aqueous solvent, e.g. in water, methanol/water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or 1,4-dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali base as for example lithium hydroxide, sodium hydroxide or potassium hydroxide, but preferably sodium hydroxide, or aprotically in the presence of e.g. iodotrimethylsilane, at temperatures between 0 and 120° C., preferably at temperatures between 10 and 100° C.
  • an aqueous solvent e.g. in water, methanol/water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or
  • An acetal or ketal can be cleaved with acetic acid, trifluoroacetic acid, hydrochloric acid, sulphuric acid or pyridiumium-p-toluene sulfonate in mixtures with water or in organic solvents like for example dichloromethane, 1,2-dichloroethane, tetrahydrofurane, 1,4-dioxane, toluene or acetone at temperatures between ⁇ 20° C. and 150° C., but preferably between 0° C. and 120° C.
  • a benzyl, methoxybenzyl or benzyloxycarbonyl group is advantageously cleaved hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetatetetrahydrofurane, 1,4-dioxane or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid or with the addition of a base such as triethylamine at temperatures between 0 and 100° C., but preferably at ambient temperatures between 20 and 60° C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
  • a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as dichloromethane, 1,4-dioxane, methanol or diethylether.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • iodotrimethylsilane optionally using a solvent such as dichloromethane, 1,4-dioxane, methanol or diethylether.
  • a trimethylsilyl- or tert.-butyldimethylsilyl-group is cleaved with a fluoride reagent like for example tetrabutylammonium fluoride or caesium fluoride or with an acid like for example trifluoroacetic acid, hydrochloric acid or sulphuric acid in a solvent like e.g. dichloromethane, 1,2-dichloroethane, diethylether, tetrahydrofurane, 1,4-dioxane, acetonitrile or toluene at temperatures between ⁇ 50° C. and 120° C., but preferably between ⁇ 20° C. and 80° C.
  • a fluoride reagent like for example tetrabutylammonium fluoride or caesium fluoride or with an acid like for example trifluoroacetic acid, hydrochloric acid or sulphuric acid in a solvent like e.g
  • the present invention also relates to intermediates (including their salts, stereoisomers and salts of these stereoisomers), methods and processes which are disclosed herein and which are useful in synthesizing final compounds according to this invention.
  • the present invention also relates to processes disclosed herein for preparing compounds according to this invention, which processes may be performed as described herein. Said processes may comprise one or more steps of converting and/or reacting the mentioned intermediates with the appropriate reaction partners, suitably under conditions as disclosed herein.
  • the compounds of general formula I or intermediates in the synthesis of compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore.
  • cis/trans mixtures may be resolved into their cis and trans isomers, and racemic compounds may be separated into their enantiomers.
  • the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof.
  • the compounds of general formula I or intermediates in the synthesis of compounds of general formula I, which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I or intermediates in the synthesis of compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
  • racemates are preferably resolved by column chromatography on chiral phases or by crystallization from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as esters or amides with the racemic compound.
  • Salts may be formed with enantiomerically pure acids for basic compounds and with enantiomerically pure bases for acidic compounds.
  • Diastereomeric derivatives are formed with enantiomerically pure auxiliary compounds, e.g. acids, their activated derivatives, or alcohols. Separation of the diastereomeric mixture of salts or derivatives thus obtained may be achieved by taking advantage of their different physico-chemical properties, e.g.
  • Optically active acids in common use for such a purpose are e.g. the D- and L-forms of tartaric acid, dibenzoyltartaric acid, ditoloyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid, or quinic acid.
  • Optically active alcohols applicable as auxiliary residues may be, for example, (+) or ( ⁇ )-menthol and optically active acyl groups in amides may be, for example, (+)- or ( ⁇ )-menthyloxycarbonyl.
  • the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the pharmaceutically acceptable salts with inorganic or organic acids.
  • Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. Corresponding processes are known for the skilled person.
  • the compounds of formula I may be obtained—depending on their individual chemical nature and the individual nature of the acid or base used—as free compound or containing said acid or base in an stoechiometric or non-stoechiometric quantity (e.g. as a salt).
  • the acid/base contained can be analyzed according to art-known procedures, e.g. by titration or NMR, and, optionally, removed according to procedures familiar to the skilled person.
  • salts of the compounds of the formula I may be converted into the free compounds.
  • Corresponding processes are known to the skilled person, e.g. via neutralization.
  • Salts can be obtained by combining or reacting the free compounds with the desired acids or bases, e.g. by dissolving or suspending the free compound in a suitable solvent (e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran or 1,4-dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, a low-molecular-weight aliphatic alcohol, such as methanol, ethanol or isopropanol, or an ester, such as ethyl acetate, or water, or a mixture thereof) which contains the desired acid or base, or to which the desired acid or base is then added.
  • a suitable solvent e.g. a ketone, such as acetone, methyl ethyl ketone or methyl is
  • the salts can be obtained by filtering, reprecipitating, precipitating with a nonsolvent for the addition salt or by evaporating the solvent. Salts obtained can be converted to another, e.g. by reaction with an appropriate acid or base or by means of a suitable ion exchanger. Likewise, salts obtained can be converted into the free compounds, which can in turn be converted into salts, by alkalization or by acidification. In this manner, pharmaceutically unacceptable salts can be converted into pharmaceutically acceptable salts.
  • the substances according to the invention are isolated and purified in a manner known per se, for example by distilling off the solvent under reduced pressure and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on a suitable support material.
  • the hereinafter described compounds have been characterized through their characteristic mass after ionisation in a mass-spectrometer, their R f -Value on thin-layer-chromatography plate and/or their retention time on an analytical HPLC.
  • the solution is diluted with diethylether and washed with 1 N hydrochloric acid, saturated aquous sodium bicarbonate solution and brine. After drying with magnesium sulphate the solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 90:10 to 30:70).
  • the diatsereomers are separated by chromatography on silica gel and are used directly in the next step.

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US9029544B2 (en) 2010-02-19 2015-05-12 Boehringer Ingelheim International Gmbh Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation
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US9029544B2 (en) 2015-05-12
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