WO2012020035A1 - New azacyclic compounds - Google Patents
New azacyclic compounds Download PDFInfo
- Publication number
- WO2012020035A1 WO2012020035A1 PCT/EP2011/063727 EP2011063727W WO2012020035A1 WO 2012020035 A1 WO2012020035 A1 WO 2012020035A1 EP 2011063727 W EP2011063727 W EP 2011063727W WO 2012020035 A1 WO2012020035 A1 WO 2012020035A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phenyl
- pyridinyl
- trifluoromethoxy
- decan
- diaza
- Prior art date
Links
- 0 C=C(*CCC1)C11CCNCC1 Chemical compound C=C(*CCC1)C11CCNCC1 0.000 description 5
- IKCIWZCTHIIFPL-UHFFFAOYSA-N Cc1cc(C)c(C2CC2)cc1 Chemical compound Cc1cc(C)c(C2CC2)cc1 IKCIWZCTHIIFPL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- 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
- A61P9/10—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
Definitions
- the present invention relates to organic compounds useful for therapy or prophyl in a mammal, and in particular to inhibitors of hormone sensitive lipase (HSL) for the treatment of diabetes, metabolic syndrome and obesity.
- HSL hormone sensitive lipase
- the present invention provides novel compounds of formula (I)
- R 1 is imidazolyl, pyrazolyl, triazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidyl, pyridazinyl or 2-oxo- 1 ,2-dihydro-pyridinyl,
- R is imidazolyl, pyrazolyl, triazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidyl, pyridazinyl or 2-oxo- 1 ,2-dihydro-pyridinyl,
- white adipose tissue The main physiological role of white adipose tissue (WAT) is to supply energy when it is needed by other tissues.
- white adipose tissue is the primary energy storage depot, accumulating fuel reserves in the form of triacylglycerol (TAG) during times of energy excess.
- TAG triacylglycerol
- FFA free fatty acids
- the release of free fatty acids (FFA) from TAG is stimulated by catecholamines and regulated by hormones such as insulin, glucagon and epinephrine.
- the most important enzyme in WAT believed responsible for hormone regulated hydrolysis of triglyceride is hormone sensitive lipase (HSL).
- HSL hormone sensitive lipase
- Dysregulation of adipocyte lipolysis, resulting in elevated circulating non-esterified fatty acids (NEFA) is associated with obesity and co-morbidities including the
- Restoring the exaggerated plasma FFA and triglyceride levels through inhibition of HSL would reduce the accumulation of triglycerides in tissues other than WAT, such as liver, muscle and the pancreas resulting in decreased hepatic glucose output, increased muscle fatty acid oxidation and improving ⁇ -cell function.
- Elevated FFAs are also associated with increased cardiovascular risk, including atherosclerosis and myocardial dysfunction. Furthermore high lipolytic activity and elevated FFAs lead to increased insulin resistance and hypertension in hypertensive rats. The FFA collect in the liver and lead to increased production of TAG, which are packaged into very low density lipoproteins (VLDL) which are secreted. Therefore, reducing the activity of HSL would decrease the release of FFA to the blood, thus limiting the supply of FFA to the liver for TAG synthesis. Thus, HSL inhibitors could have beneficial effects as treatment of nonalkoholic fatty liver disease (NAFLD) and nonalkoholic steatohepatitis (NASH).
- NAFLD nonalkoholic fatty liver disease
- NASH nonalkoholic steatohepatitis
- Objects of the present invention are the compounds of formula (I) and their aforementioned salts and esters and their use as therapeutically active substances, a process for the manufacture of the said compounds, intermediates, pharmaceutical compositions, medicaments containing the said compounds, their pharmaceutically acceptable salts or esters, the use of the said compounds, salts or esters for the treatment or prophylaxis of illnesses, especially in the treatment or prophylaxis of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis, obesity, cardiovascular diseases, myocardial dysfunction, inflammation, nonalkoholic fatty liver disease or nonalkoholic steatohepatitis and the use of the said compounds, salts or esters for the production of medicaments for the treatment or prophylaxis of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis, obesity, cardiovascular diseases, myocardial dysfunction, inflammation, nonalkoholic fatty liver disease or nonalkoholic steatohepatitis.
- alkyl signifies a straight-chain or branched- chain alkyl with 1 to 8 carbon atoms, in particular with 1 to 6 carbon atoms and further particular with 1 to 4 carbon atoms.
- Examples are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, methylbutyl, dimethylpropyl, ethylpropyl, n-hexyl, methylpentyl, dimethylbutyl, trimethylpropyl and ethylmethylpropyl.
- Particular examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and dimethylpropyl. Further particular examples are methyl and propyl.
- cycloalkyl signifies a cycloalkyl ring with 3 to 8 carbon atoms and in particular with 3 to 6 carbon atoms.
- Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- a particular example is cyclopropyl.
- alkylcycloalkyl signifies a cycloalkyl, wherein one or more hydrogen atoms are replaced by an alkyl.
- alkylcycloalkyl examples are methyl-cyclopropyl, dimethyl-cyclopropyl, methyl-cyclobutyl, dimethyl-cyclobutyl, methyl-cyclopentyl, dimethyl-cyclopentyl, methyl-cyclohexyl and dimethyl-cyclohexyl.
- Particular examples are methyl-cyclopropyl and dimethyl-cyclopropyl.
- cycloalkylalkyl alone or in combination, signifies an alkyl, wherein one or more hydrogen atoms are replaced by a cycloalkyl.
- Examples are cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl, cyclooctylmethyl and cyclooctylethyl.
- Particular examples are cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl and cyclobutylethyl.
- cycloalkylalkoxy alone or in combination, signifies an alkoxy, wherein one or more hydrogen atoms are replaced by a cycloalkyl. Examples are
- cycloalkylalkoxyalkyl signifies an alkyl, wherein one or more hydrogen atoms are replaced by a cycloalkylalkoxy. Examples are cyclopropylmethoxymethyl, cyclopropylmethoxyethyl, cyclobutylmethoxymethyl, cyclobutylmethoxyethyl, cyclopentylmethoxyethyl, cyclopentylmethoxyethyl, cyclopentylmethoxyethyl,
- cyclohexylmethoxymethyl cyclohexylmethoxyethyl, cycloheptylmethoxymethyl, cycloheptylmethoxyethyl, cyclooctylmethoxymethyl and cyclooctylmethoxyethyl.
- cycloalkoxy signifies a group of the formula cyloalkyl-O- in which the term cycloalkyl has the previously given significance. Examples are cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.
- cycloalkoxyalkyl signifies an alkyl, wherein one or more hydrogen atoms are replaced by a cyclolalkoxy. Examples are
- cyclopropoxymethyl cyclopropoxyethyl, cyclobutoxymethyl, cyclobutoxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxymethyl, cyclohexyloxyethyl, cycloheptyloxymethyl, cycloheptyloxyethyl, cyclooctyloxymethyl and cyclooctyloxyethyl.
- alkylcycloalkylalkyl signifies an alkyl, wherein one or more hydrogen atoms are replaced by an alkylcycloalkyl.
- alkylcycloalkyl examples are methyl- cyclopropylmethyl, dimethyl-cyclopropylmethyl, methyl-cyclopropylethyl, dimethyl- cyclopropylethyl, methyl-cyclobutylmethyl, dimethyl-cyclobutylmethyl, methyl- cyclobutylethyl, dimethyl-cyclobutylethyl, methyl-cylopentylmethyl, dimethyl- cylopentylmethyl, methyl-cyclopentylethyl, dimethyl-cyclopentylethyl, methyl- cyclohexylmethyl, dimethyl-cyclohexylmethyl, methyl-cyclohexylethyl, dimethyl-cyclohexylethyl, methyl-cycloheptylmethyl, dimethyl-cycl
- halocycloalkyl signifies a cycloalkyl as defined before, wherein one or more hydrogen atoms are replaced by a halogen, in particular fluorine.
- halocycloalkyl are fluorocyclopropyl, difluorocyclopropyl, fluorocyclobutyl or difluorocyclobutyl.
- halocycloalkylalkyl signifies an alkyl as defined before, wherein one or more hydrogen atoms are replaced by a halocycloalkyl.
- halocycloalkyl are fluorocyclopropylmethyl, fluorocyclopropylethyl,
- halogen and "halo”, alone or in combination, signify fluorine, chlorine, bromine or iodine. Particular examples are fluorine or chlorine.
- haloalkyl signifies an alkyl as defined before, wherein one or more hydrogen atoms are replaced by a halogen, in particular fluorine.
- haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl or pentafluoroethyl. A particular example is trifluoromethyl.
- hydroxyalkyl signifies an alkyl as defined before, wherein one or more hydrogen atoms are replaced by a hydroxy.
- examples of hydroxyalkyl are hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl and dihydroxypropyl. Particular examples are hydroxyethyl and hydroxymethylpropyl.
- alkoxy signifies a group of the formula alkyl-O- in which the term alkyl has the previously given significance. Examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Particular examples are methoxy.
- alkoxyalkyl signifies an alkyl as defined before, wherein one or more hydrogen atoms are replaced by an alkoxy. Examples are methoxymethyl, ethoxymethyl, methoxymethyl, ethoxyethyl, methoxypropyl and ethoxypropyl.
- haloalkoxy signifies an alkoxy as defined before, wherein one or more hydrogen atoms are replaced by a halogen, in particular fluorine.
- haloalkoxy are fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy, or pentafluoroethoxy.
- Particular examples are trifluoromethoxy and trifluoromethylethoxy.
- hydroxyalkoxy signifies an alkoxy as defined before, wherein one or more hydrogen atoms are replaced by a hydroxy.
- examples of hydroxyalkoxy are hydroxyethoxy, hydroxypropoxy, hydroxymethylpropoxy and dihydroxypropoxy .
- alkoxyalkoxy signifies an alkoxy as defined before, wherein one or more hydrogen atoms are replaced by an alkoxy. Examples of methoxymethoxy, ethoxymethoxy, methoxymethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy.
- alkoxyalkoxyalkyl signifies an alkyl as defined before, wherein one or more hydrogen atoms are replaced by an alkoxyalkoxy. Examples of methoxymethoxymethyl, ethoxymethoxymethyl, methoxyethoxymethyl,
- methoxymethoxyethyl methoxymethoxyethyl, ethoxymethoxyethyl, methoxyethoxyethyl, ethoxyethoxyethyl, methoxypropoxy ethyl and ethoxypropoxy ethyl.
- hydroxyhaloalkyl signifies an alkyl as defined before, wherein one or more hydrogen atoms of the alkyl are replaced by a hydroxy and wherein one or more hydrogen atoms of the alkyl are replaced by a halogen, in which the terms hydroxy and halogen have the previously given significances.
- hydroxyhaloalkyl are hydroxytrifluoroethyl, hydroxytrifluoropropyl,
- protecting group refers to groups which are used to block the reactivity of functional groups such as amino groups or hydroxy groups.
- protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) or benzyl (Bn).
- a particular protecting group is benzyl (Bn).
- Cleavage of protecting groups can be done using standard methods known by the man skilled in the art such as hydrogenation or in the presence of an acid, e.g. HCl or TFA, or a base, e.g. triethylamine.
- an acid e.g. HCl or TFA
- a base e.g. triethylamine
- salts refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
- the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like.
- salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like.
- Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N- ethylpiperidine, piperidine, polyimine resins and the like.
- Particular pharmaceutically acceptable salts of compounds of formula (I) are the hydrochloride salts , methanesulfonic acid salts and citric acid salts.
- the compounds of formula (I) can also be solvated, e.g. hydrated.
- the solvation can be effected in the course of the manufacturing process or can take place e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of formula (I) (hydration).
- pharmaceutically acceptable salts also includes physiologically acceptable solvates.
- “Pharmaceutically acceptable esters” means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters.
- any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo are within the scope of this invention.
- the compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
- the asymmetric carbon atom can be of the "R” or "S” configuration.
- an embodiment of the present invention are compounds according to formula (I) as described above and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula (I) as described above and pharmaceutically acceptable salts thereof, more particularly compounds according to formula (I) as described above.
- a further embodiment of the present invention are compounds according to formula
- R 1 is phenyl, pyridinyl, pyrazinyl, pyrimidyl, pyridazinyl or 2-oxo- 1 ,2-dihydro-pyridinyl,
- phenyl, pyridinyl, pyrazinyl, pyrimidyl, pyridazinyl and 2-oxo- 1,2- dihydro-pyridinyl which are substituted with one to three substituents independently selected from alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, alkylcycloalkylalkyl, halocycloalkyl, halocycloalkylalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl and hydroxyhaloalkyl.
- a particular embodiment of the present invention are compounds according to formula (I) as described above, wherein R 1 is phenyl substituted with one to three haloalkoxy.
- a particular embodiment of the present invention are compounds according to formula (I) as described above, wherein R 1 is trifluoromethoxyphenyl or 2,2,2-trifluoro-l- methyl-ethoxyphenyl .
- R 1 is trifluoromethoxyphenyl or 2,2,2-trifluoro-l- methyl-ethoxyphenyl .
- R is phenyl, pyridinyl, pyrazinyl, pyrimidyl, pyridazinyl or 2-oxo-l, 2-dihydro-pyridinyl,
- halocycloalkyl halocycloalkylalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl,
- the present invention also relates to compounds according to formula (I) as described above, wherein R is phenyl, pyridinyl or 2-oxo-l, 2-dihydro-pyridinyl, or is selected from phenyl, pyridinyl and 2-oxo-l, 2-dihydro-pyridinyl which are substituted with one to three substituents independently selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy and benzyloxy.
- An alternative embodiment of the present invention are compounds according to formula (I) as described above, wherein R is is pyridinyl or 2-oxo-l, 2-dihydro-pyridinyl, or is selected from pyridinyl and 2-oxo-l, 2-dihydro-pyridinyl which are substituted with one to three substituents independently selected from alkyl and hydroxy.
- a particular embodiment of the present invention are compounds according to formula (I) as described above, wherein R is pyridinyl substituted with hydroxy or 2-oxo- 1, 2-dihydro-pyridinyl substituted with alkyl.
- a further embodiment of the present invention are compounds according to formula (I) as described above, wherein R is 2-hydroxypyridinyl, l-methyl-2-oxo-l,2-dihydro- pyridinyl or 2-oxo- 1 -propyl- 1 ,2-dihydro-pyridinyl.
- enantiomers or diastereoisomers can be separated by methods described herein or known to the man skilled in the art such as e.g. chiral chromatography or crystallization.
- the substituents and indices used in the following description of the processes have the significance given herein.
- X is halogen, preferably Br or I
- compounds of formula (I) can be prepared by reacting compounds of general formula (II) with a compound of general formula ( ⁇ ), wherein X is halogen, particularly iodo or bromo, in the presence of a palladium complex such as tris(dibenzylidene acetone) dipalladium-(O) and rac 2,2'-bis(diphenylphosphanyl)-l,l'-binaphthyl (rac-BINAP) as catalysts and Na'OBu as base, in an appropriate solvent such as toluene at elevated temperature.
- a palladium complex such as tris(dibenzylidene acetone) dipalladium-(O) and rac 2,2'-bis(diphenylphosphanyl)-l,l'-binaphthyl (rac-BINAP) as catalysts and Na'OBu as base, in an appropriate solvent such as toluene at elevated temperature.
- X is halogen, preferably CI or F
- dioxane can be used as solvent and trimethylaluminium as the
- X is halogen, preferably CI or Br
- Alkyl is e.g. methyl or ethyl
- Prot is Protecting group, e.g. Bn
- an embodiment of the present invention is a process to prepare a compound of formula (I) as defined above comprising the reaction of a compound of formula ( ⁇ ) in the presence of a compound of formula (HI);
- a base particularly sodium hydride or tBuONa
- a palladium complex as catalyst particularly tris(dibenzylidene acetone) dipalladium-(O) or rac 2,2'-bis(diphenylphosphanyl)-l,l'-binaphthyl (rac-BINAP)
- a solvent particularly toluene or DMF
- R 1 , R 2 and n are as defined above and X is halogen, particularly iodine or bromine.
- Particular intermediates are selected from
- a further object of the present invention comprises a compound according to formula (I) as described above, when manufactured according to any one of the described processes.
- an object of the present invention is a compound according to formula (I) as described above for use as therapeutically active substance.
- an object of the present invention is a pharmaceutical composition
- a pharmaceutical composition comprising a compound according to formula (I) as described above and a therapeutically inert carrier.
- an object of the present invention is the use of a compound according to formula (I) as described above for the treatment or prophylaxis of illnesses which are caused by disorders associated with e.g. the enzyme hormone- sensitive lipase.
- the present invention also relates to the use of a compound according to formula (I) as described above for the treatment or prophylaxis of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity.
- an embodiment of the present invention is the use of a compound according to formula (I) as described above for the treatment or prophylaxis of cardiovascular diseases, myocardial dysfunction, inflammation, nonalkoholic fatty liver disease or nonalkoholic steatohepatitis.
- a particular embodiment of the present invention is the use of a compound according to formula (I) as described above for the treatment or prophylaxis of diabetes.
- a further particular embodiment of the present invention is the use of a compound according to formula (I) as described above for the treatment or prophylaxis of diabetes Type ⁇ .
- the present invention also relates to the use of a compound according to formula (I) as described above for the preparation of a medicament for the treatment or prophylaxis of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity.
- an embodiment of the present invention is the use of a compound according to formula (I) as described above for the preparation of a medicament for the treatment or prophylaxis of cardiovascular diseases, myocardial dysfunction, inflammation,
- nonalkoholic fatty liver disease or nonalkoholic steatohepatitis are nonalkoholic fatty liver disease or nonalkoholic steatohepatitis.
- a particular embodiment of the present invention is the use of a compound according to formula (I) as described above for the preparation of medicaments for the treatment or prophylaxis of diabetes.
- a further particular embodiment of the present invention is the use of a compound according to formula (I) as described above for the preparation of medicaments for the treatment or prophylaxis of diabetes Type II.
- a particular embodiment of the present invention is a compound according to formula (I) as described above for the treatment or prophylaxis of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity.
- a particular embodiment of the present invention is a compound according to formula (I) as described above for the treatment or prophylaxis of cardiovascular diseases, myocardial dysfunction, inflammation, nonalkoholic fatty liver disease or nonalkoholic steatohepatitis.
- a further particular embodiment of the present invention is a compound according to formula (I) as described above for the treatment or prophylaxis of diabetes.
- a further particular embodiment of the present invention is a compound according to formula (I) as described above for the treatment or prophylaxis of diabetes Type ⁇ .
- an object of the invention is a method for the treatment or prophylaxis of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity, which method comprises administering an effective amount of a compound according to formula (I) as described above. Also an embodiment of the present invention is a method for the treatment or prophylaxis of cardiovascular diseases, myocardial dysfunction, inflammation,
- nonalkoholic fatty liver disease or nonalkoholic steatohepatitis which method comprises administering an effective amount of a compound according to formula (I) as described above.
- a particular embodiment of the present invention is a method for the treatment or prophylaxis of diabetes, which method comprises administering an effective amount of a compound according to formula (I) as described above.
- a further particular embodiment of the present invention is a method for the treatment or prophylaxis of diabetes Type II, which method comprises administering an effective amount of a compound according to formula (I) as described above.
- cDNA was prepared from commercial human brain polyA+ RNA and used as a template in overlapping PCR to generate a full length human HSL ORF with a 3'-His6 tag. This full length insert was cloned into the pFast-BAC vector and the DNA-sequence of several single clones was verified. DNA from a correct full length clone with the 3'His6 tag was used to transform the E.coli strain DHIOBAC. Resulting bacmid DNA was used to generate a titered baculovirus stock for protein generation. The sequence of the encoded HSL conforms to Swissprot entry Q05469, with the additional C-terminal His6-tag.
- Soluble proteins were mixed with 60 ml of pre-washed and equilibrated Ni-NTA Agarose (Qiagen 30210) followed by tumbling end-over-end, 45 min., 4°C, centrifugation 1000 rpm 5 min and letting resin settle 5 min. Supernatant was removed, the resin washed in the centrifuge vessel using 5 volumes of Base Buffer containing 0.2% Lubrol PX. Centrifugation was done again, then the supernatant discarded. The resin wass poured onto a 0.8 ⁇ membrane in a disposable filter unit (Nalge 450-0080), and washed with 5 volumes of Base Buffer containing 0.2% Lubrol PX.
- HSL Human Hormone-Sensitive Lipase
- HSL enzyme activity was measured by a colorimetric assay using 2,3-dimercapto-l- propanol tributyrate (Aldrich, St. Louis, MO) as a substrate.
- 2,3-dimercapto-l- propanol tributyrate Aldrich, St. Louis, MO
- 1.5 mM 2,3- dimercapto-l-propanol tributyrate (DMPT) in 100 mM MOPS, pH 7.2, 0.2 mg/ml fatty acid-free BSA was prepared by sonication at 4° C to homogenous suspension.
- Test compounds (2 mM stock in DMSO) were diluted 3 fold in series in DMSO.
- Compound solutions were diluted 24 fold in 1.5 mM DMPT containing solution and 18 ul per well was added to 384-well microplates (Corning Costar).
- 3T3-L1 pre-adipocyte cells were plated into 96-well plates at a density of 20,000 cells/well in 200ul growth media (DMEM / 10% Calf Serum/ lx antibiotic-antimycotic) until confluent.
- the medium was removed and the cells were differentiated into adipocytes with differentiation medium (DMEM / 10% FBS / lx Antibiotic-Antimycotic PLUS: l uM IBMX (3 -Isobutyl-l-methylxanthine) Inhibitor of phosphodiesterases, 1 uM Dexamethasone, 1 uM Rosiglitazone, 10 ug/ml Insulin).
- the cells were incubated in said medium for 3 days and then medium was changed to post- differentiation medium (DMEM / 10% FBS PLUS: 10 ug/ ml Insulin) and the cells were incubated for an additional 3 days.
- the medium was then changed to maintenance media (DMEM / 10% FBS).
- the cells were fed every 3 days with maintenance media until use.
- the lipolysis assay may be performed on day 9-14 after the initiation of differentiation in 96 well plates.
- the lipolysis assay was performed as follows.
- the adipocytes were washed 2x with 200ul Krebs Ringer Bicarbonate Hepes buffer (KRBH) / 3% BSA.
- Test compounds were at lOmM in DMSO and were initially diluted to 5 mM in DMSO. They were then serially diluted 5-fold in DMSO (5 mM to 320 pM). Each compound was then diluted 200-fold into KRBH / 3% BSA (0.5% DMSO final). The resulting solutions range from 25 uM to 1.6 pM final.
- One hundred fifty ul of the diluted compounds were added to each well (in triplicate) and the cells were preincubated 30 min at 37° C.
- Forskolin 50 uM final was added to the wells and the cells were incubated 120 minutes at 37° C. One hundred ul was collected into a new 96-well plate for glycerol analysis. The amount of glycerol produced was determined using a glycerol determination kit (Sigma).
- the compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations).
- the pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or
- the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
- the compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatin capsules.
- Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.
- Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
- Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
- Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
- Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
- the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
- the compounds of formula (I) and their pharmaceutically acceptable salts can be used for the treatment or prophylaxis of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis, obesity, cardiovascular diseases, myocardial dysfunction, inflammation, nonalkoholic fatty liver disease or nonalkoholic steatohepatitis.
- the dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral
- Example 1 8-(2-Fluoro-4-trifluoromethyl-phenyl)-2-(4-trifluoromethoxy-phenyl)-2 ⁇ 8- diaza-spiro[4.51decan-l-one
- Step C 2-(4-Trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-l-one
- Step D 8-(2-Fluoro-4-trifluoromethyl-phenyl)-2-(4-trifluoromethoxy-phenyl)-2 ⁇ 8- diaza-spiro[4.51decan-l-one
- a sealed tube was charged with 4-bromo-3-fluorobenzotrifluoride (40 mg, 0.16 mmol), 2- (4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan- 1-one (50 mg, 0.16 mmol), sodium ie/ -butoxide (17 mg, 0.18 mmol), tris(dibenzylidene acetone) dipalladium-(O) (15 mg, 0.02 mmol), BINAP (5 mg, 0.01 mmol) and toluene (2) under argon.
- the sealed tube was closed and immersed in an oil bath and heated to 80 °C for 15h.
- Example 6 8-(2 ⁇ 6-Difluoro-phenyl)-2-(4-trifluoromethoxy-phenyl)-2 ⁇ 8-diaza- spiro[4.51decan-l-one
- Example 8 8-(2-Methoxy-5-methyl-phenyl)-2-(4-trifluoromethoxy-phenyl)-2 ⁇ 8-diaza- spiro[4.51decan-l-one
- Example 11 8-(l-methyl-2-oxo-l ⁇ 2-dihvdropyridin-3-yl)-2-(4-(trifluoromethoxy) phenyl)-2 ⁇ 8-diazaspiro[4.51decan-l-one
- Example 12 8-(2-Oxo-l-propyl-l ⁇ 2-dihvdro-pyridin-3-yl)-2-(4-trifluoromethoxy- phenyl)-2 ⁇ 8-diaza-spiro[4.51decan-l-one
- a compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:
- a compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
RU2013108748A RU2606513C2 (en) | 2010-08-13 | 2011-08-10 | 2,8-diazaspiro[4,5]decan-1-one derivatives, useful as inhibitors of hormone-sensitive lipase (hsl) |
EP11741230.4A EP2603510A1 (en) | 2010-08-13 | 2011-08-10 | New azacyclic compounds |
CA2806159A CA2806159A1 (en) | 2010-08-13 | 2011-08-10 | New azacyclic compounds |
MX2013001762A MX2013001762A (en) | 2010-08-13 | 2011-08-10 | New azacyclic compounds. |
KR1020137006473A KR20130139871A (en) | 2010-08-13 | 2011-08-10 | New azacyclic compounds |
JP2013524410A JP5886289B2 (en) | 2010-08-13 | 2011-08-10 | New azacyclic compounds |
CN201180039163.5A CN103068826B (en) | 2010-08-13 | 2011-08-10 | Nitrogen heterocyclic |
HK13108984.6A HK1181760A1 (en) | 2010-08-13 | 2013-08-01 | Azacyclic compounds |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP10172747.7 | 2010-08-13 | ||
EP10172747 | 2010-08-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2012020035A1 true WO2012020035A1 (en) | 2012-02-16 |
Family
ID=44509322
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2011/063727 WO2012020035A1 (en) | 2010-08-13 | 2011-08-10 | New azacyclic compounds |
Country Status (12)
Country | Link |
---|---|
US (3) | US8552024B2 (en) |
EP (1) | EP2603510A1 (en) |
JP (1) | JP5886289B2 (en) |
KR (1) | KR20130139871A (en) |
CN (1) | CN103068826B (en) |
AR (1) | AR082631A1 (en) |
CA (1) | CA2806159A1 (en) |
HK (1) | HK1181760A1 (en) |
MX (1) | MX2013001762A (en) |
RU (1) | RU2606513C2 (en) |
TW (1) | TW201213328A (en) |
WO (1) | WO2012020035A1 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8097634B2 (en) * | 2010-04-15 | 2012-01-17 | Hoffmann-La Roche Inc. | Azacyclic derivatives |
US8552024B2 (en) * | 2010-08-13 | 2013-10-08 | Hoffman-La Roche Inc. | Azacyclic compounds |
RS60201B1 (en) | 2014-11-14 | 2020-06-30 | Hoffmann La Roche | Antigen binding molecules comprising a tnf family ligand trimer |
CN114751989A (en) | 2015-03-31 | 2022-07-15 | 豪夫迈·罗氏有限公司 | Antigen binding molecules comprising trimeric TNF family ligands |
AR106188A1 (en) | 2015-10-01 | 2017-12-20 | Hoffmann La Roche | ANTI-CD19 HUMANIZED HUMAN ANTIBODIES AND METHODS OF USE |
CN109400608B (en) * | 2018-12-15 | 2021-08-31 | 西南大学 | Preparation and application of diazaspiro [4, 5] decane tartaric acid derivative |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007067504A2 (en) * | 2005-12-05 | 2007-06-14 | Incyte Corporation | Lactam compounds and methods of using the same |
WO2009097997A1 (en) * | 2008-02-07 | 2009-08-13 | Sanofi-Aventis | Substituted imidazolidine-2,4-diones, method for the production thereof, medicaments containing said compounds and use thereof |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001261679A (en) * | 2000-03-21 | 2001-09-26 | Mitsui Chemicals Inc | Pyrrolidinone derivative, method for producing the same and medicament containing the same compound |
ES2295963T3 (en) * | 2004-01-08 | 2008-04-16 | F. Hoffmann-La Roche Ag | DIAZA-SPIROPIPERIDINE DERIVATIVES AS INHIBITORS OF GLICINE TRANSPORTER 1 AND GLICINE TRANSPORTER 2. |
US8110581B2 (en) * | 2004-11-10 | 2012-02-07 | Incyte Corporation | Lactam compounds and their use as pharmaceuticals |
MX2007005527A (en) * | 2004-11-10 | 2007-07-09 | Incyte Corp | Lactam compounds and their use as pharmaceuticals. |
CN101336243A (en) * | 2005-12-05 | 2008-12-31 | 因塞特公司 | Lactam compounds and methods of using the same |
US8026365B2 (en) * | 2007-05-25 | 2011-09-27 | Hoffman-La Roche Inc. | 4,4-disubstituted piperidine derivatives |
US8329904B2 (en) * | 2009-05-12 | 2012-12-11 | Hoffmann-La Roche Inc. | Azacyclic derivatives |
US8389539B2 (en) * | 2009-12-01 | 2013-03-05 | Hoffman-La Roche Inc. | Azacyclic derivatives |
US8097634B2 (en) * | 2010-04-15 | 2012-01-17 | Hoffmann-La Roche Inc. | Azacyclic derivatives |
US8552024B2 (en) * | 2010-08-13 | 2013-10-08 | Hoffman-La Roche Inc. | Azacyclic compounds |
-
2011
- 2011-08-08 US US13/204,743 patent/US8552024B2/en not_active Expired - Fee Related
- 2011-08-10 CA CA2806159A patent/CA2806159A1/en not_active Abandoned
- 2011-08-10 EP EP11741230.4A patent/EP2603510A1/en not_active Withdrawn
- 2011-08-10 MX MX2013001762A patent/MX2013001762A/en unknown
- 2011-08-10 RU RU2013108748A patent/RU2606513C2/en not_active IP Right Cessation
- 2011-08-10 WO PCT/EP2011/063727 patent/WO2012020035A1/en active Application Filing
- 2011-08-10 JP JP2013524410A patent/JP5886289B2/en not_active Expired - Fee Related
- 2011-08-10 KR KR1020137006473A patent/KR20130139871A/en not_active Application Discontinuation
- 2011-08-10 CN CN201180039163.5A patent/CN103068826B/en not_active Expired - Fee Related
- 2011-08-11 AR ARP110102923A patent/AR082631A1/en unknown
- 2011-08-12 TW TW100128973A patent/TW201213328A/en unknown
-
2013
- 2013-08-01 HK HK13108984.6A patent/HK1181760A1/en not_active IP Right Cessation
- 2013-08-29 US US14/013,551 patent/US20140005400A1/en not_active Abandoned
-
2015
- 2015-01-30 US US14/609,999 patent/US20150148363A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007067504A2 (en) * | 2005-12-05 | 2007-06-14 | Incyte Corporation | Lactam compounds and methods of using the same |
WO2009097997A1 (en) * | 2008-02-07 | 2009-08-13 | Sanofi-Aventis | Substituted imidazolidine-2,4-diones, method for the production thereof, medicaments containing said compounds and use thereof |
Non-Patent Citations (1)
Title |
---|
ANGEW. CHEM. INT. ED., vol. 37, 1998 |
Also Published As
Publication number | Publication date |
---|---|
MX2013001762A (en) | 2013-03-18 |
HK1181760A1 (en) | 2013-11-15 |
US20120041013A1 (en) | 2012-02-16 |
CN103068826B (en) | 2016-08-31 |
KR20130139871A (en) | 2013-12-23 |
JP2013535510A (en) | 2013-09-12 |
TW201213328A (en) | 2012-04-01 |
EP2603510A1 (en) | 2013-06-19 |
CN103068826A (en) | 2013-04-24 |
US20150148363A1 (en) | 2015-05-28 |
US8552024B2 (en) | 2013-10-08 |
RU2606513C2 (en) | 2017-01-10 |
AR082631A1 (en) | 2012-12-19 |
CA2806159A1 (en) | 2012-02-16 |
US20140005400A1 (en) | 2014-01-02 |
JP5886289B2 (en) | 2016-03-16 |
RU2013108748A (en) | 2014-09-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2558464B1 (en) | Azacyclic spiroderivatives as hsl inhibitors | |
US20150148363A1 (en) | New azacyclic compounds | |
EP2507239B1 (en) | Azacyclic spiro derivatives | |
US8703807B2 (en) | Azaspirodecanone compounds | |
EP2688881B1 (en) | New azaspirodecanone compounds as hsl inhibitors | |
WO2012123432A1 (en) | Sec-hydroxycyclohexyl derivatives as hsl inhibitors for the treatment diabetes | |
US8470843B2 (en) | Azacyclic compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201180039163.5 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11741230 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011741230 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2806159 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2013524410 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2013/001762 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 2013108748 Country of ref document: RU Kind code of ref document: A Ref document number: 20137006473 Country of ref document: KR Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112013002953 Country of ref document: BR |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01E Ref document number: 112013002953 Country of ref document: BR |
|
ENPW | Started to enter national phase and was withdrawn or failed for other reasons |
Ref document number: 112013002953 Country of ref document: BR Free format text: PEDIDO RETIRADO EM RELACAO AO BRASIL POR NAO ATENDER AS DETERMINACOES REFERENTES A ENTRADA DO PEDIDO NA FASE NACIONAL E POR NAO CUMPRIMENTO DA EXIGENCIA FORMULADA NA RPI NO 2479 DE 10/07/2018. |