WO2007065948A1 - N-sulfamoyl-piperidine amides innovants pour la prophylaxie ou le traitement de l'obesite et des etats apparentes - Google Patents

N-sulfamoyl-piperidine amides innovants pour la prophylaxie ou le traitement de l'obesite et des etats apparentes Download PDF

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WO2007065948A1
WO2007065948A1 PCT/EP2006/069482 EP2006069482W WO2007065948A1 WO 2007065948 A1 WO2007065948 A1 WO 2007065948A1 EP 2006069482 W EP2006069482 W EP 2006069482W WO 2007065948 A1 WO2007065948 A1 WO 2007065948A1
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alkyl
substituted
formula
halogen
alkoxy
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PCT/EP2006/069482
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English (en)
Inventor
Jochen Antel
Uwe Schoen
Harald Waldeck
Michael Wurl
Michael Firnges
Dania Reiche
Peter-Colin Gregory
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Solvay Pharmaceuticals Gmbh
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Priority to BRPI0619583-0A priority Critical patent/BRPI0619583A2/pt
Priority to CA002632719A priority patent/CA2632719A1/fr
Priority to JP2008543846A priority patent/JP2009518366A/ja
Priority to EP06830478A priority patent/EP1960359A1/fr
Priority to AU2006323952A priority patent/AU2006323952A1/en
Publication of WO2007065948A1 publication Critical patent/WO2007065948A1/fr
Priority to IL192025A priority patent/IL192025A0/en
Priority to NO20083065A priority patent/NO20083065L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Novel N-sulfamoyl-piperidineamides for the prophylaxis or treatment of obesity and related conditions
  • the present invention relates to novel N-sulfamoyl-piperidineamides and their physiologically acceptable acid addition salts, to pharmaceutical compositions comprising them, processes for their preparation, and their use for the treatment of obesity and re- lated conditions.
  • WO 03/088908 discloses N-sulfamoyl-piperidineamides with a specific substitution pattern at the piperidine ring.
  • the compounds of WO03/088908 are assumedly useful for treating arrhythmia, l Kur -associated conditions, gastrointensinal disorders, diabetes, cognitive disorders, and related conditions.
  • the invention is directed to compounds of general Formula I,
  • R1 is selected from the group consisting of: H; alkyl; cycloalkyl; alkylenealkoxy; alkylenecycloalkyl; aryl unsubstituted or substituted by one or more alkyl, alkoxy, halogen, CF 3 , CN; alkylenearyl; alkylenearylenealkyl; alkylenearylenehalogen; alkylenearylene- oxyalkyl; alkylenearylenedialkylamin; heteroaryl; alkyleneheteroaryl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ;
  • R2 is selected from the group consisting of: cycloalkyl; aryl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; alkylenearyl, unsubstituted or substituted, but not substituted by furan or furanyl; alkylenealkoxy; alkylenecycloalkyl; heteroaryl; CO- alkyl; CO-cycloalkyl; CO-aryl substituted by alkyl, alkoxy, halogen, CF 3 , CN; CO- alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CF 3 , CN; CO- heteroaryl unsubstituted or substituted by alkyl, alkoxy, halogen, CF 3 , CN; CO-0-alkyl; CO-O-cycloalkyl; CO-0-aryl substituted with alkyl, alkoxy, halogen, CN, CF
  • R1 and R2 together form a 5 or 6-membered ring which may optionally con- tain from 1 to 2 additional heteroatoms independently selected from the group consisting of: nitrogen, oxygen and/or sulphur; and which may optionally bear 1 or 2 double bonds; and which may also be substituted by alkyl, halogenalkyl, aryl unsubstituted or substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF 3, and/or heteroaryl; and which may also contain a carbonyl group; and which may also be condensed with aryl;
  • R3 and R4 are independently selected from the group consisting of: H, alkyl, cycloalkyl, cycloalkyl containing 1 or more heteroatoms selected from nitrogen and/or oxygen; cycloalkyl containing 1 or more heteroatoms selected from nitrogen and/or oxygen, and optionally substituted with alkyl, alkoxy, halogen, CF 3 , CN; aryl; aryl substituted with alkyl, alkoxy, halogen, CF 3 , CN; heteroaryl unsubstiututed or substituted with alkyl, alkoxy, halogen, CF 3 , CN; alkylenearyl; or wherein R3 and R4 together form a 5 or 6- membered ring which may optionally contain from 1 to 2 heteroatoms independently selected from the group consisting of nitrogen and/or oxygen atoms and which may also be substituted by aryl or aryl substituted with alkyl, alkoxy, halogen, CF 3 and CN;
  • Compounds of general Formula I are suitable for the treatment and/or prophylaxis of glaucoma, epilepsy, bipolar disorders, migraine, neuropathic pain, obesity, type Il diabetes, metabolic syndrome, alcohol dependence, and/or cancer, and its concomitant and/or secondary diseases or conditions in mammals and humans.
  • R1 is selected from the group consisting of: H; alkyl; cycloalkyl; alkylenealkoxy; alkylenecycloalkyl; aryl; alkylenearyl; heteroaryl; alkyleneheteroaryl unsubstituted or substituted with halogen;
  • R2 is selected from the group consisting of: cycloalkyl; aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; alkylenearyl, unsubstituted or substituted, but not substituted by furan or furanyl; alkylenealkoxy; alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; CO-alkylenearyl; CO- heteroaryl; CO-O-alkyl; CO-O-cycloalkyl; CO-0-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-O-alkylene
  • R1 is selected from the group consisting of: H, alkyl; cycloalkyl; alkylenealkoxy; alkylenecycloalkyl; aryl; al- kylenearyl; heteroaryl; alkyleneheteroaryl substituted with halogen;
  • R2 is selected from the group consisting of: alkylenealkoxy; alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; CO- alkylenearyl; CO-heteroaryl; CO-NH-alkylenearyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-alkylenearyl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-heteroaryl; SO 2 -NH 2 ; or; R1 and R2 together form a 5 or 6-membered ring which may optionally contain from 1 to 2
  • R1 is only H if R2 does not contain a CO group.
  • R3 and R4 are both H.
  • substituents are or contain alkyl, cycloalkyl, alkylene, alkoxy, these may each be straight-chain or branched and possess 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms. Suitable are methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert.
  • substituents in compounds of Formula I stand for halogen, fluorine, chlorine, bromine or iodine are suitable. Chlorine and bromine are preferred.
  • substituents in compounds of Formula I stand for aryl single aromatic ring systems with an adequate number of hydrogen atoms dependent upon the substitution pattern are meant. However, condensed and spiro aryl systems are also included in this definition. Suitable aryl substituents are phenyl, 1 H-indene, 9H-fluorene, naphthalene, anthracene, and phenathrene.
  • aryl ring systems are meant wherein one or more carbon atoms from the aromatic ring system are replaced by a heteroatome selected from oxygen and/or nitrogen and/or sulphur.
  • Suitable heteroaryls are pyrrol, furane, thiophene, indolizine, indole, isoindole, cumarone, thionaphthene, pyrozole, imidozole, oxazole, isooxazole, thiazole, isothiazole, triazole, tetrazole, thiadiazole, pyridine, pyrane, thiopyrane, chinoline, isochinoline, pyridazine, pyrimidine, pyrazine, and triazine.
  • Physiologically compatible acid addition salts of compounds of general Formula I are their conventional salts with inorganic acids, for example sulphuric acid, phosphoric acids or hydrohalic acids, preferably hydrochloric acid, or with organic acids, for example lower aliphatic monocarboxylic, dicarboxylic or tricarboxylic acids such as maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, or with sulphonic acids, for example lower al- kanesulphonic acids such as methanesulphonic acid or trifluoromethanesulphonic acid, or benzenesulphonic acids optionally substituted in the benzene ring by halogen or lower alkyl, such as p-toluenesulphonic acid. Hydrochloric acid salts of the compounds of general Formula I are preferred.
  • compounds of Formula I wherein R3 and R4 are both not H can be prepared by reacting compounds of Formula IV with an amine HNR1 R2 to give compounds of Formula I
  • sulfamoylchloride which is protected with a protecting group PG, preferably tert. butyloxycarbonyl or benzyl, of Formula Via, or with the reagent of Formula VIb,
  • the protecting group is tert.-butyloxycarbonyl
  • the removal of PG can be achieved under acidic conditions, preferably in the presence of hydrogen chloride.
  • the protecting group is benzyl
  • the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd.
  • compounds of Formula I wherein R3 and R4 are both H can be prepared by reacting a compound of Formula VII with an amine HNR1 R2 to give compounds of Formula IX
  • the protecting group is tert.-butyloxycarbonyl
  • the removal of PG can be achieved under acidic conditions, preferably in the presence of hydrogen chloride.
  • the protecting group is benzyl
  • the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd.
  • R2' is selected from the group consisting of: alkyl; cycloalkyl; alkylenearyl, unsub- stituted or substituted, but not substituted by furan or furanyl; alkylenealkoxy; and alkyle- necycloalkyl;
  • the protecting group PG of compounds of Formula XII is cleaved off under suitable conditions and the unprotected compound is then reacted with sulfamoylchloride CISO 2 - NH 2 to give compounds of Formula I.
  • the protecting group is tert.-butyloxycarbonyl
  • the removal of PG can be achieved under acidic conditions, preferably in the presence of hydrogen chloride.
  • the protecting group is benzyl
  • the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd.
  • compounds of Formula I wherein R2 contains a methylene spacer CH 2 can be prepared by cleaving off the protecting group PG of compounds of Formula XII under suitable conditions and the then unprotected compound is reacted with sulfamoylchloride, which is protected with a protecting group PG, preferably tert.- butyloxycarbonyl or benzyl, of Formula Via, or with the reagent of Formula VIb,
  • the protecting group is tert.-butyloxycarbonyl
  • the removal of PG can be achieved under acidic conditions, preferably in the presence of hydrogen chloride.
  • the protecting group is benzyl
  • the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd.
  • compounds of Formula I wherein R2 contains a methylene spacer CH 2 can be prepared by reacting a compound of Formula X
  • FM ' is selected from the group consisting of: alkyl; alkylenealkoxy; alkylenecy- cloalkyl; alkylenearyl; alkylenearylenealkyl; alkylenearylenehalogen; alkylenearylene- oxyalkyl, alkylenearylenedialkylamin; and alkyleneheteroaryl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ;
  • R2' is selected from the group consisting of: alkyl; cycloalkyl; alkylenearyl, unsubstituted or substituted, but not substituted by furan or furanyl; alkylenealkoxy; and alkyle- necycloalkyl;
  • the protecting group PG of compounds of Formula XIV is then cleaved off under suitable conditions and the then unprotected compound is reacted with sulfamoylchloride, which is protected with a protecting group PG, preferably tert.-butyloxycarbonyl or benzyl, of Formula Via, or with the reagent of Formula VIb,
  • the protecting group is tert.-butyloxycarbonyl
  • the removal of PG can be achieved under acidic conditions, preferably in the presence of hydrogen chloride.
  • the protecting group is benzyl
  • the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd.
  • the protecting group PG of compounds of Formula XVIII is then cleaved off under suitable, conditions and the then unprotected compound is reacted with sulfamide to give compounds of Formula I, or with a compound of formula III to give compounds of Formula I, or with a compound of formulae Via or VIb to give a compound of formula XIX
  • the protecting group is tert.-butyloxycarbonyl
  • the removal of PG can be achieved under acidic conditions, preferably in the presence of hydrogen chloride.
  • the protecting group is benzyl
  • the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd.
  • compounds of Formula I are prepared by reacting a com- pound of Formula VXIIIa wherein R1 is H
  • R5 is selected from the group consisting of: alkyl; cycloalkyl; aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; and heteroaryl; to give a compound of formula XXI
  • the protecting group PG of compounds of Formula XXI is then cleaved off under suitable conditions and wherein the unprotected compound is then reacted with sulfamide to give compounds of Formula I, or with a compound of formula III to give compounds of Formula I, or with a compound of formulae Via or VIb to give a compound of formula XXII
  • the protecting group is tert.-butyloxycarbonyl
  • the removal of PG can be achieved under acidic con- ditions, preferably in the presence of hydrogen chloride.
  • the protecting group is benzyl
  • the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd.
  • R6 is selected from the group consisting of: alkyl; aryl unsubstiuted or substituted by alkyl, alkoxy, halogen, CF 3 , CN; to give a compound of formula XXIV
  • the protecting group PG of compounds of Formula XXIV is then cleaved off under suitable conditions and wherein the unprotected compound is then reacted with sulfamide to give compounds of Formula I, or with a compound of formula III to give compounds of Formula I, or with a compound of formulae Via or VIb to give a compound of formula XXV
  • the protecting group is tert.-butyloxycarbonyl
  • the removal of PG can be achieved under acidic conditions, preferably in the presence of hydrogen chloride.
  • the protecting group is benzyl
  • the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd.
  • compounds of Formula I can be prepared by reacting a compound of Formula Xl
  • the protecting group PG of compounds of Formula XXVI is then cleaved off under suitable conditions and wherein the unprotected compound is then reacted with sulfamide to give compounds of Formula I, or with a compound of formula III to give compounds of
  • the protecting group is tert.-butyloxycarbonyl
  • the removal of PG can be achieved under acidic conditions, preferably in the presence of hydrogen chloride.
  • the protecting group is benzyl
  • the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd.
  • compounds of Formula I can be prepared by reacting a compound of Formula VIII
  • the protecting group PG of compounds of Formula XXVIII is then cleaved off under suitable conditions to give compounds of Formula I. If the protecting group is tert.- butyloxycarbonyl, then the removal of PG can be achieved under acidic conditions, preferably in the presence of hydrogen chloride. If the protecting group is benzyl, then the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd.
  • compounds of Formula I can be prepared by reacting a compound of Formula Xl
  • the protecting group PG of compounds of Formula XXXII is then cleaved off under suit- able conditions to give compounds of Formula I. If the protecting group is tert.- butyloxycarbonyl, then the removal of PG can be achieved under acidic conditions, preferably in the presence of hydrogen chloride. If the protecting group is benzyl, then the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd.
  • the present invention also relates to a method of treating or preventing glaucoma, epilepsy, bipolar disorders, migraine, neuropathic pain, obesity, type Il diabetes, metabolic syndrome, alcohol dependence, and/or cancer, and its concomitant and/or secondary diseases or conditions in mammals and humans, comprising administering to a subject in need thereof a therapeutically effective amount of a com- pound of general Formula I or its physiologically compatible acid addition salts.
  • Obesity according to the present invention is meant to comprise any increase in body fat that results in increased bodyweight, comprising as a preferred alternative but not limited to the medical definition of obesity.
  • the invention thus also relates to non-medical weight loss, such as cosmetic weight loss and includes improving bodily appearance in general.
  • non-medical weight loss such as cosmetic weight loss and includes improving bodily appearance in general.
  • obesity also is meant to comprise drug induced obesity and/or juvenile obesity.
  • the concomitant diseases of obesity and its concomitant and/or secondary diseases or conditions in mammals and humans according to the invention include in particular the metabolic syndrome and/or syndrome X and cardiovascular diseases.
  • metabolic syndrome as used in this application is meant to cover a complex of clinical pictures which - besides central obesity - mainly comprises hypertension, in particular arterial hypertension; insulin resistance, in particular diabetes mellitus type II; glucose intolerance; dyslipoproteinaemia, in particular as hypertriglyceridaemia, accompanied by dyslipoproteinaemia occurring with lowered HDL-cholesterol, and also hyperuri- caemia, which can lead to gout.
  • the metabolic syndrome is closely linked to insulin resistance. Some people are genetically predisposed to insulin resistance. Acquired factors, such as excess body fat and physical inactivity, can elicit insulin resistance and the metabolic syndrome in these people. Most people with insulin resistance have central obesity.
  • the biologic mechanisms at the molecular level between insulin resistance and metabolic risk factors are not fully understood and appear to be complex.
  • One group of people at risk for developing metabolic syndrome are those with diabetes who have a defect in insulin action and cannot maintain a proper level of glucose in their blood.
  • a third group is heart attack survivors who, unlike hypertensives, have hyperinsulinemia without having abnormal glucose levels.
  • the metabolic syndrome has become increasingly common in higher developed countries like the United States, where it is estimated that about 20-25 percent of US adults have it. There are no well-accepted criteria for diagnosing the metabolic syndrome.
  • the term “syndrome X” is closely related to the term “metabolic syndrome” and usually is supposed to denominate the identical disease or condition. According to information from the American Heart Association, the term “Syndrome X” refers, however, additionally to a heart condition where chest pain and electrocardiographic changes that suggest ischemic heart disease are present, but where there are no angiographic findings of coro- nary disease. Patients with cardiac syndrome X also sometimes have lipid abnormalities.
  • cardiovascular diseases in conjunction with obesity is usually understood to mean coronary heart disease, which can lead to heart failure, cerebrovascular dis- eases, which may for example be accompanied by an increased risk of strokes, and peripheral occlusive arterial disease.
  • the compounds of general Formula I or their physiologically compatible acid addition salts are also expected to be useful in the treatment of diabetic conditions or diseases which are unrelated to obesity.
  • diabetic conditions or diseases comprise e.g. diabetes mellitus type II, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic microangiopathy or diabetic macroangiopathy.
  • gall-bladder diseases such as formation of gallstones, sleep apnoea syndrome, orthopaedic complica- tions such as osteoarthritis and psychosocial disorders.
  • the compounds of general Formula I are further deemed to be useful as anticonvulsants for the prophylaxis or treatment of epilepsy in mammals and humans.
  • test compounds of general Formula I in 96 well microplates were diluted with aqua bidest by using an automatic pipettor (CyBiWell ® ). From the different dilution plates, aliquots of 20 ⁇ l were transferred to the 96 well black assay plates with a pipetting station (Tecan Genesis ® ).
  • potassium phosphate buffer (20 mM, pH 7.4) was added, and as a third step, 20 ⁇ l of enzyme solution (1 ⁇ M human carbonic anhydrase isoenzyme Il from erythrocytes (Sigma-Aldrich), dissolved in potassium phosphate buffer) incubated for 60 min at room temperature and the fluorescence signal (Tecan Ultra ® fluorescence reader; excitation wavelength: 280 nm; emission wavelength: 465 nm) read at the end of the preincubation period (FLU-1 ).
  • % inhibition 100((1 -(FLU-2 Cpd -FLU-2 blank -FLU-1 cpd +FLU-1 b i a n k )/(FLU-2 CO n t r o rFLU-2 blank -
  • test substances of general Formula I listed in Table 1 below showed the IC 50 values given below:
  • the test compound of general Formula I was suspended in 1 % me- thylcellulose in water and 2% (v/v) of Poloxamer 188 (Lutrol F68 ® ) and administered by oral gavage at a dose of 100 mg/kg/day. One half of the dose was administered at 7.00- 9.00 h; the remaining half of the dose was administered between 15.00-15.30 h.
  • the test substances caused a decrease of the animals' 24h food intake to the percentages of food intake when compared to control as given in Table 2 below.
  • the present invention further provides a pharmaceutical composition or medicament comprising a pharmacologically effective quantity of a compound of general Formula I or its physiologically compatible acid addition salts and further comprising conventional pharmaceutically acceptable auxiliaries and/or carriers.
  • Suitable pharmaceutically acceptable auxiliaries and/or carriers are well known in the art and include pharmaceutical grade starch, mannitol, lactose, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose (or other sugar), magnesium carbonate, gelatin, oil, alcohol, detergents, emulsifiers or water (preferably sterile).
  • the composition may be a mixed preparation of a composition or may be a combined preparation for simultaneous, separate or sequential use (including administration).
  • the compounds according to the invention or their physiologically compatible acid addition salts for use in the aforementioned indications may be administered by any convenient method, for example by oral (including by inhalation), parenteral, mucosal (e.g.
  • the compounds can be formulated as liquids or solids, for example solutions, syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable aqueous or non-aqueous liquid carrier(s) for example water, ethanol, glycerine, polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • compositions in the form of a capsule can be prepared using routine encapsulation procedures.
  • powders, granules or pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • suitable pharmaceutical carrier(s) for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • Compositions for oral administration may be designed to protect the active ingredient against degradation as it passes through the alimentary tract, for example by an outer coating of the formulation on a tablet or capsule.
  • compositions consist of a solution or suspension of the compound or physiologically compatible acid addition salts in a sterile aqueous or non-aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous or non-aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • Compositions for nasal or oral administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser, it will contain a pharmaceutically acceptable propellant.
  • the aerosol dosage forms can also take the form of a pump-atomiser.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • Compositions for rectal or vaginal administration are conveniently in the form of suppositories (containing a conventional suppository base such as cocoa butter), pessaries, vaginal tabs, foams or enemas.
  • Compositions suitable for transdermal administration include ointments, gels, patches and injections including powder injections. Conveniently the composition is in unit dose form such as a tablet, capsule or ampoule.
  • the pharmaceutical compositions according to the invention are useful in the prevention and/or treatment of obesity, concomitant and/or secondary diseases of obesity; other medical weight loss and non-medical related weight loss; and/or diabetic conditions or diseases.
  • a pharmaceutical pack or kit comprising one or more container(s) filled with one or more of the ingredients of a pharmaceutical composition of the invention.
  • container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration.
  • composition may be in any form including a tablet, a liquid, a capsule, and a powder or in the form of a food product, e.g. a functional food. In the latter case the food product itself may act as the pharmaceutically acceptable carrier.
  • the compound or composition is preferably administered to a patient in need thereof and in a quantity sufficient to prevent and/or treat the symptoms of the condition, disorder or disease.
  • the administration of a compound or composition has a dosage regime which will ultimately be determined by the attending physician and will take into consideration such factors such as the compound being used, animal type, age, weight, severity of symptoms, method of administration, adverse reactions and/or other contraindications.
  • Specific defined dosage ranges can be determined by standard design clinical trials with patient progress and recovery being fully monitored. Such trials may use an escalating dose design using a low percent- age of the maximum tolerated dose in animals as the starting dose in man.
  • the physiologically acceptable compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 2000 mg, preferably between 30 mg and 1000 mg, e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, pref- erably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the general Formula I or a physiologically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
  • the compound used according to the invention can also be administered to children or juveniles while the individual dosage regimens in these cases will need to be particularly thoroughly adjusted by the physician and will usually comprise lower doses than will be administered to adults.
  • the compounds will be administered for a period of continuous therapy, for example for at least a week, but usually for a longer period of several weeks to several months.
  • the invention also provides a cosmetic method (non-therapeutic) for maintaining a given weight, or for cosmetic weight loss, the method comprising the administration of a compound according to the other aspects of the invention, preferably in combination with a pharmaceutically acceptable carrier or diluent.
  • the compound or composition is preferably administered to a subject in need or in desideratum thereof and in a quantity sufficient to maintain a given weight or for cosmetic weight loss.
  • the compounds of general Formula I and their physiologically compatible acid addition salts may favourably be administered in combination with one or more active agents (as a pharmaceutical combination composition) selected from antidiabetics; antiobesity or appetite-regulating agents; cardiovascular active agents, in particular antihypertensives; diuretics; active agents altering lipid levels, in particular lipid-lowering agents; and active ingredients for the treatment and/or prevention of complications caused by diabetes or associated with diabetes.
  • active agents selected from antidiabetics; antiobesity or appetite-regulating agents; cardiovascular active agents, in particular antihypertensives; diuretics; active agents altering lipid levels, in particular lipid-lowering agents; and active ingredients for the treatment and/or prevention of complications caused by diabetes or associated with diabetes.
  • Suitable antidiabetics comprise e.g. insulins, amylin, derivatives of GLP-1 and GLP- 2 such as, for example, those disclosed in WO 98/08871 and orally active hypoglycemic active ingredients.
  • the orally active hypoglycemic active ingredients preferably comprise sulfonylureas, e.g tolbutamide, glibenclamide, glimepiride, glipizide, gliquidone, gli- soxepide, glibomuride or gliclazide; biguanides, e.g. metformin; meglitinides, e.g.
  • glucosidase inhibitors e.g. alpha- glucosidase inhibitors such as miglitol or acarbose
  • glucagon receptor antagonists GLP- 1 agonists
  • potassium channel openers like diazoxide or those disclosed in WO 97/26265 or WO 99/03861
  • CB-1 (cannabinoid-1 receptor) antagonists/inverse agonists insulin sensitizers like thiazolidinediones, e.g.
  • troglitazone ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097, in particular 5-[[4-[(3,4-dihydro-3-methyl-4- oxo-2-quinazolinylmethoxy]pheny-l]methyl]-2,4-thiazolidinedione; activators of insulin re- ceptor kinase; inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenosis, for example inhibitors of glycogen phosphorylase; and modulators of glucose uptake and glucose excretion.
  • Suitable antiobesity or appetite-regulating agents comprise one or more of a 5-HT (serotonin) transporter inhibitor, a NE (norepinephrine) transporter inhibitor, a CB-1 (can- nabinoid-1 receptor) antagonist/inverse agonist, a ghrelin antibody, a ghrelin antagonist, a H3 (histamine H3) antagonist/inverse agonist, a MCH1 R (melanin concentrating hormone 1 R) antagonist, a MCH2R (melanin concentrating hormone 2R) agonist/antagonist, a NPY1 (neuropeptide Y Y1 ) antagonist, a NPY2 (neuropeptide Y Y2) agonist, a NPY5 (neuropeptide Y Y5) antagonist, leptin, a leptin derivative, an opioid antagonist, an orexin antagonist, a BRS3 (bombesin receptor subtype 3) agonist, a CCK-A
  • Suitable appetite-regulating agents comprise sibutramine or the mono- and bisdemethylated active metabolites of sibutramine; fenfluramine or dexfen- fluramine; mazindol, diethylpropion or phentermine; leptin or modified leptin; dexam- phetamine and amphetamine.
  • Suitable lipase inhibitors comprise orlistat, panclicins, lipase inhibitors isolated from micro organisms such as lipstatin (from Streptomyces toxythcini), ebelactone B (from
  • Suitable CBrcannabinoid antagonists include rimonabant, SLV319, SR147778 and CP-945598.
  • Suitable cardiovascular active agents comprise angiotensin Il receptor antagonists, e.g. abitesartan, benzyllosartan, candesartan, elisartan, embusartan, enoltasosartan, ep- rosartan, fonsartan, forasartan, glycyllosartan, irbesartan, isoteoline, losartan, milfasartan, olmesartan, opomisartan, pratosartan, ripisartan, saprisartan, saralasin, sarmesin, tasosartan, telmisartan, valsartan, zolasartan; Kissei KRH-94, Lusofarmaco LR-B/057, Lusofarmaco LR-B/081 , Lusofarmaco LR B/087, Searle SC-52458, San
  • tolazoline or phenoxybenzamine selective alpha-adrenoceptor antagonists, e.g. doxazosin, prazosin, terazosin or urapidil; beta-adrenoceptor antagonists, e.g.
  • acebutolol alprenolol, atenolol, betaxolol, bisoprolol, bupranolol, carazolol, carteolol, celiprolol, me- pindolol, metipranolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol and timolol; mixed antagonists of alpha- and beta-adrenoceptors, e.g. carvedilol or labetolol; ganglion blockers, e.g.
  • alpha2-adrenoceptor agonists including centrally acting alpha2-adrenoceptor agonists, e.g. clonidine, guanfacine, gua- nabenz methyldopa and moxonidine
  • renin-inhbitors e.g. alskiren
  • ACE-inhbitors e.g.
  • mixed ACE/NEP-inhbitors e.g. omapatrilat
  • ECE-inhbitors e.g. FR- 901533
  • PD-069185 CGS-26303; CGS-34043; CGS
  • Suitable diuretics comprise thiazide diuretics, e.g. althiazide, bemetizide, bendroflu- methiazide, benzylhydrochlorothiazide, benzthiazide, buthiazide, chlorothiazide, cyclothi- azide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, paraflutizide, polythi- azide, teclothiazide, trichlormethiazide; thiazide analogue diuretics, e.g.
  • HMGCoA synthase inhibitor a cholesterol absorption inhibitor, an acyl coenzyme A-cholesterol acyl transferase (ACAT) inhibitor, a cholesteryl ester transfer protein (CETP) inhibitor, a squalene synthetase inhibitor, an anti-oxidant, a PPAR ⁇ agonist, a FXR receptor modulator, a LXR receptor agonist, a lipoprotein synthesis inhibitor, a renin angiotensin system inhibitor, a microsomal triglyceride transport inhibitor, a bile acid reabsorption inhibitor, a PEAR8 agonist, a triglyceride synthesis inhibitor, a transcription modulator, a squalene
  • Further active agents which may be suitable for use in combination with the compound of general Formula I according to the present invention may be selected from the group consisting of CART agonists, H3 antagonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, beta3-agonists, MSH (melanocyte-stimulating hor- mone) agonists, serotonin-reuptake inhibitors, mixed serotonin- and noradrenaline- reuptake inhibitors, 5HT modulators, MAO inhibitors, galanin antagonists, growth hormone, growth hormone-releasing compounds, TRH agonists, modulators of uncoupling proteins 2 or 3, leptin agonists, dopamine agonists (bromocriptine, doprexin), RXR modulators, hCNTF agonists and TR-beta-agonists.
  • Preferred pharmaceutical combination compositions according to the invention comprise combinations of at least one compound of general Formula I and at least one bigua- nide; at least one compound of general Formula I and at least one fibric acid; at least one compound of general Formula I and at least one HMGCoA reductase inhibitor; and at least one compound of general Formula I and at least one insulin sensitizer.
  • Preferred compounds of general Formula I for combination with one or more of the above mentioned active agents are 4-phenyl-piperazine-1 -sulfonic acid amide; 4-(2- chloro-phenyl)-piperazine-1 -sulfonic acid amide; 4-(2-methoxy-phenyl)-piperazine-1 - sulfonic acid amide; 4-pyridin-4-yl-piperazine-1 -sulfonic acid amide; 4-pyrimidin-2-yl- piperazine-1 -sulfonic acid amide; 4-(4-fluoro-phenyl)-piperazine-1 -sulfonic acid amide; 4- (4-chloro-3-trifluoromethyl-phenyl)-piperazine-1 -sulfonic acid amide and/or 4-(3-chloro-5- trifluoromethyl-pyridin-2-yl)-piperazine-1 -sulfonic acid amide.
  • Metformine is the preferred biguanide for combination with at least one compound of general Formula I.
  • Preferred fibric acids for combination with at least one compound of general Formula I are bezafibrate, ciprofibrate, clofibrate, fenofibrate and/or gemfibrozil. Fenofibrate is most preferred.
  • Preferred HMGCoA reductase inhibitors for combination with at least one compound of general Formula I are atorvastatin, berivastatin, cerivastatin, crilvastatin, fluvastatin, glenvastatin, lovastatin, mevastatin, pravastatin, pravastatin, rosuvastatin and/or simvas- tatin or any physiologically compatible salts, solvates, prodrugs or esters thereof. Most preferred are simvastatin, lovastatin and/or pravastatin.
  • Preferred insulin sensitizers for combination with at least one compound of general Formula I are thiazolidinediones, in particular troglitazone, ciglitazone, pioglitazone and/or rosiglitazone. Rosiglitazone and pioglitazone are most preferred.
  • More preferred combinations according to the invention are the combinations of 4- phenyl-piperazine-1 -sulfonic acid amide with metformine; 4-phenyl-piperazine-1 -sulfonic acid amide with fenofibrate; 4-phenyl-piperazine-1 -sulfonic acid amide with simvastatin and 4-phenyl-piperazine-1 -sulfonic acid amide with rosiglitazone.
  • the compounds of general Formula I can be ob- tained and administered together with the different active agents, e.g. in one combined unit dosage form like in one tablet or capsule, i.e. in a physical combination.
  • the compound of general Formula I and the different active agents can be segregated from each other, e.g. by means of different layers in said tablet, e.g. by the use of inert intermediate layers known in the art; or by means of different com- partments in said capsule.
  • the corresponding active agents or their pharmaceutically acceptable salts may also be used in form of their hydrates or include other solvents used for crystallization.
  • a unit dosage form may be a fixed combination.
  • a unit dosage form, in particular a fixed combination of the compound of general Formula I and one or more of the different active agents is a preferred alternative of this embodiment.
  • the compounds of general Formula I and the different active agents can be obtained and administered in two or more separate unit dosage forms, e.g. in two or more tablets or capsules, the tablets or capsules being physically segregated from each other.
  • the two or more separate unit dosage forms can be administered simultaneously or stepwise (separately), e.g. sequentially one after the other in either order.
  • the compounds of general Formula I and the different active agents can be administered in either order at the same time or at different times spread over the day, the optimal dosage regimen usually being determined by prescription of a physician.
  • Example 1 is intended to explain the invention further, without limiting its scope.
  • the hydrochloride acid salt was formed by treating the amine with HCI in isopropanol and subsequent evaporation of the solvent.
  • the melting point was determined to be 240 - 242 0 C.
  • the hydrochloride acid salt was formed by treating the amine with HCI in isopropanol and subsequent evaporation of the solvent.
  • the melting point was determined to be higher than 24O 0 C.
  • the organic layer was then washed 6 times with 0.1 N HCI and the aqueous layer (combined fractions 3, 4 and 5) was made alkaline by the addition of diluted sodium hydroxide solution. After extraction with methyl-tert-butylether, the organic layer was washed with water and with a saturated solution of NaCI in water, dried over sodium sulfate and then concentrated in vacuum. 2.0 g fert-butyl 4-(4-phenylpiperazin-1 - yl)piperidine-1 -carboxylate were isolated.
  • reaction mixture was diluted with dichloromethane, washed 3 times with 0.1 N HCI (60 ml each) and with a saturated solution of NaCI in water. After drying over sodium sulfate the organic layer was concentrated in vacuum to yield 7.2 g of crude product. Purification via flash-chromatography, using a mixture of dichloro- methane/methanol (9:1 ) as eluent gave 6.0 g fert-butyl [(4-oxopiperidin-1 - yl)sulfonyl]carbamate.
  • the crude compound was purified by flash chromatography, eluting with 50% ethyl acetate/heptane, to get the boc-protected sulfama- mide as a white solid (0.185 g, 55% yield).
  • reaction mixture was filtered (0.9 g starting material was isolated) and concentrated in vacuum.
  • the residue was stirred in a mixture of 500 ml_ of MTB-E and 500 ml_ of water for 1 hour, when the product started to precipitate.
  • the solid was separated by filtration, washed with MTB-E and water and then dried in vacuum at 6O 0 C.
  • 41 .4 g fert-butyl ⁇ [4-(pyridin-3-yl ⁇ [4-(trifluoromethyl)phenyl]-carbamoyl ⁇ amino)- piperidin-1 -yl]sulfonyl ⁇ carbamate were isolated having a melting point of 145 0 C (foaming).
  • EA Ethylacetate
  • the active substance, the corn starch and the lactose are processed into a homogeneous pasty mixture using EA.
  • the paste is ground and the resulting granules are placed on a suitable tray and dried at 45 0 C in order to remove the solvent.
  • the dried granules are passed through a crusher and mixed in a mixer with the further following auxiliaries:

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Abstract

La présente invention concerne des N-sulfamoyl-pipéridine amides innovants de formule générale (I) et leurs sels d'addition d'acide physiologiquement acceptables, ainsi que les compositions pharmaceutiques qui les comprennent, leurs procédés de préparation et leur utilisation pour le traitement de l'obésité et de ses maladies concomitantes et/ou secondaires et/ou états apparentés.
PCT/EP2006/069482 2005-12-09 2006-12-08 N-sulfamoyl-piperidine amides innovants pour la prophylaxie ou le traitement de l'obesite et des etats apparentes WO2007065948A1 (fr)

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BRPI0619583-0A BRPI0619583A2 (pt) 2005-12-09 2006-12-08 n-sulfamoil-piperidinamidas para a profilaxia ou tratamento de obesidade e patologias relacionadas
CA002632719A CA2632719A1 (fr) 2005-12-09 2006-12-08 N-sulfamoyl-piperidine amides innovants pour la prophylaxie ou le traitement de l'obesite et des etats apparentes
JP2008543846A JP2009518366A (ja) 2005-12-09 2006-12-08 肥満症及び関連病状の予防又は治療のための、新規なｎ−スルファモイル−ピペリジンアミド
EP06830478A EP1960359A1 (fr) 2005-12-09 2006-12-08 N-sulfamoyl-piperidine amides innovants pour la prophylaxie ou le traitement de l'obesite et des etats apparentes
AU2006323952A AU2006323952A1 (en) 2005-12-09 2006-12-08 Novel N-sulfamoyl-piperidineamides for the prophylaxis or treatment of obesity and related conditions
IL192025A IL192025A0 (en) 2005-12-09 2008-06-10 Novel n-sulfamoyl-piperidineamides for the prophylaxis or treatment of obesity and related conditions
NO20083065A NO20083065L (no) 2005-12-09 2008-07-08 Nye N-sulfamoylpiperidinamider for profylakse eller behandling av overvekt og beslektede tilstander

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WO2008089521A1 (fr) * 2007-01-25 2008-07-31 Verva Pharmaceuticals Ltd Sensibilisateurs a l'iinsuline et procédés de traitement
US8012955B2 (en) 2006-12-28 2011-09-06 Rigel Pharmaceuticals, Inc. N-substituted-heterocycloalkyloxybenzamide compounds and methods of use
EP2424517A1 (fr) * 2009-05-01 2012-03-07 RaQualia Pharma Inc Dérivés d'acide sulfamoyl benzoïque en tant qu'antagonistes de trpm8
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2018237026A1 (fr) * 2017-06-20 2018-12-27 C4 Therapeutics, Inc. Dégrons et dégronimères à liaison n/o pour la dégradation de protéines

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CN106546740B (zh) * 2016-10-27 2019-04-09 暨南大学 Ca2在鼻咽癌中的检测、治疗的应用

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Cited By (17)

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Publication number Priority date Publication date Assignee Title
US8012955B2 (en) 2006-12-28 2011-09-06 Rigel Pharmaceuticals, Inc. N-substituted-heterocycloalkyloxybenzamide compounds and methods of use
US9181220B2 (en) 2006-12-28 2015-11-10 Rigel Pharmaceuticals, Inc. N-substituted-heterocycloalkyloxybenzamide compounds and methods of use
US8697727B2 (en) 2006-12-28 2014-04-15 Rigel Pharmaceuticals, Inc. N-substituted-heterocycloalkyloxybenzamide compounds and methods of use
WO2008089521A1 (fr) * 2007-01-25 2008-07-31 Verva Pharmaceuticals Ltd Sensibilisateurs a l'iinsuline et procédés de traitement
US10172837B2 (en) 2007-01-25 2019-01-08 NAIA Metabolic, Inc. Insulin sensitisers and methods of treatment
US9452148B2 (en) 2007-01-25 2016-09-27 Verva Pharmaceuticals Ltd Insulin sensitisers and methods of treatment
US8455432B2 (en) 2007-01-25 2013-06-04 Verva Pharmaceuticals Ltd. Insulin sensitisers and methods of treatment
EP2424517A4 (fr) * 2009-05-01 2013-01-23 Raqualia Pharma Inc Dérivés d'acide sulfamoyl benzoïque en tant qu'antagonistes de trpm8
EP2424517A1 (fr) * 2009-05-01 2012-03-07 RaQualia Pharma Inc Dérivés d'acide sulfamoyl benzoïque en tant qu'antagonistes de trpm8
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2018237026A1 (fr) * 2017-06-20 2018-12-27 C4 Therapeutics, Inc. Dégrons et dégronimères à liaison n/o pour la dégradation de protéines
US11459335B2 (en) 2017-06-20 2022-10-04 C4 Therapeutics, Inc. N/O-linked Degrons and Degronimers for protein degradation

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BRPI0619583A2 (pt) 2011-10-04
JP2009518366A (ja) 2009-05-07
CA2632719A1 (fr) 2007-06-14
ZA200804077B (en) 2009-10-28

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