OA12941A - Novel bicyclic inhibitors of hormone sensitive lipase. - Google Patents
Novel bicyclic inhibitors of hormone sensitive lipase. Download PDFInfo
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- OA12941A OA12941A OA1200500103A OA1200500103A OA12941A OA 12941 A OA12941 A OA 12941A OA 1200500103 A OA1200500103 A OA 1200500103A OA 1200500103 A OA1200500103 A OA 1200500103A OA 12941 A OA12941 A OA 12941A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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
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- 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
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D249/18—Benzotriazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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
Abstract
The invention relates to benzotriazoles of general formula (I), wherein R1 - R8 have the above mentioned meanings. The invention also relates to a method for the production thereof. Said compounds have an inhibiting effect on the hormone sensitive lipase.
Description
012941 1
Description
Benzotriazoles are already known from a wide range of fields, such as forexample pbotochemistry (US 4,255,510, Kodak) or as orexin antagonists(WO 02/090355, SKB). Also, the synthesis for preparing benzotriazoleshas been described by Katritzky et al. in J. Org'. Chem. 1997, 62, 4155-4158. Also known are carbamates for use as lipase inhibitors such as forexample Shamkant Patkar et al. in Paul Woolley, Steffen B. Petterson(ed), Lipase (1994) 207-227 or WO 03/051842).
Surprisingly, it has now been possible to show that the benzotriazoles ofthe présent invention show activity wfth regard to HSL, hormone sensitivelipase.
The invention relates to benzotriazoles of the formula I,
in which the meanings are: R1 to R8 H, where one of these radicals R2 or R3 may represent:
Br, Cl, CH3, CN, NH2i NO2, CF3i OCH3i phenoxy, benzoyl, CH(OH)-phenyl, S-cyclohexyl, CO-OCH3; or 012941 two substituents of this sériés are: R1 = Cl andR3 = CF3 or R2 = F and R3 = Cl; n an integer from 0, 1 or 2; and one of the substituents R6 or R7 may represent: R6 CH3; R7 CH3, C2H5; CH(CH3)2i C(CH3)3i CF3i Br, Cl, benzyl or CO-OC2H5; or R6 and R7 are both CH3; or the ring may contain a double bond instead of R6 and R7 or R5 and R6 or R6 and R7 may together with the carbon atoms carryingthem represent a benzo-fused ring or else if n = 0 mayrepresent cyclohexanediyl; where in the case of theR6/R7 ring closure this substituent may be optionallysubstituted singly by NH2 or NO2 or singly or doubly byOCH3; and R7 and R8 together cyclopentyl, diazepine or =CH2; where the compounds with R1 to R5 and R8 = H, n = 1 and R6/R7 =benzo-fused and R1, R3-R8 = H , R2 = CH3 and n = 1 shall be excluded.
The invention relates to compounds of the formula I in the form of theirracemates, racemic mixtures and pure enantiomers and to theirdiastereomers and mixtures thereof.
The alkyl radicals may be either straight-chain or branched. Halogen isfluorine, chlorine or bromine, in particular fluorine or chlorine.
Preference is given to benzotriazoles of the formula I in which themeanings are: R1 to R8 H; where one of these radicals R2 or R3 may represent: 012941 3 R2 Br, Cl, CN, NO2, CF3, OCH3, phenoxy, benzoyl, CH(OH)-phenyl, S-cyclohexyl, CO-OCH3; R3 CH3, CN, Br, Cl, NH2, NO2, benzoyl.
Particular preference is giveri to the benzotriazoles of the formula I inwhich the meanings are: R1 to R8 H; where one of these radicals R2 or R3 may represent: R2 Br, Cl, NO2, OCH3, phenoxy, CO-OCH3; R3 NH2; or two substituents of this sériés are: R2 = F and R3 = CI; n an integer from 1 or 2; and one of the substituents R5 or R6 may represent: R6 CH3; R7 CH3, CF3 or Br; or the ring may contain a double bond instead of R6 and R7 or R6 and R7 may together with the carbon atoms carrying them represent abenzo-fused ring which may optionally be substitutedsingly by NH2 or singly or doubly by OCH3; and R7 and R8 together cyclopentyl or n an integer from 0; and R6 and R7 may together with the carbon atoms carrying them represent abenzo-fused ring or cyclohexanediyl; or benzotriazoles of the formula l in which RI to R8 H; where one of these radicals R2 or R3 may represent: R2 Br, CN, CF3, OCH3, phenoxy, benzoyl, CH(OH)- phenyl, S-cyclohexyl; 012941 10 15 4 R3 CN, Br, Cl, NO2, benzoyl; or two substitueras of this sériés are: R1 = Cl and R3 = CF3; n an integer from 1 ; and one of the substituents R5 and R7 may represent: R6 CHa; R7 CH3, C2H5; CH(CH3)2, C(CH3)3i benzyl or CO-OC2H5; or R6 and R7 are both CH3; or the ring may contain a double bond instead of R6 and R7 or R5 and R6 or R6 and R7 may together with the carbon atoms carryingthem represent a benzo-fused ring; where the compounds with R1 ta R5 and R8 = H, n = 1 and R6/R7 =benzo-fused shall be excluded.
Very particular preference is given to the benzotriazoles of the followingstructures:
20 012941 5
N
012941
012941 7
012941
N
O
-N
N
or the benzotriazoles of the following structures:5
ch3
O 012941
H3C
N \\ -N. 0
-N
N
CH,
'N
CH, CH. 0 012941 10
ο CH, 012941
Ο 012941 12
F 012941 13
N
O
•N
Cl 017941 14
Very particular preference following structures: is further given to benzotriazoles the
10 012941 15
CH. CH.
012941
5 and the benzotriazoles of the following structures:
O 012941
Pharmaceutically acceptable salts are, because their solubility in water isgreater than that of the initial or basic' compounds, particularly suitable for 10 medical applications. These salts must hâve a pharmaceutically 012941 18 acceptable anion or cation. Suitable pharmaceutically acceptable acidaddition salts of the compounds of the invention are salts of inorganicacids such as hydrochloric acid, hydrobromic, phosphoric,metaphosphoric, nitric and sulfuric acid, and of organic acids such as, forexample, acetic acid, benzenesulfonic, benzoic, cîtric, ethanesulfonic,fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic,methanesulfonic, succinîc, p-toluenesulfonic and tartane acid. Suitablepharmaceutically acceptable basic salts are ammonium salts, alkali métalsalts (such as sodium and potassium salts), alkaline earth métal salts(such as magnésium and calcium salts), trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine orethylenediamine.
Salts with a pharmaceutically unacceptable anion such as, for example,trifluoroacetate likewise belong within the framework of the invention asuseful intermediates for the préparation or purification of pharmaceuticallyacceptable salts and/or for use in nontherapeutic, for example in vitro,applications.
The term “physiologically functionai dérivative” used herein refers to anyphysiologically tolerated dérivative of a compound of the formula I of theinvention, for example an ester, which on administration to a mammalsuch as, for example, a human is able to form (directly or indirectly) acompound of the formula I or an active métabolite thereof.
Physiologically functionai dérivatives also include prodrugs of thecompounds of the invention, as described, for example, in H. Okada et al.,Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized invivo to a compound of the invention. Thèse prodrugs may themselves beactive or not.
01294 T 19
The compounds of the invention may also exist in various polymorphousforms, for example as amorphous and crystalline polymorphous forms. Ailpolymorphous forms of the compounds of the invention belong within theframework of the invention and are a further aspect of the invention.
Ail references to “compound(s) of formula I” hereinafter refer tocompound(s) of the formula I as described above, and their salts, solvatésand physiologically functional dérivatives as described herein.
The compound(s) of formula (I) may also be administered in combinationwith other active ingrédients.
The amount of a compound of formula I necessary to achieve the desiredbiological effect dépends on a number of factors, for example the spécifiecompound chosen, the intended use, the mode of administration and theclinical condition of the patient. The daily dose is generally in the rangefrom 0.3 mg to 100 mg (typically from 3 mg and 50 mg) per day and perkilogram of bodyweight, for example 3-10 mg/kg/day. An intravenous dosemay be, for example, in the range from 0.3 mg to 1.0 mg/kg, which cansuitably be administered as infusion of 10 ng to 100 ng per kilogram andper minute. Suitable infusion solutions for these purposes may contain, forexample, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter.Single doses may contain, for example, from 1 mg to 10 g of the activeingrédient. Thus, ampoules for injections may contain, for example, from 1mg to 100 mg, and single-dose formulations which can be administeredorally, such as, for example, capsules or tablets, may contain, forexample, from 1.0 to 1000 mg, typically from 10 to 600 mg. For thetherapy of the abovementioned conditions, the compounds of formula Imay be used as the compound itself, but they are preferably in the form ofa pharmaceutical composition with an acceptable carrier. The carrier must,of course, be acceptable in the sense that it is compatible with the otheringrédients of the composition and is not harmful for the patient’s health. 012941 20
The carrier may be a soiid or a liquid or both and is preferably formulatedwith the compound as a single dose, for example as a tablet, which maycontain from 0.05% to 95% by weight of the active ingrédient. Otherpharmaceutically active substances may likewise be présent, includingother compounds of formula I. The pharmaceutical compositions of theinvention can be produced by one of the known pharmaceutical methods,which essentially consist of mixing the ingrédients with pharmacologicallyacceptable carriers and/or excipients.
Pharmaceutical compositions of the invention are those suitable for oral,rectal, topical, pérorai (for example sublingual) and parentéral (forexample subcutaneous, intramuscular, intradermal or intravenous)administration, although the most suitable mode of administration dépendsin each individual case on the nature and severity of the condition to betreated and on the nature of the compound of formula l used in each case.Coated formulations and coated slow-release formulations also belongwithin the framework of the invention. Preference is given to acid- andgastric juice-resistant formulations. Suitable coatings résistant to gastricjuice comprise cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl méthacrylate.
Suitable pharmaceutical compounds for oral administration may be in theform of separate units such as, for example, capsules, wafers, suckabletablets or tablets, each of which contain a defined amount of thecompound of formula I; as powders or granules, as solution or suspensionin an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oilémulsion. These compositions may, as already mentioned, be prepared byany suitable pharmaceutical method which includes a step in which theactive ingrédient and the carrier (which may consist of one or moreadditional ingrédients) are brought into contact. The compositions aregenerally produced by uniform and homogeneous mixing of the active 012941 21 ingrédient with a liquid and/or finely divided solid cam'er, after which theproduct is shaped if necessary. Thus, for example, a tablet can beproduced by compressing or molding a powder or granules of thecompound, where appropriate with one or more additional ingrédients.Compressed tablets can be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one (more)surface-active/dispersing agent in a suitable machine. Molded tablets canbe produced by molding the compound, which is in powder form and ismoistened with an inert liquid diluent, in a suitable machine.
Pharmaceutical compositions which are suitable for pérorai (sublingual)administration comprise suckable tablets which contain a compound offormula I with a flavoring, normally sucrose and gum arabic or tragacanth,and pastilles which comprise the compound in an inert base such asgelatin and glycerol or sucrose and gum arabic.
Pharmaceutical compositions suitable for parentéral administrationcomprise preferably stérile aqueous préparations of a compound offormula I, which are preferably isotonie with the blood of the intendedrécipient. These préparations are preferably administered intravenously,although administration may also take place by subeutaneous,intramuscular or intradermal injection. These préparations can preferablybe produced by mixing the compound with water and making the resultingsolution stérile and isotonie with blood. Injectable compositions of theinvention generally contain from 0.1 to 5% by weight of the activecompound.
Pharmaceutical compositions suitable for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of the formula I with one or more 012941 22 conventional solid carriers, for example cocoa butter, and shaping theresulting mixture.
Pharmaceutical compositions suitable for topical use on the skin arepreferably in the form of ointment, cream, lotion, paste, spray, aérosol oroil. Carriers which can be used are petrolatum, lanolin, polyethyleneglycols, alcohols and combinations of two or more of these substances.The active ingrédient is generally présent in a concentration of from 0.1 to15% by weight of the composition, for example from 0.5 to 2%.
Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal uses can be in the form of single plasters whichare suitable for long-term close contact with the patient’s epidermis. Suchplasters suitably contain the active ingrédient in an aqueous solution whichis buffered where appropriate, dissolved and/or dispersed in an adhesiveor dispersed in a polymer. A suitable active ingrédient concentration isabout 1% to 35%, preferably about 3% to 15%. A particular possibility isfor the active ingrédient to be released by electrotransport oriontophoresis as described, for example, in Pharmaceutical Research,2(6): 318 (1986).
Further active ingrédients suitable for combination products are:ail antidiabetics mentioned in the Rote Liste 2001, chapter 12. They maybe eombined with the compounds of the formula I of the invention inparticular for a synergistic improvement of the effect. Administration of theactive ingrédient combination may take place either by separateadministration of the active ingrédients to the patient or in the form ofcombination products in which a plurality of active ingrédients are présentin one pharmaceutical préparation. Most of the active ingrédients listedbelow are disclosed in the USP Dictionary of USAN and International DrugNames, US Pharmacopeia, Rockville 2001. 012941 23
Antidiabetics include insulin and insulin dérivatives such as, for example,Lantus® (see www.lantus.com) or HMR 1964, fast-acting insulins (seeUS 6,221,633), GLP-1 dérivatives such as, for example, those disclosed inWO 98/08871 of Novo Nordisk A/S, and orally effective hypoglycémieactive ingrédients.
The orally effective hypoglycémie active ingrédients include, preferably,sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones,thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1agonists, potassium channel openers such as, for example, thosedisclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulinsensitizers, inhibitors of liver enzymes involved in the stimulation ofgluconeogenesis and/or glycogenolysis, modulators of glucose uptake,compounds which alter lipid metabolism, such as antihyperlipidemic activeingrédients and antilipidemic active ingrédients, compounds which reducefood intake, PPAR and PXR agonists and active ingrédients which act onthe ATP-dependent potassium channel of the beta cells.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with an HMGCoA reductase inhibitor such assimvastatin, fluvastatin, pravastatin, lovastatin, atorvâstatin, cerivastatin,rosuvastatin.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with a cholestérol absorption inhibitor suchas, for example, ezetimibe, tiqueside, pamaqueside.
In one embodiment of the invention, the compounds of the formula I areadministered- in combination with a PPAR gamma agonist, such as, forexample, rosiglitazone, pioglitazone, JTT-501, Gl 262570. 012941 24
In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR alpha agonist, such as, for example, GW 9578, GW 7647.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with a mixed PPAR alpha/gamma agonist,such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847, or asdescribed in WO 00/64888, WO 00/64876, WO 03/020269.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with a fibrate such as, for example,fenofibrate, clofibrate, bezafibrate.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with an MTP inhibitor such as, for example,implitapide, BMS-201038, R-103757.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with bile acid absorption inhibitor (see, forexample, US 6,245,744 or US 6,221,897), such as, for example, HMR1741.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with a CETP inhibitor, such as, for example,JTT-705.
In one embodiment of the invention, the compounds of the formula I areadministered in combination with a polymeric bile acid adsorbent such as,for example, cholestyramine, colesevelam. 012941 25
In one embodiment of the invention, the eompounds of the formula I are
administered in combination with an LDL receptor inducer (see US 6,342,512), such as, for example, HMR1171, HMR1586.
In one embodiment of the invention, the eompounds of the formula I areadministered in combination with an ACAT inhibitor, such as, for example,avasimibe.
In one embodiment of the invention, the eompounds of the formula I areadministered in combination with an antioxidant, such as, for example, OPC-14117.
In one embodiment of the invention, the eompounds of the formula I areadministered in combination with a lipoprotein lipase inhibitor, such as, forexample, NO-1886.
In one embodiment of the invention, the eompounds of the formula I areadministered in combination with an ATP-citrate lyase inhibitor, such as,for example, SB-204990.
In one embodiment of the invention, the eompounds of the formula I areadministered in combination with a squalene synthetase inhibitor, such as,for example, BMS-188494.
In one embodiment of the invention, the eompounds of the formula I areadministered in combination with a lipoprotein(a) antagonist, such as, forexample, CI-1027 or nicotinic acid.
In one embodiment of the invention, the eompounds of the formula I areadministered in combination with a lipase inhibitor, such as, for example,orlistat. 012941 26
In one embodiment of the invention, the compounds of the formula I areadministered in combination with insulin.
In one embodiment, the compounds of the formula I are administered incombination with a sulfonylürea such as, for example, tolbutamide,glibenclamide, glipizide or glimepiride.
In one embodiment, the compounds of the formula I are administered incombination with a biguanide, such as, for example, metformin.
In one further embodiment, the compounds of the formula I areadministered in combination with a meglitinide, such as, for example,repaglinide.
In one embodiment, the compounds of the formula ! are administered incombination with a thiazolidinedione, such as, for example, troglitazone,ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.
In one embodiment, the compounds of the formula I are administered incombination with an α-glucosidase inhibitor, such as, for example, miglitolor acarbose.
In one embodiment, the compounds of the formula I are administered incombination with an active ingrédient which acts on the ATP-dependentpotassium channel of the beta cells, such as, for example, tolbutamide,glibenclamide, glipizide, glimepiride or repaglinide.
In one embodiment, the compounds of the formula I are administered incombination with more than one of the aforementioned compounds, e.g. in 012941 27 combination with a sulfonylurea and metformin, with a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. 5 In a further embodiment, the compounds of the formula I are administered in combination with CART modulators (see "Cocaine-amphetamine-regulatedtranscript influences energy metabolism, anxiety and gastric emptying inmice" Asakawa, A, et al., M.: Hormone and Metabolic Research (2001),33(9), 554-558), NPY antagonists, e.g. naphthalene-1-sulfonic acid {4-[(4- 10 aminoquinazolin-2-ylamino)methyl]- cyclohexylmethyl}amide hydrochloride (CGP 71683A)), MC4 agonists (e.g. 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7- hexahydropyrazoio[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-amide;(WO 01/91752)), orexin antagonists (e.g. 1 -(2-methylbenzoxazol-6-yl)-3- 15 [1,5]naphthyridin-4-ylurea hydrochloride (SB-334867-A)), H3 agonists (3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic acid sait (WO 00/63208)); TNF agonists, CRFantagonists (e.g. [2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren- 4-yl]dipropylamine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), 20 urocortin agonists, β3 agonists (e.g. 1-(4-chloro-3-methanesulfonylmethyl- phenyl)-2-[2-(2,3-dimethyl-1 H-indol-6-yloxy)ethylamino]-ethanolhydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone)agonists, CCK-A agonists (e.g. {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid 25 trifluoroacetic acid sait (WO 99/15525)), serotonin reuptake inhibitors (e.g. dexfenfluramine), mixed sertoninergic and noradrenergic compounds (e.g.WO 00/71549), 5HT agonists e.g. 1-(3-ethylbenzofuran-7-yl)piperazineoxalic acid sait (WO 01/09111), bombesin agonists, galanin antagonists,growth hormone (e.g. human growth hormone), growth hormone-releasing 30 compounds (6-benzyloxy-1 -(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro- 1 H-isoquinoline-2-carboxylic acid tertiary butyl ester (WO 01/85695)), TRHagonists (see, for example, EP 0 462 884), uncoupling protein 2 or 3 012941 28 modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung,Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonistsas a potential approach to the treatment of obesity. Drugs of the Future(2001), 26(9), 873-881), DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g.WO 00/78312), RXR modulators or TR-β agonists.
In one embodiment of the invention, the other active ingrédient is leptin;see, for example, "Perspectives in the therapeutic use of leptin", Salvador,Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion onPharmacotherapy (2001), 2(10), 1615-1622.
In one embodiment, the other active ingrédient is dexamphatamine oramphétamine.
In one embodiment, the other active ingrédient is fenfluramine ordexfenfluramine.
In another embodiment, the other active ingrédient is sibutramine.
In one embodiment, the other active ingrédient is orlistat.
In one embodiment, the other active ingrédient is mazindol orphentermine.
In one embodiment, the compounds of the formula I are administered incombination with bulking agents, preferably insoluble bulking agents (see,for example, carob/Caromax® (Zunft H J; et al., Carob pulp préparation fortreatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6.) Caromax is a carob-containing product from
Nutrinova, Nutrition Specialties & Food Ingrédients GmbH, IndustrieparkHôchst, 65926 Frankfurt/Main)). Combination with Caromax® is possible inone préparation or by separate administration of compounds of theformula l and Caromax®. Caromax® can in this connection also beadministered in the form of food products such as, for example, in bakeryproducts or muesli bars. 012941 29
It wi!l be appreciated that every suitable combination of the compounds ofthe invention with one or more of the aforementioned compounds andoptionally one or more other pharmacologically active substances isregarded as falling within the protection conferred by the présentinvention. 5 012941 30
JTT-501
The benzotriazoles of the invention of the formula I are prepared bymethods which are known per se, e.g. by acylation of substituted or . 5 unsubstituted benzotriazole 2 with carbamoyl chlorides 3 (method A), or in 012941 31 two stages by reacting benzotriazoles with phosgene and further reactionof the resulting benzotriazolecarbonyl chloride with amines or anilines(method B).
10 2 5
Since acids are usually liberated in these reactions, it is advisable to addbases such as pyridine, triethylamine, sodium hydroxide solution or alkalimétal carbonates to increase the rate. The reactions can be carried out inwide température ranges. It has usually proved to be advantageous tooperate at from 0°C to the boiling point of the solvent used. Examples ofsolvents employed are methylene chloride, THF, DMF, toluene, ethylacetate, nheptane, dioxane, diethyl ether.
The compounds of the invention of the formula I hâve a surprisinginhibitory effect on hormone-sensitive lipase, HSL, an allosteric enzyme inadipocytes, which is inhibited by insulin and is responsible for the 15 012941 32 breakdown of fats in fat cells and thus for the transfer of constituents offats into the bloodstream. Inhibition of this enzyme thus corresponds to aninsulin-like effect of the compounds of the invention, which eventuailyleads to a réduction of free fatty acids in the blood and of blood glucose.They can thus be employed in metabolic dérangements such as, forexample, in non-insulin-dependent diabètes mellitus, in diabetic syndrome,in syndrome X and in direct pancreatic damage.
An inhibition of HSL in beta cells should lead to a direct recovery of insulinrelease (M. Winzell et al., Diabètes, Vol 52, August 2003, 2057-2065). Thecompounds of formula I according to the présent invention can thereforealso be used for insulin release.
The effect of the compounds of the invention of the formula I was tested inthe following enzyme assay System:
Substrate préparation:
Préparation of NAG (NBD monoacyl glyceride) substrate: 6 mg of phosphatidylcholine and 6 mg of phosphatidylinositol are eachdissolved in 1 ml of chloroform. 10 mg of NAG are dissolved in 1 ml ofchloroform. Two parts of phosphatidylinositol solution (e.g. 83.5 μΙ) andone part of phosphatidylcholine solution (e.g. 41.5 μΙ) and 100 μΙ of NAGsolution are pipetted together into plastic scintillation vessels (finalconcentration in the assay: 0.0375 mg of phospholipid/ml;0.05 mg/NAG/ml). The chloroform (225 μΙ total volume) is completelyremoved by passing a stream of N2 over. The dried substrate can bestored at 4°C for up to 3 days, To préparé the phospholipidvesicles/micelles with intercaiated NAG (on the day of the assay), thedried substrate is taken up in 20 ml of assay buffer (25 mM Tris/HCI,pH 7.4; 150 mM NaCI) and [lacuna] two ultrasound treatments with anultrasonic probe (Branson Sonifier Type II, standard microtip): 1sttreatment setting 2, 2 χ 1 min, inbetween 1 min on ice each time; 2nd 012941 33 treatment setting 4, 2 χ 1 min, inbetween 1 min on ice each time. Duringthis procedure, the color of the substrate solution changes from yellow(extinction maximum 481 nm) to red (extinction maximum 550 nm) owingto intercalation of NAG between the phospholipid molécules in thevesicles/micelles. Before use as substrate (within the next 2 h), thesolution is incubated on ice for a further 15 min.
Indirect NAG assay:
The assay is carried out in 1.5 ml Eppendorf vessels or 96-well plates at30°C for 60 min. To find HSL inhibitors, 10 μΙ of the test substance areintroduced into assay buffer (25 mM Tris/HCI, pH 7.4; 150 mM NaCI) inthe presence of 16.6% DMSO. 180 μΙ of the substrate solution (20 pg/mlphosphatidylcholine, 10 pg/ml phosphatidylinositol, 50 pg/ml NAG in assaybuffer) are added. After preincubation at 30°C for 15 min, 20 μ! of theenzyme solution in assay buffer (diluted 1- to 4-fold are pipetted in, andthe extinction at 480 nm is immediately measured in a cuvette photometer(0.5 ml cuvette) or microtiter plate reader. After incubation at 30°C for60 min, the extinction is measured again. The increase in extinction at480 nm is a measure of the enzymic activity. Under standard conditions,20 pg of partially purified HSL lead to a change of 0.4 = 4000 arb. units inextinction.
Direct NAG assay:
As alternative to measurement of the change in extinction of the substratesolution, the products of the HSL reaction are investigated by phaseseparation/thin-layer chromatography. For this purpose, 1.3 ml ofmethanol/chloroform/heptane (10:9:7) and then 0.4 ml of 0.1 M NaOH areadded to the incubation mixture (200 μ! total volume, see indirect NAGassay) in 2 ml Eppendorf vessels. After vigorous mixing (10 sec), phaseséparation is initiated by centrifugation (800xg, 20 min, room 012941 34 température). Equivalent volumes (e.g. 0.4 ml) are taken from theaqueous upper phase, and the extinction at 4S1 nm is determined in aphotometer. For thin-layer chromatography, the aqueous phase is dried(SpeedVac) and then taken up in 50 μΙ of tetrahydrofuran. 5 μΙ samplesare loaded onto silica gel Si-60 plates (Merck). The chromatography iscarried out with 78 ml of diethyl ether/22 ml of petroleum ether/1 ml ofglacial acetic acid as mobile phase. The amount of liberated fluorescentNBD-fatty acid is determined by Phosphorimaging (Molecular Dynamics,Storm 840 and ImageQuant Software) at an excitation wavelength of460 nm and émission wavelength of 540-560 nm.
Enzyme préparation:
Préparation of the partially purified HSL:
Isolated rat fat cells are obtained from epididymal adipose tissue fromuntreated male rats (Wistar, 220-250 g) by collagénase treatment inaccordance with published methods (e.g. S. Nilsson et al., Anal. Biochem.158, 1986, 399-407; G. Fredrikson et al., J. Biol. Chem. 256, 1981,6311-6320; H. Tomquist étal., J. Biol. Chem. 251, 1976, 813-819). The fatcells from 10 rats are washed three times by flotation with 50 ml ofhomogenization buffer (25 ml Tris/HCI, pH 7.4, 0.25 M sucrose, 1 mMETDA, 1 mM DTT, 10 pg/ml leupeptin, 10 pg/ml antipain, 20 pg/mlpepstatin) each time and finally taken up in 10 ml of homogenizationbuffer. The fat· cells are homogenized in a Teflon-in-g!ass homogenizer(Braun-Melsungen) by 10 strokes at 1500 rpm and 15°C. The homogenateis centrifuged (Sorvall SM24 tubes, 5000 rpm, 10 min, 4°C). Thesubnatant between the layer of fat at the top and the pellet is removed andthe centrifugation is repeated. The subnatant resulting therefrom iscentrifuged again (Sorvall SM24 tubes, 20 000 rpm, 45 min, 4°C). Thesubnatant is removed, and 1 g of heparin-Sepharose (Pharmacia-Biotech,CL-6B, washed 5x with 25 mM Tris/HCI, pH 7.4, 150 mM NaCI) is added.After incubation at 4°C for 60 min (shaking at intervals of 15 min), the 012941 35 mixture is centrifuged (Sorvall SM24 tubes, 3000 rpm, 10 min, 4°C). Thesupernatant is adjusted to pH 5.2 by adding glacial acetic acid and isincubated at 4°C for 30 min. The précipitâtes are coilected bycentrifugation (Sorvall SS34, 12 000 rpm, 10 min, 4°C) and suspended in2.5 ml of 20 mM Tris/HCI, pH 7.0, 1 mM EDTA, 65 mM NaCI, 13%sucrose, 1 mM DTT, 10pg/ml leupeptin/pepstatin/antipain. Thesuspension is dialyzed against 25 mM Tris/HCI, pH 7.4, 50% glycerol,1 mM DTT, 10 pg/ml leupeptin, pepstatin, antipain at 4°C overnight andthen loaded onto a hydroxiapatite column (0.1 g per 1 ml of suspension,equilibrated with 10 mM potassium phosphate, pH 7.0, 30% glycerol,1 mM DTT). The column is washed with four volumes of équilibrationbuffer at a flow rate of 20 to 30 ml/h. The HSL is eluted with one volume oféquilibration buffer containing 0.5 M potassium phosphate and thendialyzed (see above) and concentrated 5- to 10-fold by ultrafiltration(Amicon Diaflo PM 10 Filter) at 4°C. The partially purified HSL can bestored at -70°C for 4 to 6 weeks.
Assay:
To préparé the substrate, 25-50 pCi of [3H]trioleôylglycerol (in toluene), 6.8 pmol of unlabeled trioleoylglycerol and 0.6 mg of phospholipids(phosphatidylcholine/phosphatidylinositol 3:1 w/v) are mixed, dried overN2 and then taken up in 2 ml of 0.1 M KPi (pH 7.0) by ultrasoundtreatment (Branson 250, tnicrotip, setting 1-2, 2 χ 1 min with an interval of1 min). After addition of 1 ml of KPi and renewed ultrasound treatment(4 χ 30 sec on ice with intervals of 30 sec), 1 ml of 20% BSA (in KPi) isadded (final concentration of trioleoylglycerol 1.7 mM). For the reaction,100 μΙ of substrate solution are pipetted into 100 μΙ of HSL solution (HSLprepared as above, diluted in 20 mM KPi, pH 7.0, 1 mM EDTA, 1 mMDTT, 0.02% BSA, 20 pg/ml pepstatin, 10 pg/ml leupeptin) and incubatedat 37°C for 30 min. Addition of 3.25 ml of methanol/chloroform/heptane(10:9:7) and of 1.05 ml of 0.1 M K2CO3, 0.1 M boric acid (pH 10.5) is 012941 36 followed by thorough mixing and finaliy centrifugation (800 χ g, 20 min).After phase séparation, one équivalent of the upper phase (1 ml) isremoved and the radioactivity is determined by liquid scintillationmeasurement.
Evaluation:
Substances are normally tested in four independent mixtures. Theinhibition of the HSL enzymatic activity by a test substance is determinedby comparing with an uninhibited control reaction. The IC50 is calculatedfrom an inhibition plot with min. 10 concentrations of the test substance.The GRAPHIT, Elsevier-BIOSOFT software package is used to analyzethe data.
The compounds of Examples 1 to 55 showed inhibitions in the IC50 range0.04-5 μΜ in this assay.
The following example describe the invention in more detail withoutrestricting it.
Exemples:
The example which follow were prepared according to the methodsdescribed in what follows:
Method A:
To a solution of 2 mmol of 1 H-benzotriazole in pyridine (5 ml) anddichloromethane (10 ml) is added a solution of the correspondingcarbamoyl chloride (1 mmol) in dichloromethane (10 ml). The reactionmixture is stirred at RT for 16 h, then admixed with EtOAc (15 ml), andfiltered through silica gel before the filtrate is concentrated. The product ispurified by préparative HPLC and freeze dried. 012941 37 10 15
Method B Examples: a) Préparation of a benzotriazole-1-carbonyl chloride solution A solution of benzotriazole (6 g, 50.4 mmol) in THF (100 ml) is addeddropwise to a phosgene solution (20% in toluene; 90 ml; 182 mmol) whilecooling in ice. The ice bath is removed and the solution is then stirred atRT for a further 2 h. The solvent is distilled out and the residue is taken upin THF to give a total volume of 25 ml. b) Reaction of the benzotriazolecarbonyl chlorides to give thecorresponding benzotriazole-1-carboxamides and anilides
In each case 10 amines or anilines (2 mmol) are introduced into THF(1 ml), and pyridine (0.2 ml) is added. The mixtures are incubated withbenzotriazole-1-carbonyl chloride solution (1 ml, ~ 2 mmol) and stirred atRT for 16 h. The mixtures are then diluted with ethyl acetate (5 ml) andfiltered through silica gel, and the filtrate is evaporated to dryness invacuo. The crude products are purified by flash chromatography.
Example 1 :
Methyl 3-(4-methylpiperidine-1-carbonyl)-3H-benzotriazole-5-carboxylate 20
M+H+: 303.14 012941 38
Example 2: (8-Az:a-spiro[4.5]dec-8-yl)-benzotria2ol-1-ylmethanone
M+H+: 285.16
Example 3:
Benzotriazol-1-yl-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-10 methanone
M+H+: 339.13 15 012941
Example 4: (5-Phenoxybenzotriazol-1-yl)-(4-trifluoromethylpiperidin-1-yl)methanone
M+H+: 391.13
Example 5: (6-Chloro-5-fluorobenzotriazol-1-yl)-(4-methylpiperidin-1-yl)methanone 10
M+H+:297.74 15 Example 6:
Benzotriazoi-1 -yl-(4-bromopiperidin-1 -yl)methanone
M+H+: 310.3 20 012941 40
Example 7:
Benzotriazol-1 -yl-(4-trifluoromethylpiperidin-1 -yl)methanone
F M+H+: 299.18
Example 8:
Benzotriazol-1-yl-(1,3-dihydroisoindol-2-yl)methanone 10
15 M+H+: 265.0
Example 9:
Methyl 1 -(3,6-dihydro-2H-pyridine-1 -carbonyl)-1 H-benzotriazole- 5-carboxylate
M+H+: 287.04 20 012941 41
Example 10: (3,6-Dihydro-2H-pyridin-1-yl)-(5-nitrobenzotriazol-1-yl)methanone
M+Na: 296.21
Example 11: (3,4-Dihydro-1H-isoquinolin-2-yl)-(5-nitrobenzotriazol-1-yl)methanone
M+H+: 324.10 15 Example 12: (5-Bromobenzotriazol-1-yl)-(3,6-dihydro-2H-pyridin-1-yl)rnethanone
20 M+H+: 306.98 012941
Example 13: (5-Bromobenzotriazol-1-y.l)-(3-trifluoromethylpiperidiri-1-yl)methanone 42
M+H+: 377.30
Example 14: (5-Bromobenzotriazol-1-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)methanone 10
15 M+H+: 357.04
Example 15:
Benzotriazol-1-yl-(octahydroisoindol-2-yI)methanone
M+H+: 271.15 20 012941
Example 16: (7-Amino-3,4-dihydro-1H-isoquinolin-2-yl)benzotriazol-1-ylmethanone
M+H+: 294.0
Example 17: (3,4-Dihydro-1H-isoquinolin-2-yl)-(5-methoxybenzotriazol-1-yl)methanone
M+H+: 309.04 15 Example 18: (5-Methoxybenzotriazol-1-yl)-(3-methylpiperidin-1-yl)methanone
20 M+H+: 275.5 012941 44
Example 19: (6-Aminobenzotriazol-1-yl)-(4-methylpiperidin-1-yl)methanone
10 M+H+: 260.1
Example 20: (5-ChIorobenzotriazol-1 -yl)-(4-methylpiperidin-1 -yl)methanone
15
Example 21:
Benzotriazol-1-yl-(1,2,6-triaza-spiro[2.5]oct-1-en-6-yl)methanone
M+Na+: 279.19 20 45
Example 22:
Benzotriazol-1 -yl-(4-ethylpsperidin-1 -yl)methanone
Example 23: (4-Methylpipendin-1-yl)-(6-nitrobenzotriazol-1-yl)methanone
M+H+: 290.4
Example 24: 15 Ethyl 1-(benzotriazole-1-carbonyl)piperidine-4-carboxylate
M+H+: 303.13
Example 25:
Benzotriazol-1-yl-(4-methylpiperidin-1-yl)methanone
46 M+H+: 245.0
Example 26: 3-(4-Methylpiperidine-1-carbonyl)-3H-benzotriazole-5-carbonitrile 10
15 M+H+: 270.12
Example 27:
Benzotriazol-1-yl-(3,4-dihydro-1H-isoquinolin-1-yl)methanone 2.0
012941 47
Example 28:
Benzotriazol-1-yl-(3,4-dihydro-2H-quinolin-1-yl)methanone
M+H+: 279.2
Example 29: (6-Methylbenzotriazol-1 -y!)-pyrrol idin-1 -ylmethanone
M+H+: 231.11 15 Example 30:
Benzotriazo!-1-yl-(3-methylpiperidin-1-yl)methanone
20 012941
Exampie 31 :
Benzotriazol-1-yl-(3,4-dimethylpiperidin-1-yl)methanone 48
M+H+: 259.14
Example 32: [1 -(4-Methylpiperidine-1 -carbonyl)-1 H-benzotriazol-5-yl]phenylmethanone 10
M+H+: 349.15
Example 33: (4-Methylpiperidin-1-yl)-(5-trifluoromethylbenzotriazol-1-yl)methanone 15
F
M+H+: 313.5 012941 49
Example 34: (6-Bromobenzotriazol-1-yl)-(4-methylpiperidin-1-yl)methanone
M+H+: 324.0
Example 35:
Benzotriazol-1-yl-(4-tert-butylpiperidin-1-yl)methanone 10
N
M+H+: 287.17 15
Example 36: [5-(Hydroxyphenylmethyl)benzotriazol-1-yl]-(4-methylpiperidin-1-yl)- methanone
CH 3 M+H+: 350.17 012941
Example 37: (4-Methylpiperidin-1-yl)-(5-phenoxybenzotriazol-1-yl)methanone
M+H+: 337.3
Example 38: (5-Cyclohexylsulfanylbenzotriazol-1-yl)-(4-methylpiperidin-1-yl)methanone 10
15 M+H+: 359.17
Example 39:
Benzotriazol-1 -yl-(4-isopropyipiperidin-1 -yi)methanone 20
M+H+: 273.3 012941 51
Example 40: (6-Chlorobenzotriazol-1-yl)-(4-methylpiperidin-1-yl)methanone
M+H+: 279.5
Example 41:
Benzotriazol-1-yl-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone 10
15 M+H+: 309.3
Example 42:
Benzotriazol-1 -yl-(4-benzylpiperidin-1 -yl)methanor.e
M+H+: 321.1 20 012941 52
Example 43: (5-Bromobenzotriazol-1-yl)-(3-methylpiperidin-1-yl)methanone
5 M+H+: 325.31
Example 44: 1-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-1H-benzotriazole-5-carbonitrile
Example 45: (4-Chloro-6-trifluoromethylbenzotriazol-1-yl)-(3,4-dihydro-1H-isoquinolin-15 2-yl)methanone
M+H+: 381.06
V 53
Example 46: 1 -(3,4-Dihydro-2H-quinoline-1 -carbonyl)-1 H-benzotriazole-5-carbonitrile
Example 47: (4-Chloro-6-trifluoromethylbenzotriazol-1-yl)-(3,6-dihydro-2H-pyridin-1-yî)- methanone
Example 48: 15 Benzotriazol-1-yl-(7-methoxy-3,4-dihydro-1 H-isoquinolin-2-yl)methanone
M+H+: 309.1 012941 54
Example 49: (5-Methoxybenzotriazol-1-yl)-(4-methylpiperidin-1-yl)methanone
Example 50: (3,4-Dihydro-1 H-isoquinolin-2-yl)-(6-nitrobenzotriazol-1-yl)methanone 10
M+H+: 324.3 15
Example 51: (6-Benzoylbenzotriazol-1-yl)-(4-methy!piperidin-1-yl)methanone 20
012941 55
Example 52:
Benzotriazol-1-yl-(7-nitro-3,4-dihydro-1H-isoquinolin-2-yl)methanone
M+H+: 324.1
Example 53:
Azepan-1 -ylbenzotriazol-1 -ylmethanone 10
N
M+H+: 245.3
Example 54:
Benzotriazol-1-yl-(4-chloropiperidin-1-yl)methanone
Cl 15 012941 56
Example 55:
BenzotriazoI-1-yl-(3,6-dihydro-2H-pyridin-1-yl)methanone
M+H+: 229.2. 5
Claims (11)
- 012941 57 Claims:1. A benzotriazole of the formula I,in which the meanings are: R1 to R8 H, where one of these radicals R2 or R3 may represent: Br, Cl, CH3, CN, NH2i NO2, CF3, OCH3, phenoxy, benzoyl, CH(OH)-phenyl, S-cyclohexyl, CO-OCH3; or two substituents of this sériés are: R1 = Cl and R3 = CF3 or R2 = F and R3 = CI; n an integer from 0,1 or 2; and one of the substituents R5 or R7 may represent: R6 CH3; R7 CH3, C2H5; CH(CH3)2, C(CH3)3, CF3i Br, Cl, benzyl or CO-OC2H5; or R6 and R7 are both CH3; or the ring may contain a double bond instead of R6 and R7 or R5 and R6 or R6 and R7 may together with the carbon atoms carryingthem represent a benzo-fused ring or else. if n = 0 mayrepresent cyclohexanediyl; where in the case of theR6/R7 ring closure this substituent may be optionally 012941 58 substituted singly by NH2 or NO2 or singly or doubly byOCH3; and R7 and R8 together cyclopentyl, diazepine or =CH2; where the compounds with R1 to R5 and R8 = H, n = 1 and R6/R7 =benzo-fused and R1, R3-R8 = H , R2 = CH3 and n = 1 shall be excluded.
- 2. A benzotriazole of the formula I as claimed in claim 1,in which the meanings are: R1 to R8 H; where one of these radicals R2 or R3 may represent: R2 Br, Cl, CN, NO2, CF3, OCH3, phenoxy, benzoyl, CH(OH)-phenyl, S-cyclohexyl, CO-OCH3; R3 CH3, CN, Br, Cl, NH2, NO2, benzoyl.
- 3. A benzotriazole of the formula l as claimed in claim 1 or 2, in whichthe meanings are: R1 to R8 H; where one of these radicals R2 or R3 may represent: R2 Br, Cl, NO2, OCH3i phenoxy, CO-OCH3; R3 NH2; or two substituents of this sériés are: R2 = F and R3 = Cl; n an integer from 1 or 2; and one of the substituents R5 or R6 may represent: 012941 59 R6 CH3; R7 CH3, CF3 or Br; or the ring may contain a double bond instead of R6 and R7 or R6 and R7 may together with the carbon atoms carrying them represent a 5 benzo-fused ring which may optionally be substituted singly by NH2 or singly or doubly by OCH3; and R7 and R8 together cyclopentyl orn an integer from 0; and R6 and R7 may together with the carbon atoms carrying them represent a 10 benzo-fused ring or cyclohexanediyl.
- 4. A benzotriazole of the formula I as claimed in daims 1 to 2, wherein R1 to R8 H; 15 where one of these radicals R2 or R3 may represent: R2 Br, CN, CF3, OCH3, phenoxy, benzoyl, CH(OH)- phenyl, S-cyclohexyl; R3 CN, Br, Cl, NO2, benzoyl; or two substituents of this sériés are: 20 R1 = Cl and R3 = CF3; n an integer from 1 ; and one of the substituents R6 and R7 may represent: R6 CH3; R7 CH3, C2H5; CH(CH3)2, C(CH3)3, benzyl or CO-OC2H5; 25 or R6 and R7 are both CH3; or the ring may contain a double bond instead of R6 and R7 or R5 and R6 or R6 and R7 may together with the carbon atoms carrying them represent a benzo-fused ring; 30 where the compounds with R1 to R5 and R8 = H, n = 1 and R6/R7 = benzo-fused shall be excluded. 012941 60
- 5. A benzotriazole of the following structure:CKO CH N 3 012941012941 62Ο 012941 10CH 3CH 3//""N
- 6. A benzotriazole of the following structure: 012941 64 N W-n'012941 655 0 1294 1 NCH 012941 Z^%v-N.012941 68/ NN 5 Ο 012941 695 7. A benzotriazole of the following structure as claimed in claim 6:N N II O O CH 3 012941 70 NI NCH3HX O 012941 71012941 72
- 8. A benzotriazole of the following structure as claimed in daim 7:10 CH3 012941 735
- 9. A process for preparing the compounds of the formula I as claimedin daims 1 to 8, which comprises a) acyiating benzotriazole 2 with carbamoyl chlorides 3, or b) initially reacting benzotriazoles 2 with phosgene and then 10 reacting the resulting benzotriazolecarbonyl chlorides 5 with amines or anilines to give the compounds of the formula l,in which the substituents hâve the abovementionéd meanings.012941 742 5
- 10. A benzotriazole of the formula I,in which the meanings are: R1 to R8 H; where one of these radicals R2 or R3 may represent: Br, Cl, CH3, CN, NH2, NO2> CF3, OCH3, phenoxy, benzoyl, CH(OH)- 10 phenyl, S-cyclohexyl, CO-OCH3; or two substituents of this sériés are: R1 = Cl and R3 = CF3 orR2 = F and R3 = Cl; 15 n an integerfrom 0, 1 or 2; and one of the substituents R6 or R7 may represent: R6 CH3; R7 CH3, C2H5; CH(CH3)2, C(CH3)3, CF3, Br, Cl, benzyl or CO-OC2H5; or 012941 75 R6 and R7are both CH3; or the ring may contain a double bond instead of R6 and R7 or R5 and R6 or R5 and R7 may together with the carbon atoms carrying them represent a benzo-fused ring or else if n = 0 may 5 represent cyclohexanediyl; where in the case of the R6/R7 ring closure this substituent may be optionallysubstituted singly by NH2 or NO2 or singly or doubly byOCH3; and R7 and R8 together cyclopentyl, diazepine or =CH2; 10 for use in a médicament.
- 11. A benzotriazole of the formula I as claimed in claim 10 for use in amédicament with an inhibitory effect on hormone-sensitive lipase, HSL. 15 12. A benzotriazole of the formula I as claimed in claim 10 for use in a médicament for the treatment of non-insulin-dependent diabètes mellitus,of diabetic syndrome or syndrome X.
- 13. A médicament for the treatment of non-insulin-dependent diabètes 20 mellitus or of diabetic syndrome comprising at least one benzotriazole of the formula I as claimed in claim 10.
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| DE10247680A DE10247680B4 (en) | 2002-10-12 | 2002-10-12 | New bicyclic inhibitors of the hormone sensitive lipase |
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| TN (1) | TNSN05105A1 (en) |
| TW (1) | TWI313265B (en) |
| UA (1) | UA79994C2 (en) |
| UY (1) | UY28015A1 (en) |
| WO (1) | WO2004035550A1 (en) |
| ZA (1) | ZA200501757B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102005002130A1 (en) | 2005-01-17 | 2006-07-27 | Sanofi-Aventis Deutschland Gmbh | New substituted aminomethylene sulfonamides useful as hormone sensitive lipase inhibitors in medicaments for treatment and/or prevention of non-insulin dependent diabetes mellitus, diabetic syndrome or obesity |
| DE102005026808A1 (en) | 2005-06-09 | 2006-12-14 | Sanofi-Aventis Deutschland Gmbh | Benzooxazol-2-one derivatives as inhibitors of lipases and phospholipases |
| DE102005026762A1 (en) | 2005-06-09 | 2006-12-21 | Sanofi-Aventis Deutschland Gmbh | Azolopyridin-2-one derivatives as inhibitors of lipases and phospholipases |
| DE102005026809A1 (en) | 2005-06-09 | 2006-12-14 | Sanofi-Aventis Deutschland Gmbh | Benzothiazol-2-one derivatives as inhibitors of lipases and phospholipases |
| DE102005048897A1 (en) | 2005-10-12 | 2007-04-19 | Sanofi-Aventis Deutschland Gmbh | Diacylindazole derivatives as inhibitors of lipases and phospholipases |
| DE102005049953A1 (en) | 2005-10-19 | 2007-04-26 | Sanofi-Aventis Deutschland Gmbh | Carbamoylbenzotriazole derivatives as inhibitors of lipases and phospholipases |
| DE102005049954A1 (en) * | 2005-10-19 | 2007-05-31 | Sanofi-Aventis Deutschland Gmbh | Triazolopyridine derivatives as inhibitors of lipases and phospholipases |
| FR2915197B1 (en) * | 2007-04-18 | 2009-06-12 | Sanofi Aventis Sa | TRIAZOLOPYRIDINE CARBOXAMIDE DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF. |
| FR2915198B1 (en) | 2007-04-18 | 2009-12-18 | Sanofi Aventis | TRIAZOLOPYRIDINE CARBOXAMIDE AND TRIAZOLOPYRIDINE -CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE. |
| FR2915199B1 (en) * | 2007-04-18 | 2010-01-22 | Sanofi Aventis | TRIAZOLOPYRIDINE-CARBOXAMIDE AND TRIAZOLOPYRIMIDINE-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE. |
| US8470841B2 (en) | 2008-07-09 | 2013-06-25 | Sanofi | Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof |
| CA2747784C (en) * | 2008-12-24 | 2018-07-31 | Bial - Portela & Ca, S.A. | Imidazole compounds for use as enzyme inhibitors |
| US8329904B2 (en) | 2009-05-12 | 2012-12-11 | Hoffmann-La Roche Inc. | Azacyclic derivatives |
| US8440710B2 (en) | 2009-10-15 | 2013-05-14 | Hoffmann-La Roche Inc. | HSL inhibitors useful in the treatment of diabetes |
| US8097634B2 (en) | 2010-04-15 | 2012-01-17 | Hoffmann-La Roche Inc. | Azacyclic derivatives |
| US8450350B2 (en) * | 2010-05-05 | 2013-05-28 | Infinity Pharmaceuticals, Inc. | Triazoles as inhibitors of fatty acid synthase |
| US8722721B2 (en) * | 2011-03-16 | 2014-05-13 | Hoffmann-La Roche Inc. | SEC-hydroxycyclohexyl derivatives |
| US8703807B2 (en) * | 2011-03-17 | 2014-04-22 | Hoffmann-La Roche Inc. | Azaspirodecanone compounds |
| US8809384B2 (en) * | 2011-03-25 | 2014-08-19 | Hoffmann-La Roche Inc. | Azaspirodecanone compounds |
| UA119247C2 (en) | 2013-09-06 | 2019-05-27 | РОЙВЕНТ САЙЕНСИЗ ҐмбГ | Spirocyclic compounds as tryptophan hydroxylase inhibitors |
| GB201321740D0 (en) * | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
| WO2015089137A1 (en) | 2013-12-11 | 2015-06-18 | Karos Pharmaceuticals, Inc. | Acylguanidines as tryptophan hydroxylase inhibitors |
| WO2016109501A1 (en) | 2014-12-30 | 2016-07-07 | Karos Pharmaceuticals, Inc. | Amide compounds as tryptophan hydroxylase inhibitors |
| US9611201B2 (en) | 2015-03-05 | 2017-04-04 | Karos Pharmaceuticals, Inc. | Processes for preparing (R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol and 1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone |
| KR20210102887A (en) | 2018-11-14 | 2021-08-20 | 알타반트 사이언시스 게엠베하 | Crystalline spirocyclic compound inhibitors of tryptophan hydroxylase 1 (TPH1) for treating diseases or disorders associated with peripheral serotonin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1124716A (en) * | 1978-10-20 | 1982-06-01 | Michael J. Simons | Blocked benzotriazole compounds as development restrainer precursors |
| DE19942354A1 (en) * | 1999-09-04 | 2001-03-08 | Aventis Pharma Gmbh | Substituted 3-phenyl-5-alkoxi-1,3,4-oxdiazol-2-one, their manufacture and use in medicinal products |
| HUP0400048A3 (en) * | 2001-05-05 | 2008-10-28 | Smithkline Beecham Plc | N-aroyl cyclic amines and pharmaceutical compositions containing them |
| BR0214967A (en) * | 2001-12-14 | 2005-05-10 | Novo Nordisk As | Compound, pharmaceutically acceptable salt, process for preparing a compound, pharmaceutical composition, use of a compound and method of treating a patient disorder |
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