ZA200501757B - Novel bicyclic inhibitors of hormone sensitive lipase. - Google Patents

Novel bicyclic inhibitors of hormone sensitive lipase. Download PDF

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Publication number
ZA200501757B
ZA200501757B ZA200501757A ZA200501757A ZA200501757B ZA 200501757 B ZA200501757 B ZA 200501757B ZA 200501757 A ZA200501757 A ZA 200501757A ZA 200501757 A ZA200501757 A ZA 200501757A ZA 200501757 B ZA200501757 B ZA 200501757B
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South Africa
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represent
benzotriazole
formula
substituents
benzo
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ZA200501757A
Inventor
Stefan Petry
Karl-Heinz Baringhaus
Norbert Tennagels
Guenter Mueller
Hubert Heuer
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Aventis Pharma Gmbh
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Publication of ZA200501757B publication Critical patent/ZA200501757B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • 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
    • 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
    • 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

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
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  • Urology & Nephrology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Description

“» a ‘w
Description
Novel bicyclic inhibitors of hormone sensitive lipase
Benzotriazoles are already known from a wide range of fields, such as for example photochemistry (US 4,255,510, Kodak) or as orexin antagonists (WO 02/090355, SKB). Also, the synthesis for preparing benzotriazoles has 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 for example 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 of the present invention show activity with regard to HSL, hormone sensitive lipase.
The invention relates to benzotriazoles of the formula |,
R1
R2 N \ “N
R3 :
I~ A Rs
R4 N
R5
R6 in which the meanings are:
R1 to R8 H, where one of these radicals R2 or R3 may represent:
Br, Cl, CHs, CN, NHz, NO; CF; OCHs, phenoxy, benzoyl, CH(OH)- phenyl, S-cyclohexyl, CO-OCHj; or
- @ two substituents of this series are:
R1 =Cland R3 = CF; 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 CHa;
R7 CH3;, CzHs; CH(CH3)2, C(CHa3)s, CFs, Br, Cl, benzyl or
CO-OC,Hs; or
R6 and RY are both CH5; 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 or else if n = 0 may represent cyclohexanediyl; where in the case of the
R6/R7 ring closure this substituent may be optionally substituted singly by NH, or NO; or singly or doubly by
OCHs3; and
R7 and R8 together cyclopentyl, diazepine or =CHj; where the compounds with R1 to R5 and R8 = H, n = 1 and R6/R7 = benzo-fused and R1, R3-R8 = H, R2 = CHj and n = 1 shall be excluded.
The invention relates to compounds of the formula | in the form of their racemates, racemic mixtures and pure enantiomers and to their diastereomers and mixtures thereof.
The alkyl radicals may be either straight-chain or branched. Halogen is fluorine, chlorine or bromine, in particular fluorine or chlorine.
Preference is given to benzotriazoles of the formula | in which the meanings are:
R1 to R8 H; where one of these radicals R2 or R3 may represent:
- @
R2 Br, Cl, CN, NO, CF; OCH; phenoxy, benzoyl,
CH(OH)-phenyl, S-cyclohexyl, CO-OCHgs;
R3 CHas, CN, Br, CI, NH,, NO», benzoyl.
Particular preference is given to the benzotriazoles of the formula l in which the meanings are:
R1to R8 H; where one of these radicals R2 or R3 may represent:
R2 Br, Cl, NO,, OCHj3, phenoxy, CO-OCHj;
R3 NH2; or two substituents of this series are:
R2=F and R3=C}; n an integer from 1 or 2; and one of the substituents R5 or R6 may represent:
R6 CHa;
RY CHs, 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 benzo-fused ring which may optionally be substituted singly by NH; 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 a benzo-fused ring or cyclohexanediyl; or benzotriazoles of the formula | in which
R1 to R8 H; where one of these radicals R2 or R3 may represent:
R2 Br, CN, CF; OCH; phenoxy, benzoyl, CH(OH)- phenyl, S-cyclohexyl;
- @
R3 CN, Br, Cl, NO,, benzoyl; or two substituents of this series are:
R1 = Cl and R3 = CFj3; n an integer from 1; and one of the substituents R6 and R7 may represent:
R6 CH;
R7 CH3, CzHs; CH(CHa)2, C(CHj3)s, benzyl or CO-OCzHs; or
R6 and R7 are both CHj3; 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; where the compounds with R1 to R5 and R8 = H, n = 1 and R6/R7 = benzo-fused shall be excluded.
Very particular preference is given to the benzotriazoles of the following structures:
N,
H,C”~ N
Oo a o CH,
N
Co
N a 0's
N
/
N pau 0 0 \ lo} /
OCG
N
/
N
IN F o F
F
F N
\
TC
/
Cl Ju
N
Pen
C0)
N
/
N
Jn
Oo Br 5
N
\
CH
/
N by 0 F
F
Cy /
N ate
O
0 0-CH,
A
N=pN oO 2 ry
Sh °
N=pN 0 2 yd
NON O
N=N 1 Br 0)
N=N
F 0]
Br
Por \
N=N
I Br
NN
N=p
N
\
Cp /
N
200 0
N
\
CL N NH,
N
~ h! ) 0 _O /
N r= 5 ) 0 _O
H,C N,
N
N CH, 20 0
N
/
H,N N
I o CH,
Cl 0
N
/
N
J
O CH,
CC
N
/
N
JN a
N
N
\ oe, /
N
J
© () or the benzotriazoles of the following structures:
N
\
CL
/
N a0
Oo
CH,
N,
O. N
SN N
I
0) pu. 0 CH,
N,
N CH, \ (
J 0 0
Oo
N
/
N pa of CH,
N,
N
N NN N
JN
O CH,
N,
N
N
IN
0}
Jon \
N
/
H,C N ae 0}
Ny
N
N CH,
J
0} (CI
N
/
N
Jn o CH,
CH,
fo)
OCS
N oN 0) CH,
F
F
20
N
/
N pa 0 CH,
N
/
Br N pau 0 CH,
Co \
N
/
N
Pu CH, © CH,
H,C
OH
TC
N
/
N
JN o! CH,
SASS
N
/
N
2 0 CH,
S N,
N
N
2 © CH,
N
CL) /
N
PN
CH,
Jos
N
/
Cl N 2 0 CH,
CC
I
N
/
N
2 0 ov ?
CH,
N
\
CL
/
N
2
1 Br
NN
N=pN
CH, 2,0
X A
N=pN cl
OL
Noy I F oh x = x A
N=pN
Cl {Of
N. F
N F
Sa
N
\
CI
/
N
»- °- _O
H.C To
N
/
N
20s
O CH,
N,
N
_ er. 0)
N,
LEN
N
0 ~n © CH,
N 0}
N \.
N N—o~ ) ©
CL
N
/
N
Jn 0 Cl
N
/
N
Jn 0 V4
Very particular preference is further given to benzotriazoles of the following structures:
N
\
Cy /
N
208 0
CH,
N, oN N
N° N
I] 5 J
Oo CH,
N
/
N
J
0 CH,
N,
N
N
IN
Oo
N,
N
N CH, p= 0)
N
/
N pany 0] CH,
CH,
CC
\
N
/
N
§ Pu CH,
CH,
H,C
N
\
CI
/
N on
CH,
Jon
N
/
Cl N pa 0 CH,
N
\
CI
/
N
2
Oo
N
\}
Cp /
N
> 2 0
SUS’
N No"
N
Jy (o} and the benzotriazoles of the following structures:
N
\
CL
/
N
2 0 CO
CH,
N
/
N a of CH,
N
\
CC A
/
N pu CH, © CH,
H,C
N
\
CL
/
N
PO
CH,
N,
N cl N ~N
Oo CH,
N
\
Cy /
N
J
0
N
/
N ju 2
Pharmaceutically acceptable salts are, because their solubility in water is greater than that of the initial or basic compounds, particularly suitable for medical applications. These salts must have a pharmaceutically
- @ acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), trometamol (2-amino-2- hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine.
Salts with a pharmaceutically unacceptable anion such as, for example, trifluoroacetate likewise belong within the framework of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.
The term “physiologically functional derivative” used herein refers to any physiologically tolerated derivative of a compound of the formula | of the invention, for example an ester, which on administration to a mammal such as, for example, a human is able to form (directly or indirectly) a compound of the formula | or an active metabolite thereof.
Physiologically functional derivatives also include prodrugs of the compounds of the invention, as described, for example, in H. Okada et al.,
Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves be active or not.
- @
The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention.
All references to “compound(s) of formula |" hereinafter refer to compound(s) of the formula | as described above, and their salts, solvates and physiologically functional derivatives as described herein.
The compound(s) of formula (I) may also be administered in combination with other active ingredients.
The amount of a compound of formula | necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range from 0.3 mg to 100 mg (typically from 3 mg and 50 mg) per day and per kilogram of bodyweight, for example 3-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.3 mg to 1.0 mg/kg, which can suitably be administered as infusion of 10 ng to 100 ng per kilogram and per minute. Suitable infusion solutions for these purposes may contain, for example, 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 active ingredient. Thus, ampoules for injections may contain, for example, from 1 mg to 100 mg, and single-dose formulations which can be administered orally, such as, for example, capsules or tablets, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. For the therapy of the abovementioned conditions, the compounds of formula may be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient's health.
- @
The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances may likewise be present, including other compounds of formula I. The pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.
Pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula | used in each case.
Coated formulations and coated slow-release formulations also belong within the framework of the invention. Preference is given to acid- and gastric juice-resistant formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, wafers, suckable tablets or tablets, each of which contain a defined amount of the compound of formula I; as powders or granules, as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact. The compositions are generally produced by uniform and homogeneous mixing of the active
. @ ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients.
Compressed tablets can be produced by tableting the compound in free- flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one (more) surface-active/dispersing agent in a suitable machine. Molded tablets can be produced by molding the compound, which is in powder form and is moistened with an inert liquid diluent, in a suitable machine.
Pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula | with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
Pharmaceutical compositions suitable for parenteral administration comprise preferably sterile aqueous preparations of a compound of formula |, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also take place by subcutaneous, intramuscular or intradermal injection. These preparations can preferably be produced by mixing the compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.
Pharmaceutical compositions suitable for rectal administration are preferably in the form of single-dose suppositories. These can be produced by mixing a compound of the formula | with one or more
- @ conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances.
The active ingredient is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%.
Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses can be in the form of single plasters which are suitable for long-term close contact with the patient's epidermis. Such plasters suitably contain the active ingredient in an aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%. A particular possibility is for the active ingredient to be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2(6): 318 (1986).
Further active ingredients suitable for combination products are: all antidiabetics mentioned in the Rote Liste 2001, chapter 12. They may be combined with the compounds of the formula | of the invention in particular for a synergistic improvement of the effect. Administration of the active ingredient combination may take place either by separate administration of the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation. Most of the active ingredients listed below are disclosed in the USP Dictionary of USAN and International Drug
Names, US Pharmacopeia, Rockville 2001.
- @
Antidiabetics include insulin and insulin derivatives such as, for example,
Lantus® (see www.lantus.com) or HMR 1964, fast-acting insulins (see
US 6,221,633), GLP-1 derivatives such as, for example, those disclosed in
WO 98/08871 of Novo Nordisk A/S, and orally effective hypoglycemic active ingredients.
The orally effective hypoglycemic active ingredients include, preferably, sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers such as, for example, those disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of . gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, compounds which alter lipid metabolism, such as antihyperlipidemic active ingredients and antilipidemic active ingredients, compounds which reduce food intake, PPAR and PXR agonists and active ingredients which act on the ATP-dependent potassium channel of the beta cells.
In one embodiment of the invention, the compounds of the formula | are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
In one embodiment of the invention, the compounds of the formula | are administered in combination with a cholesterol absorption inhibitor such as, for example, ezetimibe, tiqueside, pamaqueside.
In one embodiment of the invention, the compounds of the formula | are administered in combination with a PPAR gamma agonist, such as, for example, rosiglitazone, pioglitazone, JTT-501, Gl 262570.
In one embodiment of the invention, the compounds of the formula | 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 | are administered in combination with a mixed PPAR alpha/gamma agonist, such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in WO 00/64888, WO 00/64876, WO 03/020269.
In one embodiment of the invention, the compounds of the formula | are administered in combination with a fibrate such as, for example, fenofibrate, clofibrate, bezafibrate.
In one embodiment of the invention, the compounds of the formula | are administered 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 | are administered in combination with bile acid absorption inhibitor (see, for example, US 6,245,744 or US 6,221,897), such as, for example, HMR 1741.
In one embodiment of the invention, the compounds of the formula | are administered in combination with a CETP inhibitor, such as, for example,
JTT-705.
In one embodiment of the invention, the compounds of the formula | are administered in combination with a polymeric bile acid adsorbent such as, for example, cholestyramine, colesevelam.

Claims (13)

- @ Claims:
1. A benzotriazole of the formula |, R1 R2 " ra N o R7 RS R6 in which the meanings are: R1 to R8 H, where one of these radicals R2 or R3 may represent: Br, Cl, CH;, CN, NHz, NO,, CFs OCH; phenoxy, benzoyl, CH(OH)- phenyl, S-cyclohexyl, CO-OCHj; or two substituents of this series are: R1=Cland R3 =CF;or R2 =F and R3 = CI; n an integer from 0, 1 or 2; and one of the substituents R6 or R7 may represent: R6 CHs; R7 CHs, C2Hs; CH(CHa)2, C(CHza)s, CFs, Br, Cl, benzyl or CO-0OCuHs; or R6 and R7 are both CH3; or the ring may contain a double bond instead of R6 and R7 or RS and R6 or R6 and R7 may together with the carbon atoms carrying them represent a benzo-fused ring or else if n = 0 may represent cyclohexanediyl; where in the case of the R6/R7 ring closure this substituent may be optionally
- @ substituted singly by NH; or NO, or singly or doubly by OCHjs;; and R7 and R8 together cyclopentyl, diazepine or =CH;; where the compounds with R1 to R5 and R8 = H, n = 1 and R6/R7 = benzo-fused and R1, R3-R8 = H , R2 = CH; and n = 1 shall be excluded.
2. A benzotriazole of the formula | as claimed in claim 1, R1 R2 N _a N lo I~ ye o R6 Ra R5 in which the meanings are: R1 to R8 H; where one of these radicals R2 or R3 may represent: R2 Br, CI, CN, NO, CFs, OCHs, phenoxy, benzoyl, CH(OH)-phenyl, S-cyclohexyl, CO-OCHjs; R3 CHs, CN, Br, Cl, NH;, NO, benzoyl.
3. A benzotriazole of the formula | as claimed in claim 1 or 2, in which the meanings are: R1 to R8 H; where one of these radicals R2 or R3 may represent: R2 Br, Cl, NO,, OCH3;, phenoxy, CO-OCHg; R3 NH; or two substituents of this series are: R2=F and R3 =Cl; n an integer from 1 or 2; and one of the substituents R5 or R6 may represent:
R6 CHg; R7 CHas, 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 benzo-fused ring which may optionally be substituted singly by NH; or singly or doubly by OCHs;; 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 a benzo-fused ring or cyclohexanediyl.
4. A benzotriazole of the formula | as claimed in claims 1 to 2, wherein R1 to R8 H; where one of these radicals R2 or R3 may represent: R2 Br, CN, CF3, OCHj; phenoxy, benzoyl, CH(OH)- phenyl, S-cyclohexyl, R3 CN, Br, CI, NO, benzoyl; or two substituents of this series are: R1 = Cl and R3 = CFj3; n an integer from 1; and one of the substituents R6 and R7 may represent: R6 CH; R7 CHs, CzHs; CH(CHa3),, C(CHs3)s, benzyl or CO-OC,Hs; 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; where the compounds with R1 to R5 and R8 = H, n = 1 and R6/R7 = benzo-fused shall be excluded.
5. A benzotriazole of the following structure: N, oO N H,C”~ N Jn Oo CH, N \ CL / N als Oo 5 N / N Hn 0 0 \ Oo / JC N / N ys © F F F N / Cl Ju N
N / N Jn Oo Br N \ CL / N by 0 F F N \ CL»
/ . N ~~ fo) 1 CT 7) AT N=N Oo 2 ye Sh ° N=N 0 2 ry NN O N=pN
1 Br BE N=N F 0) E PR Br F N N ) N=p 1 Br NN N= os / N C0) 0
N N NH, N — 0 _0O H,C TO N / N x § )
0 N
H.C n TC N N CH, ~~ Oo N / HN N ) 0 CH, ROW N / N 20s 0 CH, C3 N / N )—N a®~ N N / N J © ()
6. A benzotriazole of the following structure:
N N Cy / N 20S 0 CH, N, O- N “N° N 1 0 pa el CH, CH N ( 3 JN 0 0 0 N / N Jn 0 CH, N, N N NN N ~O- : O CH, N, N N N
0 N N H,C a0 Oo Ny N N CH, pa 0) N / N Jn 0 CH, CH, 0 CIC N pa 0 CH, F F 20 N / N a 0 CH,
N / Br N Jn 0 CH, N / N JN CH, © CH, H,C OH N, N N rr o} CH, 0) N, N N Nn 0 CH, Ss N,Q N N — O CH,
/ N I N CH, 0 CH,
Jou N / Cl N Jn O CH, N / N a : ov CH, N \ CL / N In Oo Jy Br oN N= CH, I =N NN N=pN Cl aN
N. F N F
2,0 VN N=N Cl F N VT N F or N \ Cp / N > 2 0) ple N
H.C / N rn oO CH, N, N a) N o} pu 0 SUBS: N 5 JN O CH,
N Crk / N—o~ N r~{ PD! ) 0 N / N IN oO Cl N / N Jn 0 Y%
7. A benzotriazole of the following structure as claimed in claim 6: N \ CI / N J Oo CH, N, _ N Os’ N H Oo pay oO CH,
N / N J Oo CH, N, N N IN 0 Ny N N CH, J Oo CC [NY N / N oN o CH, CH, C0 \ N / N dT oH, © CH,
H.C
N \ CI / N 7 CH, JON N / Cl N Pa O CH, N \ CL
V4 . N pay o N \ CL / N EP o N 0] oS / N—qg- N , 0] CI N / N pany
Nl rv 7 £
8. A benzotriazole of the following structure as claimed in claim 7: N \ CL / N J © ON CH, N / N J 0 CH, CL [\Y N / N pu CH, © CH, H,C N \ Cy / N pa N CH, 0] CH
A rd La ' toe JO N / cl N Oo CH, N \ / N 2 Oo N \ / N a N CH, Oo
9. A process for preparing the compounds of the formula | as claimed in claims 1 to 8, which comprises a) acylating benzotriazole 2 with carbamoyl chlorides 3, or b) initially reacting benzotriazoles 2 with phosgene and then reacting the resulting benzotriazolecarbonyl chlorides 5 with amines or anilines to give the compounds of the formula 1, in which the substituents have the abovementioned meanings. R1 cl RA R2 N ()n “Nos pu N R& Re Ny / (o} R?7 N R3 N Ra N R5 On R4 R6 ba p= R8 0 R7 RS R6 2 3 1
N ) A Id ) wv I J (ny rs R7 R2 cl R2 N 0 CTT MN / R6 4 Ee — N —_— J R3 N R3 Ju R4 cl R4 o 2 5
10. A benzotriazole of the formula |, R1 R2 Ny N N R3 I Un Re R4 N R5 R6 in which the meanings are: R1to R8 H; where one of these radicals R2 or R3 may represent: Br, Cl, CHjs, CN, NHz, NO,, CF; OCHs, phenoxy, benzoyl, CH(OH)- phenyl, S-cyclohexyl, CO-OCHg; or two substituents of this series are: R1=Cland R3 = CF3 or R2 =F and R3 = CI; n an integer from 0, 1 or 2; and one of the substituents R6 or R7 may represent: R6 CHa; R7 CHjs, CzHs; CH(CHs)2, C(CHs)s, CF3, Br, Cl, benzyl or CO-OC;,Hs; or
- @ R6 and R7are both CHj3; 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 or else if n = 0 may represent cyclohexanediyl; where in the case of the R6/R7 ring closure this substituent may be optionally substituted singly by NHz or NO; or singly or doubly by OCHgs; and R7 and R8 together cyclopentyl, diazepine or =CHy; for use in a medicament.
11. A benzotriazole of the formula | as claimed in claim 10 for use in a medicament with an inhibitory effect on hormone-sensitive lipase, HSL.
12. A benzotriazole of the formula | as claimed in claim 10 for use in a medicament for the treatment of non-insulin-dependent diabetes mellitus, of diabetic syndrome or syndrome X.
13. A medicament for the treatment of non-insulin-dependent diabetes mellitus or of diabetic syndrome comprising at least one benzotriazole of the formula | as claimed in claim 10.
ZA200501757A 2002-10-12 2005-03-01 Novel bicyclic inhibitors of hormone sensitive lipase. ZA200501757B (en)

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