UA79994C2 - Bicyclic inhibitors of hormone sensitive lipases - Google Patents

Abstract

The invention relates to benzotriazoles of general formula (I), wherein R1-R8 have the above mentioned meanings as well to a method for the production thereof. Said compounds have an inhibiting effect on hormone sensitive lipases. , I

Description

Description of the invention

Benzotriazoles are already known from various fields, such as, for example, photochemistry (patent O5 4 255 510, Kodak) or as 2 orexin antagonists (MUO 02/090355, ZKVI. In addition, the synthesis of benzotriazoles (described by KaipiKu ei aim,, U. Ogd . Spet. 1997, 62, 4155-4158). Further, carbamates are also known as lipase inhibitors, such as (for example, described by Znatkanpi RaikKag eyi a). ip Ratsi MUsoIPieu, Z(epPep V. Rebegzop (ed), I iIraze (1994 ) 207-227 or MO 03/0518421.

Unexpectedly, it was shown that the benzotriazoles according to the invention exhibit activity against NOI sensitive to lipase hormones. 70 The invention relates to benzotriazoles of the general formula a

And where is the village?

K1-K8 mean H, and one of these residues K2 or KZ can mean:

Вг, СИ, СН5, СМ, МН», MO», СЕз, OSН3, phenoxy, benzoyl, CH(OH)-phenyl, 5-cyclohexyl, СО-ОСН»; or two substitutes from this series mean: "I

K1-SI and k3-SE" or Fu

K22BE and K32SI; n means an integer 0, 1 or 2; and Ge) one of the substitutes Kb or K7 can mean: Fu

Kv - SNU;

K7 - СН, СонН5; СН(СНУ)», С(СН»у)»з, CE», Vg, SI, benzyl or CO-OSONB; - or

Kb and K7 both mean CH"; or the ring instead of Kb and K7 may contain a double bond, or "

К5 and Кб, or Кб and К7 can mean, together with the C atoms to which they are connected, a benzanellated ring, or in the case that n-0, also cyclohexanedyl, and in the case of cyclization Кб/К7 this substituent, in the case of shi if necessary, it can be replaced once with the help of МН»о or МО», or once or twice with the help of Осн»; and , K?7 and K8 together mean cyclopentyl, diazepine or "CH"; at the same time, compounds where K1-K5 and K8-H, n-1 and iii are excluded

Kbv/K7 - benzanellated ring, and K1, K3-K8-H, K2-CH" and n-1. - The invention relates to compounds of the formula | in the form of their racemates, racemic mixtures and pure enantiomers, as well as their diastereomers and their mixtures.

Alkyl residues can be both unbranched and branched. Halogen means fluorine, chlorine or se) bromine, especially fluorine or chlorine. c 50 Preferred are benzotriazoles of formula I, where K1-K8 mean H, and one of these residues K2 or KZ can mean: K2 - Вг, СИ, СМ, МО», СЕз, OSНз, phenoxy, benzoyl,

I" CH(OH)-phenyl, 5-cyclohexyl, CO-OSH"; KZ - CHz, SM, Vg, SI, MN», MO», benzoyl.

Particularly preferred are benzotriazoles of formula I, where K1-K8 mean H, and one of these residues K2 or KZ can mean: K2 - Bg, SI, MO», OSN»z, phenoxy, СО-ОСН»; Short circuit -

MN"; or two substitutes from this series are: K2-E and KZ3-SI; n means an integer 1 or 2 and one of the substituents КЕ or К7 can mean: Кб -СН»У; where B7 is SNU, SEz or Bg, or the ring instead of Kb and K7 may contain a double bond, or Kb and K7 may mean, together with the C atoms to which they are connected, a benzanellated ring, which, if necessary, can be substituted once with MH»o, or once or twice with OSNaz; and K7 and K8 together represent cyclopentyl, or n represents the integer 0; and

Kb and K7 can mean, together with the C atoms to which they are connected, a benzanellated ring or cyclohexanediyl; or benzotriazoles of the general formula I, where 65 K1-K8 mean H, and one of these residues K2 or KZ can mean:

K2 - W, CM, SEz, OSN", phenoxy, benzoyl, CH(ION)-phenyl, 5-cyclohexyl;

KZ - SM, Vg, SI, MO", benzoyl; or two substitutes from this series are: K1-SI and KZ-Sg"; n means the integer 1; and one of the substituents Kb or K7 can mean: Kb - CH";

K7 - СН, СонН5; СН(СНУ)», С(СНУ)з, benzyl or СО-ОШОН»; or

Kb and K7 both mean CH"; or the ring instead of Kb and K7 may contain a double bond, or K5 and Kb or Kb and K7 may mean, together with /o C atoms to which they are connected, a benzanellated ring, while excluding compounds where K1-K5 and K8-H, n-1 and K6/K7 - benzanellated ring.

The most particularly preferred are benzotriazoles of the following structures: o shcha, se (o) "I

Fo

Gee)

Ge) m. - s with -I (se) (se) at 50

GT" (F) ko bo b5

« chi Y y i yu pk x tt Z shva Y

SG я че щ Iе ц ж І я пи . and a: sx s with fra s o)

There is another st (X set z. z h

F

I. M.Y F

Y vi and sinna - - in se E « 20 and she still shsh - z oi o Shi - tk shch (se) (se) s

I" (F. ko bo 65 a, and in MV rya De ch a a o. 70 vn,

M i Me o v i

Mountain; Beck with her

And p this with her. j y U shchi y a g MELONS - - Y Shi! And U and

And" in SYA in -1 st

Ge

Ge

Gee! 50th"

F) t bo b5 s chi to y S

TSE ke: Ts "A M.

SS" same

I and MID dis

In even Zha and tr

ХА inn I rn b dk a Y y y y ooo su s owls you: ше

unit at

She "A - and with the same h

And F

Her is still I, FU that; What is it?

He; 4 international -N y " i u z s Ky g" Kyy r. en.

F | Ff

Fo ak SHI f B: o (F) Nr ssshnyi I

GI tsa and Ya. and doku. In Y: vo - "m or benzotriazoles of the following structures: 65 and ran i

Y - 710 "eco. M. for, "y - ; r t i

Ha lava I | ich that and in zt SYA, and sch o "I

Fo

Gee)

Ge) i- « - s z -I (se) (se) o 50

I" (F) ko bo 65 in "Y y, sei

SR M 0 sne so o v a sh Y a (A di i o ne z dn i zhk 4 r ws y y y y y y y y y F o DY ey Ne Y y chi y-

Kya ZE I and and M ". SU : ts Dn p ke - ; (se) (se) p

I" (F) ko vo b5 g

I Y yaoshch sor so ya Yatav CH Y I sh- (U vn, her -y u

In... and . with Gi iy ri sr vini ta: -x " shk s" ; Y o

So no: and I am F

Sha She ku Ya

Ох чн Меш ши о» | і- and I dec, : nnya t "y ИЙ y - - s Ko av; НШШІ і" ох Ін, -I (se) (se) so 20

I" (F) ko vo 65

"Ko zhk

With and or with. eh in, beat "

Fen, -y shchi i h o i Shche « zo : ' F "y V, F

In and r: and i-

And about | "

Vo and M - s, at 18 more -I (se) (se) sg

Y" (F) ko vo 65

I. OO ee 170 ra her no I gray I

With 4 uE-

Y dnk tn iy zyystya U V td (z y i schi i. a ge) o p « it s ta "De; Fo

More eat-

WITH

B a s « s DRchN u

M ' MO : o -I (se) (se) p

I" (F) ko 60 65 and u

And Shi She. and Sh sko

Xiang NI stok about what; i-Z 15 7 a ' i i i . Ah!

Sat and Fri: August 20 R, I ih "V 5 not le mit, at DU. i, from what shin zavi zhk; WE o)

Ks - head;

From sa « 30 | about z and I; m ev MA in khz" and t zhk i ra ce. fi ge) she ik : tsyib; .

Next, the most particularly preferred are benzotriazoles of the following structures: "from"

F) name) 6o 65

GfkI called and and in , . eat y y chi ' i

VO Inc., 70

B. and sienia and gav 2 K- . and

And I VI y y "y SYA. z y SHE ve,

M i still t I "what is sch y ; 337 and -b and o

ShK as z zo Yad M is Fi- « - s z -I (se) (se) so

Her" (F) ko 60 b5 r o i" s ie u, fu; vve, - і A v, F schi vh - se naik: sake IY 2 s rya х х» іs Med, - | і li. " schi i g Sx zt y Z di -i I i

I" ' pt I, because Shshch y and Z s: Ki »

And -16-

and benzotriazoles of the following structures:

Not "What. 70, yes, yes

WITH

CHI k cha i yo t y 7 dates: what. and trucks Anna

N

In a swarm that is

U: I am SHE SN, se 2 che o as M: tya o their dreams THAT "

With ;

Khrt: «shchi I g shchi i i, i DI SCHO sl F

I sn, F sv V i-

Y ii En strii s: v: "i. i Y : whose TSY 7 Uh. r 7 « - т - -- к» M SCHE dvy - . "" - я t A

AND I . and her Y AH and se) UDC she SVK i" (MK.

And ich - L..

MORE like - a. university:

In | ; Pharmaceutically compatible salts, due to their higher solubility in water in relation to the parent or parent compounds, are particularly suitable for medical use. These salts must have a pharmaceutically compatible anion or cation. Suitable pharmaceutically compatible acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, as well as organic acids, such as, for example, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, b5 maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric acid. Suitable pharmaceutically compatible base 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 one pharmaceutically incompatible anion, such as, for example, trifluoroacetate, within the scope of the invention are also suitable as useful intermediates for the preparation or purification of pharmaceutically compatible salts and/or for use in non-therapeutic, for example, ip mio, applications.

The term "physiologically functional derivative" as used means any physiologically compatible derivative of a compound of formula I according to the invention, for example an ester, which, when administered to a mammal, for example a human, is capable (directly or indirectly) of forming a compound of formula I or its active metabolite . 70 Physiologically functional derivatives also include prodrugs of compounds according to the invention, such as

For example, those described by N. Okada ei ai,, Spet. RIagt. You. 1994, 42, 57-61). Such prodrugs may be metabolized to compounds of the invention. These prodrugs may or may not be active themselves.

The compounds according to the invention can also exist in different polymorphic forms, for example, in the form of amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention fall within the scope of the invention and are a further aspect of the invention.

In the following, all references to "compound(s) of formula I" refer to compound(s) of formula | as described above, as well as their salts, solvates and physiologically functional derivatives, as described above.

The compound(s) of formula (I) can also be administered in combination with other biologically active substances.

The amount of a compound of formula I that is required to achieve the desired biological effect depends on a number of factors, for example, the specific compound selected, the intended use, the type of administration and the clinical condition of the patient. In general, the daily dose is in the range from O.Zmg to 100mg (usually from Zmg and 5Omg) per day per kilogram of body weight, for example, 3-1Omg/kg/day. The intravenous dose can be, for example, in the range of 0.2 mg to 1.0 mg/kg, the dose suitable as an infusion can be administered in the amount of 100 ng to 100 ng per kilogram per minute. Suitable infusion solutions may contain, for example, from 0.ng to 10 mg, usually from 10 ng to 10 mg per milliliter. Single doses can contain, for example, from mg to 10 g of biologically active substance.

Thus, ampoules for injections can contain, for example, from 1mg to 10Omg, and preparative ready forms, (8) taken orally with a single dose, such as tablets or capsules, can contain, for example, from 1 to 1000 mg, usually from 10 to bOOmg. For the treatment of the conditions mentioned above, compounds of the formula | can be used directly in the form of a compound, but mostly they are found with a compatible carrier in the form of pharmaceutical compositions. The carrier must be naturally compatible in the sense that it is compatible with other components of the composition and does not harm the health of the patient. The carrier can be a solid Me) substance or a liquid, or both, and is preferably formulated with the compound in the form of a single dose, He! for example, in the form of a tablet, which can contain from 0.0595 to О5wag.9о of a biologically active substance. Further, pharmaceutically active substances may also be present, including other compounds according to the formula |. me)

Pharmaceutical compositions according to the invention can be obtained by one of the known pharmaceutical methods, which basically consist in mixing the components with pharmacologically compatible carriers and/or excipients.

The pharmaceutical compositions of the invention are suitable for oral, rectal, topical, oral (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable route of administration in each individual case is depends on the type and severity of the condition to be treated, and on the type of compound according to the formula. I. The scope of the invention also includes drugged preparative ready-made forms and drugged preparative ready-made forms and? prolonged action. Ready-made preparative forms resistant to the action of acids and gastric juice are preferable. Suitable gastric juice resistant coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, pydroxypropylmethylcellulose phthalate, and anionic polymers of methacrylic acid and methacrylic acid methyl ester -I.

Suitable pharmaceutical compounds for oral administration may be in individual unit and dose forms such as, for example, capsules, coated wafers, lozenges or tablets, respectively, containing

Ge) a certain amount of the compound according to formula I; in the form of powders or granules; in the form of a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions can be obtained by any suitable pharmaceutical method, which includes the stage at which the biologically active substance and the carrier (which may consist of one or more additional components) are brought into contact. In general, compositions are obtained by uniform and homogeneous mixing of a biologically active substance with a liquid and/or finely ground solid carrier, after which the product is, if necessary, formed. This can be obtained, for example, a tablet, in which the powder or granulate of the compound is pressed or formed, if necessary, with one or more additional components.

F) Pressed tablets can be made by tableting the compound in a free-flowing form, such as, for example, a powder or granulate, if necessary mixed with a binder, lubricant, inert diluent and/or one (several) surface-active / dispersant in a suitable device. for Molded tablets can be made by molding a powdered compound moistened with an inert liquid diluent in a suitable device.

Pharmaceutical compositions suitable for oral (sublingual) administration include lozenges containing compounds of formula I and a flavoring agent, typically sucrose and gum arabic or tragacanth, and pastilles containing compounds on an inert base such as such as gelatin and glycerin, or 65 sucrose and gum arabic.

Suitable pharmaceutical compositions for parenteral administration include preferably sterile aqueous formulations of the compound of formula !, which are preferably isotonic with respect to the blood of the intended recipient. These compositions are preferably administered intravenously, although administration may also occur subcutaneously, intramuscularly, or intradermally in the form of injections. These ready-made forms can preferably be made in such a way that the compound is mixed with water and the resulting solution is sterilized and made isotonic with respect to blood. Injectable compositions according to the invention contain a total of 0.1 to 5 wt.9Uo of the active compound.

Suitable pharmaceutical compositions for rectal administration are mainly in the form of disposable suppositories. They can be made by combining compounds according to the formula | mixed with one or 7/0 several conventional solid carriers, for example, cocoa butter, and the resulting mixture is molded.

Suitable pharmaceutical compositions for topical application are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil. Vaseline, lanolin, polyethylene glycol, alcohols and combinations of two or more of these substances can be used as a carrier. The biologically active substance in general /5 is present in the composition in a concentration from 0.1 to 15 wt.9o, for example, from 0.5 to 2905.

Transdermal administration is also possible. Suitable pharmaceutical compositions for intradermal administration may be in the form of separate patches that are suitable for prolonged close contact with the patient's epidermis. Such plasters are made in such a way that the biologically active substance, if necessary, is dissolved and/or dispersed in the adhesion promoter in a buffered aqueous solution, or 2o dispersed in the polymer. A suitable concentration of the biologically active substance is about 1905-3595, preferably about 3965-1595. As a special possibility, the biologically active substance can be released by means of electrotransport or electrophoresis, as this (described, for example, in Rpagtaseciisa! Kezeagsy, 2(6): 318 (1986)).

As other biologically active substances in combined preparations, all the antidiabetic agents listed in the Red Pages 2001, chapter 12 |Koiep Givie 2001, Kariye! 12). They can be combined with compounds according to the invention of the formula | especially to ensure synergistic action. The introduction of a combination of i) biologically active substances can take place either by separate intake of biologically active substances by the patient, or in the form of combined preparations, where several biologically active substances are in one pharmaceutical preparative ready form. Most of the following biologically active substances "g zo" (described in OZR Oisiopagu oi OZAM apa Ipiegpayopa! Ogyd Matev, OZ Rpagtasoreia, KoskmiPe 20011.

Antidiabetic agents include insulin and insulin derivatives, such as I apishg 9? (see ml. apiiv.sot.) ia or NM 1964, fast-acting insulins | see patent 05 62216331), SI P-1 derivatives, such as, for example, those that Ge»! (described in the UMO application 98/08871 mop Momo MogaizK A/5), as well as orally acting hypoglycemic biologically active substances. Orally acting hypoglycemic biologically active substances mainly include sulfonylureas, o-biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, CI P-1 agonists, potassium channel openers, such as those (which are described in applications MO 97/26265 and MO 99/03861 mop Momo Mogaizk A/5), insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, modulators of glucose absorption, compounds that change "fat metabolism, such as antihyperlipidemic and antilipidemic substances , compounds that reduce food intake, 70 PRAC and PHE agonists, and biologically active substances acting on the ATP-(ATP)-dependent potassium channel of beta cells. 8 c In one embodiment of the invention, compounds of the formula I are administered in combination with an inhibitor of NMOSOOA-reductase and such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin. "» In one embodiment of the invention, compounds of the formula | are administered in combination with a cholesterol resorption inhibitor, such as ezetimibe, tiqueside, pamaqueside.

In one embodiment of the invention, compounds of formula I! in combination with a gamma PRAC agonist, such as rosiglitazone, pioglitazone, /TT-501, and 262570.

In one form of implementation of the invention, compounds of the formula | in combination with an alpha PRAC agonist, such as, for example, SUMU 9578, SMU 7647. (Se) In one embodiment of the invention, compounds of formula I are administered in combination with a mixed alpha/gamma PRAC agonist, such as, for example, MU 1536, AME 8042, АМЕ 8134, АМЕ 0847, or such as (described in MO и-о 00/64888, UMO 00/64876, UMO 03/020269).

Chl» In one form of implementation of the invention, compounds of the formula | in combination with a fibrate, such as fenofibrate, clofibrate, bezafibrate.

In one embodiment of the invention, compounds of formula I are administered in combination with an MTP inhibitor, such as, for example, implitapide, VM5-201038, K-103757.

In one form of implementation of the invention, compounds of formula I are introduced! in combination with an inhibitor of bile acid resorption (see, for example, patents OZ 6245744 or 05 6221897), such as NMA 1741. In one embodiment of the invention, compounds of formula I are administered! in combination with a CERT inhibitor (TBEX), such as //TT-705. In one embodiment of the invention, compounds of formula I are administered in combination with a polymeric bile acid adsorber, such as, for example, cholestyramine, colesevelam.

In one form of implementation of the invention, compounds of the formula ! in combination with an inducer of receptors I 0. (LPNG) See patent 05 6342512, as, for example, NMK1171, NMK 1586.

In one form of implementation of the invention, compounds of the formula | in combination with an ASAT inhibitor, such as, for example, avasimib.

In one embodiment of the invention, compounds of formula I are administered in combination with an antioxidant, such as, for example,

ORS-14117.

In one form of implementation of the invention, compounds of formula I are introduced! in combination with a lipoprotein lipase inhibitor, such as MO-1886.

In one form of implementation of the invention, compounds of formula I are introduced! in combination with an ATP-citrate-lyase inhibitor, such as 58-204990.

In one embodiment of the invention, compounds of formula I are administered in combination with a squalene synthetase inhibitor, such as, for example, BM5-188494.

In one form of implementation of the invention, compounds of formula I are introduced! in combination with a lipoprotein agonist such as CI-1027 or nicotinic acid.

In one form of implementation of the invention, compounds of the formula | in combination with a lipase inhibitor, such as orlistat.

In one embodiment of the invention, compounds of formula I are administered in combination with insulin.

In one embodiment of the invention, compounds of formula I are administered in combination with a sulfonylurea, such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.

In one form of implementation of the invention, compounds of the formula | in combination with a biguanide, such as metformin.

In one embodiment of the invention, compounds of formula I are administered in combination with meglitinide, such as repaglinide.

In one embodiment of the invention, compounds of the formula !/| are introduced in combination with a thiazolidinedione, such as troglitazone, kiglitazone, pioglitazone, rosglitazone or compounds (described by J.

Eoimpaiop in IV) 97/41097), especially 5((4-((3,4-dihydro-3-methyl-4-oxo-2-quinazolinyl-methoxy|phenyl|methyl)-2,4-thiazolidinedione.

In one embodiment of the invention, compounds of formula I are administered in combination with an A-glucosidase inhibitor, such as

For example, miglitol or acarbose.

In one embodiment of the invention, compounds of formula I are administered in combination with a biologically active substance i) acting on the ATP-dependent potassium channel of beta cells, such as tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment of the invention, compounds of formula I are administered in combination with more than one of the above-mentioned compounds, for example, in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and Me troglitazone, insulin and lovastatin, etc. Gee!

In one further embodiment, compounds of the formula | in combination with SACT modulators (see "Sosaipe-atrpe(atipe-gedsiaivii igapesghtiri ipicepsez oepegdu teyaroiist, aphieiu apa davzigis eptriuiipd ip me) tise", AvzaKaua, A, ei aYi.,, M.: Noppope apa Meiaroiis Kezeagsp (2001) , 33(9), 554-558), MRU antagonists of i- (for example, 14-(4-amino-quinazolin-2-ylamino)-methyl|-cyclohexylmethyl)-amidenaphthalene-1-sulfonic acid; hydrochloride (COP 71683A)), Mc4 agonists (for example, (2-(Za-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo|4,3-c| Ipyridin-5-yl)-1-(4-chloro-phenyl)-2-oxo-ethyl

I-amide of 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid; (MO 01/917521), orexin antagonists "(for example, 1--2-methyl-benzoxazol-b-yl)-3-11,5)Inaphthyridin-4-yl-urea; hydrochloride (58-334867-A)), ptv) c agonists nc (3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydro-imidazo|4,5-c|Ipyridine-5 -yl)-propan-1-one salt of oxalic acid MO 00/632081); TME agonists, SKE antagonists (for example, y? (2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triaza-fluoren-4-yl|-dipropylamine (M/O 00/66585)), SKE antagonists vk (e.g. urocortin), urocortin agonists, vz agonists (e.g. 1-(a4-chloro-3-methanesulfonylmethyl-phenyl)-2-(2-(2,3-dimethyl-1H- indol-6-yloxy)-ethylamino|-ethanol; hydrochlorides -I IMO 01/834511), agonists of M5H (melanocyte-stimulating hormone), agonists of SSK-A (for example, trifluoroacetic acid salt and ik 12-I4-(4-chloro -2,5-dimethoxy-phenyl)-5-(2-cyclohexyl-ethyl)-thiazol-2-ylcarbamoyl|-5,7-dimethyl-indol-1-yl)-acetic

Ge) and acids MO 99/155251); serotonin reuptake inhibitors (for example, dexfenfluramine), mixed serotonin-5p | noradrenergic compounds (for example, UMO 00/71549), 5HT agonists, for example, oxalic acid salt and 1-(3-ethyl-benzofuran-7-yl)-piperazine (MUO 01/09111), bombesin agonists, galanin antagonists, hormone growth hormone" (for example, human growth hormone), growth hormone-releasing compounds (tert-butyl ester of b-benzyloxy-1-(2-diisopropylamino-ethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carbon acids MO 01/856951), agonists of TKN | see, for example, EP 0 462 884) splitting 2- or 3-modulators of proteins, agonists of leptin see, for example: I ee, Yuapiei MU.; And eeipipd, Maiyemzhm S; CogpauseKaua-Agepa, Magipa: Ogazvgo, Raigisia.

Iyerip adopiziz az a roiepiiai arrgoasp (0 (She igeaitepi oi oresyu. Ogydv oi (She Eshshge (2001), 26 (9),

Ф) 873-881), BA agonists (bromocriptine, doprexin), lipase/amylase inhibitors | for example, UUO 00/405691, ka modulators of PRAC I, for example, UMO 00/783121, KKK modulators or TAK-B agonists.

In one embodiment of the invention, the next biologically active substance is leptin; see, for example, in "Regeresiimez ip (She (Ppegareciis ve oi Ieriiiip), Zaimadog, Uamieg; Sote-Atrgbovi, Uamieg; EgoypresK, Seta,

Ehreti Oripiop op RipagtasoiPpegaru (2001), 2(10), 1615-1622.

In one embodiment of the invention, the next biologically active substance is dexamphetamine or amphetamine.

In one embodiment of the invention, the next biologically active substance is fenfluramine or 65 dexfenfluramine.

In another embodiment of the invention, the next biologically active substance is sibutramine.

In one embodiment of the invention, the next biologically active substance is orlistat.

In one embodiment of the invention, the next biologically active substance is mazindol or phentermine.

In one form of implementation of the invention, compounds of formula I are introduced! in combination with fillers, mainly insoluble fillers (see, for example, Sagor/Sagotakh? , 230-6).

Ipdivigieratk Nospzi, 65926 Egapiig/Maip). A combination with Sagots? can occur in one preparation form, or with the help of separate intake of the compound of formula I and Sagotah?. Sagotah? can also be introduced in the form of a food product, such as, for example, bakery products or muesli (Miisiigiedeip).

It is understood that every suitable combination of compounds according to the invention with one or more of the above-mentioned compounds and, optionally, one or more other pharmacologically active substances, is considered as falling within the scope of the claims of this invention. e | ? th IF, th ; with ! (8) baths and "I (22) (22) eyes (22) and - t ate 70 and si and not) s vyvlany She v. y ' ,» " i. y N - " your" ik ay. amy" vi yi-o pe s" . . and I

Preparation of benzotriazoles of the general formula I according to the invention occurs by known methods, for example, by acylation of substituted or unsubstituted benzotriazoles with 2 carbamoyl chlorides C (method A), or in two stages by means of the conversion of benzotriazoles with phosgene and subsequent conversion of the obtained benzotriazole carboxylic acid chloride with amines or anilines (method B).

F) name) 60 b5 flight, 70 a a Z her with ra t . at 7 a.m. M le ho Ma s Is, 5 th va. clay in etc

H is. and V. and yang and show

Xia BIKE iy

And

Since acids are usually released during these reactions, it is recommended to add bases, such as pyridine, triethylamine, sodium hydroxide, or alkali metal carbonates, for acceleration. Reactions can be i) carried out in a wide temperature range. As a rule, the preferred temperature is from 02C up to the boiling point of the solvent used. As a solvent, for example, methylene chloride, THF, DMF, toluene, ethyl acetate, n-heptane, dioxane, simple diethyl ether are used. "AND

The compounds of the general formula I according to the invention have an unexpected inhibitory effect on hormone-sensitive lipase, NO, an allosteric enzyme in adipocytes (fat cells), which is inhibited by insulin and is responsible for the breakdown of fats in fat cells, and thus for the transfer of F components of fat into the bloodstream. Inhibition of this enzyme thus corresponds to the insulin-like action of the compounds according to the invention, which subsequently leads to a reduction of free fatty acids in the blood and blood sugar. o 3z5 Thus, they can be used in metabolic disorders, such as non-insulin-dependent diabetes mellitus, diabetic syndrome, X syndrome and direct damage to the pancreas.

Inhibition of LEGS. in B-cells should lead to a direct restoration of insulin release by MI.

Mipgay! ей ай., Oiarebfe5z, Mo! 52, Atsytsdivy 2003, 2057-2065). Therefore, compounds of formula I! according to the invention can " 70 also serve to release insulin. The activity of the compounds of formula I according to the invention was tested in the following enzyme test systems. and Preparation of the substrate "" Preparation of the substrate MAC (MVO-monoacylglyceride) bmg of phosphatidylcholine and bmg of phosphatidylinositol are dissolved in iml of chloroform (each). 100 mg of MAE is dissolved in ml of chloroform. Two parts of the phosphatidylinositol solution (for example, 83.5 μl) and 1 part of the phosphatidylcholine solution (for example, 41.5 μl) and 100 μl of the MAC solution are poured together with a pipette into plastic scintillation vessels (final concentration in the test: 0.0375 mg phospholipid/ml; O .05mg/MAcS/ml). Chloroform o (total volume 225 μl) is completely removed with the flow of Mo by blowing. Dried substrate can

Te) can be stored up to 3 days at 42C. To obtain phospholipid vesicles/micelles with introduced MAC (on the day of testing), the dried substrate is absorbed in 20 ml of the buffer for analysis (25 mM Ttiv/HCI, pH7.4; 150 mM Mass) and it is twice sonicated using an ultrasonic rod (Vgapzop Zopiyeg Toure I, "from" standard micropeaks): 1. processing of positioning 2.2 microseconds, meanwhile each time on ice; 2. positioning processing 4.2 minutes, meanwhile each time on ice During this procedure, the color of the standard solution changes from yellow (extinction maximum 48 nm) to red (extinction maximum 55 nm) by introducing MAC between the phospholipid molecules of the vesicles/micelles. Before using as a substrate (within the next 2 hours) the solution for another 15 minutes. incubate on ice.

Indirect analysis of MAS eats) The analysis is carried out in 1.5-ml Eppendorf vessels or a 96-well plate for 60 minutes. at 3020. To detect NRI inhibition. 1 µl of the substance to be tested is added to the buffer (25 mM Tris/HCl, pH7.4; 150 mM mass) 60 in the presence of 16.696 DMSO. Add 18 µl of substrate solution (2 µg/ml phosphatidylcholine, 1 µg/ml phosphatidylinositol, 5 µg/ml MAC in buffer for analysis). After preliminary incubation for 15 min. at 302, 20 μl of the enzyme solution in the buffer is diluted 1- to 4-fold with a pipette and the extinction is measured at 480 nm in a photometer with cuvettes (0.5 ml cuvettes) or a device with a microtiter tablet. Through bOkhv. incubations at 302 again measure extinction. The increase in extinction at 48O0nm is a measure of enzyme activity. Under standard conditions, 20 μg of partially purified NO. lead to a change in extinction of 0.4-4000u.o0.

Direct analysis of MAO

Alternatively, to measure the change in the extinction of the substrate solution, the NO reaction products are investigated. by phase separation/thin layer chromatography. To do this, the incubated sample (total volume 20 μl, see indirect MAC analysis) in ml Eppendorf vessels is mixed with 1.3 ml of a mixture of methanol/chloroform/heptane (10:9:7) and then with 04 ml of 0.1 M Mahon. After intensive mixing (TOsec.), phases are separated by centrifugation (800x, 20 min., room temperature). Equivalent volumes (for example, 0.4 ml) are taken from the upper aqueous phase, and the extinction at 481 nm is determined photometrically. For thin-layer chromatography, the aqueous phase is dried (ZreedmMas) (under vacuum) and then absorbed in 5Ocl/o tetrahydrofuran. A 5-μl sample is applied to silica gel plates 51-60 (Meg). Chromatography is carried out with a mixture of: 78 ml of simple diethyl ether/22 ml of petroleum ether/I ml of glacial acetic acid as an eluent.

The amount of released fluorescent fatty acid MVO is determined by phosphor imaging (molecular dynamics, 840 excitation and ItadeOtsapi software) at an excitation wavelength of d4bonm and an emission wavelength of 540-56Ohm.

Preparation of enzyme

Preparation of partially purified NOI.

Isolated rat adipose cells are obtained from epididymal adipose tissue of untreated male rats (UMiziag, 220-250g) by collagenase treatment according to published methods

For example, 5. Miivvop ei ai, Apai. Viospet. 158, 1986, 399-407; (3. Egeaigikpop ei ai., 9. Vioi. Spet. 256, 1981, 6311-6320; N. Totatsivi ei ai., U. Vioi. Spet. 251, 1976, 813-819). Fat cells from 10 rats are washed three times by flotation, each time with 500 ml of homogenization buffer (25 ml Ttgiv/HCl, pH 4; 0.25 M sucrose, 1 mM EOTA, 1 mM OT, 10 µg/ml leupeptin, 1 µg/ml antipain, 20 µg /ml of pepstatin) and finally absorb 1 Oml of buffer for homogenization. Fat cells are homogenized in a Teflon-in-glass homogenizer (Vgashp-MeiIzypdep) in 10 steps at 1500 rpm. and at 15923. The homogenate is centrifuged (tubes manufactured by Zomai! ZM24, 5000 rpm, 10 min., 422). The intermediate layer between the fat layer located above and the granules is removed and the centrifugation is repeated. The intermediate layer obtained as a result of this is centrifuged again (Zogmai test tubes! M24, 20,000 rpm, 45 min., 42). The intermediate layer is selected and mixed with 1 g of heparin-sepharose (Rpaptasia-Vioiesi, SI-6B, washed 5 times with 25 mM Tris/HCl, pH 7.4; 150 mM Masi). After incubation for two minutes. at 42C (with shaking at 15-min intervals) the sample is centrifuged (Zogmai test tubes! 5M24, 3000 rpm, 1 revolution, 42C). The supernatant liquid is adjusted to pH 5.2 by adding glacial acetic acid and incubated at 42°C. The sediment is collected by centrifugation (Zogmai! 5534, 12,000 rpm, 10 min, 423) and suspended in 2.5 ml of 20 mM Ttiv/HCI, pH 7/, CO, mM OETA, bb5mM Masi, 1395 sucrose, mM OtTT, 1Omkg/ml (2) leupeptin/pepstatin/antipain. After standing overnight at 4 °C, the suspension is subjected to dialysis against 25 mM Tgiz/HCl, pH7.4; 5095 glycerol, 1 mM OTT, 1 Ωkg/ml leupeptin, pepstatin, antipain and 32 are then applied to a hydroxyapatite column (0.1 g per 1 ml of a suspension equilibrated with 10 mM potassium phosphate, pH7.0; - 3095 glycerol, TMM OTT). The column is washed with four volumes of equilibration buffer at a flow rate of 20 to ZOml/hour. NRI eluted with one volume of equilibration buffer containing 0.5M potassium phosphate, then subjected to dialysis (see above) and concentrated 5-10 times by means of ultrafiltration (filter "

Artichoke Oiayo RM 10) at 42. Partially purified H5Y. can be stored for 4-6 weeks at -7026. 70 Analysis 8 s To obtain the substrate, mix 25-50 cCi (2Nigrioleoylglycerol (in toluene), 6.dmmol of unlabeled trioleoylglycerol and 0.bmg of phospholipid (phosphatidylcholine/phosphatidylinositol 3:106./06.) dry with Mo and then absorb in 2 ml of 0.1 M KRI (pH7.0) using ultrasound treatment (Vgapzop 250, micropeaks, positioning 1-2, 2 h!min., with an interval of 1 min.). After adding iml KRI and repeated treatment - 15 ultrasounds (4xZOsec . on ice with 30-second intervals) add iml of 2095o-VZA (in CRI) (final concentration of trioleoylglycerol 1.7 mM). For the reaction, add 1000 μl of substrate solution to 100 μl (se) of NI solution with a pipette. (NZI. prepared as indicated above, diluted in 20 mM KRIi, pH 7.0, mM EOTA, 1 mM OT, 0.02965 s VZA, 20 µg/ml pepstatin, 1 µg/ml leupeptin) and incubated for 30 minutes at 372. After adding 3.25 ml of a mixture of methanol/chloroform /heptane (10:9:7) and 1.55 ml of 0.1M KSOOz, 0.1M boric acid (pH10.5) are mixed well and finally centrifuged (800 ho9, 20 min.). After phase separation, one equivalent is selected

Their" upper phase (ml) and determine the radioactivity by measuring liquid scintillation.

Processing of results

The substances are tested in the usual way in four independent samples. Inhibition of enzymatic activity of NOI with the help of substances under test is determined by comparison with an uninhibited control reaction. The calculation of the value of IS 590 is carried out according to the inhibition curve with at least 70 (F) concentrations of the substances being tested. A software package is used for data analysis

GI SCARNIT, EIIVemieg-VIOBOBET.

In this test, the compounds of examples 1-55 show inhibition in the ISvo range of 0.04-5 µM. The following examples describe the invention in more detail without limiting it.

Examples

The following examples were obtained by the following methods.

Method A

To a solution of 2mmol of 1H-benzotriazole in pyridine (ml) and dichloromethane (1Oml) add a solution of the corresponding 65% carbamoyl chloride (Immol) in dichloromethane (1Oml). The reaction mixture was stirred for 16 hours at room temperature, then EtOAc (ethyl acetate) (15 ml) was added, filtered through silica gel and the filtrate was concentrated.

The product is purified by preparative HPLC and freeze-dried.

Method B a) Obtaining a solution of benzotriazole-1-carboxylic acid chloride

A solution of benzotriazole (bg, 50.4 mmol) in THF (100 ml) was added dropwise to a solution of phosgene (2095 in toluene; UOml; 182 mmol) while cooling with ice. The ice bath is removed, and the solution is stirred for another 2 hours at room temperature. The solvent is distilled off, and the precipitate is absorbed in THF to a total volume of 25 ml.

B) Conversion of benzotriazole carboxylic acid anhydride into the corresponding benzotriazole-1-carboxylic acid amides and anilides 70 Each time, 10 amines or anilines (2 mmol) are introduced into THF (1 ml) and mixed with pyridine (0.2 ml). The starting mixture with a solution of benzotriazole-1-carboxylic acid anhydride chloride (1 ml, x"2 mmol) is incubated and stirred for 16 hours at room temperature. Then the starting mixture is diluted with ethyl acetate (bml), filtered through silica gel, and the filtrate is concentrated to dryness under vacuum. Crude the product is purified by flash chromatography.

Example 1

Methyl ether of 3-(4-methyl-piperidine-1-carbonyl)-ZH-benzotriazole-5-carboxylic acid,

MANk: 303.14

Example 2 c (8-aza-spiro|4.5)|dec-8-yl)-benzotriazol-1-yl-methanone d) « o Fo

MNk: 285.16 F

Example With Ge)

Benzotriazol-1-yl-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl-methanone m o - s;» ' -I MANzhk: 339.13

Example 4 (5-phenoxy-benzotriazol-1-yl)-(4-fluoromethyl-piperidin-1-yl)-methanone se) o 50 s» i)

Mane Z1yZ

HF) Example 5 7 (b-chloro-5-fluoro-benzotriazol-1-yl)-(4-methyl-piperidin-1-yl-methanone)

IS

60 o b5 MNk: 297.74

Example 6

Benzotriazol-1-yl-(4-bromo-piperidin-1-yl-methanone)

MNK: 310.3

Example 7

Benzotriazol-1-yl-(4-fluoromethyl-piperidin-1-yl)-methanone

MANk: 299.18

Example 8

Benzotriazol-1-yl-(1,3-dihydro-isoindol-2-yl)-methanone c (8) o "

Fo

MaNzhk: 265.0

Example 9 (22)

Methyl ether of 1-(3,6-dihydro-2H-pyridine-1-carbonyl)-1H-benzotriazole-5-carboxylic acid Ge! m. o « shi s Men: 287.04 "» Example 10 " (3,6-dihydro-2H-pyridin-1-yl)-(5-nitro-benzotriazol-1-yl)-methanone 0 -i o se ) se)

M'-Ma: 296.21 se) Example 11" (3,4-dihydro-1H-isoquinolin-2-yl)-(5-nitro-benzotriazol-1-yl)-methanone c)

Same about

F) name) 60 MNzhk: 324.10

Example 12 (5-bromo-benzotriazol-1-yl)-(3,6-dihydro-2H-pyridin-1-yl-methanone b5

Ve

MAN: 306.98

Example 13 70 (5-bromo-benzotriazol-1-yl)-(3-trifluoromethyl-piperidin-1-yl-methanone and Y and , di

MNK: 377.30

Example 14 (5-bromo-benzotriazol-1-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone with (8)

MNK: 357.04

Example 15

Benzotriazol-1-yl-(octahydro-isoindol-2-yl)-methanone "

Fo (22) (22) at m.

MNK: 271.15

Example 16 "(7-amino-3,4-dihydro-1H-isoquinolin-2-yl)-benzotriazol-1-yl-methanone - c;" o -I so MNK: 294.0

Example 17 (3,4-dihydro-1H-isoquinolin-2-yl)-(5-methoxy-benzotriazol-1-yl)-methanone se) 59 e "U,

F)

MAN: 309.04 o Example 18 (5-methoxy-benzotriazol-1-yl)-(3-methyl-piperidin-1-yl)-methanone 60 o 65 9-0

MNK: 275.5

Example 19 (6b-amino-benzotriazol-1-yl)-(4-methyl-piperidin-1-yl)-methanone ch 70 o

MNk: 260.1

Example 20 (5-chloro-benzotriazol-1-yl)-(4-methyl-piperidin-1-yl)-methanone

My

MNK: 279.6

Example 21

Benzotriazol-1-yl-(1,2,6-triaza-spiro|2.5|oct-1-en-6-yl)-methanone c 6 7 (o) b these in "and"

Fo

M--Matk: 279.19 b

Example 22

Benzotriazol-1-yl-(4-ethyl-piperidin-1-yl)y-methanone me) m.

Example 23 15 (4-methyl-piperidin-1-yl)-(b-nitro-benzotriazol-1-yl)-methanone - Kk t

I"e) sh- se) shchi b sn, s"

MaNzhk: 290.4

Example 24

1-(Benzotriazole-1-carbonyl)-piperidine-4-carboxylic acid ethyl ester

IF) with and ( because o o o

MANk: 303.13 65 Example 25

Benzotriazol-1-yl-(4-methyl-piperidin-1-yl-methanone)

MNK: 245.0

Example 26 3-(4-methyl-piperidine-1-carbonyl)-ZH-benzotriazole-5-carbonitrile

MaNzhk: 270.12

Example 27

Benzotriazol-1-yl-(3,4-dihydro-1H-isoquinolin-1-yl)y-methanone c (8) o zo MANk: 279.11 h

Example 28 (o)

Benzotriazol-1-yl-(3,4-dihydro-2H-quinolin-1-yl)y-methanone b» m (c) m. o

Me: 279.2 "

Example 29 with (b-methyl-benzotriazol-1-yl)-pyrrolidin-1-yl-methanone, Mana: 231.11

Ge) Example 30

Benzotriazol-1-yl-(3-methyl-piperidin-1-yl-methanone se) n U o

F)

Mnk: 245.13 ke ,

Example 31 in Benzotriazol-1-yl-(3,4-dimethyl-piperidin-1-yl)y-methanone b5 at 70 MANk: 259.14

Example 32 (1-(4-methyl-piperidine-1-carbonyl)-1H-benzotriazol-5-yl|-phenyl-methanone 7 cc,

MANzhk: 349.15

Example 33 (4-methyl-piperidin-1-yl)-(5-trifluoromethyl-benzotriazol-1-yl)y-methanone c in (8) o C

MNK: 313.5 F

Example 34 Ge) (6-bromo-benzotriazol-1-yl)-(4-methyl-piperidin-1-yl-methanone b" and - o "

MNK: 324.0 C s Example 35 i » Benzotriazol-1-yl-(4-tert-butyl-piperidin-1-yl)-methanone -I (se; o sn,

I"e) t so 50 MaNzhk: 287.17 Example 36 (5-(hydroxy-phenyl-methyl)-butiotriazol-1-yl)-(4-methyl-piperidin-1-yl)-methanone c"

F) 0 name)

MAN: 350.17 60 Example 37 (4-methyl-piperidin-1-yl)-(5-phenoxy-benzotriazol-1-yl)-methanone b5 o

MNK: 337.3

Example 38 70 (3-cyclohexylsulfanyl-benzotriazol-1-yl)-(4-methyl-piperidin-1-yl-methanone)

With M. o

MANk: 359.17

Example 39

Benzotriazol-1-yl-(4-isopropyl-piperidin-1-yl)-methanone o i i) i, (5)

MNK: 273.3

Example 40 g zo (b-chloro-benzotriazol-1-yl)-(4-methyl-piperidin-1-yl)-methanone (22) (22) (22) o i -

MNK: 279.5

Example 41 "

Benzotriazol-1-yl-(b-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)y-methanone with c;" 0 -I se) MaNzhk: 309.3 so Example 42

Benzotriazol-1-yl-(4-benzyl-piperidin-1-yl-methanone se) c» o

F)

MNK: 321.3 o Example 43 (5-bromo-benzotriazol-1-yl)-(3-methyl-piperidin-1-yl-methanone) 60 b5 s

MAN: 325.31

Example 44 1-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-1H-benzotriazole-5-carbonitrile 5 . DZ no

SHE

MaNzhk: 270.12

Example 45 /5 (4-chloro-6-trifluoromethyl-benzotriazol-1-yl)-(3,4-dihydro-1H-isoquinolin-2-yl-methanone; : c

MANk: 381.06 o

Example 46 1-(3,4-dihydro-2H-quinoline-1-carbonyl)-1H-benzotriazole-5-carbonitrile "

Pho (22) (22)

MANk: 304.11 cha

Example 47 (4-chloro-6-trifluoromethyl-benzotriazol-1-yl)-(3,6-dihydro-2H-pyridin-1-yl-methanone "shi c ;" im МНк: 331.04 (se) Example 48 so Benzotriazol-1-yl-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)y-methanone o 50 s» o o MANk: 309.1 ime) Example 49 (5-methoxy-benzotriazole -1-yl)-(4-methyl-piperidin-1-yl)-methanone 60 a b5

MNK: 275.3

Example 50 (3,4-dihydro-1H-isoquinolin-2-yl)-(b-nitro-benzotriazol-1-yl)-methanone 70 o y )

MN: 324.3

Example 51 (6-benzoyl-benzotriazol-1-yl)-(4-methyl-piperidin-1-yl)-methanone, t o

MANzhk: 349.15

Example 52

Benzotriazol-1-yl-(7-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone

MNk: 324.1

Example 53 F

Azepan-1-yl-benzotriazol-1-yl-methanone (o) (22) m. 0

MNK: 245.3 "

Example 54 - with Benzotriazol-1-yl-(4-chloro-piperidin-1-yl)-methanone;» -I s se) jan: s MNK: 265.7

Example 55 (Ce) 20 Benzotriazol-1-yl-(3,6-dihydro-2H-pyridin-1-yl)-methanone c»

Claims (13)

Formula of the invention 55 e 1. Benzotriazoles of the general formula HF) Kk that ko 2 M "m 60 eZ M Hom vv Kk a M Kk 65 KE where: K1-K8 mean H, and one of the residues K2 or KZ can mean Bg, SI, CH3, CM, MH», MO», CE3, OSH»3, phenoxy, benzoyl, CH(OH)-phenyl, 5-cyclohexyl, SO-OSN"; or two substitutes from this series mean K1- SI and KZ - SEz or K2- GE and Kz - SI; n means an integer 0, 1 or 2; and 70 one of the substitutes Kb or K7 can mean Kb - SNU"; Kk? - СН», СОН; СН(СНУ)», С(СН»у)»з, CE», Vg, SI, benzyl or СО-ОСОН5Б; or Kv and K7 both mean CH"; or the ring instead of Kb and K7 may contain a double bond, or K5 and Kb, or Kb and K7 may mean, together with the C atoms to which they are connected, a benzanellated ring, or in the case of p-O also cyclohexanediyl, and in in the case of cyclization of Kb/K7, this substituent, if necessary, can be replaced once with the help of МН» or MO», or once or twice with the help of OSN»; and K?7 and K8 together mean cyclopentyl, diazepine or "CH"; at the same time, compounds where K1-K5 and КВ - H, n - 1 and Кб/Кк7 - benzanellated ring, and К1, К3-К8 - Н, 2 - Snzip - 1 are excluded. 2. Benzotriazoles of the general formula I according to claim 1 E M Iv MI i s M o Z Mra 4 I o M chn h 5 F EV where: o K1-K8 mean H, He»! and one of the K2 or KZ residues can mean КО - В, СИ, СМ, МО», СЕз, ОСН»з, phenoxy, benzoyl, CH(OH)-phenyl, 5-cyclohexyl, СО-ОСН»; - KZ - CH», SM, Vg, SI, MH», MO», benzoyl. 3. Benzotriazoles of the general formula | according to claim 1 or 2, where: 21-28 mean H, "and one of the K2 or KZ residues can mean: - т0 в2 - В, СИ, МО", ОСН3, phenoxy, СО-ОСН"; с 3 - МН», or Из» two substituents from this series are: К2-БгЕ КЗ - СИ; n means an integer 1 or 2; and one of the substitutes K5 or Kb can mean: and вв - СН; (se) KK? - СН», СЕз or Вг, or the ring instead of Кб and К7 may contain a double bond, or ОКб and К7 may mean, together with the C atoms with which they are connected, a benzanellated ring, which, in the case of (се) 20 if necessary, can be replaced once with the help of MH", or once or twice with the help of OSN"; and K?7 and K8 together mean cyclopentyl, or T» n means an integer 0; and Kb and K7 can mean, together with the C atoms to which they are connected, a benzanellated ring or cyclohexanediyl. 4. Benzotriazoles of the general formula I according to any of claims 1-2, where HF) K1-K8 mean H, and one of the residues K2 or KZ can mean: o K2 - W, CM, CEz, OSN", phenoxy, benzoyl , CH(ION)-phenyl, 5-cyclohexyl; KZ - SM, Vg, SI, MO", benzoyl; or 60 two substitutes from this series are: K1-SIi KZ - SE"; n means the integer 1; and one of the substitutes Kb or K7 can mean: Kb - SNU"; because 7 - СНа, СоНв; СН(СНаИ)», С(СНа)з, benzyl or СО-ОСоН; or Kb and K7 both mean CH"; or the ring instead of Kb and K7 may contain a double bond, or K5 and Kb, or Kb and K7 may mean, together with the C atoms with which they are connected, a benzanellated ring, this excludes compounds where K1-k5ik8-H ,p-1st Kv/K7 - benzanelled ring. 5. Benzotriazoles according to claim 1 of the following structures: vn 'n | y 70 - -sh-O--M N ya U y TV) ICH o sn, an, M scho M y de-n a ee, ' M she M s y y--m (o) p y u « r F a , Me de te, M F s shle M - y dm ; IV) E E « E khan M, , - s | p, I I o sn, -I vij ' Ge) | M shi (se) Zh-sh7 ish (v. Ve GT» Za, ' M dom Y GF) y E ka E E bo p M, ' M y M y o De Shyny a-sUNya, A. V I that Os Mary a ss 70 nn to S syn sht m Za t M ri -E a Ш щ Ше o Ve o E Z E I M er "I zo o o Venya Ge) u Ge) Ho m M. --E E - , s yam i» mg) -| y M ' h--T (se) 7 you I" - shi. o o a ko -y M , in Zh nd; I sleep and - about b5 Btevn M se Kk N I is (8) sn, S - M, , 70 | M ne M Zh u o sna MI deE-m /y a a her MI Schi MI yam o d-m 8) 6. Benzotriazoles according to claim 1 of the following structures: - Still M | Me. IR where in. (2) p (o) І и и сн that | 5 - I with 40 ok sh-E M - I! in xz" o u. SNI I , She nya o S Y sn (se) OM ( a Ж Ф dm b o se) I» 9 IC that y y F) M mime) 9 sna bo zem, ' MI and -E to U ХК MI 9 s b5 same ' Moyshe M x -t-- d-k a y rya not U M V, o M ' V; M sna no Ge: same M, 'in shk te) srya o o snu sna h | with TO) | n M.; F M - - M Me -k7 F 9 Sn, - E , E E tery, " M detl-ki - s z-- y . M i o i She M. ' m; (se) Ve yam / so U still sleep, Y» nim, ' M i -M iy d-k sleep, F) 9 sleep with o) Not ON , because s I Sean M. her no pnyo M y- b5 o dream WITH? eh, ' M sh- dk and dk o sn, 5 p M. ; | she and dk about sleep, in M , M m - Y m sleep, about SNI same, ' m sch s det in (5) dm about sleep "I earth, M F KOM -- Ge) d-shch . and more (is) dream i-m t M - « d-7 in uk - s o ni o shchi nrav i . M sir (se) so sleep Fo her -aM GT» Sho M - M ev | - F) ko 60 65 si ! and and 9 M. E ICH E that | and I (8) --EM shk more / M sir --; that si E m, sch M. and E about TP; on the 1st day of the 8th iy - M o o oi still "sna sh - In p-o M, ' " not I. And (se) Go and (Ge) (Ge) - sa, і" that | r Y m o d-m y sn, o 1 I ko Shk M o, in: bo 4 y ry Shik: oi Ky b5 te, ' M i -M /y Ba that Shchi MI - m 2-7 about her 7. Benzotriazoles of the following structures according to claim 6: p y , s - And p -mi; and M o I ra (8) D-k 9 « sn, M Fo i y in; iy nt M F nu i- o sna IC ' -- x vina 5 dim o d--- s y rya ;" they, M - ; t em sna KE no se) o o 50 I ' en, iz» | m sche -m 99 Hm 7 o GF) SNI o snia in Zenn M, ' M -E M sche o 65 sn, No Zones, ' M m - y o pk sna si M u nku. o sn z te, ' M -E M Shk Kk ben h y zim, ' M sm de (o) dn teo oN a | a tya « U M ' M K Ko (22) that M -- on Ge") Kk d-- F i - Shchi M sh--M « y-m7 - s o re "» 8. Benzotriazoles of the following structures according to claim 7: And ' | She m -| k- M se) Kk Hm so y s sna 2» , t tlia, M nt M y F) U. sn, ime) ZM, ' because | M -E M -k7 sleep (8) sleep, 65 ny -A1- Zones, ' M m - y MI sna o SNI 70 topics, M y si M unku. o sn z te, ' M -E M Shk /y y-m x y (8) zim, M cm M dn teo oN shchi a | and the mouth! ko, M zo 9. The method of obtaining compounds of formula I according to claims 1-8, which differs in that: a) benzotriazole 2 is acylated with carbamoyl chlorides 3, or Me B) benzotriazoles 2 are first subjected to transformation with phosgene, and then the obtained anhydrides of He! benzotriazole carboxylic acids 5 are subjected to reaction with amines or anilines to obtain compounds of formula I, in which the substituents have the above-mentioned values, M 3 M Ez U p V ch ia Ro sche pdyati sche - s z» ko kb 2 z 1 - s M slya SHY; NE so v aa R 7 se) she M y iy M, 5 ge IC! ---- M -- - -yayu- 1 (se) i i eZ M eZ M I» rya pi SI 4 o Ge) 2 no kyu 10. Benzotriazoles of the general formula I: 60 б5 в что жо MI Мх еЗ Мра 4 а MI Кк ко ЕБб where: К1-К8 mean H, and one of the residues К2 or КЗ can mean Вг, СИ, СН3, СМ, МН », MO», SEz, OSN»z, phenoxy, benzoyl, CH(OH)-phenyl, 5-cyclohexyl, СО-ОСН»; 19 or two substitutes from this series are: K1- SI 3 - SEz; or K2-g iz - SI; n means an integer 0, 1 or 2; and one of the substitutes Kb or K7 can mean: Kb - SNU"; Kk? - СН», СОН; СН(СНУ)», С(СН»у)»з, CE», Vg, SI, benzyl or СО-ОСОН5Б; or Kb and K7 both mean CH"; or c ring instead of Kb and K7 can contain a double bond, or Ge) K5 and Kb, or Kb and K7 can mean, together with the C atoms with which they are connected, a benzanellated ring, or in the case of n - 0 also cyclohexanediyl , and in the case of cyclization of Kb/K7, this substituent, if necessary, can be replaced once with the help of МН» or MO», or once or twice with the help of OSN»; and K?7 and K8 together mean cyclopentyl, diazepine or "CH"; With for use in a medicinal product. Gee! 11. Benzotriazoles of formula I! according to claim 10 for use in a medicinal product with an inhibitory effect on hormone-sensitive lipases, NOI. ia 12. Benzotriazoles of the formula ! according to claim 10 for use in a medicinal product for the treatment of He! non-insulin-dependent diabetes mellitus, diabetic syndrome or H. Zo syndrome 13. Medicinal product for the treatment of non-insulin-dependent diabetes mellitus or diabetic syndrome, which - contains at least one benzotriazole of formula I according to claim 10. - c ;" -I se) se) o 50 s» F) ime) 60 b5