HK1120500A

HK1120500A - Benzothiazol-2-on derivatives as lipase and phospholipase inhibitors

Info

Publication number: HK1120500A
Application number: HK08112253.9A
Authority: HK
Inventors: Gerhard Zoller; Stefan Petry; Günter Müller; Hubert Heuer; Norbert Tennagels
Original assignee: Sanofi-Aventis
Priority date: 2005-06-09
Filing date: 2006-05-27
Publication date: 2009-04-03

Description

benzothiazol-2-one derivatives as lipase and phospholipase inhibitors

The present invention relates to benzothiazol-2-one derivatives of general formula I, their pharmaceutically acceptable salts and their use as pharmaceutical substances.

Benzothiazolone derivatives of similar structure are described in EP 0334134, EP 0391186 and DE 2101150. However, these compounds are used as insecticides and fungicides.

Compounds having an inhibitory effect on hormone sensitive lipase are described in the prior art, for example in WO2004/035550, WO2005/073199 or WO 03/051842. Compounds having an inhibitory effect on endo-sebacase are described in the prior art, for example in WO2004/094394, WO 2004/094393.

It is an object of the present invention to provide compounds having an inhibitory effect on hormone sensitive lipase or endothelial lipase.

The invention relates to benzothiazol-2-one derivatives of general formula (I)

Wherein the radicals have the following meanings:

r1 is (C)₅-C₁₆) Alkyl radicals, (C)₁-C₄) -alkylene- (C)₆-C₁₀) -aryl, (C)₁-C₄) -alkylene radical

-(C₅-C₁₂) -heteroaryl, (C)₁-C₄) -alkylene- (C)₄-C₁₂) -cycloalkyl, (C)₈-C₁₄) -two

Ring, wherein aryl, heteroaryl, cycloalkyl or bicyclic ring may be substituted by halogen, (C)₁-C₆)-

Alkyl, (C)₁-C₃) -alkoxy, hydroxy, (C)₁-C₆) Alkylthio, amino, (C)₁-C₆)-

Alkylamino, di- (C)₂-C₁₂) Alkylamino, mono- (C)₁-C₆) -alkylaminocarbonyl radical,

Di- (C)₂-C₈) -alkylaminocarbonyl, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) -alkylcarbonyl

Radical, cyano, trifluoromethyl, trifluoromethoxy, (C)₁-C₆) -alkylsulfonyl or amino

Sulfonyl is substituted one or more times;

r2 is hydrogen, (C)₁-C₆) -an alkyl group; or

R1 and R2 together with the nitrogen atom to which they are attached form a monocyclic saturated or partially unsaturated 4-to

A 7-membered ring system or a bicyclic saturated or partially unsaturated 8-to 14-membered ring system, wherein the ring

Each member of the series may be substituted by 1 to 3 groups selected from-CHR 8-, -CR8R8a-,

-(C＝R8)-、-NR9-、-C(＝O)-、-O-、-S-、-SO-、-SO₂of an atom of (A) or

Radicals are substituted, provided that two are selected from-O-, -S-, -SO-, -SO%₂-a unit of

May not be contiguous;

r3, R4 and R5 are hydrogen, halogen, (C)₁-C₆) Alkyl radicals, (C)₁-C₃) -alkoxy- (C)₁-C₃) Alkylene, hydroxy

Base, (C)₁-C₆) Alkylthio, amino, (C)₁-C₆) Alkylamino, di- (C)₂-C₁₂) -alkanes

Alkylamino radical, (C)₁-C₆) -alkylcarbonyl, CO-OR7, trifluoromethyl, (C)₁-C₆) -alkyl radical

Sulfonyl group, (C)₁-C₆) -alkylsulfinyl, aminosulfonyl, pentafluorothio, (C)₆-C₁₀)-

Aryl group, (C)₅-C₁₂) -heteroaryl, CO-NR9R10, O-CO-NR9R10,

O-CO-(C₁-C₆) alkylene-CO-O- (C)₁-C₆) Alkyl, O-CO- (C)₁-C₆) Alkylene (E) s

The radicals-CO-OH, O-CO- (C)₁-C₆) alkylene-CO-NR 9R10 or unsubstituted or

Mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

r6 is hydrogen, (C)₁-C₃) -alkoxy- (C)₁-C₃) Alkylene, hydroxy, (C)₁-C₆) -an alkylthio group,

Amino group, (C)₁-C₆) Alkylamino, di- (C)₂-C₁₂) -alkylamino, pentafluorothio,

(C₆-C₁₀) -aryl, (C)₅-C₁₂) -heteroaryl, CO-NR9R10, O-CO-NR9R10,

The radicals-CO-OH, O-CO- (C)₁-C₆) alkylene-CO-NR 9R10 or unsubstituted or

Mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

with the proviso that at most one of the substituents R3, R4, R5 is halogen, trifluoromethyl or

(C₁-C₆) -an alkyl group;

r7 is hydrogen, (C)₁-C₆) -alkyl, benzyl;

r8, R8a are, identically or differently, (C)₁-C₆) Alkyl, haloPlain, trifluoromethyl, CO-OR7, Ring

Propyl, cyclopropylene;

r9, R10 are hydrogen, (C) identically or differently₁-C₆) Alkyl, - (C)₆-C₁₀) -aryl, (C)₅-C₁₂) -hetero

Aryl group, (C)₃-C₁₂) -cycloalkyl, (C)₁-C₄) -alkylene- (C)₆-C₁₀) -aryl, (C)₁-C₄)-

Alkylene- (C)₅-C₁₂) -heteroaryl, (C)₁-C₄) -alkylene- (C)₃-C₁₂) -a cycloalkyl group,

(C₈-C₁₄) -a bicyclic ring;

tautomeric forms of the compounds and their physiologically tolerated salts.

Preferred compounds of the formula I are those in which the radicals have the following meanings:

r1 is (C)₆-C₁₂) Alkyl radicals, (C)₁-C₃) -alkylene- (C)₆-C₁₀) -aryl, (C)₁-C₃) -alkylene radical

-(C₅-C₁₂) -heteroaryl, (C)₁-C₃) -alkylene- (C)₄-C₁₂) -cycloalkyl, (C)₄-C₁₂) -two

Alkyl, (C)₁-C₃) -alkoxy, hydroxy, amino, (C)₁-C₆) -alkylamino, trifluoro

Methyl substitution one or more times;

r2 is hydrogen, (C)₁-C₆) -an alkyl group; or

R1 and R2 together with the nitrogen atom which carries them are monocyclic, saturated 5-to 6-membered ring systems or bicyclic rings

A saturated or partially unsaturated 9-to 10-membered ring system of (a), wherein each member of the ring system may be

Is substituted by 1 to 3 groups selected from-CHR 8-, -CR8R8a-, - (C ═ R8) -, -NR9-, -O-, (C ═ R8) -, -C-R9-),

-S-is replaced by an atom or group of atoms, provided that two units selected from-O-, -S-are not available

Are contiguous;

r3, R4 and R5 are, identically or differently, hydrogen, halogen, trifluoromethyl, (C)₁-C₆) Alkyl radicals, (C)₁-C₃)-

Alkoxy radical- (C₁-C₃) Alkylene, hydroxy, amino, mono- (C)₁-C₆) -alkylaminocarbonyl radical,

Di- (C)₂-C₈) -alkylaminocarbonyl, COOR7, (C)₁-C₆) -alkylsulfonyl, amino

Sulfonyl, pentafluorothio, (C)₆-C₁₀) -aryl, (C)₅-C₁₂) -heteroaryl, (C)₁-C₆)-

Alkylcarbonyl, CO-NR9R10, O-CO-NR9R10, O-CO- (C)₁-C₆) Alkylene (E) s

radical-CO-O- (C)₁-C₆) Alkyl, O-CO- (C)₁-C₆) -alkylene-CO-OH,

O-CO-(C₁-C₆) alkylene-CO-NR 9R10 or unsubstituted or mono-or poly-F-substituted

Generation (C)₁-C₆) -an alkoxy group;

r6 is hydrogen, (C)₁-C₃) Alkoxy radical- (C₁-C₃) Alkylene, hydroxy, amino, (C)₁-C₆) -alkanes

Alkylamino, di- (C)₂-C₁₂) Alkylamino, mono- (C)₁-C₆) -alkylaminocarbonyl, di

-(C₂-C₈) -alkyl-aminocarbonyl group, (C)₆-C₁₀) -aryl, (C)₅-C₁₂) -a heteroaryl group,

CO-NR9R10 or unsubstituted or mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

(C₁-C₆) -an alkyl group;

r7 is hydrogen, (C)₁-C₆) -alkyl, benzyl;

r8, R8a are, identically or differently, (C)₁-C₆) Alkyl, halogen, trifluoromethyl, COOR7, Ring

Propyl, cyclopropylene;

r9, R10 are hydrogen, (C) identically or differently₁-C₆) Alkyl radicals, (C)₆-C₁₀) -aryl, (C)₅-C₁₂) -hetero

Alkylene- (C)₅-C₁₂) -heteroaryl, (C)₁-C₄) -alkylene- (C)₄-C₁₂) -a cycloalkyl group.

Preferred compounds of the formula I are also those in which the radicals have the following meanings:

Methyl substitution one or more times;

r2 is hydrogen, (C)₁-C₆) -an alkyl group; or

Are contiguous;

Alkoxy radical- (C₁-C₃) Alkylene, hydroxy, amino, COOR7, (C)₁-C₆) -alkyl sulfonic acid

Acyl, aminosulfonyl, pentafluorothio, (C)₆-C₁₀) -aryl, (C)₅-C₁₂) -a heteroaryl group,

(C₁-C₆) -alkylcarbonyl, CO-NR9R10, O-CO-NR9R10,

The radicals-CO-OH, O-CO- (C)₁-C₆) alkylene-CO-NR 9R10 or unsubstituted or

Mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

-(C₂-C₈) -alkylaminocarbonyl, (C)₆-C₁₀) -aryl, (C)₅-C₁₂) Heteroaryl or not

Substituted or mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

(C₁-C₆) -an alkyl group;

r7 is hydrogen, (C)₁-C₆) -alkyl, benzyl;

Propyl, cyclopropylene;

r9, R10 are hydrogen, (C) identically or differently₁-C₆) Alkyl radicals, (C)₆-C₁₀) -aryl, (C)₁-C₄) Alkylene (E) s

Radical- (C)₆-C₁₀) -an aryl group.

Particularly preferred compounds of the formula I are those in which the radicals have the following meanings:

Methyl substitution one or more times;

r2 is hydrogen, (C)₁-C₆) -an alkyl group; or

Are contiguous;

r3, R4 and R5 are, identically or differently, hydrogen, halogen, trifluoromethyl, (C)₁-C₆) Alkyl, hydroxy, ammonia

Group, COOR7, (C)₁-C₆) -alkylsulfonyl, aminosulfonyl, pentafluorothio,

(C₁-C₆) -alkylcarbonyl, CO-NR9R10, O-CO-NR9R10,

The radical-CO-OH or unsubstituted or mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

r6 is hydrogen, hydroxy, amino, (C)₁-C₆) -alkylamino radicalDi- (C)₂-C₁₂) -alkylamino, alkylamino,

Mono- (C)₁-C₆) -alkylaminocarbonyl, di- (C)₂-C₈) -alkylaminocarbonyl or unsubstituted

Or mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

(C₁-C₆) -an alkyl group;

r7 is hydrogen, (C)₁-C₆) -an alkyl group;

r8, R8a are, identically or differently, (C)₁-C₆) -alkyl, halogen, trifluoromethyl, cyclopropyl;

r9, R10 are hydrogen, (C) identically or differently₁-C₆) -an alkyl group.

Further particularly preferred compounds of the formula I are those in which the radicals have the following meanings:

r1 is (C)₆-C₁₂) -alkyl, benzyl, (C)₁-C₃) -alkylene- (C)₅-C₁₂) -heteroaryl, (C)₁-C₃)-

Alkylene- (C)₄-C₁₂) -cycloalkyl, (C)₈-C₁₄) -bicyclic, wherein benzyl, heteroaryl, C,

Cycloalkyl or bicyclic rings may be substituted by halogen, (C)₁-C₆) Alkyl radicals, (C)₁-C₃) -alkoxy or tri

Fluoromethyl substitution;

r2 is hydrogen; or

R1 and R2 together with the nitrogen atom carrying them form a monocyclic, saturated 5-to 6-membered ring system which is a cyclic ring

Each member of the mesoring system may be substituted by 1 to 2 atoms selected from-CHR 8-, -NR 9-or

Radical substitution, wherein R8 is as defined above, and R9 is (C)₁-C₆) -alkyl or

And (3) cyclopropyl.

Further particularly preferred compounds of the formula I are also those in which the radicals have the following meanings:

r1 is (C)₆-C₁₂) -alkyl, benzyl, (C)₁-C₂) -alkylene- (C)₅-C₁₂) -heteroaryl, (C)₁-C₂)-

Fluoromethyl substitution;

r2 is hydrogen; or

Each member of the mesoring system may be interrupted by 1 to 2 atoms selected from-CHR 8-, -NR 9-)

Or a radical substitution, wherein R8 is as defined above, and R9 is (C)₁-C₆) -alkyl radical

Or a cyclopropyl group.

Very particularly preferred compounds of the formula I are those in which the radicals have the following meanings:

r1 is (C)₇-C₁₂) -alkyl, benzyl, (C)₁-C₃) -alkylene- (C)₅-C₁₂) -heteroaryl, (C)₁-C₃)-

Alkylene- (C)₄-C₁₂) -cycloalkyl or (C)₈-C₁₄) -bicyclic, wherein benzyl, heteroaryl, C,

Fluoromethyl substitution;

r2 is hydrogen;

r3, R4 and R5 are, identically or differently, hydrogen, halogen, hydroxy, (C)₁-C₆) -alkyl, trifluoromethyl or not

Substituted or mono-or poly-F-substituted (C)₁-C₆) -alkoxy groups.

Very particularly preferred compounds of the formula I are also those in which the radicals have the following meanings:

r1 is (C)₆-C₁₂) -alkyl, benzyl, CH₂-(C₅-C₁₂) -heteroaryl or (C)₈-C₁₄) -a bicyclic ring,

wherein benzyl, heteroaryl or bicyclic radicals may be substituted by halogen, (C)₁-C₆) Alkyl radicals, (C)₁-C₃)-

Alkoxy or trifluoromethyl substitution;

r2 is hydrogen;

r3, R4 and R5 are, identically or differently, hydrogen, halogen, hydroxy, (C)₁-C₆) -alkyl, trifluoromethyl or

Unsubstituted or mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

r6 is hydrogen.

Further very particularly preferred compounds of the formula I are those in which the radicals have the following meanings:

r1 is (C)₆-C₁₂) -alkyl, benzyl, wherein benzyl may be substituted by methyl;

r2 is hydrogen;

r3 is hydrogen;

r4, R5 are, identically or differently, hydrogen, halogen, trifluoromethyl;

r6 is hydrogen.

Compounds of formula I wherein R3 is hydrogen are a preferred embodiment of the present invention.

Further preferred compounds of the formula I are those in which R3, R6 are hydrogen and R4 or R5 are not hydrogen.

The present invention relates to compounds of formula I in the form of their salts, racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.

The alkyl groups in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R8a, R9 and R10 may be straight-chain or branched. Halogen is fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

Aryl means an aromatic carbocyclic monocyclic or bicyclic ring system containing 6 to 10 atoms in one or more rings.

Heteroaryl is a monocyclic or bicyclic aromatic ring system having 5-12 ring members, wherein at least one atom in the ring system is a heteroatom selected from N, O and S.

Suitable "heteroaryl rings" or "heteroaryl groups" are, for example, benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, furanyl, furazanyl, imidazolyl, 1H-indazolyl, indolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, thiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thienyl.

Preferred heteroaryl groups are thienyl, pyridyl and pyrazolyl. The heteroaryl ring or heteroaryl group may be substituted one or more times with suitable groups.

Cycloalkyl is a ring system comprising one or more rings, which is saturated or partially unsaturated (having one or two double bonds), consisting exclusively of carbon atoms. The cycloalkyl group may be substituted one or more times by a suitable group.

Bicyclic means bicyclic ring systems which are in saturated or partially unsaturated form and which may contain, in addition to carbon, one or more heteroatoms such as nitrogen, oxygen or sulfur. This definition also includes ring systems comprising a fused benzene nucleus. Examples which may be mentioned are tetrahydronaphthyl, alpha-or beta-tetrahydronaphthalenonyl, indanyl or indan-1-one-yl. Preferred bicyclic radicals are those of the formula Ic

q is 1 or 2.

Pharmaceutically acceptable salts are particularly suitable for pharmaceutical applications because they are more water soluble than the starting or base compound. 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 acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and salts of organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric acid. Suitable pharmaceutically acceptable base salts are ammonium, alkali metal (e.g. sodium and potassium) and alkaline earth metal (e.g. magnesium and calcium) salts and salts of tromethamine (2-amino-2-hydroxymethyl-1, 3-propanediol), diethanolamine, lysine or ethylenediamine.

Salts with pharmaceutically unacceptable anions such as trifluoroacetate are likewise encompassed by the scope of the present invention, as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic, e.g. in vitro, applications.

The term "physiologically functional derivative" as used herein refers to any physiologically tolerated derivative of a compound of formula I according to the invention, for example an ester, which on administration to a mammal such as a human is capable of (directly or indirectly) generating a compound of formula I or an active metabolite thereof.

Physiologically functional derivatives also include prodrugs of the compounds of the invention, for example as described in h.okada et al, chem.pharm.bull.1994, 42, 57-61. Such prodrugs can be metabolized in vivo to the compounds of the invention. These prodrugs may themselves be active or inactive.

The compounds of the present invention may also exist in various polymorphic forms, for example in amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are covered by the scope of the invention and are a further aspect of the invention.

All references hereinafter to "compounds of formula I" refer to compounds of formula I as described above, as well as their salts, solvates and physiologically functional derivatives as described herein.

Use of

The compounds of the general formula I according to the invention in which the radicals have the following meanings:

Radical, cyano, trifluoromethyl, trifluoromethoxy, (C)₁-C₆) -alkylsulfonyl, amino

Sulfonyl is substituted one or more times;

r2 is hydrogen, (C)₁-C₆) -an alkyl group; or

-(C＝R8)-、-NR9-、-C(＝O)-、-O-、-S-、-SO-、-SO₂of an atom of (A) or

May not be contiguous;

r3, R4 and R5 are, identically or differently, hydrogen, halogen, (C)₁-C₆) Alkyl radicals, (C)₁-C₃) -alkoxy- (C)₁-C₃)-

Alkylene, hydroxy, (C)₁-C₆) Alkylthio, amino, (C)₁-C₆) -alkylamino, di

-(C₂-C₁₂) -alkylamino, - (C)₁-C₆) -alkylcarbonyl, CO-OR7, trifluoromethyl,

(C₁-C₆) -alkylsulfonyl, (C)₁-C₆) -alkylsulfinyl, aminosulfonyl, pentakis

Fluorosulfonyl group, (C)₆-C₁₀) -aryl, (C)₅-C₁₂) -heteroaryl, CO-NR9R10,

O-CO-NR9R10、O-CO-(C₁-C₆) alkylene-CO-O- (C)₁-C₆) -an alkyl group,

O-CO-(C₁-C₆) alkylene-CO-OH, O-CO- (C)₁-C₆) -alkylene radical

-CO-NR9R10 or unsubstituted or mono-orpoly-F-substituted (C)₁-C₆) -an alkoxy group;

(C₆-C₁₀) -aryl, (C)₅-C₁₂) -heteroaryl, CO-NR9R10, O-CO-NR9R10,

The radicals-CO-OH, O-CO- (C)₁-C₆) alkylene-CO-NR 9R10 or unsubstituted or

Mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

r7 is hydrogen, (C)₁-C₆) -alkyl, benzyl;

r8, R8a are, identically or differently, (C)₁-C₆) Alkyl, halogen, trifluoromethyl, CO-OR7, Ring

Propyl, cyclopropylene;

(C₈-C₁₄) -a bicyclic ring;

the tautomeric form of the compound and its physiologically tolerated salts have a surprising inhibitory effect on hormone sensitive lipase (HSL, an allosteric enzyme) in adipocytes that are inhibited by insulin, responsible for the destruction of fat in adipocytes and thus for the transfer of fat components into the bloodstream. Thus, inhibition of this enzyme equates to an insulin-like action of the compounds of the invention, which ultimately results in a reduction of free fatty acids in the blood and blood glucose. They are therefore useful in metabolic disorders, for example in non-insulin dependent diabetes mellitus, diabetic syndrome (diabetes syndrome) and direct pancreatic damage (direct pancreatic lesion).

The compounds of the general formula I according to the invention, in particular those in which R2 is hydrogen, can also have an inhibitory effect on Endothelial Lipase (EL). For EL, the preferred substrate is HDL, which has anti-atherosclerotic activity. The reduction of HDL levels leads to the progression of atherosclerosis and its sequelae, such as coronary heart disease, and also contributes to the development of metabolic syndrome and its sequelae diabetes. Inhibition of EL should therefore generally lead to the prevention of atherosclerotic disorders and indirectly reduce the possibility of disease development in people at increased risk of diabetes.

It has also been found that the inhibition by the compounds of formula I according to the invention is selective with respect to other lipases.

The compounds of formula I according to the invention may also have an inhibitory effect on triglyceride lipase.

The compounds are particularly suitable for the treatment and/or prophylaxis

1. Disorders of fatty acid metabolism and glucose utilization

2. Insulin sensitivity disorder (insulin resistance) of muscle cells, adipocytes and hepatocytes metabolic syndrome.

3. Diabetes, particularly type 2 diabetes, includes the prevention of its associated sequelae.

In this case, the specific aspects are

-a high blood sugar level,

-an improvement in insulin resistance, and,

-an improvement in glucose tolerance,

-protection of the pancreatic beta cells,

prevention of macrovascular and microvascular disorders.

4. Dyslipidemia (dyslipemia) and its sequelae such as atherosclerosis, coronary heart disease, cerebrovascular disorders, etc., especially those characterized by one or more of the following factors (but not limited thereto):

-high plasma triglyceride concentration, high postprandial plasma triglyceride concentration,

-a low concentration of HDL cholesterol,

-a low apoA lipoprotein concentration,

-a high LDL cholesterol concentration,

-low-density LDL cholesterol particles,

high apoB lipoprotein concentration.

5. Various other conditions that may be associated with metabolic syndrome, such as:

obesity (overweight), including central obesity,

thrombotic, hypercoagulable and prothrombotic stages (arteries and veins),

-a blood pressure level which is higher than the blood pressure level,

heart failure, such as (but not limited to) myocardial infarction, hypertensive heart disease or heart failure after cardiomyopathy.

6. Among other disorders or conditions that may, for example, involve inflammatory responses or cell differentiation are:

atherosclerosis, such as (but not limited to) coronary arteriosclerosis, including angina pectoris or myocardial infarction, stroke,

-restenosis or reocclusion of the blood vessel,

chronic inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis,

-the pancreatitis of a human,

-other inflammatory states of the body of the patient,

-a retinal pathology in which the retina is affected,

-a tumor of an adipose cell,

-adipose cell carcinoma, such as liposarcoma,

solid tumors and neoplasms such as, but not limited to, gastrointestinal cancer, liver cancer, bile duct cancer and pancreatic cancer, endocrine tumors, lung cancer, kidney cancer and urinary tract cancer, genital tract cancer, prostate cancer, and the like,

acute and chronic myeloproliferative disorders and lymphomas,

-an angiogenesis-dependent process of the human,

-a neurodegenerative disorder,

-the onset of Alzheimer's disease,

-a form of multiple sclerosis,

-a Parkinson's disease,

erythrosquamous dermatoses (erythro-squamous dermatoses), such as psoriasis,

-the acne vulgaris,

other skin disorders and dermatological conditions modulated by PPARs,

-eczema and neurodermatitis,

dermatitis, such as seborrheic dermatitis or solar dermatitis,

keratitis and keratoses, such as seborrheic keratosis, senile keratosis, actinic keratosis, photo-induced keratosis (photo-induced keratoses) or follicular keratosis,

keloid and keloid prevention,

warts, including condyloma or condyloma acuminata,

human Papillomavirus (HPV) infections such as venereal papilloma (venereal papillomas), viral warts such as molluscum contagiosum, leukoplakia,

papular dermatitis, such as lichen planus,

skin cancer, such as basal cell carcinoma, melanoma or cutaneous T-cell lymphoma,

localized benign epidermal tumors, such as keratoderma, epidermal nevi,

-a chilblain, which is a cold injury,

-a blood pressure level which is higher than the blood pressure level,

-a syndrome X, wherein the syndrome X is,

-polycystic ovary syndrome (PCOS),

-an asthma treatment,

-a form of bone-setting agent,

lupus Erythematosus (LE) or inflammatory rheumatic disorders, such as rheumatoid arthritis,

-the inflammation of the blood vessels,

-wasting (cachexia),

-the onset of gout,

-ischemia/reperfusion syndrome,

acute Respiratory Distress Syndrome (ARDS).

Compounds which inhibit endothelial lipase are particularly suitable for the treatment and/or prophylaxis

1. Dyslipidemia and systemic impairment of lipid metabolism and their sequelae, such as atherosclerosis, coronary heart disease, cerebrovascular disorders, etc., especially (but not limited to) those characterized by one or more of the following factors:

-a low concentration of HDL cholesterol,

-a low ApoA lipoprotein concentration,

-a high LDL cholesterol concentration,

-low-density LDL cholesterol particles,

high ApoB lipoprotein concentration.

2. Various other conditions that may be associated with metabolic syndrome, such as:

obesity (overweight), including central obesity,

thrombotic, hypercoagulable and prothrombotic stages (arteries and veins),

-a blood pressure level which is higher than the blood pressure level,

heart failure, such as (but not limited to) myocardial infarction, hypertensive heart disease or heart failure after cardiomyopathy,

diabetes, in particular type 2 diabetes, including the prevention of the sequelae associated therewith (hyperglycemia, glucose intolerance, pancreatic beta cell loss, macrovascular and microvascular disorders).

3. Among other disorders or conditions that may, for example, involve inflammatory responses or cell differentiation are:

-restenosis or reocclusion of the blood vessel,

-the pancreatitis of a human,

-other inflammatory states of the body of the patient,

-a retinal pathology in which the retina is affected,

-a tumor of an adipose cell,

-adipose cell carcinoma, such as liposarcoma,

acute and chronic myeloproliferative disorders and lymphomas,

-an angiogenesis-dependent process of the human,

-a neurodegenerative disorder,

-the onset of Alzheimer's disease,

-a form of multiple sclerosis,

-a Parkinson's disease,

erythrodermic diseases, such as psoriasis,

-the acne vulgaris,

other skin disorders and dermatological conditions modulated by PPARs,

-eczema and neurodermatitis,

dermatitis, such as seborrheic dermatitis or solar dermatitis,

keratitis and keratoses, such as seborrheic keratosis, senile keratosis, actinic keratosis, light-induced keratosis or follicular keratosis,

keloid and keloid prevention,

warts, including condyloma or condyloma acuminata,

human Papillomavirus (HPV) infections such as venereal papilloma, viral warts such as molluscum contagiosum, leukoplakia,

papular dermatitis, such as lichen planus,

localized benign epidermal tumors, such as keratoderma, epidermal nevi,

-a chilblain, which is a cold injury,

-a blood pressure level which is higher than the blood pressure level,

-a syndrome X, wherein the syndrome X is,

-polycystic ovary syndrome (PCOS),

-an asthma treatment,

-a form of bone-setting agent,

-the inflammation of the blood vessels,

-wasting (cachexia),

-the onset of gout,

-ischemia/reperfusion syndrome,

acute Respiratory Distress Syndrome (ARDS).

Preparation

The amount of a compound of the invention necessary to achieve a desired biological effect will depend on a variety of factors, such as the particular compound selected, the intended use, the mode of administration, and the clinical condition of the patient. The daily dose is generally in the range 0.3mg to 100mg (usually 3mg to 50mg) per day per kilogram body weight, for example 3-10 mg/kg/day. The intravenous dose may be, for example, from 0.3mg to 1.0mg/kg, which may suitably be administered in an infusion of from 10ng to 100 ng/kg/minute. Suitable infusions for these purposes may contain, for example, 0.1ng to 10mg, usually 1ng to 10mg per ml. Single doses may contain, for example, from 1mg to 10g of active ingredient. Thus, ampoules for injection may contain, for example, from 1mg to 100mg, and single-dose preparations for oral administration, such as tablets or capsules, may contain, for example, from 0.05 to 1000mg, usually from 0.5 to 600 mg. For the treatment of the above conditions, the compounds of formula I may be used as the compounds themselves, but they are preferably in the form of a pharmaceutical composition containing an acceptable carrier. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the health of the patient. 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, including other compounds of the invention, may also be present. The pharmaceutical compositions of the present invention may be prepared by known pharmaceutical methods which consist essentially of admixing the ingredients with a pharmacologically acceptable carrier and/or excipient.

The pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, but 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 the formula I used in each case. Coated formulations and coated sustained release formulations are also encompassed by the scope of the present invention. Acid-and gastric juice-resistant preparations are preferred. Suitable coatings resistant to gastric juices include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical preparations for oral administration may be in the form of individual units such as capsules, cachets, suckable tablets (suckable tablets) or tablets, each containing a defined amount of a compound of formula I; in the form of a powder or granules; in the form of a solution or suspension in an aqueous or non-aqueous liquid; or in the form of an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions may be prepared by any suitable pharmaceutical process which includes a step in which the active ingredient is brought into contact with a carrier, which may contain one or more additional ingredients. Compositions are generally prepared by uniformly and homogeneously mixing the active ingredient with liquid and/or finely divided solid carriers, and then, if necessary, shaping the product. Thus, for example, a tablet may be prepared by compressing or molding a powder or granules of the compound (and where appropriate one or more additional ingredients). Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, which may be mixed as appropriate with binders, glidants, inert diluents and/or one or more surfactants/dispersants. Molded tablets may be prepared by molding the compound in powder form and moistened with an inert liquid diluent in a suitable machine.

Pharmaceutical compositions suitable for oral (sublingual) administration include sucking tablets containing a compound of formula I and a flavoring agent, usually sucrose and acacia or tragacanth, and pastilles (pastilles) comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administration preferably comprise sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the intended recipient. These formulations are preferably administered intravenously, but may also be administered by subcutaneous, intramuscular or intradermal injection. These formulations can preferably be prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with blood. The injectable compositions of the invention generally contain from 0.1 to 5% by weight of active compound.

Pharmaceutical compositions suitable for rectal administration are preferably in the form of single dose suppositories. They may be prepared by mixing a compound of formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.

Pharmaceutical compositions suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, sprays, aerosols or oils. Carriers which may be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these. The active ingredient is generally present at a concentration of 0.1 to 15%, for example 0.5 to 2% by weight of the composition.

It can also be administered transdermally. Pharmaceutical compositions suitable for transdermal use may be in the form of a single patch suitable for prolonged intimate contact with the epidermis of a patient. Such patches suitably contain the active ingredient dissolved and/or dispersed in an adhesive or dispersed in a polymer in an aqueous solution, buffered as appropriate. Suitable active ingredient concentrations are about 1% to 35%, preferably about 3% to 15%. The active ingredient can be released in particular by electrotransport or iontophoresis, such as, for example, Pharmaceutical Research, 2 (6): 318 (1986).

The compounds of formula I wherein R2 is hydrogen are characterized by a favourable effect on lipid metabolism disorders. They beneficially influence the ratio of HDL to LDL, in particular increase HDL levels, and are suitable for the prevention and treatment of dyslipidemia and metabolic syndrome and their various sequelae, such as atherosclerosis, coronary heart disease, heart failure, obesity and diabetes.

Combinations with other drugs

The compounds of the invention may be administered alone or in combination with one or more additional pharmacologically active substances which, for example, have a beneficial effect on metabolic disorders or disorders frequently associated therewith. Examples of such drugs are

1. Hypoglycemic agents, antidiabetics,

2. an active ingredient for the treatment of dyslipidemia,

3. an anti-atherosclerotic medicament,

4. an anti-obesity agent which is an anti-obesity agent,

5. an anti-inflammatory active ingredient, which is,

6. an active component for treating malignant tumor,

7. an anti-thrombotic active ingredient, which is,

8. an active ingredient for the treatment of hypertension,

9. active ingredients for the treatment of heart failure, and

10. active ingredients for the treatment and/or prevention of complications resulting from or associated with diabetes.

They can be used in combination with the compounds of the formula I according to the invention, in particular for achieving a synergistic increase in the effect. The administration of the active ingredient combination can be carried out by separate administration of the active ingredients to the patient or in the form of a combination product in which a plurality of active ingredients are present in one pharmaceutical preparation.

Examples which may be mentioned are:

antidiabetic agent

Suitable antidiabetic agents are disclosed, for example, in Rote Liste 2001, Chapter 12 or the USP specificity of USAN and International Drug Names, US Pharmacopeia, Rockville 2003. Antidiabetic agents include all insulins and insulin derivatives, e.g. Lantus^®(see www.lantus.com) or Apidra^®And other fast acting insulins (see US6,221,633), GLP-1 receptor modulators as described in WO 01/04146 etc., such as those disclosed in WO 98/08871 to NovoNordisk a/S.

Orally active hypoglycemic active ingredients preferably include sulfonylureas which act on the ATP-dependent potassium channel of beta cells (as disclosed, for example, in WO 97/26265 and WO 99/03861), biguanides, meglitinides, glucagon antagonists, oral GLP-1 agonists, DPP-IV inhibitors, insulin sensitizers, e.g., PPAR and PXR modulators, and active ingredients such as oxadiazolidinediones, thiazolidinediones, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, e.g., glucosidase inhibitors, compounds which alter lipid metabolism and lead to a change in the composition of blood lipids, compounds which reduce food intake or food absorption.

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

In one embodiment of the invention, the compounds of the formula I are administered in combination with substances which influence hepatic glucose production, for example glycogen phosphorylase inhibitors (cf. WO 01/94300, WO 02/096864, WO03/084923, WO 03/084922, WO 03/104188).

In one embodiment, the compounds of the formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, for example sulfonylureas (e.g. tolbutamide, glyburide, glipizide, glimepiride) or glinides (e.g. repaglinide).

In one embodiment, the compounds of formula I are administered in combination with a biguanide, for example, metformin.

In one embodiment, the compounds of formula I are administered in combination with a PPAR γ agonist or a thiazolidinedione such as ciglitazone, pioglitazone, rosiglitazone or a compound disclosed in WO 97/41097 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 formula I are used in combination with DPPIV inhibitors such as WO98/19998, WO99/61431, WO99/67278, WO99/67279, WO01/72290, WO 02/38541, those described in WO03/040174, in particular P93/01 (1-cyclopentyl-3-methyl-1-oxo-2-pentanaminium chloride), P-31/98, LAF237(1- [2- [ 3-hydroxyadamantan-1-ylamino ] acetyl ] pyrrolidine-2- (S) -carbonitrile), TS021((2S, 4S) -4-fluoro-1- [ [ (2-hydroxy-1, 1-dimethylethyl) amino ] acetyl ] pyrrolidine-2-carbonitrile monobenzenesulfonate).

In one embodiment, the compounds of the formula I are administered in combination with compounds having an inhibitory effect on SGLT-1 and/or 2, such as those disclosed directly or indirectly in WO2004/007517, WO2004/052902, WO2004/052903 and WO 2005/121161.

In one embodiment, the compounds of the formula I are administered in combination with an α -glucosidase inhibitor, for example miglitol or acarbose.

In one embodiment, the compound of formula I is administered in combination with more than one of the above compounds, e.g., in combination with sulfonylureas and metformin, in combination with sulfonylureas and acarbose, in combination with repaglinide and metformin, in combination with insulin and sulfonylureas, in combination with insulin and metformin, in combination with insulin and troglitazone, in combination with insulin and lovastatin, and the like.

Lipid modulators

In one embodiment of the invention, the compound of formula I is administered in combination with an HMGCoA reductase inhibitor such as lovastatin, fluvastatin, pravastatin, simvastatin, ivastatin, itavastatin, atorvastatin, rosuvastatin.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a bile acid absorption inhibitor (see, e.g., US6,245,744, US6,221,897, US6,277,831, EP 0683773, EP 0683774).

In one embodiment of the invention, the compounds of the formula I are administered in combination with polymeric bile acid adsorbents such as cholestyramine, colesevelam.

In one embodiment of the invention, the compounds of the formula I are administered in combination with cholesterol absorption inhibitors such as those described in WO 02/50027 or ezetimibe, tiquinan, pamabrin.

In one embodiment of the invention, the compounds of formula I are administered in combination with an LDL receptor inducing agent (see, e.g., US6,342,512).

In one embodiment, the compound of formula I is administered in combination with a bulking agent, preferably an insoluble bulking agent (see, e.g., Carob/Caromax ® (Zunft H J et al, Carob pulppregenation for treatment of hypercholesterolemia, ADVANCES INTHERAPY (9-10 months 2001), 18(5), 230-6.) Caromax is a Carob-containing product provided by Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industiepark Hoechst, 65926 Frankfurt/Main. combination with Caromax ® can be achieved in one formulation or by administering the compound of formula I and Caromax ® separately.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR α agonist.

In one embodiment of the invention, the compounds of formula I are combined with a mixed PPAR α/γ agonist such as AZ 242(tesaglitazar, (S) -3- (4- [2- (4-methanesulfonyloxyphenyl) ethoxy ] phenyl) -2-ethoxypropionic acid), BMS 298585(N- [ (4-methoxyphenoxy) carbonyl ] -N- [ [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy ] phenyl ] methyl ] glycine) or WO 99/62872, WO 99/62871, WO 01/40171, WO 01/40169, those described in WO 96/38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO 00/64876.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate such as fenofibrate, gemfibrozil, clofibrate, bezafibrate.

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

In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, for example CP-529, 414 (torcetrapib).

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

In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor, for example, inputapi.

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

In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein (a) antagonist. Anti-obesity agent

In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor, for example orlistat.

In one embodiment, the further active ingredient is fenfluramine or dexfenfluramine.

In another embodiment, the additional active ingredient is sibutramine.

In another embodiment, the compounds of formula I are administered in combination with: CART modulators (see "Cocaine-amphetamine-regulated transcript-in-synthesis, and anxiety and structural-encoding in mice," Asakawa, A et al, M.: Hormone and Metabolic Research (2001), 33(9), 554), 558), NPY antagonists such as naphthalene-1-sulfonic acid {4- [ (4-aminoquinazolin-2-ylamino) methyl ] cyclohexylmethyl } amide hydrochloride (CGP 71683A)), MC4 agonists such as 1-amino-1, 2, 3, 4-tetrahydronaphthalene-2-carboxylic acid [2- (3A-benzyl-2-methyl-3-oxo-2, 3, 3A, 4, 6, 7-hexahydropyrazolo [4, 3-c ] pyridin-5-yl) -1- (4-chlorophenyl) -2-oxoethyl ] amide (WO 01/91752)) (see, Orexin antagonists (e.g., 1- (2-methylbenzoxazol-6-yl) -3- [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 oxalate (WO00/63208)), TNF agonists, CRF antagonists (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 (urocortin)),), Urocortin agonists, beta 3 agonists (e.g. 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2, 3-dimethyl-1H-indol-6-yloxy) ethylamino ] ethanol hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g. trifluoroacetate {2- [4- (4-chloro-2, 5-dimethoxyphenyl) -5- (2-cyclohexylethyl) thiazol-2-ylcarbamoyl ] -5, 7-dimethylindol-1-yl } acetic acid (WO 99/15525), serotonin reuptake inhibitors (e.g. dextrofenfluramine), mixed serotonergic and noradrenergic compounds (e.g. WO 00/71549), 5HT agonists such as 1- (3-ethylbenzofuran-7-yl) piperazine oxalate (WO 01/09111), bombesin agonists, galanin antagonists, growth hormones (e.g. human growth hormone), growth hormone releasing compounds (6-benzyloxy-1- (2-diisopropylaminoethylcarbamoyl) -3, 4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)), TRH agonists (see, e.g. EP 0462884), uncoupling protein 2 or 3 modulators, leptin (leptin) agonists (see, e.g. Lee, Daniell W.; Leinug, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. leptin as a potential utilizing to the peptide promoter of interest (881.) drugs of the drug of the tissue (2001), 26(9), 873), DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors (e.g., WO 00/40569), PPAR modulators (e.g., WO 00/78312), RXR modulators, or TR-beta agonists.

In another embodiment, the further active ingredient is a cannabinoid receptor 1 antagonist (e.g. rimonabant, SR147778 or as described in, e.g., EP 0656354, WO 00/15609, WO 02/076949, WO2005/080345, WO2005/080328, WO2005/080343, WO2005/075450, WO2005/080357, WO2001/70700, WO2003/026647-48, WO2003/02776, WO2003/040107, WO2003/007887, WO2003/027069, US 027069, WO2001/32663, WO2003/027069, WO 2004/027069, WO 2003/0843, WO 2004/027069, WO 2004/364972, WO 2004/027069, WO 2004/362004/027069, WO 2004/362004/027069, WO 2004/027069, WO, WO2005/000809, WO2004/099157, US2004/0266845, WO2004/110453, WO2004/108728, WO2004/000817, WO2005/000820, US2005/0009870, WO2005/00974, WO2004/111033-34, WO2004/11038-39, WO2005/016286, WO2005/007111, WO2005/007628, US2005/0054679, WO2005/027837, WO2005/028456, WO2005/063761-62, WO2005/061509, WO 2005/077897).

In one embodiment of the invention, the further active ingredient is leptin.

In one embodiment, the additional active ingredient is dextroamphetamine, amphetamine, mazindole, or phentermine.

In one embodiment, the compounds of formula I are administered in combination with drugs having an effect on the coronary circulation and vascular system, such as ACE inhibitors (e.g., ramipril), drugs acting on the angiotensin-renin system, calcium antagonists, beta blockers, and the like.

In one embodiment, the compounds of the formula I are administered in combination with a drug having an anti-inflammatory action.

In one embodiment, the compounds of formula I are administered in combination with a drug that is used for cancer treatment and cancer prevention.

It is to be understood that every suitable combination of a compound of the invention with one or more of the above-mentioned compounds and optionally one or more other pharmacologically active substances is to be considered as falling within the scope of the present invention.

The activity of the compounds of formula I of the invention was tested in the following enzyme assay system:

HSL inhibition assay

1.1. Preparation of partially purified HSL:

ex vivo rat adipocytes were obtained from epididymal adipose tissue from untreated male rats (Wistar, 220-. Adipocytes from 10 rats were washed three times by floating with 50ml each time of homogenization buffer (25mM Tris/HCl, pH7.4, 0.25M sucrose, 1mM ETDA, 1mM DTT, 10. mu.g/ml leupeptin, 10. mu.g/ml antipain, 20. mu.g/ml pepstatin) and finally taken up in 10ml of homogenization buffer. Adipocytes were homogenized for 10 strokes at 1500rpm and 15 ℃ in a Teflon-in-glass homogenizer (Braun-Melsungen). The homogenate was centrifuged (Sorvall SM24 tube, 5000rpm, 10 min, 4 ℃). The lower clear liquid between the top fat layer and the pellet was removed and centrifugation repeated. The thus obtained subnatant was centrifuged again (Sorvall SM24 tube, 20000rpm, 45 min, 4 ℃). The lower layer clear solution was removed and 1g heparin-Sepharose (Pharmacia-Biotech, CL-6B, 5X washed with 25mM Tris/HCl, pH7.4, 150mM NaCl) was added. After incubation at 4 ℃ for 60 minutes (shaking at 15 minute intervals), the mixture was centrifuged (Sorvall SM24 tube, 3000rpm, 10 minutes, 4 ℃). The supernatant was adjusted to pH 5.2 by adding glacial acetic acid and incubated at 4 ℃ for 30 minutes. The precipitate was collected by centrifugation (Sorvall SS34, 12000rpm, 10 minutes, 4 ℃) and suspended in 2.5ml of 20mM Tris/HCl, pH7.0, 1mM EDTA, 65mM NaCl, 13% sucrose, 1mM DTT, 10. mu.g/ml leupeptin/antipain. The suspension was dialyzed overnight at 4 ℃ against 25mM Tris/HCl, pH7.4, 50% glycerol, 1mM DTT, 10. mu.g/ml leupeptin, pepstatin, antipain, and then loaded onto a hydroxyapatite (hydroxyapatite) column (0.1 g per 1ml suspension, equilibrated with 10mM potassium phosphate, pH7.0, 30% glycerol, 1mM DTT). The column was washed with four volumes of equilibration buffer at a flow rate of 20-30 ml/h. HSL was eluted with one volume of equilibration buffer containing 0.5M potassium phosphate, then dialyzed (see above) and concentrated 5-to 10-fold by ultrafiltration (Amicon Diaflo PM 10 Filter) at 4 ℃. Partially purified HSL can be stored at-70 ℃ for 4-6 weeks.

1.2 HSL Activity assay:

to prepare the substrate, 25-50. mu. Ci [3H ] is mixed]Trioleoyl glycerol (in toluene), 6.8. mu. mol unlabelled trioleoyl glycerol and 0.6mg phospholipid (phosphatidylcholine/phosphatidylinositol 3: 1w/v), with N₂Dried and then taken up in 2ml of 0.1M KPi (pH7.0) by sonication (Branson 250, microtip, setting 1-2, 2X 1 min, time interval 1 min). After addition of 1ml of KPi and renewed sonication (4X 30 seconds on ice, 30 seconds intervals), 1ml of 20% BSA (in KPi) was added (final concentration of trioleoyl glycerol 1.7 mM). To carry out the reaction, 100. mu.l of the substrate solution was transferred to 100. mu.l of an HSL solution (HSL prepared as above, diluted in 20mM KPi, pH7.0, 1mM EDTA, 1mM DTT, 0.02% BSA, 20. mu.g/ml pepstatin, 10. mu.g/ml leupeptin) and incubated at 37 ℃ for 30 minutes. 3.25ml of methanol/chloroform/heptane (10: 9: 7) and 1.05ml of 0.1M K were added₂CO₃0.1M boric acid (pH10.5), then mixed well and finally centrifuged (800 Xg, 20 min). After phase separation, an aliquot of the upper phase (1ml) was removed and radioactivity was determined by liquid scintillation measurement.

1.3 evaluation of HSL-inhibition:

the substances are usually tested in four separate mixtures. The inhibition of HSL enzyme activity by the test substance is determined by comparison with an uninhibited control reaction. Calculating IC from inhibition curves with concentrations of at least 10 test substances₅₀. Data were analyzed using the GRAPHIT, Elsevier-BIOSOFT software package.

EL inhibition assay:

preparation of EL

EL is released as a secreted protein by recombinant cell lines (CHO, HEK293) into cell culture medium (conditioned medium) at high concentrations. After concentration, it was used as an enzyme solution.

EL Activity assay method

The enzymatic activity of endothelial lipase and the action of inhibitors were characterized with the phospholipase-specific substrate 1, 2-bis (4, 4-difluoro-5, 7-dimethyl-4-bora-3 a, 4 a-diaza-s-indacene (indacene) -3-undecanoyl) -sn-glycero-3-phosphocholine (manufacturer molecular probes). The A1 ester bond of the phospholipid was hydrolyzed with enzyme to release the fluorescent dye Bodipy, which can be detected after separation by thin layer chromatography on HPTLC plates (silica gel 60, Merck) or directly in the reaction vessel by measuring fluorescence.

A substrate solution was prepared by absorbing 100. mu.g of 1, 2-bis (4, 4-difluoro-5, 7-dimethyl-4-bora-3 a, 4 a-diaza-s-indacene-3-undecanoyl) -sn-glycero-3-phosphocholine (manufacturer Molecular Probes), 2.4mg of glyceryl palmitate (Sigma) and 7.9mg of DOP-choline (1, 2-dioleoyl-sn-glycero-3-phosphocholine) in 393. mu.l of chloroform, and then transferring 157. mu.l to a new reaction vessel. After evaporation of the solvent, the lipid mixture was dissolved in 4ml of 200mM Tris-HCl, 150mM sodium chloride, pH7.4 by sonication twice. The subsequent enzymatic reaction was carried out at 37 ℃ for 60 minutes. For this purpose, 45. mu.l of substrate solution were incubated with 1. mu.l of the appropriate concentration of inhibitor (dissolved in DMSO, using pure DMSO solution as a control) and 5. mu.l of enzyme solution (conditioned medium). Mu.l of the assay mixture was then loaded onto HPTLC plates (silica gel 60, Merck) and the liberated fluorochrome was separated with an eluent (diethyl ether: petroleum ether: acetic acid [ 78: 22: 1]) for detection. After evaporation of the eluent, the plates were read in a fluorescence scanner. The increase in fluorochrome release in the uninhibited reaction was observed as a measure of enzyme activity.

Evaluation of EL-inhibition:

the enzyme activity decreased as a function of the inhibitor concentration used, and the inhibitor concentration at which half the maximum enzyme activity was observed was designated as IC 50.

2.4. Another EL inhibition assay:

the enzymatic activity of endothelial lipase and the action of inhibitors were characterized with the phospholipase-specific substrate 1, 2-bis (4, 4-difluoro-5, 7-dimethyl-4-bora-3 a, 4 a-aza-s-indacene-3-undecanoyl) -sn-glycero-3-phosphocholine (manufacturer Molecular Probes). The A1 ester bond of the phospholipid was hydrolyzed with enzyme to release the fluorescent dye Bodipy, which can be detected after separation by thin layer chromatography on HPTLC plates (silica gel 60, Merck) or directly in the reaction vessel by measuring fluorescence.

The substrate solution was prepared by dissolving 100 μ g of 1, 2-bis (4, 4-difluoro-5, 7-dimethyl-4-bora-3 a, 4 a-diaza-s-indacene-3-undecanoyl) -sn-glycero-3-phosphocholine (manufacturer Molecular Probes) in 100 μ l DMSO and uptake with 2.4mg of glyceryl palmitate (Sigma) in 393 μ l chloroform containing 20mg/ml DOP-choline (1, 2-dioleoyl-sn-glycero-3-phosphocholine). 39.3. mu.l of the lipid mixture were transferred to a new reaction vessel and the solvent was evaporated. The lipid mixture was dissolved in 4ml 200mM TRIS-HCl, 150mM sodium chloride, pH7.4 by sonication twice. The subsequent enzymatic reaction was carried out at 37 ℃ for 90 minutes. For this, 20. mu.l of substrate solution were incubated with 2. mu.l of the appropriate concentration of inhibitor (dissolved in 10% DMSO, using 10% DMSO as a control) and 2. mu.l of enzyme solution (conditioned medium). Mu.l of the assay mixture was then loaded onto HPTLC plates (silica gel 60, Merck) and the liberated fluorochrome was separated with an eluent (diethyl ether: petroleum ether: acetic acid [ 78: 22: 1]) for detection. After evaporation of the eluent, the plates were read in a fluorescence scanner. The increase in fluorochrome release in the uninhibited reaction was observed as a measure of enzyme activity.

In this assay, the compounds of the examples show the following IC₅₀The value:

examples	IC₅₀[μM]EL
examples	IC₅₀[μM]EL	1	0.16
2	0.051	1	0.16
2	0.051	3	0.052
4	0.215	3	0.052

5	0.435
5	0.435	6	0.014
7	0.12	6	0.014

Preparation method

The compounds of the general formula I according to the invention are prepared by methods known per se, for example by acylation of substituted or unsubstituted benzothiazol-2-one derivatives II with carbamoyl chloride III (method A) or in two stages by reacting a benzothiazol-2-one derivative II with phosgene or its equivalent, such as trichloromethyl chlorocarbonate, trichloromethyl carbonate or 4-nitrophenyl chloroformate and further reacting the resulting benzothiazol-2-one carboxylic acid derivative with an amine IV (method B). For compounds in which R2 is hydrogen, it is also possible to react benzothiazol-2-one derivatives II with the appropriate isocyanate VR1-N ═ C ═ O (method C).

Since acids are usually released in these reactions, it is advisable to add a base such as pyridine, triethylamine, sodium hydroxide solution or alkali metal carbonate to accelerate the reaction. The reaction can be carried out over a wide temperature range. It has generally been shown to be advantageous to work at from 0 ℃ to the boiling point of the solvent used. Examples of solvents used are dichloromethane, THF, DMF, toluene, ethyl acetate, n-heptane, dioxane, diethyl ether or pyridine. If anhydrous conditions are used, it has also been shown to be convenient to use a strong base such as lithium hydride, sodium hydride or potassium tert-butoxide in an aprotic solvent such as THF or DMF.

The benzothiazol-2-one derivatives used as starting compounds II are commercially available or can be prepared by methods known from the literature (e.g.C.Fluzat, Y.Bresson, A.Mattio, J.Bonnet, G.Guillaume J: Med.Chem 1993, 36, 497-503; F.Mutterer, C.D.Weis, J.het.Chem.1976, 13, 1103-1104; K.Takeda; H.Ogura, Synthetic Communications (1982), 12(3), 213-17; K.Konishi, I.Nishiguchi; T.Hirashima, N.Sonoda; S.Murai, Synthesis (1984), (3), 254-5).

The following detailed examples are intended to illustrate the invention, but not to limit it.

Examples

Example 1:

2-oxobenzothiazole-3-hexylformamide

75mg (0.45mmol) of 3H-benzothiazol-2-one are dissolved in 10ml of pyridine. 76mg (0.59mmol) of 1-isocyanatohexane are added and then stirred at 100 ℃ for 6 hours, the same amount of isocyanatohexane is added again and stirring is carried out at 100 ℃ for 6 hours. The reaction mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 38mg (28%), M + H +: 279.15.

example 2:

2-oxobenzothiazole-3-heptylcarboxamide

In analogy to example 1, 300mg (1.98mmol) of 3H-benzothiazol-2-one are reacted with 336mg (2.38mmol) of 1-isocyanatoheptane in dioxane at 80 ℃. Yield: 125mg (22%), M + H +: 293.11.

example 3:

2-oxobenzothiazole-3- (2-methylbenzyl) carboxamides

In analogy to example 1, 300mg (1.98mmol) of 3H-benzothiazol-2-one are reacted with 350mg (2.38mmol) of 1-isocyanatomethyl-2-methylbenzene. Yield: 129mg (22%), M + H +: 299.05.

example 4:

2-oxobenzothiazole-3- (3-methylbenzyl) carboxamides

In analogy to example 1, 300mg (1.98mmol) of 3H-benzothiazol-2-one are reacted with 350mg (2.38mmol) of 1-isocyanatomethyl-3-methylbenzene in dioxane at 80 ℃. Yield: 130mg (22%), M + H +: 299.05.

example 5:

6-bromo-2-oxobenzothiazole-3-hexylformamide

In analogy to example 1, 200mg (0.869mmol) of 6-bromo-3H-benzothiazol-2-one are reacted with 132.7mg (1.04mmol) of 1-isocyanatohexane in dioxane at 80 ℃. Yield: 185mg (59%), M + H +: 357.1.

example 6:

5-chloro-2-oxobenzothiazole-3-heptylcarboxamide

In analogy to example 1, 300mg (1.37mmol) of 5-chloro-3H-benzothiazol-2-one are reacted with 174mg (1.37mmol) of 1-isocyanatoheptane in dioxane at 80 ℃. Yield: 100mg (19%), M + H +: 327.38.

example 7:

2-oxo-5-trifluoromethylbenzothiazole-3-hexylcarboxamide

In analogy to example 1, 300mg (1.37mmol) of 5-trifluoromethyl-3H-benzothiazol-2-one are reacted with 202mg (1.37mmol) of 1-isocyanatohexane in dioxane at 80 ℃. Yield: 125mg (26%), M + H +: 347.05.

Claims

1. A compound of formula I:

wherein the radicals have the following meanings:

Sulfonyl is substituted one or more times;

r2 is hydrogen, (C)₁-C₆) -an alkyl group; or

-(C＝R8)-、-NR9-、-C(＝O)-、-O-、-S-、-SO-、-SO₂of an atom of (A) or

May not be contiguous;

r3 is hydrogen;

r4, R5 are, identically or differently, hydrogen, halogen, (C)₁-C₆) Alkyl radicals, (C)₁-C₃) -alkoxy- (C)₁-C₃)-

Alkylene, hydroxy, (C)₁-C₆) Alkylthio, amino, (C)₁-C₆) -alkylamino, di

-(C₂-C₁₂) -alkylamino, (C)₁-C₆) -alkylcarbonyl, CO-OR7, trifluoromethyl,

O-CO-NR9R10、O-CO-(C₁-C₆) alkylene-CO-O- (C)₁-C₆) -an alkyl group,

O-CO-(C₁-C₆) alkylene-CO-OH, O-CO- (C)₁-C₆) -alkylene radical

-CO-NR9R10 or unsubstituted or mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

(C₆-C₁₀) -aryl, (C)₅-C₁₂) -heteroaryl, CO-NR9R10, O-CO-NR9R10,

The radicals-CO-OH, O-CO- (C)₁-C₆) alkylene-CO-NR 9R10 or unsubstituted or

Mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

(C₁-C₆) -an alkyl group;

r7 is hydrogen, (C)₁-C₆) -alkyl, benzyl;

Propyl, cyclopropylene;

(C₈-C₁₄) -a bicyclic ring;

tautomeric forms of the compounds and their physiologically tolerated salts.

2. A compound of formula I according to claim 1, wherein:

Ring, wherein aryl, heteroarylCycloalkyl or bicyclic ring may be substituted by halogen, (C)₁-C₆)-

Methyl substitution one or more times;

r2 is hydrogen, (C)₁-C₆) -an alkyl group; or

Are contiguous;

r3 is hydrogen;

r4, R5 are, identically or differently, hydrogen, halogen, trifluoromethyl, (C)₁-C₆) Alkyl radicals, (C)₁-C₃)-

(C₁-C₆) -alkylcarbonyl, CO-NR9R10, O-CO-NR9R10,

The radicals-CO-OH, O-CO- (C)₁-C₆) alkylene-CO-NR 9R10 or unsubstituted or

Mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

r6 is hydrogen, hydroxy, amino, (C)₁-C₆) Alkylamino, di- (C)₂-C₁₂) -alkylamino, alkylamino,

Mono- (C)₁-C₆) -alkylaminocarbonyl, di- (C)₂-C₈) -alkylaminocarbonyl, (C)₆-C₁₀)-

Aryl group, (C)₅-C₁₂) Heteroaryl or unsubstituted or mono-or poly-F-substituted (C)₁-C₆)-

An alkoxy group;

(C₁-C₆) -an alkyl group;

r7 is hydrogen, (C)₁-C₆) -alkyl, benzyl;

Propyl, cyclopropylene;

Radical- (C)₆-C₁₀) -an aryl group.

3. Compounds of the general formula I as claimed in claim 1 or 2, wherein

Ring of which aryl groupHeteroaryl, cycloalkyl or bicyclic ring can be substituted by halogen, (C)₁-C₆)-

Methyl substitution one or more times;

r2 is hydrogen, (C)₁-C₆) -an alkyl group; or

Are contiguous;

r3 is hydrogen;

r4, R5 are, identically or differently, hydrogen, halogen, trifluoromethyl, (C)₁-C₆) Alkyl, hydroxy, ammonia

Group, COOR7, (C)₁-C₆) -alkylsulfonyl, aminosulfonyl, pentafluorothio,

(C₁-C₆) -alkylcarbonyl, CO-NR9R10, O-CO-NR9R10,

Or mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

(C₁-C₆) -an alkyl group;

r7 is hydrogen, (C)₁-C₆) -an alkyl group;

r9, R10 are hydrogen, (C) identically or differently₁-C₆) -an alkyl group.

4. A compound of formula I as claimed in claim 1, 2 or 3, wherein

Fluoromethyl substitution;

r2 is hydrogen; or

R1 and R2 together with the nitrogen atom which carries them are a monocyclic, saturated 5-to 6-membered ring system in which

Each member of the ring system may be substituted by 1 to 2 atoms or atoms selected from-CHR 8-, -NR 9-)

Subgroup substitution, wherein R8 is as defined above, and R9 is (C)₁-C₆) -alkyl or cyclic

And (4) propyl.

5. A compound of formula I as claimed in claims 1 to 4, wherein

Alkoxy or trifluoromethyl substitution;

r2 is hydrogen;

r3 is hydrogen;

r4, R5 are, identically or differently, hydrogen, halogen, hydroxy, (C)₁-C₆) -alkyl, trifluoromethyl or not

Substituted or mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

r6 is hydrogen.

6. Compounds of formula I as claimed in claims 1 to 5, wherein

r2 is hydrogen;

r3 is hydrogen;

r4, R5 are, identically or differently, hydrogen, halogen, trifluoromethyl;

r6 is hydrogen.

7. Compounds of formula I as claimed in claims 1 to 6, wherein

R3, R6 are hydrogen and R4 or R5 are not hydrogen.

8. Medicaments comprising one or more compounds of the formula I in which the radicals have the meanings indicated

R1 is (C)₅-C₁₆) -alkanesBase, (C)₁-C₄) -alkylene- (C)₆-C₁₀) -aryl, (C)₁-C₄) -alkylene radical

Sulfonyl is substituted one or more times;

r2 is hydrogen, (C)₁-C₆) -an alkyl group; or

-(C＝R8)-、-NR9-、-C(＝O)-、-O-、-S-、-SO-、-SO₂of an atom of (A) or

May not be contiguous;

Alkylene, hydroxy, (C)₁-C₆) Alkylthio, amino, (C)₁-C₆) -alkylamino, di

O-CO-NR9R10、O-CO-(C₁-C₆) alkylene-CO-O- (C)₁-C₆) -an alkyl group,

O-CO-(C₁-C₆) alkylene-CO-OH, O-CO- (C)₁-C₆) -alkylene radical

(C₆-C₁₀) -aryl, (C)₅-C₁₂) -heteroaryl, CO-NR9R10, O-CO-NR9R10,

The radicals-CO-OH, O-CO- (C)₁-C₆) alkylene-CO-NR 9R10 or unsubstituted or

Mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

with the proviso that at most one of the substituents R3, R4, R5 is halogen, trifluoromethyl or (C)₁-C₆) -an alkyl group;

r7 is hydrogen, (C)₁-C₆) -alkyl, benzyl;

Propyl, cyclopropylene;

(C₈-C₁₄) -a bicyclic ring;

tautomeric forms of the compounds and their physiologically tolerated salts or one or more compounds of the formula I as claimed in claims 1 to 7.

9. Wherein the radicals have the meanings given below

-(C₅-C₁₂) -heteroaryl, (C)₁-C₄) -alkylene- (C)₄-C₁₂) -RingAlkyl, (C)₈-C₁₄) -two

Sulfonyl is substituted one or more times;

r2 is hydrogen, (C)₁-C₆) -an alkyl group; or

-(C＝R8)-、-NR9-、-C(＝O)-、-O-、-S-、-SO-、-SO₂of an atom of (A) or

May not be contiguous;

AAlkyl, hydroxy, (C)₁-C₆) Alkylthio, amino, (C)₁-C₆) -alkylamino, di

O-CO-NR9R10、O-CO-(C₁-C₆) alkylene-CO-O- (C)₁-C₆) -an alkyl group,

O-CO-(C₁-C₆) alkylene-CO-OH, O-CO- (C)₁-C₆) -alkylene radical

(C₆-C₁₀) -aryl, (C)₅-C₁₂) -heteroaryl, CO-NR9R10, O-CO-NR9R10,

The radicals-CO-OH, O-CO- (C)₁-C₆) alkylene-CO-NR 9R10 or unsubstituted or

Mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

r7 is hydrogen, (C)₁-C₆) -alkyl, benzyl;

Propyl, cyclopropylene;

(C₈-C₁₄) -a bicyclic ring;

use of the tautomeric forms of the compounds and their physiologically tolerated salts or the compounds of the formula I as claimed in claims 1 to 7 for the preparation of a medicament for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders.

10. The use of compounds of the formula I as claimed in claims 1 to 9 for the preparation of medicaments for the treatment and/or prophylaxis of disorders in which insulin resistance is involved.

11. The use of compounds of the formula I as claimed in claims 1 to 9 for the preparation of medicaments for the treatment and/or prophylaxis of diabetes mellitus and the sequelae associated therewith.

12. The use of compounds of the formula I as claimed in claims 1 to 9 for the preparation of medicaments for the treatment and/or prophylaxis of dyslipidemia and its sequelae.

13. Use of a compound of formula I as claimed in claims 1 to 9 for the preparation of a medicament for the treatment and/or prevention of disorders associated with the metabolic syndrome.

14. The use of compounds of the formula I as claimed in claims 1 to 9 for the preparation of medicaments for the treatment and/or prophylaxis of disorders which are associated with a reduced HDL level.

15. The use of a compound of formula I as claimed in claims 1 to 9 for the preparation of a medicament for the treatment and/or prevention of atherosclerotic disorders.

16. The use of a compound of the formula I as claimed in claims 1 to 9 in combination with at least one further active ingredient for the preparation of a medicament for the treatment and/or prevention of disorders in which insulin resistance is involved.

17. A process for the preparation of a medicament comprising one or more compounds of formula I as claimed in claims 1 to 9, which comprises mixing the compounds with a pharmaceutically suitable carrier and converting the mixture into a form suitable for administration.

18. A process for the preparation of compounds of the general formula I as claimed in claims 1 to 7, which comprises reacting a benzothiazol-2-one derivative of the formula II

a) Acylation with a carbamoyl chloride of formula III;

or

b) The reaction is carried out in two stages, first with phosgene or its equivalent, such as trichloromethyl chlorocarbonate, ditrichlormethyl carbonate or 4-nitrophenyl chloroformate, and in a second step with an amine of the formula IV,

wherein the substituents have the above-mentioned meanings.

19. A process for the preparation of a compound of formula I as described in claims 1 to 7 wherein R2 is hydrogen, comprising reacting a benzothiazol-2-one derivative of formula II with a compound of formula V: and (3) reacting the isocyanate with O, C, N-R1.