DE102010008643A1 - New 5'-biphenyl substituted cyclic ketoenol compounds are acetyl-coenzyme A carboxylase 1 inhibitors, useful for treating cancer e.g. breast cancer, pancreatic cancer, renal cell carcinoma, hepatocellular carcinoma and skin tumor - Google Patents

Abstract

5'-Biphenyl substituted cyclic ketoenol compounds (I), are new : 5'-Biphenyl substituted cyclic ketoenol compounds of formula (I), are new. X : 1-3C alkyl or 1-3C alkoxy (both optionally substituted by at least a halo) or halo; W1, Y1 : H, halo or 1-3C alkyl (optionally substituted by at least a halo); either V1-V3 : H, halo, 1-3C (halo)alkyl, 1-3C (halo)alkoxy or 1-3 alkoxy-1-3C; or C+V1+V2 : optionally saturated and optionally at least a further heteroatom containing 5 or 6 membered cycle T1 (optionally substituted by one or more halo and/or 1-3C alkyl); either A : 1-6C alkyl- or 1-6C alkoxy-1-6C alkyl (both optionally substituted by at least a halo), 3-7C cycloalkyl or 4- to 7-membered monocyclic heterocyclyl (both optionally substituted by one or more halo and/or 1-3C alkyl) or H; and B1 : H, 1-6C alkyl or 1-3C alkoxy-1-3C alkyl; or C+A+B1 : optionally saturated, optionally one or two heteroatoms containing 3-8 membered cycle T2 (optionally substituted by one or more R1-R3); either R1-R3 : 1-4C alkyl, 1-4C alkoxy, 1-3C alkoxy-1-3C alkyl, 1-3C alkoxy-1-3C alkoxy, halo-1-3C-alkyl or halo-1-3C alkoxy (all optionally substituted by OH in alkyl residue), halo or OH; or two of R1-R3 together with cycle T2 : saturated or aromatic, optionally one or two heteroatoms containing 5-7 membered cycle T3 (optionally substituted by one or more R4-R6); and R4-R6 : 1-3C alkyl or 1-3C alkoxy. [Image] ACTIVITY : Cytostatic; Antipsoriatic; Vulnerary. MECHANISM OF ACTION : Acetyl-coenzyme A carboxylase 1 inhibitor; Acetyl-coenzyme A carboxylase 2 inhibitor. The ability of (I) to inhibit acetyl-coenzyme A carboxylase 2 was tested in vitro. The results showed that (5R,8S)-3-(4'-chloro-4,6-dimethylbiphenyl-3-yl)-4-hydroxy-1,9-dioxadispiro[4.2.4.2]tetradec-3-en-2-one exhibited an IC 50value of 0.032 mu ole/l.

Description

The present invention relates to 5'-biphenyl-substituted cyclic ketoenols for therapeutic purposes, pharmaceutical agents and their use in therapy, in particular for the prophylaxis and therapy of tumor diseases.

Acetyl-CoA carboxylases (ACCs) play a key role in cellular fatty acid homeostasis. ACCs are biotin-containing enzymes that catalyze the carboxylation of acetyl-CoA to malonyl-CoA in an ATP-dependent manner ( Kim, 1997 ; Harwood, 2005 ; Tong, 2005 ). This reaction, which runs as two half reactions, a biotin carboxylase (BC) reaction and a carboxyl transferase (CT) reaction, is the first preliminary step in fatty acid biosynthesis and is the rate-limiting step for the pathway. Two human ACC isoforms are known, ACC1 and ACC2, which are encoded by two different genes ( LuTFI ABU-ELHEIGA, et al, 1995 . Jane WIDMER, et al. 1996 ). ACC1 is expressed in lipogenic tissue (liver, adipose tissue), located in the cytosol, and fills the malonyl-CoA pool, which serves as a C2 unit donor for the de novo synthesis of long-chain fatty acids by FASN and subsequent chain extension. ACC2 is mainly expressed in oxidative tissues (liver, heart, skeletal muscle) ( Bianchi et al., 1990 ; Kim, 1997), associated with the mitochondria, and regulates a second pool of malonyl-CoA. It controls fatty acid oxidation by inhibiting carnitinipalmitoyltransferase I, the enzyme that facilitates the entry of long-chain fatty acids into the mitochondria for h-oxidation ( Milgraum LZ, et al., 1997 Widmer J. et al., 1996). Both enzymes show a very large sequence homology and are similarly regulated by a combination of transcriptional, translational and prosttranslational mechanisms. In humans as well as in animals, ACC activity is strictly controlled by a series of dietary, hormonal and other physiological mechanisms involving forward allosteric activation by citrate, feedback inhibition by long-chain fatty acids, reversible phosphorylation and inactivation and modulation of enzyme production altered gene expression.

ACC1 knockout mice are embryonic lethal ( Swinnen, et al., 2006 . Abu-Elheiga, et al. 2005 ). ACC2 knockout mice show reduced malonyl-CoA levels in skeletal and cardiac muscle, increased fatty acid oxidation in muscle, decreased liver fat levels, decreased levels of total body fat, increased levels of UCP3 in skeletal muscle (as a sign of increased energy expenditure), decreased body weight, decreased levels of plasma free fatty acids, decreased plasma glucose levels, decreased levels of glycogen in tissues and are protected from diet-induced diabetes and obesity ( Abu-Elheiga et al., 2001, 2003 ; Oh et al., 2005 ).

In addition to involvement in fatty acid synthesis in lipogenic tissues and fatty acid oxidation in oxidative tissues, up-regulation of ACC and increased lipogenesis has been observed in many tumor cells ( Swinnen, et al., 2004 . Heemers, et al., 2000 . Swinnen, et al., 2002 . Rossi, et al., 2003 . Milgraum, et al., 1997 . Yahagi, et al., 2005 ). This phenotype most likely contributes to the development and progression of tumors, but the regulatory mechanisms for this have yet to be clarified.

A number of substances have been discovered that are capable of inhibiting insect ACC.

The PCT patent application PCT / EPP99 / 01787 , published as WO 99/48869 that the European patent EP 1 066 258 B1 refers to new arylphenyl-substituted cyclic ketoenols, to a majority of the processes for their preparation and their use as pesticides and herbicides.

Of 3-acyl-pyrrolidine-2,4-diones pharmaceutical properties are described above ( Suzuki, S. et al. Chem. Pharm. Bull. 15 1120 (1967) ). Furthermore, N-phenylpyrrolidine-2,4-diones of R. Schmierer and H. Mildenberger (Liebigs Ann. Chem. 1985, 1095) synthesized. Biological activity of these compounds has not been described.

In EP-A-0 262 399 and GB-A-2 266 888 similarly structured compounds (3-aryl-pyrrolidine-2,4-diones) are disclosed, but of which no herbicidal, insecticidal or acaricidal activity has become known. Are known herbicidal, insecticidal or acaricidal action unsubstituted, bicyclic 3-aryl-pyrrolidine-2,4-dione derivatives ( EP-A-355 599 . EP-A-415 211 and JP-A-12-053 670 ) and substituted monocyclic 3-arylpyrrolidine-2,4-dione derivatives ( EP-A-377 893 and EP-A-442,077 ).

Also known are polycyclic 3-arylpyrrolidine-2,4-dione derivatives ( EP-A-442 073 ) and 1H-arylpyrrolidinone-dione derivatives ( EP-A-456 063 . EP-A-521 334 . EP-A-596 298 . EP-A-613,884 . EP-A-613,885 . WO 95/01 971 . WO 95/26954 . WO 95/20 572 . EP-A-0 668 267 . WO 96/25 395 . WO 96/35 664 . WO 97/01 535 . WO 97/02 243 . WO 97/36868 . WO 97/43275 . WO 98/05638 . WO 98/06721 . WO 98/25928 . WO 99/24437 . WO 99/43649 . WO 99/48869 . WO 99/55673 . WO 01/17972 . WO 01/23354 . WO 01/74770 . WO 03/013249 . WO 03/062244 . WO 2004/007448 . WO 2004/024 688 . WO 04/065366 . WO 04/080962 . WO 04/111042 . WO 05/044791 . WO 05/044796 . WO 05/048710 . WO 05/049569 . WO 05/066125 . WO 05/092897 . WO 06/000355 . WO 06/029799 . WO 06/056281 . WO 06/056282 . WO 06/089633 . WO 07/048545 . DEA 102 00505 9892 . WO 07/073856 . WO 07/096058 . WO 07/121868 . WO 07/140881 . WO 08/067873 . WO 08/067910 . WO 08/067911 . WO 08/138551 . WO 09/015801 . WO 09/039975 . WO 09/049851 . PCT / EP2008 / 005973 . PCT / EP2008 / 007517 . EP application numbers 08153002 and 08170489 , In addition, ketal-substituted 1-H-arylpyrrolidine-2,4-diones are made WO 99/16748 and (spiro) ketalsubstituted N-alkoxy-alkoxy-substituted aryl-pyrrolidinediones JP-A-14 205 984 and Ito M. et al. Bioscience, Biotechnology and Biochemistry 67, 1230-1238, (2003) known. The addition of safeners to ketoenols is also in principle from the WO 03/013249 known. Besides, are off WO 06/024411 Herbicidal agents containing ketoenols known.

It is known that certain substituted Δ ³ -dihydrofuran-2-one derivatives have herbicidal properties (cf. DE-A-4 014 420 ). The synthesis of the tetronic acid derivatives (such as 3- (2-methylphenyl) -4-hydroxy-5- (4-fluorophenyl) -Δ ³ -dihydrofuranone- (2)) used as starting compounds is also disclosed in DE-A-4 014 420 described. Similarly structured compounds without indication of an insecticidal and / or acaricidal activity are from the publication Campbell et al., J. Chem. Soc., Perkin Trans. 1, 1985, (8) 1567-76 known. Furthermore, 3-aryl-Δ ³ -dihydrofuranone derivatives having herbicidal, acaricidal and insecticidal properties are known from: EP-A-528 156 . EP-A-647 637 . WO 95/26954 . WO 96/20 196 . WO 96/25 395 . WO 96/35 664 . WO 97/01 535 . WO 97/02 243 . WO 97/36868 . WO 98/05 638 . WO 98/06 721 . WO 99/16748 . WO 98/25 928 . WO 99/43 649 . WO 99/48869 . WO 99/55673 . WO 01/23354 . WO 01/74 770 . WO 01/17972 . WO 04/024 688 . WO 04/080 962 . WO 04/111 042 . WO 05/092 897 . WO 06/000355 . WO 06/029 799 . WO 07/048545 . WO 07/073856 . WO 07/096058 . WO 07/121868 . WO 07/140881 . WO 08/067911 . WO 08/083950 . PCT / EP2008 / 005973 . PCT / EP / 2008/007517 ,

Also 3-aryl-Δ ³ -dihydrothiphen-on derivatives are known from ( WO 95/26 345 . 96/25 395 . WO 97/01 535 . WO 97/02 243 . WO 97/36868 . WO 98/05638 . WO 98/25928 . WO 99/16748 . WO 99/43649 . WO 99/48869 . WO 99/55673 . WO 01/17972 . WO 01/23354 . WO 01/74770 . WO 03/013249 . WO 04/080 962 . WO 04/111 042 . WO 05/092897 . WO 06/029799 and WO 07/096058 ,

Certain phenyl-pyrone derivatives unsubstituted in the phenyl ring have already become known (cf. AM Chirazi, T. Kappe and E. Ziegler, Arch. Pharm. 309, 558 (1976) and K.-H. Boltze and K. Heidenbluth, Chem. Ber. 91, 2849 ). In the phenyl ring substituted phenyl-pyrone derivatives having herbicidal, acaricidal and insecticidal properties are in EP-A-588,137 . WO 96/25 395 . WO 96/35 664 . WO 97/01 535 . WO 97/02 243 . WO 97/16436 . WO 97/19941 . WO 97/36868 . WO 98/05638 . WO 99/43649 . WO 99/48869 . WO 99/55673 . WO 01/17972 . WO 01/74770 . WO 03/013249 . WO 04/080 962 . WO 04/111 042 . WO 05/092897 . WO 06/029799 and WO 07/096058 described.

Certain, unsubstituted in the phenyl ring 5-phenyl-1,3-thiazine derivatives have already become known (see. E. Ziegler and E. Steiner, Monatsh. 95, 147 (1964) . R. Ketcham, T. Kappe and E. Ziegler, J. Heterocycl. Chem. 10, 223 (1973) ). In the phenyl ring substituted 5-phenyl-1,3-thiazine derivatives with herbicidal, acaricidal and insecticidal activity are in WO 94/14785 . WO 96/25 395 . WO 96/35 664 . WO 97/01 535 . WO 97/02 243 . WO 97/02 243 . WO 97/36868 . WO 99/43649 . WO 99/48869 . WO 99/55673 . WO 01/17972 . WO 01/74770 . WO 03/013249 . WO 04/080 962 . WO 04/111 042 . WO 05/092897 . WO 06/029799 and WO 07/096058 described.

It is known that certain substituted 2-arylcyclopentanediones have herbicidal, insecticidal and acaricidal properties (cf., for example, ( U.S. 4,283,348 ; 4,338,122 ; 4,436,666 ; 4 526 723 ; 4 551 547 ; 4,632,698 ; WO 96/01 798 ; WO 96/03366 . WO 97/14667 such as WO 98/39281 . WO 99/43649 . WO99 / 48869 . WO 99/55673 . WO 01/17972 . WO 01/74770 . WO 03/062244 . WO 04/080962 . WO04 / 111042 . WO05 / 092897 . WO06 / 029799 . WO07 / 080066 . WO07 / 096058 and EP-A imeldnumber 08166352 , In addition, similarly substituted compounds are known; 3-hydroxy-5,5-dimethyl-2-phenylcyclopent-2-en-1-one from the publication Micklefield et al., Tetrahedron, (1992), 7519-26 and the natural product Involutin (-) - cis-5- (3,4-dihydroxyphenyl) -3,4-dihydroxy-2- (4-hydroxyphenyl) -cyclopent-2-en-one from the publication Edwards et al., J. Chem. Soc. S, (1967), 405-9 , An insecticidal or acaricidal action is not described. Also, 2- (2,4,6-trimethylphenyl) -1,3-indanedione is from the publication J. Economic Entomology, 66, (1973), 584 and the publication DE-A 2 361 084 with indication of herbicidal and acaricidal effects.

It is known that certain substituted 2-arylcyclohexanediones possess herbicidal, insecticidal and acaricidal properties ( U.S. 4,175,135 . 4 256 657 . 4 256 658 . 4 256 659 . 4,257,858 . 4,283,348 . 4,303,669 . 4,351,666 . 4 409 153 . 4,436,666 . 4 526 723 . 4 613 617 . 4,659,372 . DE-A 2 813 341 , such as Wheeler, TN, J. Org. Chem. 44, 4906 (1979) ) WO 99/43649 . WO 99/48869 . WO 99/55673 . WO 01/17972 . WO 01/74770 . WO 03/013249 . WO 04/080 962 . WO 04/111 042 . WO 05/092897 . WO 06/029799 . WO 07/096058 . WO 08/071405 . WO 08/110307 . WO 08/110308 . WO 09/074314 and WO 08/145336 ,

It is known that certain substituted 4-aryl-pyrazolidine-3,5-diones have acaricidal, insecticidal and herbicidal properties (cf. WO 92/16510 . EP-A-508 126 . WO 96/11 574 . WO 96/21 652 . WO 99/47525 . WO 01/17351 . WO 01/17352 . WO 01/17353 . WO 01/17972 . WO 01/17973 . WO 03/028 466 . WO 03/062 244 . WO 04/080 962 . WO 04/111 042 . WO 05/005428 . WO 05/016873 . WO 05/092897 . WO 06/029799 and WO 07/096058 ,

It is known that certain tetrahydropyridones have herbicidal properties ( JP 0832530 ). In addition, special 4-hydroxytetrahydropyridones with acaricidal, insecticidal and herbicidal properties are known (US Pat. JP 11152273 ). Also known were 4-hydroxytetrahydropyridones as pesticides and herbicides in WO 01/79204 and WO 07/096058 , 4-hydroxy-quinolones are disclosed in WO 03/01045 ,

It is known that certain 5,6-dihydropyrone derivatives have antiviral properties as protease inhibitors ( WO 95/14012 ). Furthermore, the 4-phenyl-6- (2-phenethyl) -5,6-dihydropyron from the synthesis of kawalactone derivatives is known ( Cap et al., Arch. Pharm. 309, 558-564 (1976). , In addition, 5,6-dihydropyrone derivatives are known as intermediates ( White, JD, Brenner, JB, Deinsdale, MJ, J. Amer. Chem. Soc. 93, 281-282 (1971) , 3-phenyl-5,6-dihydropyrone derivatives with applications in crop protection are in WO 01/98288 and WO 07/09658 described.

4'Biphenyl-substituted tetronic acid are in WO 2008/022725 for the therapy of viral diseases.

WO 2005/089118 and WO2007 / 039286 disclose generic nitrogen-containing bicyclic structures for therapy, with 5'-biphenyl-substituted cyclic ketoenols not being specifically named.

4-phenyl-substituted [1.2] oxazine-3,5-diones are the first herbicides in WO 01/17972 described. Furthermore, 4-acyl-substituted [1.2] oxazine-3,5-diones have been described as pesticides but above all as herbicides and growth regulators z. In EP-A-39 48 89 ; WO 92/07837 . US 5,728,831 and as herbicides and pesticides in WO 03/048138 ,

Starting from this prior art, the object of the present invention is to provide new structures for the therapy of diseases. In particular, the structures according to the invention should be suitable for the prophylaxis and therapy of tumor diseases and have advantages over structures known in the prior art.

It has now surprisingly been found that a specific subgroup of the aryl-substituted cyclic ketoenols described in the prior art also inhibit human ACC and are suitable for the therapy of diseases.

It was unpredictable whether and which of the structures known as insecticides or herbicides would achieve the object according to the invention, namely structures which can be used in the therapy of human diseases.

The Applicant is not aware that in the prior art 5'-biphenyl-substituted cyclic ketoenols according to the present invention are described for the therapy of diseases, in particular not for the therapy of tumor diseases.

The object is achieved by compounds of the formula (I).

in welcher
X für Halogen steht oder
für einen gegebenenfalls mit Halogen ein- oder mehrfach substituierten C₁-C₃-Alkyl- oder C₁-C₃-Alkoxyrest, und
W und Y unabhängig voneinander für Wasserstoff oder Halogen stehen oder
für einen gegebenenfalls mit Halogen ein- oder mehrfach substituierten C₁-C₃-Alkylrest, und
V¹, V² und V³ unabhängig voneinander für Wasserstoff oder Halogen stehen oder für einen C₁-C₃-Alkyl-, C₁-C₃-Halogenalkyl-, C₁-C₃-Alkoxy-, C₁-C₃-Halogenalkoxy- oder C₁-C₃-Alkoxy-C₁-C₃-Alkylrest, und/oder
V¹ und V² mit den Kohlenstoffatomen, an denen sie gebunden sind, einen gesättigten oder ungesättigten und gegebenenfalls mindestens ein weiteres Heteroatom enthaltenden Zyklus T¹ mit 5 oder 6 Ringatomen bilden, dessen ringbildenden Atome mit Halogen und/oder einem C₁-C₃-Alkylrest ein- oder mehrfach, gleich oder verschieden substituiert sein können,
A für Wasserstoff steht oder
für einen gegebenenfalls mit Halogen ein- oder mehrfach substituierten C₁-C₆-Alkyl- oder C₁-C₆-Alkoxy-C₁-C₆-alkylrest oder
für einen C₃-C₇-Cycloalkylrest oder 4- bis 7-gliedrigen monocyclischen Heterocyclylrest, die mit Halogen und/oder einem C₁-C₃-Alkylrest ein- oder mehrfach, gleich oder verschieden substituiert sein können, und
B für Wasserstoff steht oder für einen C₁-C₆-Alkyl- oder C₁-C₃-Alkoxy-C₁-C₃-alkylrest, oder
A und B gemeinsam mit dem Kohlenstoffatom, an das sie gebunden sind, einen gesättigten oder ungesättigten, gegebenenfalls ein oder zwei Heteroatome enthaltenden Zyklus T² mit 3 bis 8 Ringatomen bilden, dessen ringbildenden Atome ein- oder mehrfach, gleich oder verschieden substituiert sein können mit den Resten R¹, R² und R³,
wobei R¹, R² und R³ unabhängig voneinander stehen

• a) für Halogen oder Hydroxy oder
• b) für einen gegebenenfalls im Alkylteil mit Hydroxy substituierten C₁-C₄-Alkyl-, C₁-C₄-Alkoxy-, C₁-C₃-Alkoxy-C₁-C₃-alkyl-, C₁-C₃-Alkoxy-C₁-C₃-alkoxy-, Halogen-C₁-C₃-alkyl- oder Halogen-C₁-C₃-alkoxyrest und/oder
• c) zwei der Reste R¹, R² und R³ gemeinsam mit dem oder den Ringatomen des Zyklusses T², an dem sie gebunden sind, einen weiteren gesättigten oder aromatischen, gegebenenfalls ein oder zwei Heteroatome enthaltenden Zyklus T³ mit 5 bis 7 Ringatomen bilden können, der ein- oder mehrfach, gleich oder verschieden substituiert sein kann mit den Resten R⁴, R⁵ und R⁶, wobei R⁴, R⁵ und R⁶ unabhängig voneinander stehen für einen C₁-C₃-Alkyl- oder C₁-C₃-Alkoxyrest,

geeignet sind für die Verwendung als Arzneimittel.It has now been found that compounds of the formula (I)

in which
X is halogen or
for a optionally mono- or polysubstituted with halogen C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy, and
W and Y are independently hydrogen or halogen or
for a optionally mono- or polysubstituted with halogen C ₁ -C ₃ alkyl, and
V ¹ , V ² and V ^{3 are} independently hydrogen or halogen or a C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ Haloalkoxy or C ₁ -C ₃ alkoxy-C ₁ -C ₃ -alkyl radical, and / or
V ¹ and V ² with the carbon atoms to which they are attached form a saturated or unsaturated and optionally at least one further heteroatom-containing cycle T ¹ with 5 or 6 ring atoms whose ring-forming atoms with halogen and / or a C ₁ -C ₃ Alkyl radical may be mono- or polysubstituted by identical or different substituents,
A is hydrogen or
for a C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl radical optionally mono- or polysubstituted by halogen or
for a C ₃ -C ₇ -cycloalkyl radical or 4- to 7-membered monocyclic heterocyclyl radical which may be mono- or polysubstituted by identical or different substituents with halogen and / or a C ₁ -C ₃ -alkyl radical, and
B is hydrogen or a C ₁ -C ₆ -alkyl or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical, or
A and B together with the carbon atom to which they are attached form a saturated or unsaturated, optionally one or two heteroatoms containing cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or polysubstituted by identical or different substituents the radicals R ¹ , R ² and R ³ ,
wherein R ¹ , R ² and R ^{3 are} independently

• a) for halogen or hydroxy or
• b) for a optionally substituted in the alkyl moiety with hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, C ₁ -C ₃ Alkoxy C ₁ -C ₃ alkoxy, halo C ₁ -C ₃ alkyl or halo C ₁ -C ₃ alkoxy and / or
• c) two of the radicals R ¹ , R ² and R ³ together with the ring or atoms of the cycle T ² to which they are attached, another saturated or aromatic, optionally containing one or two heteroatoms cycle T ³ with 5 to 7 ring atoms can form mono- or polysubstituted by identical or different substituents with the radicals R ⁴ , R ⁵ and R ⁶ , wherein R ⁴ , R ⁵ and R ^{6 are} independently a C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy radical,

are suitable for use as pharmaceuticals.

The medicaments are suitable for the prophylaxis and therapy of human or animal diseases, in particular for the prophylaxis and therapy of tumor diseases.

Particularly suitable compounds of the invention for the prophylaxis and therapy of cancer.

The present invention therefore 5'Biphenyl-substituted ketoenols of the formula (I) for therapeutic purposes, pharmaceutical agents and their use in therapy, in particular for the prophylaxis and therapy of tumor diseases.

The invention is based on the following definitions:

alkyl:

Alkyl is a linear or branched, saturated, monovalent hydrocarbon radical having generally 1 to 6 (C ₁ -C ₆ -alkyl), preferably 1 to 4 (C ₁ -C ₄ -alkyl), and particularly preferably 1 to 3 carbon atoms (C ₁ -C ₃ -alkyl).

Examples and preferred are:
Methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, 1-methylbutyl , 1-ethylpropyl,
1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3, 3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl-1,2-dimethylbutyl. Particularly preferred is a methyl, ethyl, propyl or isopropyl radical.

cycloalkyl:

Cycloalkyl is a mono- or bicyclic, saturated, monovalent hydrocarbon radical having generally 3 to 10 (C ₃ -C ₁₀ -cycloalkyl), preferably 3 to 8 (C ₃ -C ₈ -cycloalkyl), and particularly preferably 3 to 7 (C ₃ -C ₇ cycloalkyl) carbon atoms.

By way of example and with preference for monocyclic cycloalkyl radicals, mention may be made:
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Particularly preferred is a cyclopropyl, cylopentyl or cyclohexyl radical.

Examples of bicyclic cycloalkyl radicals are:
Perhydropentalenyl, decalinyl.

alkoxy:

Alkoxy represents a linear or branched, saturated alkyl ether radical of the formula -O-alkyl having generally 1 to 6 (C ₁ -C ₆ -alkoxy), preferably 1 to 4 (C ₁ -C ₄ -alkoxy), and particularly preferably 1 to 3 (C ₁ -C ₃ alkoxy) carbon atoms.

Examples and preferred are:
Methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

alkoxyalkyl

Alkoxyalkyl is an alkoxy-substituted alkyl radical.

C _n -Alkoxy-C _m -alkyl means that the alkoxy part has n carbon atoms and the alkyl part, via which the radical is bonded, has m carbon atoms.

alkoxyalkoxy

Alkoxyalkoxy is an alkoxy-substituted alkoxy radical. C _n -Alkoxy-C _m -alkoxy means that the outer alkoxy part has n carbon atoms and the alkoxy part, via whose oxygen function the radical is bonded, has m carbon atoms.

aryl

Aryl is a monovalent, aromatic mono- or bicyclic ring system without a heteroatom having 6 or 10 carbon atoms.

Examples and preferred are:
Phenyl (C ₆ -aryl), naphthyl (C ₁₀ -aryl).

Preference is given to phenyl.

heteroatoms

Heteroatoms are oxygen, nitrogen or sulfur atoms.

heteroaryl

Heteroaryl is a monovalent, mono- or bicyclic ring system having at least one heteroatom and at least one aromatic ring. As heteroatoms nitrogen atoms, oxygen atoms and / or sulfur atoms may occur. The bond valency may be at any aromatic carbon atom or at a nitrogen atom.

A monocyclic heteroaryl group according to the present invention has 5 or 6 ring atoms.

For example, heteroaryl radicals having 5 ring atoms include the rings:
Thienyl, thiazolyl, furyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl and thiadiazolyl.

Heteroaryl radicals having 6 ring atoms include, for example, the rings:
Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

A bicyclic heteroaryl group according to the present invention has 9 or 10 ring atoms.

For example, heteroaryl radicals having 9 ring atoms include the rings:
Phthalidyl, thiophthalidyl, indolyl, isoindolyl, indazolyl, benzothiazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, azocinyl, indolizinyl, purinyl, indolinyl.

Heteroaryl radicals with 10 ring atoms include, for example, the rings:
Isoquinolinyl, quinolinyl, quinolizinyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, pteridinyl, chromanyl.

Monocyclic heteroaryl rings with 5 or 6 ring atoms are preferred.

heterocyclyl

Heterocyclyl in the context of the invention is a non-aromatic mono- or bicyclic ring system having at least one heteroatom or a hetero group. As heteroatoms nitrogen atoms, oxygen atoms and / or sulfur atoms may occur. Hetero groups can be -S (O) -, -S (O) ₂ - or -N ⁺ (O ^- ) -.

A monocyclic heterocyclyl ring according to the present invention may have 3 to 8, preferably 5 to 8, more preferably 5 or 6 ring atoms.

By way of example and preferably, monocyclic heterocyclyl radicals having 3 ring atoms may be mentioned:
Aziridinyl.

By way of example and preferably, monocyclic heterocyclyl radicals having 4 ring atoms may be mentioned:
Azetidinyl, oxetanyl.

By way of example and with preference for monocyclic heterocyclyl radicals having 5 ring atoms, mention may be made:
Pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, dioxolanyl and tetrahydrofuranyl.

By way of example and preferably, monocyclic heterocyclyl radicals having 6 ring atoms may be mentioned:
Piperidinyl, piperazinyl, morpholinyl, dioxanyl, tetrahydropyranyl and thiomorpholinyl

By way of example and with preference for monocyclic heterocyclyl radicals having 7 ring atoms, mention may be made of:
Azepanyl, oxepanyl, [1,3] -diazepanly, [1,4] -diazepanyl.

By way of example and with preference for monocyclic heterocyclyl radicals having 8 ring atoms, mention may be made:
Oxocanyl, azocanyl

A bicyclic heterocyclyl group according to the present invention may have 5 to 12, preferably 8 to 10, ring atoms.

Preference is given to 5- to 8-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S.

Particularly preferred are morpholinyl, piperidinyl and pyrolidinyl.

halogen

The term halogen includes fluorine, chlorine, bromine and iodine. Preference is given to fluorine and chlorine.

haloalkyl:

Haloalkyl is an alkyl radical having at least one halogen substituent. Examples and preferred are:
Trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 5,5,5,4,4-pentafluoropentyl or 5,5,5,4,4,3,3-heptafluoropentyl group.

Preference is given to perfluorinated alkyl radicals such as trifluoromethyl or pentafluoroethyl.

haloalkoxy

Haloalkoxy is an alkoxy radical having at least one halogen substituent.

Preference is given to fluoroalkoxy radicals.

Examples and preferred are:
Trifluoromethoxy or 2,2,2-trifluoroethoxy radical.

cycle

Cycle includes all ring systems.

Unsaturated cycle

An unsaturated cycle includes ring systems having at least one double bond in the ring and aromatic ring systems.

In the formula (I), X may stand for:
Halogen or an optionally halogen-mono- or polysubstituted C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy.

In the formula (I), X may preferably stand for:
Chlorine or a methyl radical.

In the formula (I), W and Y may be independently of one another for:
Is hydrogen or halogen or an optionally halogen-mono- or polysubstituted C ₁ -C ₃ -alkyl radical.

In the formula (I), W and Y independently of one another may preferably stand for:
Hydrogen or a methyl radical.

In the formula (I), X, W and Y depending on one another may be extremely preferably:
X is methyl and W and Y is hydrogen or
X and W are methyl and Y is hydrogen or
X and Y are methyl and W is hydrogen.

In the formula (I), V ¹ , V ² and V ^{3 may} independently represent:
Hydrogen or halogen or
for a C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy- or C ₁ -C ₃ -alkoxy-C ₁ -C _3- alkyl radical, and / or
V ¹ and V ² form with the carbon atoms to which they are attached a saturated or unsaturated and optionally at least one further heteroatom containing cycle T ¹ with 5 or 6 ring atoms whose ring-forming atoms with halogen and / or a C ₁ -C ₃ Alkyl radical may be mono- or polysubstituted by identical or different substituents,

In the formula (I), V ¹ , V ² and V ^{3 may} independently of one another preferably stand for:
is hydrogen, chlorine or fluorine or a methyl or trifluoromethyl radical.

In the formula (I), V ¹ , V ² and V ³ more preferably represent:
V ^{1 represents} hydrogen, chlorine or fluorine or a methyl or a trifluoromethyl radical, and
V ² and V ^{3 are} independently hydrogen, chlorine or fluorine.

In the formula (I), V ¹ , V ² and V ³ independently of one another may be particularly preferably:
Hydrogen, chlorine or fluorine.

In the formula (I), V ¹ can be extremely preferably chlorine or fluorine, in particular chlorine.

In formula (I), A can stand for:
for hydrogen or
for a C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl radical optionally monosubstituted or polysubstituted or for a C ₃ -C ₇ -cycloalkyl radical or 4 to 7 monohydric monocyclic heterocyclyl radical which may be mono- or polysubstituted by identical or different substituents with halogen and / or a C ₁ -C ₃ -alkyl radical.

In the formula (I), A may preferably stand for:
Is hydrogen or an optionally halogen-substituted C ₁ -C ₄ -alkyl or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical or
for a C ₃ -C ₆ -cycloalkyl radical which may be mono- or polysubstituted by identical or different substituents with halogen and / or a C ₁ -C ₃ -alkyl radical.

In the formula (I), A may more preferably stand for:
Hydrogen or
for an optionally halogen-substituted C ₁ -C ₄ -alkyl or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical or for a C ₃ -C ₆ -cycloalkyl radical.

In the formula (I), A may be particularly preferably:
Hydrogen or
for a C ₁ -C ₄ -alkyl, methoxy-C ₁ -C ₂ -alkyl- or for a C ₃ -C ₆ -cycloalkyl radical.

In the formula (I), B may stand for:
Is hydrogen or a C ₁ -C ₆ -alkyl or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical.

In the formula (I), B may preferably stand for:
Hydrogen or a C ₁ -C ₃ alkyl radical.

In the formula (I), B may more preferably stand for:
Is hydrogen or a methyl radical.

• a) für Halogen oder Hydroxy oder
• b) für einen gegebenenfalls im Alkylteil mit Hydroxy substituierten C₁-C₄-Alkyl-, C₁-C₄-Alkoxy-, C₁-C₃-Alkoxy-C₁-C₃-alkyl-, C₁-C₃-Alkoxy-C₁-C₃-alkoxy-, Halogen-C₁-C₃-alkyl- oder Halogen-C₁-C₃-alkoxyrest und/oder
• c) zwei der Reste R¹, R² und R³ gemeinsam mit dem oder den Ringatomen des Zyklusses T², an dem sie gebunden sind, einen weiteren gesättigten oder aromatischen, gegebenenfalls ein oder zwei Heteroatome enthaltenden Zyklus T³ mit 5 bis 7 Ringatomen bilden können, der ein- oder mehrfach, gleich oder verschieden substituiert sein kann mit den Resten R⁴, R⁵ und R⁶, wobei R⁴, R⁵ und R⁶ unabhängig voneinander stehen für einen C₁-C₃-Alkyl- oder C₁-C₃-Alkoxyrest.

In the formula (I), A and B together with the carbon atom to which they are attached may form:
a saturated or unsaturated, optionally containing one or two heteroatoms cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or polysubstituted by identical or different substituents with the radicals R ¹ , R ² and R ³ ,
wherein R ¹ , R ² and R ^{3 are} independently

• a) for halogen or hydroxy or
• b) for a optionally substituted in the alkyl moiety with hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, C ₁ -C ₃ Alkoxy C ₁ -C ₃ alkoxy, halo C ₁ -C ₃ alkyl or halo C ₁ -C ₃ alkoxy and / or
• c) two of the radicals R ¹ , R ² and R ³ together with the ring or atoms of the cycle T ² to which they are attached, another saturated or aromatic, optionally containing one or two heteroatoms cycle T ³ with 5 to 7 ring atoms can form mono- or polysubstituted by identical or different substituents with the radicals R ⁴ , R ⁵ and R ⁶ , wherein R ⁴ , R ⁵ and R ^{6 are} independently a C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy.

• a) für einen gegebenenfalls im Alkylteil mit Hydroxy substituierten C₁-C₃-Alkyl-, C₁-C₃-Alkoxy-, C₁-C₃-Alkoxy-C₁-C₃-alkyl-, C₁-C₃-Alkoxy-C₁-C₃-alkoxy- oder Halogen-C₁-C₃-alkoxyrest, und/oder
• b₁) zwei der Reste R¹, R² und R³ gemeinsam mit dem Ringatom des Zyklusses T², an dem sie gebunden sind, einen weiteren gesättigten, gegebenenfalls ein oder zwei Sauerstoffatome enthaltenden Zyklus T³ mit 5 bis 7 Ringatomen bilden können, der mit einem C₁-C₃-Alkylrest ein- oder zweifach substituiert sein kann, oder
• b₂) zwei der Reste R¹, R² und R³ gemeinsam mit den benachbarten Ringatomen des Zyklusses T2, an denen sie gebunden sind, einen weiteren aromatischen Zyklus T³ mit 6 Ringatomen bilden können, der mit einem C₁-C₃-Alkylrest ein- oder zweifach substituiert sein kann.

In the formula (I), A and B together with the carbon atom to which they are attached may preferably form:
a saturated, optionally an oxygen atom-containing cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or disubstituted by identical or different substituents with the radicals R ¹ , R ² and R ³ , wherein R ¹ , R ² and R ^{3 are} independent of each other

• a) for a optionally substituted in the alkyl moiety with hydroxy C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, C ₁ -C ₃ Alkoxy C ₁ -C ₃ alkoxy or halo C ₁ -C ₃ alkoxy, and / or
• b ₁₎ two of R ^1, R ² and R ³ optionally can form one or two oxygen atom-containing cycle T ³ having 5 to 7 ring atoms, together with the ring atom of the cycle T ^2, to which they are attached form a further saturated, which may be mono- or disubstituted by a C ₁ -C ₃ -alkyl radical, or
• b ₂ ) two of the radicals R ¹ , R ² and R ^3, together with the adjacent ring atoms of the cycle T ² to which they are attached, can form a further aromatic cycle T ³ having 6 ring atoms which is substituted by a C ₁ -C ₃ Alkyl radical may be substituted once or twice.

• a) für einen C₁-C₃-Alkyl-, C₁-C₃-Alkoxy-, C₁-C₃-Alkoxy-C₁-C₃-alkyl- oder Halogen-C₁-C₃-alkoxyrest und/oder
• b) zwei der Reste R¹, R² und R³ gemeinsam mit dem Ringatom des Zyklusses T², an dem sie gebunden sind, einen weiteren gesättigten, gegebenenfalls ein oder zwei Sauerstoffatome enthaltenden Zyklus T³ mit 5 oder 6 Ringatomen bilden können.

In the formula (I), A and B together with the carbon atom to which they are bonded may more preferably form:
a saturated, optionally an oxygen or sulfur atom-containing cycle T ² having 5 to 7 ring atoms whose ring-forming atoms may be monosubstituted or disubstituted by identical or different substituents with the radicals R ¹ , R ² and R ³ ,
wherein R ¹ , R ² and R ^{3 are} independently

• a) a C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl or halogeno-C ₁ -C ₃ -alkoxy radical and / or or
• b) two of the radicals R ¹ , R ² and R ³ together with the ring atom of the cycle T ² , to which they are attached, can form a further saturated, optionally one or two oxygen atoms containing cycle T ³ with 5 or 6 ring atoms.

• a) für einen C₁-C₃-Alkyl-, C₁-C₄-Alkoxy-, Methoxy-C₁-C₂-alkyl-, 2,2,2-Trifluorethoxyrest und/oder
• b) zwei der Reste R¹, R² und R³ gemeinsam mit dem Ringatom des Zyklusses T², an dem sie gebunden sind, einen weiteren gesättigten, gegebenenfalls ein oder zwei Sauerstoffatome enthaltenden Zyklus T³ mit 5 oder 6 Ringatomen bilden können, der ein- oder zweifach substituiert sein kann mit einem Methylrest.

In the formula (I), A and B together with the carbon atom to which they are bonded may particularly preferably form:
a saturated, optionally an oxygen atom-containing cycle T ² having 5 to 6 ring atoms whose ring-forming atoms may be mono- or disubstituted by identical or different substituents with the radicals R ¹ , R ² and R ³ , wherein R ¹ , R ² and R ^{3 are} independent of each other

• a) for a C ₁ -C ₃ -alkyl, C ₁ -C ₄ -alkoxy, methoxy-C ₁ -C ₂ -alkyl, 2,2,2-trifluoroethoxy and / or
• b) two of the radicals R ¹ , R ² and R ³ together with the ring atom of the cycle T ² , to which they are attached, can form a further saturated, optionally one or two oxygen atoms containing cycle T ³ with 5 or 6 ring atoms, the may be substituted once or twice with a methyl radical.

In the formula (I), A and B together with the carbon atom to which they are bonded may form extremely preferably:
a saturated, optionally an oxygen atom-containing cycle T ² having 6 ring atoms whose ring-forming atoms may be mono- or disubstituted by identical or different substituents with the radicals R ¹ , R ² and R ³ , wherein R ¹ , R ² and R ^{3 are} independent each other is a C ₁ -C ₃ -alkyl, C ₁ -C ₄ -alkoxy, methoxy-C ₁ -C ₂ -alkyl, 2,2,2-trifluoroethoxy.

In formula (I), A and B together with the carbon atom to which they are attached may very preferably form a cyclohexane ring or tetrahydropyran ring.

The optionally present substituents R ¹ , R ² and R ^{3 of} the cycle T ² formed by A and B very preferably independently of one another represent a C ₁ -C ₃ -alkyl, C ₁ -C ₂ -alkoxy, methoxy-C ₁ C ₂ alkyl or 2,2,2-trifluoroethoxy.

Particularly preferred is only one substituent, wherein R ^{1 is} a C ₁ -C ₃ alkyl, C ₁ -C ₂ alkoxy, methoxy-C ₁ -C ₂ alkyl or 2,2,2-trifluoroethoxy.

• a) für einen gegebenenfalls im Alkylteil mit Hydroxy substituierten C₁-C₃-Alkyl-, C₁-C₃-Alkoxy-, C₁-C₃-Alkoxy-C₁-C₃-alkyl-, C₁-C₃-Alkoxy-C₁-C₃-alkoxy- oder Halogen-C₁-C₃-alkoxyrest, und/oder
• b₁) zwei der Reste R¹, R² und R³ gemeinsam mit dem Ringatom des Zyklusses T², an dem sie gebunden sind, einen weiteren gesättigten, gegebenenfalls ein oder zwei Sauerstoffatome enthaltenden Zyklus T³ mit 5 bis 7 Ringatomen bilden können, der mit einem C₁-C₃-Alkylrest ein- oder zweifach substituiert sein kann, oder
• b₂) zwei der Reste R¹, R² und R³ gemeinsam mit den benachbarten Ringatomen des Zyklusses T², an denen sie gebunden sind, einen weiteren aromatischen Zyklus T³ mit 6 Ringatomen bilden können, der mit einem C₁-C₃-Alkylrest ein- oder zweifach substituiert sein kann.

A particularly preferred subgroup is formed by compounds of the general formula (I)
in which
X is chlorine or a methyl radical, and
W and Y independently of one another represent hydrogen or a methyl radical,
V ¹ , V ² and V ³ independently of one another are hydrogen, chlorine or fluorine or a methyl or a trifluoromethyl radical, and
A is hydrogen or an optionally halogen-substituted C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical or
for a C ₃ -C ₆ -cycloalkyl radical which may be mono- or polysubstituted by identical or different substituents with halogen and / or a C ₁ -C ₃ -alkyl radical, and
B is hydrogen or a C ₁ -C ₃ -alkyl radical, or
A and B together with the carbon atom to which they are attached form a saturated, optionally oxygen-containing cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be monosubstituted or disubstituted by identical or different substituents with the radicals R ¹ , R ² and R ³ , wherein R ¹ , R ² and R ^{3 are} independently

• a) for a optionally substituted in the alkyl moiety with hydroxy C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, C ₁ -C ₃ Alkoxy C ₁ -C ₃ alkoxy or halo C ₁ -C ₃ alkoxy, and / or
• b ₁₎ two of R ^1, R ² and R ³ optionally can form one or two oxygen atom-containing cycle T ³ having 5 to 7 ring atoms, together with the ring atom of the cycle T ^2, to which they are attached form a further saturated, which may be mono- or disubstituted by a C ₁ -C ₃ -alkyl radical, or
• b ₂ ) two of the radicals R ¹ , R ² and R ³ together with the adjacent ring atoms of the cycle T ² to which they are attached, can form a further aromatic cycle T ³ with 6 ring atoms, which is a C ₁ -C ₃ Alkyl may be mono- or di-substituted.

• a) für einen C₁-C₃-Alkyl-, C₁-C₃-Alkoxy-, C₁-C₃-Alkoxy-C₁-C₃-alkyl- oder Halogen-C₁-C₃-alkoxyrest und/oder
• b) zwei der Reste R¹, R² und R³ gemeinsam mit dem Ringatom des Zyklusses T², an dem sie gebunden sind, einen weiteren gesättigten, gegebenenfalls ein oder zwei Sauerstoffatome enthaltenden Zyklus T³ mit 5 oder 6 Ringatomen bilden können.

A particularly preferred subgroup within the group of compounds of formula (I) are compounds of formula (I) in which
X is chlorine or a methyl radical, and
W and Y independently of one another represent hydrogen or a methyl radical,
V ^{1 is} hydrogen, chlorine or fluorine, and
V ² and V ³ independently of one another represent hydrogen, chlorine or fluorine,
A is hydrogen or a C ₁ -C ₃ -alkyl or C ₃ -C ₆ -cycloalkyl radical, and
B is hydrogen or methyl, or
A and B together with the carbon atom to which they are attached form a saturated cycle T ² optionally containing an oxygen or sulfur atom having 5 to 7 ring atoms whose ring-forming atoms may be monosubstituted or disubstituted by identical or different substituents Radicals R ¹ , R ² and R ³ ,
wherein R ¹ , R ² and R ^{3 are} independently

• a) a C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl or halogeno-C ₁ -C ₃ -alkoxy radical and / or or
• b) two of the radicals R ¹ , R ² and R ³ together with the ring atom of the cycle T ² , to which they are attached, can form a further saturated, optionally one or two oxygen atoms containing cycle T ³ with 5 or 6 ring atoms.

• – 3-(4'-Chlor-4-methylbiphenyl-3-yl)-8-ethyl-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-1),
• – 3-(4'-Chlor-2,4-dimethylbiphenyl-3-yl)-4-hydroxy-1-oxaspiro[4.4]non-3-en-2-on (Bsp. 1-2),
• – 3-(4'-Chlor-4-methylbiphenyl-3-yl)-4-hydroxy-5,5-dimethylfuran-2(5H)-on (Bsp. 1-3),
• – 3-(4'-Chlor-2,4-dimethylbiphenyl-3-yl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-4),
• – 3-(4'-Chlor-2,4,6-trimethylbiphenyl-3-yl)-4-hydroxy-5,5-dimethylfuran-2(5H)-on (Bsp. 1-5),
• – 3-(4'-Chlor-2,4,6-trimethylbiphenyl-3-yl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-on (Bsp.1-6),
• – 3-(2'-Chlor-4-methylbiphenyl-3-yl)-4-hydroxy-8-methoxy-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-7),
• – 6-(4'-Chlor-4-methylbiphenyl-3-yl)-7-hydroxy-4-oxaspiro[2.4]hept-6-en-5-on (Bsp. 1-8),
• – 3-(4'-Chlor-4-methylbiphenyl-3-yl)-4-hydroxy-1,7-dioxaspiro[4.5]dec-3-en-2-on (Bsp. 1-9),
• – 3-(4'-Chlor-4-methylbiphenyl-3-yl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-10),
• – 3-(4'-Chlor-4,6-dimethylbiphenyl-3-yl)-4-hydroxy-7-methoxy-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-11),
• – 3-(4'-Chlor-2,4,6-trimethylbiphenyl-3-yl)-4-hydroxy-7-methoxy-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-12),
• – 3-(4,4'-Dichlorbiphenyl-3-yl)-4-hydroxy-7-methoxy-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-13),
• – 3-(4'-Chlor-4-methylbiphenyl-3-yl)-4-hydroxy-7-methoxy-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-14),
• – 11-(4'-Chlor-4-methylbiphenyl-3-yl)-12-hydroxy-1,4,9-trioxadispiro[4.2.4.2]tetradec-11-en-10-on (Bsp. 1-15),
• – 3-(4,4'-Dichlorbiphenyl-3-yl)-4-hydroxy-8-(methoxymethyl)-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-16),
• – 3-(4'-Chlor-2,4-dimethylbiphenyl-3-yl)-4-hydroxy-8-(methoxymethyl)-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-17),
• – 3-(4'-Chlor-4-methylbiphenyl-3-yl)-4-hydroxy-7-(2-methoxyethyl)-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-18),
• – 3-(4,4'-Dichlorbiphenyl-3-yl)-4-hydroxy-7-(2-methoxyethyl)-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-19),
• – 3-(4'-Chlor-4-methylbiphenyl-3-yl)-4-hydroxy-8-(methoxymethyl)-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-20),
• – 3-(4'-Fluor-4-methylbiphenyl-3-yl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-21),
• – 3-(3',4'-Difluor-4-methylbiphenyl-3-yl)-4-hydroxy-1-oxaspiro[4.4]non-3-en-2-on (Bsp. 1-22),
• – 3-(3'-Chlor-4'-fluor-4-methylbiphenyl-3-yl)-4-hydroxy-1-oxaspiro[4.4]non-3-en-2-on (Bsp. 1-23),
• – 3-(4-Chlor-3',4',5'-trifluorbiphenyl-3-yl)-4-hydroxy-1-oxaspiro[4.4]non-3-en-2-on (Bsp. 1-24),
• – 3-(4-Chlor-3',4'-difluorbiphenyl-3-yl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-25),
• – (5s,8r)-3-(4'-Chlor-2,4-dimethylbiphenyl-3-yl)-4-hydroxy-1,9-dioxadispiro[4.2.4.2]tetradec-3-en-2-on (Bsp. 1-26),
• – 3-(4,4'-Dichlorbiphenyl-3-yl)-4-hydroxy-1,9-dioxadispiro[4.2.4.2]tetradec-3-en-2-on (Bsp. 1-27),
• – (5r,8s)-3-(4'-Fluor-4-methylbiphenyl-3-yl)-4-hydroxy-1,9-dioxadispiro[4.2.4.2]tetradec-3-en-2-on (Bsp. 1-28),
• – 3-(4'-Chlor-4-methylbiphenyl-3-yl)-4-hydroxy-1,9-dioxadispiro[4.2.4.2]tetradec-3-en-2-on (Bsp. 1-29),
• – (5r,8s)-3-(4'-Chlor-4,6-dimethylbiphenyl-3-yl)-4-hydroxy-1,9-dioxadispiro[4.2.4.2]tetradec-3-en-2-on (Bsp. 1-30),
• – (5r,8s)-3-(4'-Chlor-2,4,6-trimethylbiphenyl-3-yl)-4-hydroxy-1,9-dioxadispiro[4.2.4.2]tetradec-3-en-2-on (Bsp. 1-31),
• – 3-(4'-Chlor-2,4-dimethylbiphenyl-3-yl)-4-hydroxy-8-(2,2,2-trifluorethoxy)-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-32),
• – 3-(4'-Chlor-4-methylbiphenyl-3-yl)-4-hydroxy-8-(2,2,2-trifluorethoxy)-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-33),
• – 3-(4'-Chlor-2,4-dimethylbiphenyl-3-yl)-4-hydroxy-8-methoxy-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-34),
• – 5-tert-Butyl-3-(4'-chlor-4-methylbiphenyl-3-yl)-4-hydroxyfuran-2(5H)-on (Bsp. 1-35),
• – 3-(4'-Chlor-4-methylbiphenyl-3-yl)-4-hydroxy-8-propyl-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-36),
• – 3-(4'-Chlor-4-methylbiphenyl-3-yl)-4-hydroxy-1,8-dioxaspiro[4.5]dec-3-en-2-on (Bsp. 1-37),
• – 3-(4'-Chlor-4-methylbiphenyl-3-yl)-4-hydroxy-1-oxaspiro[4.6]undec-3-en-2-on (Bsp. 1-38),
• – 3-(4'-Chlor-4-methylbiphenyl-3-yl)-4-hydroxy-8-methoxy-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-39),
• – 3-(4'-Chlor-4-methylbiphenyl-3-yl)-5-cyclohexyl-4-hydroxy-5-methylfuran-2(5H)-on (Bsp. 1-40),
• – 3-(4'-Chlor-4,6-dimethylbiphenyl-3-yl)-4-hydroxy-1,8-dioxaspiro[4.5]dec-3-en-2-on (Bsp. 1-41),
• – 3-(4'-Chlor-4,6-dimethylbiphenyl-3-yl)-4-hydroxy-1-oxa-8-thiaspiro[4.5]dec-3-en-2-on (Bsp. 1-42),
• – 3-(4'-Chlor-4,6-dimethylbiphenyl-3-yl)-4-hydroxy-1-oxaspiro[4.6]undec-3-en-2-on (Bsp. 1-43),
• – 3-(4'-Chlor-4,6-dimethylbiphenyl-3-yl)-4-hydroxy-8-methoxy-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-44),
• – 3-(4'-Chlor-4,6-dimethylbiphenyl-3-yl)-4-hydroxy-5-methylfuran-2(5H)-on (Bsp. 1-45),
• – 3-(4'-Chlor-4,6-dimethylbiphenyl-3-yl)-4-hydroxy-1,7-dioxaspiro[4.5]dec-3-en-2-on (Bsp. 1-46),
• – 3-(4'-Chlor-4,6-dimethylbiphenyl-3-yl)-4-hydroxy-8-propoxy-1-oxaspiro[4.5]dec-3-en-2-on (Bsp. 1-47),
• – 3-(4'-Chlor-2,4,6-trimethylbiphenyl-3-yl)-4-hydroxy-1-oxaspiro[4.6]undec-3-en-2-on (Bsp. 1-48),
• – 3-(4'-Chlor-2,4,6-trimethylbiphenyl-3-yl)-4-hydroxy-1-oxaspiro[4.4]non-3-en-2-on (Bsp. 1-49),
• – 3-(3'-Chlor-4-methylbiphenyl-3-yl)-4-hydroxy-1-oxaspiro[4.6]undec-3-en-2-on (Bsp. 1-50),

Extraordinary preference is also given to the following compounds of the formula I:

• 3- (4'-chloro-4-methylbiphenyl-3-yl) -8-ethyl-4-hydroxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex 1-1),
• 3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.4] non-3-en-2-one (Ex: 1-2),
• 3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-5,5-dimethylfuran-2 (5H) -one (Ex. 1-3),
• 3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex. 1-4),
• 3- (4'-chloro-2,4,6-trimethyl-biphenyl-3-yl) -4-hydroxy-5,5-dimethylfuran-2 (5H) -one (Ex: 1-5),
• 3- (4'-chloro-2,4,6-trimethyl-biphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex.1-6),
• 3- (2'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 1-7),
• 6- (4'-chloro-4-methylbiphenyl-3-yl) -7-hydroxy-4-oxaspiro [2.4] hept-6-en-5-one (Ex: 1-8),
• 3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-1,7-dioxaspiro [4.5] dec-3-en-2-one (Ex: 1-9),
• 3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex 1-10),
• 3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-7-methoxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 1-11) .
• 3- (4'-chloro-2,4,6-trimethyl-biphenyl-3-yl) -4-hydroxy-7-methoxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex. 12)
• 3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-7-methoxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 1-13),
• 3- (4'-chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-7-methoxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 1-14),
• - 11- (4'-chloro-4-methylbiphenyl-3-yl) -12-hydroxy-1,4,9-trioxadispiro [4.2.4.2] tetradec-11-en-10-one (Ex 1-15) .
• 3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8- (methoxymethyl) -1-oxaspiro [4.5] dec-3-en-2-one (Ex: 1-16),
• 3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (methoxymethyl) -1-oxaspiro [4.5] dec-3-en-2-one (Ex. 17)
• 3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-7- (2-methoxyethyl) -1-oxaspiro [4.5] dec-3-en-2-one (Ex. 18)
• 3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-7- (2-methoxyethyl) -1-oxaspiro [4.5] dec-3-en-2-one (Ex 1-19) .
• 3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (methoxymethyl) -1-oxaspiro [4.5] dec-3-en-2-one (Ex 1-20) .
• 3- (4'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 1-21),
• 3- (3 ', 4'-difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.4] non-3-en-2-one (Ex: 1-22),
• 3- (3'-chloro-4'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.4] non-3-en-2-one (Ex: 1-23),
• 3- (4-chloro-3 ', 4', 5'-trifluorobiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.4] non-3-en-2-one (Ex: 1-24) .
• 3- (4-chloro-3 ', 4'-difluorobiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 1-25),
• - (5s, 8r) -3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-1,9-dioxadispiro [4.2.4.2] tetradec-3-en-2-one ( Ex. 1-26),
• 3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-1,9-dioxadispiro [4.2.4.2] tetradec-3-en-2-one (Ex: 1-27),
• - (5r, 8s) -3- (4'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-1,9-dioxadispiro [4.2.4.2] tetradec-3-en-2-one (Ex. 1-28),
• 3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-1,9-dioxadispiro [4.2.4.2] tetradec-3-en-2-one (Ex: 1-29),
• - (5r, 8s) -3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-1,9-dioxadispiro [4.2.4.2] tetradec-3-en-2-one ( Ex. 1-30),
• - (5r, 8s) -3- (4'-chloro-2,4,6-trimethyl-biphenyl-3-yl) -4-hydroxy-1,9-dioxadispiro [4.2.4.2] tetradec-3-ene-2 on (Ex. 1-31),
• 3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (2,2,2-trifluoroethoxy) -1-oxaspiro [4.5] dec-3-ene-2 on (Ex. 1-32),
• 3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (2,2,2-trifluoroethoxy) -1-oxaspiro [4.5] dec-3-en-2-one ( Ex. 1-33),
• 3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 1-34) .
• 5-tert-butyl-3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxyfuran-2 (5H) -one (Ex. 1-35),
• 3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8-propyl-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 1-36),
• 3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-1,8-dioxaspiro [4.5] dec-3-en-2-one (Ex. 1-37),
• 3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.6] undec-3-en-2-one (Ex: 1-38),
• 3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 1-39),
• 3- (4'-chloro-4-methylbiphenyl-3-yl) -5-cyclohexyl-4-hydroxy-5-methylfuran-2 (5H) -one (Ex: 1-40),
• 3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-1,8-dioxaspiro [4.5] dec-3-en-2-one (Ex: 1-41),
• 3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-1-oxa-8-thiaspiro [4.5] dec-3-en-2-one (Ex: 1-42) .
• 3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.6] undec-3-en-2-one (Ex: 1-43),
• 3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 1-44) .
• 3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-5-methylfuran-2 (5H) -one (Ex: 1-45),
• 3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-1,7-dioxaspiro [4.5] dec-3-en-2-one (Ex: 1-46),
• 3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-8-propoxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 1-47) .
• 3- (4'-chloro-2,4,6-trimethyl-biphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.6] undec-3-en-2-one (Ex: 1-48),
• 3- (4'-chloro-2,4,6-trimethyl-biphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.4] non-3-en-2-one (Ex: 1-49),
• 3- (3'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.6] undec-3-en-2-one (Ex 1-50),

Saturated or unsaturated hydrocarbon radicals such as alkyl, alkanediyl or alkenyl can, even in combination with heteroatoms, such as. As in alkoxy, as far as possible, each be straight-chain or branched.

Unless otherwise specified, optionally substituted radicals may be monosubstituted or polysubstituted, with multiple substituents the substituents being the same or different.

Also to be considered as encompassed by the present invention are all compounds which result from any combination of the above-mentioned possible, preferred and particularly preferred meanings of the substituents.

Particular embodiments of the invention moreover exist in compounds which result from combination of the substituent meanings disclosed directly in the examples.

Also to be considered as encompassed by the present invention is the use of the physiologically acceptable salts of the compounds.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, eg. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention and at least one or more further active ingredients, in particular for the treatment and / or prophylaxis of tumor diseases.

The compounds according to the invention can act systemically and / or locally. For this purpose, they can be applied in a suitable manner, such as. As oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or implant or stent.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For oral administration are according to the prior art functioning rapidly and / or modified compounds of the invention donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as. As tablets (uncoated or coated tablets, for example, with enteric or delayed dissolving or insoluble coatings that control the release of the compound of the invention), quickly disintegrating in the oral cavity tablets or films / wafers, films / lyophilisates, capsules (for example, hard or Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be carried out bypassing a resorption step (eg intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or using absorption (for example intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). For parenteral administration are suitable as application forms u. a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are z. Inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, Pastes, foams, scattering powders, implants or stents.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include u. a. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecylsulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (For example, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.

The formulation of the compounds according to the invention into pharmaceutical preparations is carried out in a manner known per se by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.

As auxiliaries may, for example, vehicles, fillers, disintegrants, binders, humectants, lubricants, adsorbents and agents, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents, colorants, preservatives, stabilizers, wetting agents, salts for changing the osmotic pressure or buffers are used.

It is up Remington's Pharmaceutical Science, 15th ed Mack Publishing Company, East Pennsylvania (1980) to point.

The pharmaceutical formulations can
in solid form, for example as tablets, dragees, pills, suppositories, capsules, transdermal systems or
in semi-solid form, for example as ointments, creams, gels, suppositories, emulsions or
in liquid form, for example as solutions, tinctures, suspensions or emulsions.

Auxiliaries for the purposes of the invention may be, for example, salts, saccharides (mono-, di-, tri-, oligo-, and / or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils, hydrocarbons and derivatives thereof, the auxiliaries may be of natural origin or synthetically or partially synthetically obtained.

For oral or oral administration, in particular tablets, dragees, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions come into question. For parenteral administration in particular suspensions, emulsions and above all solutions in question.

The present invention relates to the use of the compounds according to the formula (I) for the prophylaxis and therapy of human diseases, in particular of tumor diseases.

The compounds according to the formula (I) can be used in particular to inhibit or reduce cell proliferation and / or cell division and / or to induce apoptosis.

• – Psoriasis,
• – Keloide und andere Hyperplasien, die die Haut betreffen,
• – gutartige Prostathyperplasien (BPH),
• – solide Tumore und
• – hämatologische Tumore.

The compounds of the invention are particularly suitable for the treatment of hyperproliferative diseases such as

• - psoriasis,
• - keloids and other skin-related hyperplasias
• - benign prostate hyperplasia (BPH),
• - solid tumors and
• - hematological tumors.

As solid tumors according to the invention, for example, tumors of the breast, the respiratory tract, the brain, the reproductive organs, the gastrointestinal tract, the genitourinary tract, the eye, the liver, the skin, the head and neck, the thyroid gland, the parathyroid gland, are treatable Bone and connective tissue and metastases of these tumors.

As haematological tumors according to the invention, for example, treatable multiple myelomas, lymphomas or leukemias.

• – Mammakarzinome mit positivem Hormonrezeptorstatus
• – Mammakarzinome mit negativem Hormonrezeptorstatus
• – Her-2 positive Mammakarzinome
• – Hormonrezeptor- und Her-2 negative Mammakarzinome
• – BRCA-assoziierte Mammakarzinome
• – entzündliches Mammakarzinom.

For example, treatable as breast tumors are:

• - Breast cancer with positive hormone receptor status
• - Breast cancer with negative hormone receptor status
• - Her-2 positive breast cancers
• - Hormone receptor and Her-2 negative breast cancers
• - BRCA-associated breast cancer
• - inflammatory breast cancer.

• – nicht-kleinzellige Bronchialkarzinome und
• – kleinzellige Bronchialkarzinome.

For example, tumors of the respiratory tract are treatable

• - non-small cell lung carcinomas and
• - small cell bronchial carcinomas.

• – Gliome,
• – Glioblastome,
• – Astrozytome,
• – Meningiome und
• – Medulloblastome.

For example, tumors of the brain are treatable

• - glioma,
• - glioblastomas,
• - astrocytomas,
• - Meningiomas and
• - Medulloblastomas.

• – Prostatakarzinome,
• – Maligne Hodentumore und
• – Peniskarzinome.

For example, tumors of the male reproductive organs are treatable:

• - prostate carcinomas,
• - Malignant testicular tumors and
• - Penile carcinomas.

• – Endometriumkarzinome
• – Zervixkarzinome
• – Ovarialkarzinome
• – Vaginalkarzimome
• – Vulvarkarzinome

For example, tumors of the female reproductive organs are treatable:

• - endometrial carcinomas
• - cervical carcinomas
• - ovarian carcinomas
• - vaginal carcinomas
• - Vulvar carcinomas

• – Kolorektale Karzinome
• – Analkarzinome
• – Magenkarzinome
• – Pankreaskarzinome
• – Osophagukarzinome
• – Gallenblasenkarzinome
• – Dünndarmkarzinome
• – Speicheldrüsenkarzinome
• – Neuroendokrine Tumore
• – Gastrointestinale Stromatumore

For example, tumors of the gastrointestinal tract are treatable:

• - Colorectal carcinomas
• - Anal carcinomas
• - gastric carcinoma
• - Pancreatic carcinomas
• - Osophagocarcinomas
• - Gallbladder carcinomas
• - Small intestinal carcinomas
• - Salivary gland carcinomas
• - Neuroendocrine tumors
• - Gastrointestinal stromal tumors

• – Harnblasenkarzinome
• – Nierenzellkarzinome
• – Karzinome des Nierenbeckens und der ableitenden Harnwege

For example, tumors of the urogenital tract are treatable:

• - bladder carcinomas
• - renal cell carcinomas
• - carcinomas of the renal pelvis and the urinary tract

• – Retinoblastome
• – Intraokulare Melanome

For example, tumors of the eye are treatable:

• - Retinoblastomas
• - Intraocular melanomas

• – Hepatozelluläre Karzinome
• – Cholangiozelluläre Karzinome

Treatable as tumors of the liver, for example:

• - Hepatocellular carcinomas
• - Cholangiocellular carcinomas

• – Maligne Melanome
• – Basaliome
• – Spinaliome
• – Kaposi-Sarkome
• – Merkelzellkarzinomes

For example, tumors of the skin are treatable:

• - Malignant melanomas
• - basaliomas
• - Spinaliomas
• - Kaposi's sarcoma
• - Merkel cell carcinoma

• – Larynxkarzinome
• – Karzinome des Pharynx und der Mundhöhle

Tumors of the head and neck, for example, are treatable:

• - Laryngeal carcinomas
• - Carcinoma of the pharynx and oral cavity

• – Weichteilsarkome
• – Osteosarkome

For example, sarcomas are treatable:

• - soft tissue sarcoma
• - Osteosarcomas

• – Non-Hodgkin-Lymphome
• – Hodgkin-Lymphome
• – Kutane Lymphome
• – Lymphome des zentralen Nervensystems
• – AIDS-assoziierte Lymphome

For example, lymphomas are treatable:

• - Non-Hodgkin's lymphoma
• - Hodgkin lymphoma
• - cutaneous lymphomas
• - Lymphomas of the central nervous system
• - AIDS-associated lymphomas

• – Akute myeloische Leukämien
• – Chronische myeloische Leukämien
• – Akute lymphatische Leukämien
• – Chronische lymphatische Leukämien
• – Haarzellleukämien

Treatable as leukemias, for example:

• - Acute myeloid leukemias
• - Chronic myeloid leukemia
• - Acute lymphocytic leukemia
• - Chronic lymphocytic leukemia
• - hair cell leukemia

Particularly advantageously, the compounds according to the formula (I) can be used for the treatment of:
Breast cancers, in particular of hormone receptor negative, hormone receptor positives or BRCA-associated breast carcinomas, as well as
Pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell lung carcinoma,
Colorectal carcinoma and prostate cancer.

These diseases are well characterized in humans, but also exist in other mammals.

An object of the invention are the compounds of the general formula (I) according to the invention for use as medicaments.

Another object of the invention is the use of the compounds of general formula (I) according to the invention for the manufacture of a medicament.

Another object of the invention is the use of the compounds of the invention for the treatment of diseases associated with proliferative processes.

The compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects. Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.

For example, the compounds of the present invention may be combined with known anti-hyperproliferative, cytostatic or cytotoxic agents for the treatment of cancers. The combination of the compounds according to the invention with other substances commonly used for cancer therapy or also with radiotherapy is particularly indicated.

Examples of suitable combination active ingredients are:
Afinitor, aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabine, arsenic trioxide, aromasine, 5-azacytidine, azathioprine, BCG or tice-BCG, Bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, clodronic acid, cyclophosphamide, cytarabine, Dacarbazine, Dactinomycin, DaunoXome, Decadron, Decadron Phosphate, Delestrogen, Denileukin Diftitox, Depomedrol, Deslorelin, Dexrazoxane, Diethylstilbestrol, Diflucan, Docetaxel, Doxifluridine, Doxorubicin, Dronabinol, DW-166HC, Eligard, Elitek, Ellence, Emend, Epirubicin, Epoetin -alfa, Epogen, Eptaplatin, Ergamisole, Estrace, Estradiol, Estramustine Sodium Phosphate, Ethinylestradiol, Ethyol, Etidronic Acid, Etopophos, Etoposide, Fadrozole, Farston , Filgrastim, Finasteride, Fligrastim, Floxuridine, Fluconazole, Fludarabine, 5-Fluorodeoxyuridine Monophosphate, 5-Fluorouracil (5-FU), Fluoxymesterone, Flutamide, Formestane, Fosteabin, Fotemustine, Fulvestrant, Gammagard, Gemcitabine, Gemtuzumab, Gleevec, Gliadel, Goserelin, granisetron hydrochloride, histrelin, hycamtin, hydrocorton, erythro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon-alpha, interferon-alpha-2, interferon-alpha-2α, interferon-alpha alpha-2β, interferon-alpha-n1, interferon-alpha-n3, interferon-beta, interferon-gamma-1α, interleukin-2, intron A, Iressa, irinotecan, cytril, lapatinib, lentinan sulfate, letrozole, leucovorin, leuprolide , Leuprolide Acetate, Levamisole, Levofolic Acid Calcium Salt, Levothroid, Levoxyl, Lomustine, Lonidamine, Marinol, Mechlorethamine, Mecobalamin, Medroxyprogesterone Acetate, Megestrol Acetate, Melphalan, Menest, 6-Mercaptopurine, Mesna, Methotrexate, Metvix, Miltefosine, Minocycline , Mitomycin C, Mitotane, Mitoxantrone, Modrenal, Myocet, Nedaplatin, Neulasta, Neumega, Neupogen, Nilutamide, Nolvadex, NSC-631570, OCT-43, Octreotide, Ondansetron hydrochloride, Orapred, Oxaliplatin, Paclitaxel, Pediapred, Pegaspargase, Pegasys, Pentostatin, Picibanil, Pilocarpine Hydrochloride, Pirarubicin, Plicamycin, Porfimer Sodium, Prednimustine, Prednisolone, Prednisone, Premarin, Procarbazine, Procrit, Raltitrexed, RDEA119, Rebif, Rhenium-186 Etidronate, Rituximab, Roferon-A, Romurtide, Salagen, Sandostatin, Sargramostim, S emustin, sizofiran, sobuzoxan, solu-medrol, streptozocin, strontium-89-chloride, synthroid, tamoxifen, tamsulosin, tasonermine, tastolactone, taxoter, teceleukin, temozolomide, teniposide, testosterone propionate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, Topotecan, Toremifene, Tositumomab, Tastuzumab, Teosulfan, Tretinoin, Trexall, Trimethylmelamine, Trimetrexate, Triptorelin Acetate, Triptorelin Pamoate, UFT, Uridine, Valrubicin, Vesnarinone, Vinblastine, Vincristine, Vindesine, Vinorelbine, Virulizine, Zinecard, Zinostatin Stimalamer, Zofran; ABI-007, Acolbifen, Actimmun, Affinitak, Aminopterin, Arzoxifen, Asoprisnil, Atamestan, Atrasentan, BAY 43-9006 (Sorafenib), Avastin, CCI-779, CDC-501, Celebrex, Cetuximab, Crisnatol, cyproterone acetate, decitabine, DN-101, doxorubicin MTC, dSLIM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166-DOTMP, ibandronic acid, interferon-gamma, intron-PEG, ixabepilone, keyhole limpet Hemocyanin, L-651582, Lanreotide, Lasofoxifen, Libra, Lonafarnib, Miproxifen, Minodronate, MS-209, Liposomal MTP-PE, MX-6, Nafarelin, Nemorubicin, Neovastat, Nolatrexed, Oblimersen, Onko-TCS, Osidem, Paclitaxel Polyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1549, raloxifene, ranpirnas, 13-cis-retinoic acid, satraplatin, seocalcitol, T-138067, tarceva, taxoprexin, thymosin-alpha-1, tiazofurin, Tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acid, s as well as combinations thereof.

In a preferred embodiment, the compounds of the present invention may be combined with anti-hyperproliferative agents, which may be by way of example, without being exhaustive:
Aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, 2 ', 2'-difluorodoxycytidine, docetaxel, doxorubicin ( Adriamycin), epirubicin, epothilone and its derivatives, erythro-hydroxynonyladenine, ethinyl estradiol, etoposide, fludarabine phosphate, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, fluoxymesterone, flutamide, hexamethylmelamine, hydroxyurea, hydroxyprogesterone caproate, idarubicin, Ifosfamide, interferon, irinotecan, leucovorin, lomustine, mechlorethamine, medroxyprogesterone acetate, megestrol acetate, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitotane, mitoxantrone, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA ), Plicamycin, prednisolone, prednisone, procarbazine, raloxifene, semustine, streptozocin, tamoxifen, teniposide, testosterone propionate, thioguanine, thiotepa, to potecan, trimethylmelamine, uridine, vinblastine, vincristine, vindesine and vinorelbine.

Promisingly, the compounds of the invention may also be combined with biological therapeutics such as antibodies (eg, Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins.

The compounds according to the invention can also achieve positive effects in combination with other anti-angiogenic therapies, for example with Avastin, axitinib, DAST, recentin, sorafenib or sunitinib. Combinations with proteasome and mTOR inhibitors as well as antihormones and steroidal metabolic enzyme inhibitors are particularly suitable because of their favorable side effect profile.

• • eine verbesserte Wirksamkeit bei der Verlangsamung des Wachstums eines Tumors, bei der Reduktion seiner Größe oder sogar bei seiner völligen Eliminierung im Vergleich zu einer Behandlung mit einem einzelnen Wirkstoff;
• • die Möglichkeit, die verwendeten Chemotherapeutika in geringerer Dosierung als bei der Monotherapie einzusetzen;
• • die Möglichkeit einer verträglicheren Therapie mit weniger Nebeneffekten im Vergleich zur Einzelgabe;
• • die Möglichkeit zur Behandlung eines breiteren Spektrums von Tumorerkrankungen;
• • das Erreichen einer höheren Ansprechrate auf die Therapie;
• • eine längere Überlebenszeit der Patienten im Vergleich zur heutigen Standardtherapie.

In general, the combination of compounds of the present invention with other cytostatic or cytotoxic agents may have the following aims:

• • improved efficacy in slowing down the growth of a tumor, reducing its size or even eliminating it completely compared to treatment with a single drug;
• • the possibility of using the chemotherapeutic agents used in lower doses than in monotherapy;
• • the possibility of a more tolerable therapy with fewer side effects compared to a single dose;
• • the ability to treat a wider range of tumors;
• • achieving a higher response rate to therapy;
• • longer patient survival compared to today's standard therapy.

In addition, the compounds of the invention may also be used in conjunction with radiotherapy and / or surgical intervention.

Comparative Examples

Table V.1 lists related structures of the prior art and indicates in which law manufacturing is disclosed.

Table V.1

Examples

The compounds which are the subject of the present application and their preparation are state of the art.

Table 1 lists the structures of the prior art formula (I) and indicates in which law the preparation is disclosed.

Table 1

Method 1 (UPLC-MS):

• Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 50 × 2.1 mm; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow 0.8 ml / min; Temperature: 60 ° C; Injection: 2 μl; DAD scan: 210-400 nM.

ASSAYS

Human ACC1 enzyme assay

The inhibitory activity of the substances of this invention against acetyl-CoA carboxylase 1 (ACC1) was measured in the ACC1 assay described in the following paragraphs. Basic principle of the assay is to measure the Adenosindiphoshats formed as co-product (ADP) using a HTRF ^® -based competitive immunoassay (HTRF = Homogeneous Time Resolved Fluorescence).

As an enzyme, C-terminal FLAG-tagged recombinant human ACC1 (GenBank Accession # NM_198834, amino acids 39- end) expressed in baculovirus transfected insect cells (Hi5) and purified by affinity chromatography on Anti- ^FLAG® M2 affinity gel (Sigma Aldrich). Alternatively, commercially available C-terminal His-tagged ACC1 from BPS Bioscience (San Diego, CA, Catalog No. 50200. Amino Acids 39- End) can be used. For the assay, 50 μl of a 100X concentrated solution of the test substance in DMSO were pipetted into a black low-volume 384 well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of a solution of ACC1 in assay buffer [50 mM HEPES / NaOH pH 7.5, 12mM sodium bicarbonate, 2mM MgCl ₂ , 2mM potassium citrate, 0.005% (w / v) bovine serum albumin (BSA)] and the mixture incubated for 15 min to pre-bind the substances to the enzyme prior to the enzyme reaction to enable. Then, the enzyme reaction was started by adding 3 μl of a solution of adenosine triphosphate (ATP, 83.5 μM = final concentration in 5 μl of assay volume is 50 μM, Amersham Pharmacia Biotech # 27-2056-01) and acetyl-CoA (33.4 μM => final concentration in 5 μl assay volume is 20 μM, Roche Bioscience # 10101893001) in assay buffer and the resulting mixture incubated for 20 min at 22 ° C for the reaction time. The concentration of the ACC1 was adjusted to the respective activity of the enzyme and adjusted so that the assay worked in the linear range. Typical concentrations were in the range of 2.5 ng / μl.

The reaction was quenched by successive additions of 2.5 microliters of a solution of d2-labeled ADP (HTRF ^® Trans Screener ^TM ADP kit, Cis biointernational, Marcoule, France) (in the EDTA-containing HTRF ^® Trans Screener ^TM ADP detection buffer in HTRF ^® Transscreener ^™ ADP Kit containing 50mM HEPES pH 7.0, 60mM EDTA, 0.1% (w / v) BSA, 0.02% sodium azide, 400mM potassium fluoride) and 2.5μl of a solution of europium cryptate labeled anti-ADP antibody (HTRF ^® Trans Screener ^TM ADP Kit) Trans Screener in HTRF ^{® TM} ADP detection buffer.

The resulting mixture was incubated for one hour at 22 ° C to allow binding of the europium cryptate-labeled anti-ADP antibody to the enzyme-produced ADP and the d2-labeled ADP. Subsequently, the amount of the complex of d2-labeled ADP and europium-cryptate-labeled anti-ADP antibody was determined by measuring the resonance energy transfer from the europium cryptate to the d2. For this purpose, in an HTRF meter, z. B. a Rubystar or Pherastar (both BMG Labtechnologies, Offenburg, Germany), the fluorescence emissions measured at 620 nm and 665 nm after excitation at 350 nm. The ratio of the emissions at 665 nm and at 622 nm was used as a measure of the amount of the complex of d2-labeled ADP and europium cryptate-labeled anti-ADP antibody and thus indirectly as a measure of the amount of unlabelled formed in the enzyme reaction ADP taken (higher ratio of emissions at 665 nm and at 622 nm ⇔ more complex of d2-labeled ADP and europium-cryptate-labeled anti-ADP antibody ⇔ less ADP). The data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components but no enzyme = 100% inhibition). Usually, the test substances were incubated on the same microtiter plates at 10 different concentrations ranging from 20 μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9 , 2 nM, 3.1 nM and 1 nM, serial dilutions were assayed at 100-fold concentrated solution level by serial 1: 3 dilutions) in duplicate for each concentration prior to assay and IC50 values were calculated using a 4-parameter -Fit, for which an in-house software was used.

Human ACC2 enzyme assay

The inhibitory activity of the substances of this invention on acetyl-CoA carboxylase 2 (ACC2) was measured in the ACC2 assay described in the following paragraphs. Basic principle of the assay is to measure the Adenosindiphoshats formed as co-product (ADP) using a HTRF ^® -based competitive immunoassay (HTRF = Homogeneous Time Resolved Fluorescence).

As an enzyme, commercially available C-terminal His-tagged ACC2 from BPS Bioscience (San Diego, CA, Catalog No. 50201. Amino Acids 39- end, expressed in baculovirus-infected Sf9 insect cells and purified by Ni-NTA affinity chromatography) was used.

For the assay, 50 μl of a 100X concentrated solution of the test substance in DMSO were pipetted into a black low-volume 384 well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of a solution of ACC2 in assay buffer [50 mM HEPES / NaOH pH 7.5, 12mM sodium bicarbonate, 2mM MgCl ₂ , 2mM potassium citrate, 0.005% (w / v) bovine serum albumin (BSA)] and the mixture incubated for 15 min to pre-bind the substances to the enzyme prior to the enzyme reaction to enable. Then the enzyme reaction was started by adding 3 μl of a solution of adenosine triphosphate (ATP, 83.5 μM => final concentration in 5 μl assay volume is 50 μM, Amersham Pharmacia Biotech # 27- 2056-01) and acetyl-CoA (33.4 μM => final concentration in 5 μl of assay volume is 20 μM, Roche Bioscience # 10101893001) in assay buffer and the resulting mixture incubated for 20 min at 22 ° C for the reaction time. The concentration of the ACC2 was adjusted to the respective activity of the enzyme and adjusted so that the assay worked in the linear range. Typical concentrations were in the range of 0.6 ng / μl.

The reaction was quenched by successive additions of 2.5 microliters of a solution of d2-labeled ADP (HTRF ^® Trans Screener ^TM ADP kit, Cis biointernational, Marcoule, France) (in the EDTA-containing HTRF ^® Trans Screener ^TM ADP detection buffer in HTRF ^® Transscreener ^™ ADP Kit containing 50mM HEPES pH 7.0, 60mM EDTA, 0.1% (w / v) BSA, 0.02% sodium azide, 400mM potassium fluoride) and 2.5μl of a solution of europium cryptate labeled anti-ADP antibody (HTRF ^® Trans Screener ^TM ADP Kit) Trans Screener in HTRF ^{® TM} ADP detection buffer.

The resulting mixture was incubated for one hour at 22 ° C to allow binding of the europium cryptate-labeled anti-ADP antibody to the enzyme-produced ADP and the d2-labeled ADP. Subsequently, the amount of the complex of d2-labeled ADP and europium-cryptate-labeled anti-ADP antibody was determined by measuring the resonance energy transfer from the europium cryptate to the d2. For this purpose, in an HTRF meter, z. B. a Rubystar or Pherastar (both BMG Labtechnologies, Offenburg, Germany), the fluorescence emissions measured at 620 nm and 665 nm after excitation at 350 nm. The ratio of the emissions at 665 nm and at 622 nm was used as a measure of the amount of the complex of d2-labeled ADP and europium cryptate-labeled anti-ADP antibody and thus indirectly as a measure of the amount of unlabelled formed in the enzyme reaction ADP taken (higher ratio of emissions at 665 nm and at 622 nm ⇔ more complex of d2-labeled ADP and europium-cryptate-labeled anti-ADP antibody ⇔ less ADP). The data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components but no enzyme = 100% inhibition). Usually, the test substances were incubated on the same microtiter plates at 10 different concentrations ranging from 20 μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9 , 2 nM, 3.1 nM and 1 nM, serial dilutions were assayed at 100-fold concentrated solution level by serial 1: 3 dilutions) in duplicate for each concentration prior to assay and IC50 values were calculated using a 4-parameter -Fit, for which an in-house software was used.

Non-human ACCase assay

The assay was performed at room temperature in a transparent 384-well microtiter plate. It determines the inorganic phosphate released from ATP Inder ACCase reaction.

The assay contained 50 mM Tris-HCl pH 8.3, 50 mM KCl, 2.5 mM MgCl ₂ , 0.5 mM ATP, 0.8 mM dithiothreitol (DTT), 30 mM NaHCO ₃ , 0.1 mM acetyl-CoA, 0.04% bovine serum albumin and 0.4 μg partially purified ACCase enzyme in a final volume of 40 μl. After 45 minutes of incubation, the reaction was stopped with 150 μl of malachite green solution and the absorbance was read out at 620 after 30 minutes.

The malachite green (MG) solution was prepared by mixing 3 parts of 0.6 mM MG-HCl solution in distilled water with 1 part of 8.5 mM ammonium molybdate in 4 M HCl. The solution was allowed to stand for 30 minutes. After filtration through a 0.45 μm polytetrafluoroethylene (PTFE) filter, 0.1 part of Triton X-100 (1.5%) in distilled water was added.

ACCase enzyme was extracted from oat seedlings harvested 9 days after seeding and partially purified by 0-40% ammonium sulfate precipitation followed by ion exchange chromatography on Q-sepharose.

Mode-of-action test

Before determining the efficacy in the MCF-7 model, part of the test substances were tested in a mode of action experiment. The principle of this experiment is that the short-term application of a test substance which is able to inhibit ACC1 and / or ACC2 in the living organism after oral administration leads to a reduction of malonyl-CoA in the tumor. Experimentally, 2 million human MCF-7 breast cancer cells were injected subcutaneously into female nude mice (NMRI-nude (nu / nu) mice, Taconic M & B A / S, 1 day before administration of a pellet for the release of estrogen over a period of at least 60 days) , As soon as the tumor reached an area of about 60-70 mm ² , oral administration of the test substance took place over a period of 1-3 days, subsequently at defined times determined the intratumoral content of malonyl-CoA and compared with the vehicle control. The method is described in Anal Chem. 2008 Aug 1; 80 (15): 5736-42. Epub 2008 Jul 9. ).

Cell assays

In accordance with the invention, the substances were tested in cell-based assays, which means the ability of the substances to inhibit tumor cell proliferation after a 96-hour substance incubation. Cell viability was tested using the CellTiter-Glo Luminescent Cell Viability Assay ^® (Promega). The cells were seeded at a density of 2000-5000 cells / well (depending on the cell line) in 100 μl growth medium on 96 well microtiter plates. For each cell line examined, cells were seeded on a separate plate to determine luminescence at t = 0 hours and t = 96 hours. After overnight incubation at 37 ° C, the luminescence values were determined for the t = 0 samples. The dose plates for the t = 96 hour time points were treated with substances diluted in growth medium. The cells were then incubated for 96 hours at 37 ° C, then the luminescence values were determined for the t = 96-hour samples. For data analysis, the t = 0 values were subtracted from the t = 96 hours values for treated and untreated samples. The percentage differences in luminescence between substance-treated and control values were used to determine the percent growth inhibition.

The substances were investigated in the following cell lines, which exemplify the indicated indications: cell line source indication MDA-MB-436 ATCC Hormone receptor negative breast cancer MDA-MB-468 ATCC Hormone receptor negative breast cancer HCC-1937 ATCC BRCA-associated breast cancer MCF7 ATCC Hormone receptor positive breast cancer MiaPaCa ATCC pancreatic cancer 786 O ATCC Renal cell carcinoma PLC / PRF5 ATCC Hepatocellular carcinoma A431 ATCC Carcinoma of the skin MDA-MB-435 ATCC Malignant melanoma NCI-H2135 ATCC Non-small cell lung carcinoma DLD1 ATCC Colorectal carcinoma PC3 ATCC prostate cancer

Xenograft model

Xenograft models were used in immunosuppressed mice to determine antitumoral efficacy in the living organism.

First, the maximum tolerable dose (MTD) was determined according to the following protocol: Female nude mice (NMRI-nude (nu / nu) mice, Taconic M & B A / S) received daily orally a defined dose over a period of 1, 2 or 3 weeks the test substance and were daily observed for mortality and body weight. MTD was defined as the highest dose that could be administered, during which no animal died during the treatment phase and during the 7-day follow-up period and there was no more than 10% decrease in body weight compared to baseline.

To determine the antitumoral efficacy then various xenograft models were used in which the test substances were given at their MTD and in lower dosages. Among several other models, the breast cancer model with human MCF-7 cells in female nude mice (NMRI-nude (nu / nu) mice, Taconic M & B A / S) was used primarily. For this purpose, these mice were subcutaneously administered a pellet on the day before the tumor cell implantation for the release of estrogen over a period of at least 60 days. Two million tumor cells were injected subcutaneously into the flank of each animal the next day. Therapy with the test substance was started as soon as the tumor covers an area of approx. 25 mm ^{2 had} reached. Therapy was then continued with 2-3 times weekly measurement of tumor area and body weight until the average tumor size in the control group, which had received only the vehicle of the test substance or in one of the treatment groups, reached 120 mm ² . At this time, the experiment was stopped in all groups and the prepared tumors were weighed. As a primary parameter of success, the T / C value (average tumor weight in the therapy group divided by the average tumor weight in the vehicle control group) was calculated.

Analysis of ACC1 expression in tumor and normal tissues

The ACC1 expression was determined by means of a microrray. For this, the RNA was isolated from different tumor tissues and the corresponding normal tissues. Methodically, Trizol RNA extraction reagent (Invitrogen) was used and purification was performed using the RNeasy Mini Kit (Qiagen). In addition, DNase I (Qiagen) digestion was performed to eliminate genomic DNA. For quality control, total RNA analysis was performed using an RNA LabChip on an Agilent Bioanalyzer 2100 Platform (Agilent Technologies) and RNA concentration determined using the Peqlab NanoDrop System. For hybridization, the "one-cycle eukaryotic target labeling assay" from Affymetrix was used and the array was then read on an Affymetrix GeneChip 3000 scanner (Affymetrix). Evaluation and quality control were performed using the Expressionist Pro 4.0 Refiner (GeneData) software.

Results:

Table 2 summarizes the results of the enzyme assays and the mode-of-action experiment with respect to the compounds of formula (I). Tab. 2 Example no. ACC1 IC50 [μmol / l] ACC2 IC50 [μmol / l] % Inhibition of malonyl-CoA after 7 h, 10 mg / kg (vs vehicle) 1-1 0243 4150 1-2 0260 5285 1-3 0581 11696 1-4 12:19 1.5 1-5 1478 5715 1-6 2151 0139 1-7 0500 > 20 1-8 0420 > 20 1-9 0334 > 20 1-10 0161 2354 1-11 0666 1547 1-12 4173 1152 1-13 0816 > 20 1-14 0562 19353 1-15 0204 3676 1-16 0180 3336 1-17 0158 0652 1-18 0479 3409 1-19 0530 10007 1-20 0137 1929 1-21 12:40 > 20 1-22 0824 > 20 1-23 1369 > 20 1-24 0997 > 20 1-25 0442 > 20 1-26 12:26 4.8 1-27 0822 4146 1-28 12:14 2.5 1-29 0321 0789 1-30 0281 0032 36 1-31 0.88 0048 1-32 12:45 1.6 1-33 0229 3586 39 1-34 0286 1274 1-35 1024 > 20 1-36 nd 1936 1-37 0342 > 20 1-38 0416 3785 1-39 0216 3533 1-40 1216 > 20 1-41 0791 4217 1-42 0357 1021 1-43 0504 0330 1-44 0297 0160 1-45 0568 17 1-46 0580 7610 1-47 0592 0453 1-48 1800 0204 1-49 5776 1281 1-50 0903 8593

Table V.2 summarizes the results of the enzyme assays for the comparison compounds. Tab. V.2 Example no. ACC1 IC50 [μmol / l] ACC2 IC50 [μmol / l] ACC-non human IC50 [μmol / l] V-1 > 20 > 20 0.0005 V-2 > 20 > 20 12:04 V-3 > 20 > 20 0002 V-4 5.4 > 20 12:02

The results make it very clear that, despite structural similarity, no predictions are possible as to whether structures that inhibit non-human ACC are also inhibitors of human ACCs.

Table 3 summarizes the results of the cell assays for compounds according to formula (I). Tab. 3 Example no. MCF7 IC50 [μmol / l] MDA-MB 436 IC50 [μmol / l] MDA-MB 468 IC50 [μmol / l] HCC 1937 IC50 [μmol / l] MiaPaca IC50 [μmol / l] 1-1 1-2 1-3 1060 1-4 0624 1-5 1-6 0724 1-7 1-8 1-9 1-10 1-11 1-12 1240 1-13 1-14 1-15 1-16 1-17 0400 1-18 0935 1-19 1-20 0214 1-21 1-22 1-23 1-24 1-25 1-26 5520 1-27 1-28 0296 1-29 1-30 0064 0115 0153 1.5 0255 1-31 0490 1-32 0112 1-33 0246 1-34 0429 1-35 1-36 1-37 1-38 1-39 1-40 1-41 1-42 0466 1-43 0263 1-44 0121 1-45 6.7 1-46 1-47 0302 1-48 0762 1-49 1-50

ACC1 expression in tumor and normal tissue

The expression of ACC1 in tumor and corresponding normal tissue was determined by microarray ( 1 ). The expression of ACC1 was significantly upregulated compared to normal tissue in breast, colorectal, bronchogenic and pancreatic carcinoma.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

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Claims (11)

Compounds of the formula (I)

in which X is halogen or an optionally halogen-mono- or polysubstituted C ₁ -C ₃ -alkyl or C ₁ -C ₃ alkoxy, and W and Y are independently hydrogen or halogen or an optionally with Halogen mono- or polysubstituted C ₁ -C ₃ -alkyl radical, and V ¹ , V ² and V ³ independently of one another represent hydrogen or halogen or a C ₁ -C ₃ -alkyl-, C ₁ -C ₃ -haloalkyl- , C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkoxy or C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, and / or V ¹ and V ² with the carbon atoms to which they are attached are bound to form a saturated or unsaturated and optionally at least one further heteroatom-containing cycle T ¹ with 5 or 6 ring atoms, the ring-forming atoms with halogen and / or a C ₁ -C ₃ alkyl radical mono- or polysubstituted by identical or different substituents A, A is hydrogen or an optionally with halogen on or polysubstituted C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl radical or a C ₃ -C ₇ -cycloalkyl radical or 4- to 7-membered monocyclic heterocyclyl radical which are reacted with halogen and or a C ₁ -C ₃ -alkyl radical may be mono- or polysubstituted by identical or different substituents, and B is hydrogen or a C ₁ -C ₆ -alkyl or C ₁ -C ₃ -alkoxy-C ₁ - C ₃ alkyl radical, or A and B together with the carbon atom to which they are attached form a saturated or unsaturated, optionally one or two heteroatoms containing cycle T ² having 3 to 8 ring atoms, the ring-forming atoms one or more times, the same or may be differently substituted by the radicals R ¹ , R ² and R ³ , where R ¹ , R ² and R ^{3 are} independently of one another a) halogen or hydroxy or b) an optionally substituted in the alkyl moiety with hydroxy C ₁ -C _4- alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy-C C ₁ -C ₃ -alkoxy, halogeno-C ₁ -C ₃ -alkyl or halogeno-C ₁ -C ₃ -alkoxy and / or c) two of the radicals R ¹ , R ² and R ³ together with the ring or atoms of the cycle T ² , to which they are attached, can form another saturated or aromatic, optionally containing one or two heteroatoms cycle T ³ with 5 to 7 ring atoms, which may be mono- or polysubstituted by identical or different substituents with the radicals R ⁴ , R ⁵ and R ⁶ , wherein R ⁴ , R ⁵ and R ^{6 are} independently a C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy. for use as a medicine. Compounds according to claim 1 according to formula (I) in which X is chlorine or a methyl radical, for use as a medicine. Compounds according to claim 1 according to formula (I) in which W and Y are hydrogen or a methyl radical, for use as a medicine. Compounds according to claim 1 according to formula (I) in which V ¹ , V ² and V ^{3 are} independently hydrogen, chlorine or fluorine for use as pharmaceuticals. Compounds according to claim 1 of formula (I) wherein A is hydrogen or C ₁ -C ₄ alkyl, methoxy C ₁ -C ₂ alkyl or C ₃ -C ₆ cycloalkyl, for use as a medicine. Compounds according to claim 1 of formula (I) in which A and B together with the carbon atom to which they are attached form a saturated cycle T ² having 5 to 6 ring atoms optionally containing an oxygen atom, the ring-forming atoms of which are one or two times , identical or different, may be substituted by the radicals R ¹ , R ² and R ³ , where R ¹ , R ² and R ^{3 are} independently of one another a) a C ₁ -C ₃ -alkyl-, C ₁ -C ₄ - Alkoxy, methoxy-C ₁ -C ₂ -alkyl, 2,2,2-trifluoroethoxy and / or b) two of the radicals R ¹ , R ² and R ³ together with the ring atom of the cycle T ² to which they are attached are capable of forming another saturated, optionally one or two oxygen atoms containing cycle T ³ having 5 or 6 ring atoms, which may be monosubstituted or disubstituted with a methyl radical, for use as a drug. Compounds according to claim 1 according to formula (I) in which B is hydrogen or a methyl radical, for use as a medicine. Compounds according to claim 1 of the formula (I) in which X is chlorine or a methyl radical and W and Y independently of one another represent hydrogen or a methyl radical, V ¹ , V ² and V ³ independently of one another represent hydrogen, chlorine or Are fluorine or a methyl or a trifluoromethyl radical, and A is hydrogen or an optionally halogen-substituted C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl radical or a C ₃ -C ₆ -cycloalkyl radical which may be mono- or polysubstituted by identical or different substituents with halogen and / or a C ₁ -C ₃ -alkyl radical, and B is hydrogen or a C ₁ -C ₃ -alkyl radical, or A and B together with the carbon atom to which they are attached form a saturated cycle T ² having 3 to 8 ring atoms, optionally containing an oxygen atom, whose ring-forming atoms may be monosubstituted or disubstituted by identical or different substituents n R ¹ , R ² and R ³ , where R ¹ , R ² and R ^{3 are} independently of one another a) is an optionally substituted in the alkyl moiety with hydroxy C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxy-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy or halogeno-C ₁ -C ₃ -alkoxy, and / or b ₁ ) two of the radicals R ¹ , R ² and R ³ together with the ring atom of the cycle T ² , to which they are attached, can form a further saturated, optionally one or two oxygen atoms containing cycle T ³ having 5 to 7 ring atoms, with a C ₁ -C ₃ -alkyl radical may be monosubstituted or disubstituted, or b ₂ ) two of the radicals R ¹ , R ² and R ³ together with the adjacent ring atoms of the cycle T ² to which they are attached form a further aromatic cycle T ³ can form with 6 ring atoms, which may be mono- or disubstituted by a C ₁ -C ₃ alkyl. for use as a medicine. Use of a compound according to formula (I) according to any one of claims 1 to 8 for the manufacture of a medicament. Use according to claim 9 for the preparation of a medicament for the therapy of tumor diseases. Use according to claim 10 for the manufacture of a medicament for the therapy of breast, pancreatic, renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell, bronchial carcinoma, colorectal carcinoma and prostate carcinoma.

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