DE19832159A1 - New tetrahydronaphthalene derivatives - Google Patents

Abstract

Substituted tetrahydronaphthalene derivatives (I) are new. Substituted tetrahydronaphthalene derivatives (I) and their salts are new: A = cycloalkyl, or aryl or heterocyclyl (both optionally substituted by 15 groups); D = R<5>-L-, -CR<6>R<7>R<8> or -X-V-T-R<9>; R<5>, R<6> and R<9> = cycloalkyl, aryl or 5-7 membered saturated or heterocyclyl optionally substituted by 19 groups; or R<5> and/or R<6> = difluoromethylenedioxy-phenyl or 2-trifluoromethyl-benzofuranyl; R<7> = H, halo or methyl; and R<8> = H, halo, N3, CF3, OH, OCF3, alkyl, alkoxy or optionally mono- or disubstituted amino; R<7>+R<8> = O or optionally substituted imino; L = alkylene or alkenylene optionally substituted by OH; T, X = alkylene; or T or X = a bond; V = O, S or optionally mono- or disubstituted amino; E = cycloalkyl, alkyl optionally substituted by cycloalkyl or phenyl optionally substituted by halo or CF3; R<1>, R<2> = alkylene substituted by oxo and/or by 5 other given groups. The full definitions are given in the DEFINITIONS (Full Definitions) Field. An Independent claim is also included for the preparation of (I).

Description

The present invention relates to substituted tetrahydro-naphthalenes, processes for their manufacture and their use in medicinal products.

Publication US-5 169 857-A2 describes 7- (polysubstituted pyridyl) -6-heptenoates for the treatment of arteriosclerosis, lipoprotein anemia and hyperprotein anemia knows. In addition, the preparation of 7- (4-aryl-3-pyridyl) -3,5-dihydroxy-6-hep tenoate in the publication EP-325 130-A2.

The present invention relates to substituted tetrahydro-naphthalenes of the general formula (I),

in which
A represents cycloalkyl having 3 to 8 carbon atoms or
represents aryl having 6 to 10 carbon atoms, or
represents a 5- to 7-membered, saturated, partially unsaturated or unsaturated, optionally benzocondensed heterocycle with up to 4 carbon atoms from the series S, N and / or O,
where aryl and the heterocyclic ring systems listed above, where appropriate, up to 5 times the same or different by cyano, halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy each have up to 7 carbon atoms, or are substituted by a group of the formula -NR ³ R ⁴ ,
wherein
R ³ and R ^{4 are} identical or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,
D for a residue of the formula

R ⁵ -L-,

or

R ⁹ -TVX-

stands in what
R ⁵ , R ⁶ and R ⁹ independently of one another are cycloalkyl having 3 to 6 carbon atoms, or
Aryl having 6 to 10 carbon atoms or a 5- to 7-membered, optionally benzocondensed, saturated or unsaturated, mono-, bi- or tricyclic heterocycle with up to 4 heteroatoms from the series S, N and / or O,
where the cycles, optionally, in the case of the nitrogen-containing rings also via the N function, up to 5 times the same or different by halogen, trifluoromethyl, nitro, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkyl alkoxy, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, aryl substituted by aryl or trifluoromethyl each having 6 to 10 carbon atoms or by an optionally benzo-condensed aromatic 5- to 7-membered heterocycle with up to 3 heteroatoms from the series S, N and / or O are substituted,
and / or are substituted by a group of the formula -OR ¹⁰ , -SR ¹¹ , -SO ₂ R ¹² or -NR ¹³ R ¹⁴ ,
wherein
R ¹⁰ , R ¹¹ and R ¹² independently of one another are aryl having 6 to 10 carbon atoms, which in turn is up to 2 times the same or different substituted by phenyl, halogen or by straight-chain or branched alkyl having up to 6 carbon atoms,
R ¹³ and R ^{14 are the} same or different and have the meaning of R ³ and R ⁴ given above,
or
R ⁵ and / or R ^{6 is} a radical of the formula

mean,
R ^{7 represents} hydrogen, halogen or methyl,
and
R ⁸ denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkyl each having up to 6 carbon atoms or a radical of the formula -NR ¹⁵ R ¹⁶ ,
wherein
R ¹⁵ and R ^{16 are} identical or different and have the meaning of R ³ and R ⁴ given above,
or
R ⁷ and R ⁸ together form a radical of the formula = O or = NR ¹⁷ ,
wherein
R ¹⁷ denotes hydrogen or straight-chain or branched alkyl, alkoxy or acyl each having up to 6 carbon atoms,
L represents a straight-chain or branched alkylene or alkenylene chain each having up to 8 carbon atoms, which are optionally substituted up to twice by hydroxy,
T and X are the same or different and represent a straight-chain or branched alkylene chain with up to 8 carbon atoms,
or
T or X represents a bond,
V represents an oxygen or sulfur atom or an -NR ¹⁸ group,
wherein
R ¹⁸ denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,
E represents cycloalkyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or hydroxyl, or represents phenyl which is optionally substituted by halogen or trifluoromethyl is substituted,
R ¹ and R ² together form a straight-chain or branched alkylene chain with up to 7 carbon atoms, which is represented by a carbonyl group and / or by a radical of the formula

must be substituted
wherein
a and b are the same or different and represent a number 1, 2 or 3,
R ^{19 is} hydrogen, cycloalkyl having 3 to 7 carbon atoms, straight-chain or branched silylalkyl having up to 8 carbon atoms or straight-chain or branched alkyl having up to 8 carbon atoms, which may be by hydroxyl, straight-chain or branched alkoxy having up to 6 carbon atoms or by Phenyl is substituted, which in turn can be substituted by halogen, nitro, trifluoromethyl, trifluoromoxy or phenyl substituted by phenyl or tetrazole,
and alkyl is optionally substituted by a group of the formula -OR ²² ,
wherein
R ²² denotes straight-chain or branched acyl with up to 4 carbon atoms or benzyl,
or
R ¹⁹ denotes straight-chain or branched acyl with up to 20 carbon atoms or benzoyl, which is optionally substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or denotes straight-chain or branched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,
R ²⁰ and R ^{21 are} identical or different, are hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,
or
R ²⁰ and R ²¹ together form a 3 to 6-membered carbocycle,
and, optionally also geminal, the carbocycles formed, if necessary, 6 times identically or differently by trifluoromethyl, hydroxy, nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy each having 3 to 7 carbon atoms by straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio each with up to 6 carbon atoms or substituted by straight-chain or branched alkyl with up to 6 carbon atoms, which in turn are up to 2 times the same or different by hydroxyl, benzyloxy, trifluoromethyl, benzoyl, straight-chain or branched alkoxy, oxyacyl or carboxyl each with up to 4 carbon atoms and / or phenyl is substituted, which in turn can be substituted by halogen, trifluoromethyl or trifluoromethoxy,
and / or the carbocycles formed, also geminal, optionally up to 5-fold identical or differently substituted by phenyl, benzoyl, thiophenyl or sulfonylbenzyl, which in turn are optionally substituted by halogen, trifluoromethyl, trifluoromethoxy or nitro,
and / or optionally by a radical of the formula

-SO ₂ -C ₆ H ₅ , - (CO) _d NR ²³ R ²⁴ or = O
are substituted,
wherein
c represents a number 1, 2, 3 or 4,
d represents a number 0 or 1,
R ²³ and R ^{24 are the} same or different and are hydrogen, cycloalkyl having 3 to 6 carbon atoms, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, optionally up to 2 times the same or different by halogen, trifluoromethyl, cyano , Phenyl or nitro is substituted,
and / or the carbocycles formed, if appropriate by a spiro-linked radical of the formula

are substituted,
wherein
W represents either an oxygen or a sulfur atom,
Y and Y 'together form a 2- to 6-membered straight-chain or branched alkylene chain,
e represents a number 1, 2, 3, 4, 5, 6 or 7,
f represents a number 1 or 2,
R ²⁵ , R ²⁶ R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ and R ³ , are the same or different and what is hydrogen, trifluoromethyl, phenyl, halogen or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
or
R ²⁵ and R ²⁶ or R ²⁷ and R ²⁸ each together form a straight-chain or branched alkyl chain with up to 6 carbon atoms,
or
R ²⁵ and R ²⁶ or R ²⁷ and R ²⁸ each together represent a radical of the formula

form,
wherein
W has the meaning given above,
g represents a number 1, 2, 3, 4, 5, 6 or 7,
R ³² and R ³³ together form a 3- to 7-membered heterocycle which contains an oxygen or sulfur atom or a group of the formula SO, SO ₂ or -NR ³⁴ ,
wherein
R ³⁴ denotes hydrogen, phenyl, benzyl or straight-chain or branched alkyl having up to 4 carbon atoms,
and their salts.

The substituted tetrahydro-naphthalenes according to the invention can also be in the form of their salts are present. In general, here are salts with organic or anorga African bases or acids called.

In the context of the present invention, physiologically acceptable salts prefers. Physiologically acceptable salts of the compounds according to the invention can salts of the inventive substances with mineral acids, carboxylic acids or Be sulfonic acids. Z are particularly preferred. B. salts with hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethane sulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, vinegar acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts compounds of the invention which have a free carboxyl group. Z are particularly preferred. B. sodium, potassium, magnesium or calcium salts, and ammonium salts derived from ammonia or organic amines, such as ethylamine, di- or triethylamine, di- or triethanolamine, di  cyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylene diamine or 2-phenyl ethylamine.

The compounds according to the invention can exist in stereoisomeric forms either like image and mirror image (enantiomers), or which are not like image and Mirror image (diastereomers) behave, exist. The invention relates to both Enantiomers or diastereomers and their respective mixtures. This Wed Schemes of the enantiomers and diastereomers can be known in the separate stereoisomerically uniform constituents.

Heterocycle, optionally benzocondensed, is within the scope of the invention in general for a saturated, partially unsaturated or unsaturated 5- to 7 glie third, preferably 5- to 6-membered heterocycle of up to 4 heteroatoms from the series S, N and / or O can contain. Examples include: indolyl, Isoquinolyl, quinolyl, benzo [b] thiophene, benzo [b] furanyl, pyridyl, thienyl, furyl, Pyrrolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Are preferred Quinolyl, furyl, pyridyl and thienyl.

The compounds of the general formula (I) according to the invention are preferred
in which
A stands for cyclopentyl or for cyclohexyl, or for naphthyl, phenyl, pyridyl, thienyl, imidazolyl, pyrryl or morpholine, which is optionally up to 2 times the same or different by fluorine, chlorine, bromine, amino, hydroxy, trifluoromethyl, trifluoromethoxy or by straight-chain or branched Alkyl or alkoxy are each substituted with up to 6 carbon atoms,
D for a residue of the formula

R ⁵ -L-,

or

R ⁹ -TVX-

stands in what
R ⁵ , R ⁶ and R ⁹ independently of one another are cyclopropyl, cyclopentyl or cyclohexyl, or
Phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin- 2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl,
the cycles, optionally up to 3 times in the case of the nitrogen-containing rings also via the N function, the same or different by fluorine, chlorine, bromine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkyl thio , Alkylalkoxy, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, triazolyl, tetrazolyl, benzoxathiazolyl, or trifluoromethyl-substituted phenyl or phenyl,
and / or are substituted by a group of the formula -OR ¹⁰ , -SR ¹¹ or -SO ₂ R ¹² ,
wherein
R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are phenyl, which in turn is substituted up to 2 times the same or different by phenyl, fluorine, chlorine or by straight-chain or branched alkyl having up to 4 carbon atoms,
or
R ⁵ and / or R ^{6 is} a radical of the formula

mean,
R ⁷ denotes hydrogen, fluorine, chlorine or bromine,
and
R ^{8 is} hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkyl each having up to 5 carbon atoms or a radical of the formula -NR ¹⁵ R ¹⁶ ,
wherein
R ¹⁵ and R ^{16 are} identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms,
or
R ⁷ and R ⁸ together form a radical of the formula = O or = NR ¹⁷ ,
wherein
R ¹⁷ denotes hydrogen or straight-chain or branched alkyl, alkoxy or acyl each having up to 4 carbon atoms,
L is a straight-chain or branched alkylene or alkenylene chain each having up to 6 carbon atoms, which are optionally substituted up to twice by hydroxy,
T and X are the same or different and represent a straight-chain or branched alkylene chain with up to 6 carbon atoms,
or
T or X represents a bond,
V represents an oxygen or sulfur atom or a group of the formula -NR ¹⁸ -,
wherein
R ¹⁸ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or phenyl,
E represents cyclopropyl, butyl, pentyl, hexyl or heptyl, or represents straight-chain or branched alkyl having up to 6 carbon atoms, which may be cyclopropyl, butyl, hexyl, pentyl, heptyl or by hydroxy is substituted, or represents phenyl which is optionally substituted by fluorine, chlorine or trifluoromethyl,
R ¹ and R ² together form a straight-chain or branched alkylene chain with up to 6 carbon atoms, which is represented by a carboxyl group and / or by a radical of the formula

must be substituted
wherein
b represents a number 1, 2 or 3,
R ^{19 is} hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, straight-chain or branched silylalkyl having up to 7 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl, straight-chain or branched alkoxy having up to 4 carbon atoms or by phenyl which in turn can be substituted by fluorine, chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy or phenyl substituted by phenyl or tetrazole,
and alkyl is optionally substituted by a group of the formula -OR ²² ,
wherein
R ²² denotes straight-chain or branched acyl with up to 3 carbon atoms or benzyl,
or
R ¹⁹ denotes straight-chain or branched acyl having up to 18 carbon atoms or benzoyl, which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or trifluoromethoxy, or denotes straight-chain or branched fluoroacyl having up to 6 carbon atoms,
R ²⁰ and R ^{21 are the} same or different, are hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms,
or
R ²⁰ and R ²¹ together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring,
and the carbocycles formed are optionally up to 5-fold identical or different, optionally also geminal, by trifluoromethyl, hydroxyl, carboxyl, azido, fluorine, chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, are substituted by straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio each having up to about 5 carbon atoms or straight-chain or branched alkyl having up to 5 carbon atoms, which in turn is up to 2 times the same or different by hydroxyl, benzyloxy, benzoyl, straight-chain or branched alkoxy or oxyacyl is each substituted with up to 3 carbon atoms, trifluoromethyl and / or phenyl, which in turn can be substituted by fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy,
and / or the carbocycles formed are also geminal, optionally up to 4-fold identical or different substituted by phenyl, benzoyl, thiophenyl or sulfonylbenzyl, which in turn are optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or nitro,
and / or optionally by a radical of the formula

-SO ₂ -C ₆ H ₅ , - (CO) _d -NR ²³ R ²⁴ or = O
are substituted,
wherein
c represents a number 1, 2, 3 or 4,
d represents a number 0 or 1,
R ²³ and R ^{24 are the} same or different and are hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, straight-chain or branched alkyl having up to 5 carbon atoms, benzyl or phenyl, which is optionally substituted by fluorine, chlorine, bromine, phenyl or trifluoromethyl,
and / or the carbocycles formed, optionally by a spiro-linked radical of the formula

are substituted,
wherein
W represents either an oxygen or a sulfur atom,
Y and Y 'together form a 2- to 5-membered straight-chain or branched alkyl chain,
e represents a number 1, 2, 3, 4, 5 or 6,
f represents a number 1 or 2,
R ²⁵ , R ²⁶ , R ²⁷ and R ^{28 are the} same or different and are hydrogen, trifluoromethyl, phenyl, fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms,
or
R ²⁵ and R ²⁶ or R ²⁷ and R ²⁸ each together form a straight-chain or ver branched alkyl chain with up to 5 carbon atoms or
R ²⁵ and R ²⁶ or R ²⁷ and R ²⁸ each together represent a radical of the formula

form,
wherein
W has the meaning given above,
g represents a number 1, 2, 3, 4, 5 or 6,
R ³² and R ³³ together form a 5- to 6-membered heterocycle which contains an oxygen or sulfur atom or a group of the formula NH or NCH ₃ ,
and their salts.

Compounds of the general formula (I) according to the invention are particularly preferred
in which
A represents phenyl, pyridyl or thienyl, which are optionally substituted up to twice in the same or different manner by fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms,
D for a residue of the formula

or

R ⁹ -TVX-

stands,
wherein
R ⁶ and R ⁹ independently of one another are cyclopropyl, cyclopentyl or cyclohexyl, or
Phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8-yl, where the cycles, optionally up to Triple, in the case of nitrogen-containing rings also via the N function, the same or different by fluorine, chlorine, trifluoromethyl, hydroxy, cyano, carboxyl, tri fluoromethoxy, straight-chain or branched alkyl, alkylthio, alkyl alkoxy, alkoxy or alkoxycarbonyl, each with up to to 4 carbon atoms, triazolyl, tetrazolyl, benzothiazolyl, trifluoromethyl substituted phenyl or phenyl are substituted
and / or are substituted by a group of the formula -OR ¹⁰ , -SR ¹¹ or -SO ₂ R ¹² ,
wherein
R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are phenyl, which in turn is substituted up to 2 times the same or different by phenyl, fluorine, chlorine or by straight-chain or branched alkyl having up to 3 carbon atoms,
or
R ^{6 is} a radical of the formula

means
R ^{7 represents} hydrogen or fluorine,
and
R ^{8 is} hydrogen, fluorine, chlorine, azido, trifluoromethyl, hydroxy, trifluoromoxy, or straight-chain or branched alkoxy or alkyl each having up to 4 carbon atoms or a radical of the formula -NR- ¹⁵ R ¹⁶ ,
wherein
R ¹⁵ and R ^{16 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
or
R ⁷ and R ⁸ together form a radical of the formula = O or = NR ¹⁷ ,
wherein
R ¹⁷ denotes hydrogen or straight-chain or branched alkyl, alkoxy or acyl each having up to 4 carbon atoms,
L is a straight-chain or branched alkylene or alkenylene chain each having up to 5 carbon atoms, which are optionally substituted up to twice by hydroxy,
T and X are the same or different and represent a straight-chain or branched alkylene chain with up to 3 carbon atoms,
or
T or X represents a bond,
V represents an oxygen or sulfur atom or a group of the formula -NR ¹⁸ ,
wherein
R ¹⁸ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
E represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl, which is optionally substituted by fluorine or trifluoromethyl, or represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxy,
R ¹ and R ² together form a straight-chain or branched alkylene chain with up to 5 carbon atoms, which is represented by a carbonyl group and / or a radical of the formula

must be substituted
wherein
R ^{19 is} hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, straight-chain or branched silylalkyl having up to 6 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl, straight-chain or branched alkoxy having up to 3 carbon atoms or by phenyl which in turn can be substituted by fluorine, chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy or phenyl substituted by phenyl or tetrazole,
and alkyl is optionally substituted by a group of the formula -OR ²² ,
wherein
R ²² denotes straight-chain or branched acyl with up to 3 carbon atoms or benzyl,
or
R ¹⁹ denotes straight-chain or branched acyl having up to 15 carbon atoms or benzoyl, which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or trifluoromethoxy, or denotes straight-chain or branched fluoroacyl having up to 4 carbon atoms,
and the carbocycles formed may be up to 4 times the same or different, optionally also geminal, by fluorine, hydroxyl, trifluoromethyl, carboxyl, azido, chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy , are substituted by straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio each having up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which in turn is up to 2 times the same or different by hydroxyl, benzyloxy, trifluoromethyl, benzoyl, methoxy, oxyacetyl and / or substituted phenyl, which in turn can be substituted by fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy,
and / or the carbocycles formed, also geminal, optionally up to 4 times the same or different, are substituted by phenyl, benzoyl, thiophenyl or sulfonylbenzyl, which in turn are optionally substituted by fluorine, trifluoromethyl, trifluoromethoxy or nitro,
and / or optionally by a radical of the formula

-SO ₂ -C ₆ H ₅ , - (CO) _d -NR ²³ R ²⁴ or = O
are substituted,
wherein
c represents a number 1, 2, 3 or 4,
d represents a number 0 or 1,
R ²³ and R ^{24 are the} same or different and are hydrogen, cyclopropyl, cyclopentyl, benzyl, straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, which is optionally substituted by fluorine, chlorine or bromine,
and / or the carbocycles formed, if appropriate by a spiro-linked radical of the formula

are substituted,
wherein
W represents either an oxygen or a sulfur atom,
Y and Y 'together form a 2- to 6-membered straight-chain or branched alkylene chain,
e represents a number 1, 2, 3, 4 or 5,
f represents a number 1 or 2,
R ²⁵ , R ²⁶ , R ²⁷ and R ^{28 are the} same or different and are hydrogen, trifluoromethyl, phenyl, fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
or
R ²⁵ and R ²⁶ or R ²⁷ and R ²⁸ each together form a straight-chain or branched alkyl chain with up to 4 carbon atoms,
or
R ²⁵ and R ²⁶ or R ²⁷ and R ²⁸ each together represent a radical of the formula

form,
wherein
W has the meaning given above,
g represents a number 1, 2, 3, 4, 5, 6 or 7,
and their salts.

The compounds of the general formula (I) according to the invention are very particularly preferred
in which
A represents phenyl which is optionally substituted by fluorine,
or those in which
D for a residue of the formula

stands,
wherein
R ⁶ denotes phenyl or trifluoromethyl-substituted phenyl,
R ^{7 represents} hydrogen,
R ⁸ denotes hydrogen, fluorine, methoxy or hydroxy,
or
R ⁷ and R ⁸ together form a carbonyl group,
or those in which
E represents cyclopropyl, cyclopentyl or cyclohexyl or represents straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by hydroxy,
or those in which
R ¹ and R ² together for a radical of the formula

stand,
wherein
R ¹⁹ denotes hydrogen or the group -Si (CH ₃ ) ₂ C (CH ₃ ) ₃ ,
and their salts.

The compounds of general formula (I) can be prepared by:
[A] compounds of the general formula (II)

in which
A has the meaning given above,
R ³⁵ and R ^{36 are} identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms,
R ¹ and R ² together represent the straight-chain or branched alkylene chain with up to 7 carbon atoms specified under R ¹ and R ² above, which is substituted by tert-butyl-dimethyl-silanyloxy (OTBS),
and
E 'and E "together with the carbon atom bound to them comprise the scope of E given above,
first by selective reduction of the aliphatic ester and subsequent reaction with compounds of the general formula (III)

R ³⁷ halogen (III)

in which
R ^{37 represents} mesyl, tosyl or sulfonyl,
and
Halogen is chlorine, bromine or iodine, preferably chlorine,
in inert solvents, in the presence of a base,
into the compounds of the general formula (IV)

in which
A, E ', E'', R ^1' , R ^{2 '} , R ³⁵ and R ^{37 have} the meaning given above,
convicted,
in a further step depending on the definitions of E '/ E''given either by a double reduction or by saponification, Barton reaction and a reduction in the compounds of the general formula (V)

in which

A, E, R ^{1 '} and R ^{2' have} the meaning given above,
convicted,
then by oxidation into the aldehydes of the general formula (VI)

in which
A, E, R ^{1 '} and R ^{2' have} the meaning given above,
manufactures,
and finally introduces the rest D by a Grignard reaction and cleaves the TBS group by conventional methods,
or
[B] Compounds of the general formula (VI)

in which
A, E, R ^{1 '} and R ^{2' have} the meaning given above,
initially as described under [A] in a Grignard reaction with compounds of the general formula (VII)

R ³⁸ -MgBr (VII)

in which
R ³⁸ includes the meaning of R ⁵ and R ^{6 given} above,
in inert solvents and under a protective gas atmosphere in the compounds of the general formula (VIII)

in which
A, D, E, R ³⁸ , R ^{1 '} and R ^{2' have} the meaning given above,
convicted,
optionally introducing the substituents R ⁷ / R ⁸ indicated under D at this stage, starting from the hydroxyl function, using customary methods,
and finally cleaves the TBS group with tetrabutylammonium fluoride in inert solvents,
or
[C] compounds of the general formula (IX)

in which
A, E, R ^{1 '} , R ^2' and R ^{38 have} the meaning given above
and
R ^{7 '} and R ^8' together represent the carbonyl group,
first reduced to the compounds of the general formula (VIII) and finally reacted as described under [A],
and separates in the case of the enantiomers / racemates by customary methods.

The processes according to the invention can be illustrated by the following formula scheme:

Suitable solvents for all processes are ethers such as diethyl ether, dioxane, tetra hydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, Hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichlor methane, trichloromethane, carbon tetrachloride, dichlorethylene, trichlorethylene or chlorine benzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, Hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is the same possible to use mixtures of the solvents mentioned. Toluene and Dichloromethane.  

The usual strongly basic compounds come in as bases for the individual steps Question. These preferably include organolithium compounds such as N-butyl lithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as for example lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali hydrides such as sodium hydride or potassium hydride. Especially N-butyllithium, sodium hydride or lithium diisopropylamide is preferably used.

The usual inorganic bases are also suitable for the processes. For this ge prefer to hear alkali hydroxides or alkaline earth hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali carbonates such as sodium or Potassium carbonate or sodium hydrogen carbonate. Sodium is particularly preferred hydride or potassium hydroxide used.

Systems such as Mg / bromobenzo are, for example, suitable as organometallic reagents trifluoride and p-trifluoromethylphenyllithium.

The reductions of the compounds of the general formulas (II) and (IV) generally take place under the following reaction conditions:
The reductions are generally carried out using reducing agents, preferably those which are suitable for the reduction of ketones to hydroxy compounds. Reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane, is particularly suitable. The reduction is preferably carried out with complex metal hydrides such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydridoboranate, diisobutylaluminium hydride or lithium aluminum hydride. The reduction is very particularly preferably carried out using diisobutylaluminum hydride and sodium borohydride.

The reducing agent is generally preferred in an amount of 1 mol to 6 mol from 1 mol to 4 mol based on 1 mol of the compounds to be reduced.  

The reduction generally takes place in a temperature range from -78 ° C. to + 50 ° C., preferably from -78 ° C. to 0 ° C. in the case of the DIBAH, from 0 ° C. to room temperature in the case of the NaBH ₄ , particularly preferably at -78 ° C, depending on the choice of reducing agent and solvent.

The reduction generally takes place at normal pressure, but it is also possible at to work under increased or reduced pressure.

The reactions with the compounds of the general formula (III) proceed in one of the solvents listed above, preferably with diethyl ether.

The bases which are generally suitable for this purpose are the customary strongly basic compounds. These preferably include di- and trialkylamines such as triethylamine or organolithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as lithium diisopropyl amide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali hydrides such as sodium hydride or potassium hydride. Triethylamine is particularly preferred used.

The usual inorganic bases are also suitable as bases. These include be preferably alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, Potassium hydroxide or barium hydroxide, or alkali carbonates such as sodium or potassium carbonate or sodium bicarbonate. Potassium hydroxide is particularly preferred used.

The bases are generally used in an amount of 1 mol to 4 mol, preferably 1 mol to 2 mol based on 1 mol of the compounds of the general formula (III) used.

The reaction generally takes place at a temperature from -30 ° C to room temperature, preferably from -20 ° C to 0 ° C.  

The reaction generally takes place under normal pressure, but it is also possible with it to work at high or low pressure.

The compounds of the general formula (V) are generally reacted under the following reaction conditions:
Suitable solvents for all processes are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichlorethylene, trichlorethylene or trichlorethylene or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric acid triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Dichloromethane is preferred.

The usual strongly basic compounds come in as bases for the individual steps Question. These preferably include pyridine or organolithium compounds such as for example N-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali hydrides such as sodium hydride or potassium hydride. Pyridine is particularly preferably used.

The usual inorganic bases are also suitable for processes [B] and [C]. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as, for example Sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali carbonates such as Na trium or potassium carbonate or sodium hydrogen carbonate. Is particularly preferred Sodium hydride or potassium hydroxide used.

Systems such as Mg / bromobenzo are, for example, suitable as organometallic reagents trifluoride and p-trifluoromethylphenyllithium.

The base is used in an amount of 0.1 mol to 5 mol, preferably 0.5 mol to 2 mol, each based on 1 mol of the starting compound used.  

The reaction with Grignard reagents is generally carried out in a temperature range from 0 ° C to 150 ° C, preferably at 25 ° C to 40 ° C, performed.

The Grignard reactions are generally carried out at normal pressure. It is but it is also possible to carry out the process under negative pressure or overpressure (e.g. in a range from 0.5 to 5 bar).

The halogenations are generally carried out in one of the chlorinated ones listed above Hydrocarbons and hydrocarbons, with methylene chloride and toluene before are moving.

Examples of suitable halogenating agents are diethylamino sulfur trifluoride (DAST), morpholino sulfur trifluoride or SOCl ₂ .

The halogenation generally takes place in a temperature range from -78 ° C to + 50 ° C, preferably from -78 ° C to 0 ° C, depending on the choice of halogen agent and solvent.

The halogenation generally takes place at normal pressure, but it is also possible at to work under increased or reduced pressure.

The protective group is generally split off in one of the above Alcohols and THF, preferably methanol / THF in the presence of hydrochloric acid in one Temperature range from 0 ° C to 50 ° C, preferably at room temperature, and normal pressure. In special cases, the protective group is split off with tetrabutylammo nium fluoride (TBAF) preferred in THF at room temperature.

The compounds of the general formula (VI) are reacted with the verbin The general formula (VII) is carried out in one of the ethers listed above preferably in tetrahydrofuran under a protective gas atmosphere in a temperature range from -78 ° C to -10 ° C, preferably at -25 ° C.  

The derivatization of the hydroxy function in the compounds of the general formula (VIII) is carried out, for example, by oxidation, sulfonation, alkylation, hydration stanchions, halogenation, Wittig / Grignard reactions and sulfoamidation.

The usual strongly basic compounds come in as bases for the individual steps Question. These preferably include organolithium compounds such as n-butyl lithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as for example lithium diisopropylamide, sodium amide or potassium amide, or lithium hexa methylsilylamide, or alkali hydrides such as sodium hydride or potassium hydride. Especially N-butyllithium, sodium hydride or lithium diisopropylamide is preferably used.

The usual inorganic bases are also suitable as bases. This includes preferably alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, Potassium hydroxide or barium hydroxide or alkali carbonates such as sodium or potassium carbonate or sodium bicarbonate. Sodium hydroxide is particularly preferred or potassium hydroxide used.

It may be necessary to carry out a few reaction steps under a protective gas atmosphere to lead.

The reduction of the carbonyl group in the compounds of the general formula (IX) is generally carried out under the reduction conditions given above, preferably wise with sodium bis (2-methoxyethoxy) dihydroaluminate in toluene, in a tempera tur range from -20 ° C to 140 ° C, preferably from 0 ° C to 110 ° C and normal pressure.

The compounds of the general formulas (X) and (XI) are generally reacted under the following conditions:
Suitable solvents for all processes are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichlorethylene, trichlorethylene or trichlorethylene or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric acid triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Tetrahydro furan is preferred.

The usual strongly basic compounds come in as bases for the individual steps Question. These preferably include organolithium compounds such as N-butyl lithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides as for for example lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali hydrides such as sodium hydride or potassium hydride. Especially N-butyllithium, sodium hydride or lithium diisopropylamide is preferably used.

The base is used in an amount of 0.1 mol to 10 mol, preferably 1 mol to 5 mol, each based on 1 mol of the starting compound used.

The reaction is generally carried out in a temperature range from -10 ° C to + 10 ° C, preferably from 5 ° C to 10 ° C and normal pressure.

The compounds of the general formula (II) are new and can be prepared, for example, by
Compounds of the general formula (X)

in which
R ^{1 "} and R ^2" stand for a straight-chain or branched alkylene chain with up to 7 carbon atoms,
and
R ³⁹ and R ^{40 are the} same or different and represent straight-chain or branched alkyl having up to 4 carbon atoms,
by double reaction with compounds of the general formula (XI)

in which
R ^{35 has} the meaning given above,
into the compounds of the general formula (XII)

in which
R ^{35 has} the meaning given above
and
R ^{1 '''} and R ^{2''' have} the meaning of R ^{1 ''} and R ^{2 ''} given above, the alkylene chain being substituted by a carbonyl group,
and then by exposure to Tf ₂ O / pyridine and reaction in a further step with compounds of the general formula (XIII)

AB (OH) ₂ (XIII)

in which
A has the meaning given above,
in inert solvents and in the presence of a palladium complex in the compounds of the general formula (XIV)

in which
R ³⁵ , R ^{1 '''} and R ^{2''' have} the meaning given above,
the carbonyl function to the hydroxy function reduces this blocked by reaction with TBSOTf and finally alkylation with compounds of the general formula (XV)

E '''- J (XV)

in which
E '''includes the scope of E' and E '' given above,
carries out.

The introduction of the substituent A is generally carried out in two steps, the first reaction being with Tf ₂ O in pyridine. In a further step, the reaction with the compounds of the general formula (XIII) takes place.

Suitable solvents for all processes are ethers such as diethyl ether, dioxane, tetra hydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, Hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichlor methane, trichloromethane, carbon tetrachloride, dichlorethylene, trichlorethylene or chlorine benzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, Hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is the same possible to use mixtures of the solvents mentioned. Dioxane is preferred.

PdCl ₂ ((C ₆ H ₅ ) ₃ ) ₂ , palladium-bis-dibenzylidene acetone (Pd (dba) ₂ ), [1,1'-bis (diphenylphosphino) ferrocene] are generally suitable as palladium compounds in the context of the present invention: -Palladium (II) chloride (Pd (dppf) Cl ₂ ) or Pd (P (C ₆ H ₅ ) ₃ ) ₄ . Pd (P (C ₆ H ₅ ) ₃ ) ₄ is preferred.

The reaction is generally in a temperature range from room temperature to + 150 ° C, preferably from + 40 ° C to + 110 ° C, carried out.

The reaction is generally carried out at normal pressure. It is also possible to carry out the process under negative pressure or overpressure (e.g. in a Range from 0.5 to 5 bar).

The compounds of the general formula (XIV) are generally reduced in one of the solvents listed above, preferably with DIBAH.

The reductions are generally preferred with reducing agents with those which are suitable for the reduction of ketones to hydroxy compounds become. Reduction with metal hydrides or complex is particularly suitable Metal hydrides in inert solvents, optionally in the presence of a trialkylborane. Reduction with complex metal hydrides such as lithium is preferred  boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydridoboronate, Diisobutylaluminiumhydrid or Lithiumaluminiumhydrid performed. Most notably reduction with diisobutylaluminium hydride and sodium borohydride is preferred carried out.

The reducing agent is generally preferred in an amount of 1 mol to 6 mol from 1 mol to 4 mol based on 1 mol of the compounds to be reduced.

The reduction generally takes place in a temperature range from -78 ° C. to + 50 ° C., preferably from -78 ° C. to 0 ° C. in the case of the DIBAH, from 0 ° C. to room temperature in the case of the NaBH ₄ , particularly preferably at -78 ° C, depending on the choice of reducing agent and solvent.

The reduction generally takes place at normal pressure, but it is also possible at to work under increased or reduced pressure.

The subsequent introduction of the TBS group takes place in one of the above Solvent, preferably with toluene, in a temperature range from -30 ° C to room temperature, preferably -20 ° C to 0 ° C and normal pressure.

The alkylation with alkyl halides is generally carried out in inert solvents in Presence of a base.

Suitable solvents are, depending on the type of alkylating agent, all inert orga African solvents. These preferably include ethers such as diethyl ether, dioxane or tetra hydrofuran, or hydrocarbons such as benzene, toluene or xylene, or dimethyl formamide or hexamethylphosphoric triamide, or mixtures of the solutions mentioned medium.

The usual basic compounds are suitable as bases for the alkylation. For this preferably include alkali hydrides such as sodium hydride, alkali amides such as sodium amide or Lithium diisopropylamide, alkali alcoholates such as sodium methoxide, sodium ethoxide,  Potassium methanolate, potassium ethanolate or potassium ter.butylate, or organic amines such as Trialkylamines, e.g. B. triethylamine, or organolithium compounds such as butyllithium or phenyllithium. Lithium diisopropylamide is preferred.

The alkylation generally takes place in a temperature range from -70 ° C to + 80 ° C, preferably from -70 ° C to 0 ° C.

The alkylation is generally carried out at normal pressure. It is also possible to carry out the process under vacuum or overpressure (e.g. in a Range from 0.5 to 5 bar).

The compounds of the general formulas (III), (X), (XI), (XII), (XIII) and (XV) are known per se or can be produced by customary methods.

The compounds of the general formula (XIV) are new and can be as above described.

The compounds of general formula (IV) are new and can be as above be made.

The compounds of general formula (VIII) are new and can be as above described.

The compounds of general formula (VI) are new and can be prepared by
Compounds of the general formula (Va)

in which
A, E, R ^{1 '} and R ^{2' have} the meaning given above,
under a protective gas atmosphere in inert solvents with one of the oxidizing agents listed above in the presence of a base, preferably with the SO ₃ -pyridine complex.

Suitable solvents for the individual steps are ethers such as diethyl ether, dioxane, Tetrahydrofuran, glycol dimethyl ether, diisopropyl ether or hydrocarbons such as Benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated coal substances such as dichloromethane, trichloromethane, carbon tetrachloride, dichlorethylene, tri chlorethylene or chlorobenzene. It is also possible to use mixtures of the solvents mentioned to use.

The oxidizing agent is used in an amount of 1 mol to 10 mol, preferably 2 mol to 5 mol, based on 1 mol of the compounds of the general formula (Va), are used.

The usual basic compounds come in as bases for the individual steps Question. These preferably include pyridine or organolithium compounds such as for example N-, butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali hydrides such as sodium hydride or potassium hydride. Pyridine is particularly preferably used.

The base is used in an amount of 1 mol to 10 mol, preferably 2 mol to 5 mol based on 1 mol of the compounds of the general formula (Va) used.

The oxidation generally takes place at a temperature of -50 ° C to + 100 ° C, preferably from 0 ° C to room temperature.  

The compounds of the general formulas (V), (VIII) and (IX) are new and can be prepared by
Compounds of the general formula (XVI)

in which
A, R ^{1 '''} and R ^{2''' have} the meaning given above,
and
R ⁴¹ either for the rest of the formula

first by reaction with citric acid in the compounds of the general formula (XVII)

in which
A, R ^{1 '''} , R ^2''' and R ^{41 have} the meaning given above,
transferred, then an oxidation to the compounds of the general formula (XVIII) in inert solvents

in which
A, R ^{1 '''} , R ^2''' and R ^{41 have} the meaning given above,
carries out in a further step the compounds of the general formula (XIX)

in which
A, R ^{1 '''} , R ^2''' and R ^{41 have} the meaning given above,
prepared by reaction with trifluoromethanesulfonic anhydride in pyridine, then with compounds of the general formula (XX)

E ^IV (XX)

in which
E ^{IV stands} for cycloalkenyl with 3 to 8 carbon atoms or stands for straight-chain or branched alkenyl with up to 8 carbon atoms, or
represents a radical of the formula -R ⁴² -Sn (R ⁴³ R ⁴⁴ R ⁴⁵ ),
in which
R ⁴² denotes straight-chain or branched alkenyl with up to 8 carbon atoms,
R ⁴³ , R ⁴⁴ and R ^{45 are the} same or different and represent straight-chain or branched alkyl having up to 8 carbon atoms,
in the system Pd (dba) ₂ / 1,2-bis (diphenylphosphino) ethane, Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ and LiCl in the presence of an inert solvent and a base under pressure and protective gas atmosphere to the compounds of general formula (XXI)

in which
A, E ^IV , R ^{1 '''} , R ^2''' and R ^{41 have} the meaning given above,
produces a hydrogenation in the presence of a catalyst to give the compounds of the general formula (XXII)

in which
A, E, R ^{1 '''} , R ^2''' and R ^{41 have} the meaning given above,
carries out, in a further step, the selective reduction of the carbonyl group (R ^{1 ''} / R ^{2 ''} ) in ethers to give the compounds of the general formula (XXIII)

in which
A, E and R ^{41 have} the meaning given above
and
R ^1IV and R ^{2IV have} the abovementioned meaning of R ^{1 '} and R ^2' , the alkylene chain being substituted by hydroxy,
carried out and finally by protecting the free hydroxy function with tert-butyl dimethylsilyl triflate (TBS) in inert solvents to give the compounds of the general formula (XXIV)

in which
A, E, R ^{1 '} , R ^2' and R ⁴ which have the meaning given above,
and in the case R ³⁸ = CO ₂ R ^35, the alkoxycarbonyl function is selectively reduced by customary methods for the hydroxymethyl function.

The compounds of the general formula (XVI) are reacted with Citric acid at 60 ° C and normal pressure.

The oxidation to the compounds of the general formula (XVIII) takes place in the context of the present invention under the following conditions:
Suitable solvents for the oxidation are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichlorethylene, trichlorethylene or trichlorethylene or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric acid triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Toluene is preferred.

Suitable oxidizing agents are, for example, cerium (IV) ammonium nitrate, 2,3-dichloro-5,6-dicyan benzoquinone, pyridinium chlorochromate (PCC), pyridinium chlorochromate basic aluminum oxide, osmium tetroxide, sodium acetate / iodine and manganese dioxide. Be 2,3-dichloro-5,6-dicyanobenzoquinone is preferred.

The oxidizing agent is used in an amount of 1 mol to 10 mol, preferably 2 mol to 5 mol, based on 1 mol of the compounds of the general formula (XVIII), used.

The oxidation generally takes place in a temperature range from 0 ° C to + 100 ° C, preferably from room temperature to 80 ° C.

The oxidation generally takes place at normal pressure. But it is also possible that To carry out oxidation at elevated or reduced pressure.

The introduction of the hydroxy protecting group trifluoromethanesulfonyl in the compounds of general formula (XVIII) is generally carried out in pyridine with trifluoromethanesulfone acid anhydride in a temperature range from -30 ° C to + 40 ° C, preferably at -20 ° C up to 0 ° C and normal pressure.

The reaction with the compounds of the general formula (XX) takes place in the case of Olefins in a Heck reaction in an autoclave with a phosphino and palladium complex, in the presence of an inert solvent and a base under nitrogen atmosphere, in a temperature range of + 80 ° C to + 120 ° C, preferably at 100 ° C or in the case of the alkenylstannyl compounds at room temperature up to 100 ° C.  

The cyclic hydrocarbons listed above are suitable as solvents Ethers, with toluene and dioxane being preferred.

Suitable bases are the dialkylamines listed above, preferably ethyldiiso propylamine.

The base is generally used in an amount of 0.5 mol to 5 mol, preferably 1 mol up to 3 mol, based on 1 mol of the compounds of the general formula (XX).

PdCl ₂ ((C ₆ H ₅ ) ₃ ) ₂ , palladium-bis-dibenzylideneacetone (Pd (dba) ₂ ), [1,1'-bis (diphenylphospnino) ferrocene] are generally suitable as palladium compounds in the context of the present invention: -Palladium (II) chloride (Pd (dppf) Cl ₂ ) or Pd (P (C ₆ H ₅ ) ₃ ) ₄ .

The reduction of the double bond in radical E '' 'is generally carried out with a hydrie tion.

The hydrogenation is carried out using conventional methods with hydrogen in the presence of Precious metal catalysts, such as Pd / C Pt / C or Raney nickel in one of the solvents listed above, preferably in alcohols such as methanol, Ethanol or propanol in a temperature range from -20 ° C to + 100 ° C, preferred from 0 ° C to + 50 ° C, at normal pressure or overpressure.

The reduction to the compounds of general formula (XXIII) takes place in generally in one of the ethers listed above, preferably tetrahydrofuran in one Temperature range from 0 ° C to + 40 ° C, preferably 0 ° C to room temperature and Normal pressure.

Suitable reducing agents are generally 1R, 2S-amino alcohol with 7-borane complexes in BH ₃ × THF, BH ₃ × DMS, BH ₃ × (Et ₂ ) NC ₆ H ₅ or borane-dimethyl sulfide solution in tetrahydrofuran. Borane dimethyl sulfide solution in tetrahydro furan is preferred.

The introduction of the TBS group for blocking the hydroxy function takes place in all in toluene with tert-butyl-dimethylsilyl triflate in a temperature range of -30 ° C to + 10 ° C, preferably -20 ° C to 0 ° C and normal pressure.

The compounds of the general formula (XXIV) are generally reduced in one of the cyclic hydrocarbons listed above, preferably toluene in a temperature range from -78 ° C to -20 ° C, preferably from -78 ° C to -40 ° C and Normal pressure.

The reductions are generally carried out with reducing agents, preferably with those which are suitable for the reduction of ketones to hydroxy compounds become. Reduction with metal hydrides or complex is particularly suitable Metal hydrides in inert solvents, optionally in the presence of a trialkylborane. Reduction with complex metal hydrides such as lithium is preferred boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydridoboronate, Diisobutylaluminiumhydrid or Lithiumaluminiumhydrid performed. Most notably reduction with diisobutylaluminium hydride and sodium borohydride is preferred carried out.

The reducing agent is generally preferred in an amount of 1 mol to 6 mol from 1 mol to 4 mol based on 1 mol of the compounds to be reduced.

The reduction generally takes place in a temperature range from -78 ° C. to + 50 ° C., preferably from -78 ° C. to 0 ° C. in the case of the DIBAH, from 0 ° C. to room temperature in the case of the NaBH ₄ , particularly preferably at -78 ° C, depending on the choice of reducing agent and solvent.

The reduction generally takes place at normal pressure, but it is also possible at to work under increased or reduced pressure.  

The compounds of the general formulas (XVI), (XVII), (XVIII), (XIX), (XXI), (XXII), (XXIII) and (XXIV) are new and can be prepared as described above become.

The compounds of the general formula (XX) are known.

The compounds of the general formula (XVI) are new and can be prepared by reacting dimedone with compounds of the general formula (XXV)

A-CHO (XXV)

in which
A has the meaning given above
and compounds of the general formulas (XXVI)

in which
R ^{41 has} the meaning given above,
in saturated cyclic hydrocarbons, preferably cyclohexane, under reflux and normal pressure.

The compounds of the general formulas (XXV) and (XXVI) are known or can be produced by customary methods.  

The compounds of the general formula (I) according to the invention have not been previously visible pharmacological spectrum of action.

The compounds of general formula (I) according to the invention have valuable im Compared to the prior art, pharmacological properties, in particular they are highly effective inhibitors of cholesterol ester transfer protein (CETP) and stimulate reverse cholesterol transport. The active compounds according to the invention cause a decrease in the LDL cholesterol level in the blood with a simultaneous increase of the HDL cholesterol level. They can therefore be used to treat and prevent Hypolipoproteinemia, dyslipidemia, hypertriglyceridaemia, hyperlipidaemia or arte riosclerosis can be used.

The pharmacological effect of the substances according to the invention was tested in the following test certainly:

CETP inhibition testing Obtaining CETP

CETP is made from human plasma by differential centrifugation and column chro Matography obtained in partially purified form and used for the test. This will human plasma with NaBr adjusted to a density of 1.21 g per ml and at 18 h Centrifuged 50,000 rpm at 4 ° C. The soil fraction (d <1.21 43706 00070 552 001000280000000200012000285914359500040 0002019832159 00004 43587g / ml) is divided into one Sephadex®Phenyl-Sepharose 4B (Pharmacia) column applied, with 0.15 m NaCl / 0.001 m TrisHCl pH 7.4 and then washed with dist. Water eluted. The CETP-active fractions are pooled, dialyzed against 50 mM NaAcetat pH 4.5 and applied to a CM-Sepharose® (Pharmacia) column. With a linear gradient ten (0-1 M NaCl) is then eluted. The pooled CETP fractions are dialyzed against 10 mM TrisHCl pH 7.4 and then by chromatography over a Mono Q® column (Pharmacia) further cleaned.  

Obtaining radioactively labeled HDL

50 ml of fresh human EDTA plasma is adjusted to a density of 1.12 with NaBr and centrifuged at 4 ° C. in a Ty 65 rotor for 18 h at 50,000 rpm. The upper phase is used to obtain cold LDL. The lower phase is dialyzed against 3.4 l of PDB buffer (10 mM Tris / HCl pH 7.4, 0.15 mM NaCl, 1 mM EDTA, 0.02% NaN ₃ ). 20 ml of 3H-cholesterol (Dupont NRT-725; 1 mC / ml dissolved in ethanol!) Are then added per 10 ml of retentate volume and incubated for 72 h at 37 ° C. under N ₂ .

The batch is then adjusted to the density 1.21 with NaBr and in the Ty 65 rotor for 18 h centrifuged at 50,000 rpm at 20 ° C. You win the upper phase and clean it Lipoprotein fractions by gradient centrifugation. For this, the isolated, marked Lipoprotein fraction adjusted to a density of 1.26 with NaBr. 4 ml each of this solution are placed in centrifuge tubes (SW 40 rotor) with 4 ml of a solution with a density of 1.21 as well as 4.5 ml of a solution of 1.063 (sealing solutions made of PDB buffer and NaBr) and then centrifuged for 24 h at 38,000 rpm and 20 ° C in a SW 40 rotor. The intermediate between the density 1.063 and 1.21 containing the marked HDL The layer is dialyzed against 3,100 volumes of PDB buffer at 4 ° C.

The retentate contains radioactively labeled ³ H-CE-HDL, which is set to approx. 5 × 10 cmp per ml and used for the test.

CETP test

To test the CETP activity, the transfer of ³ H-cholesterol esters from human HD lipoproteins to biotinylated LD lipoproteins is measured.

The reaction is ended by adding streptavidin-SPA®beads (from Amersham) and the transmitted radioactivity is determined directly in the Liquid Scintillation Counter.

In the test mixture, 10 ml of HDL- ³ H-cholesterol esters (∼ 50,000 cpm) with 10 ml of biotin-LDL (from Amersham) in 50 mM Hepes / 0.15 m NaCl / 0.1% bovine serum albumin / 0.05% NaN ₃ pH 7.4 with 10 ml CETP (1 mg / ml) and 3 ml solution of the substance to be tested (dissolved in 10% DMSO / 1% RSA), incubated for 18 h at 37 ° C. Then 200 ml of the SPA streptavidin bead solution (TRKQ 7005) are added, incubated for 1 h while shaking and then measured in the scintillation counter. Corresponding incubations with 10 ml of buffer, 10 ml of CETP at 4 ° C and 10 ml of CETP at 37 ° C serve as controls.

The activity transferred in the control batches with CETP at 37 ° C. is rated as 100% transfer. The substance concentration at which this transfer is reduced to half is given as the IC ₅₀ value.

The following Table A shows the IC ₅₀ values (mol / l) for CETP inhibitors:

Table A

Ex vivo activity of the compounds according to the invention

Syrian golden hamsters from in-house breeding are anesthetized after fasting for 24 hours (0.8 mg / kg atropine, 0.8 mg / kg Ketavet® sc, 30 'later 50 mg / kg Nembutal ip). The jugular vein is then dissected and cannulated. The test substance is dissolved in a suitable solvent (usually Adalat placebo solution: 60 g glycerol, 100 ml H ₂ O, ad 1000 ml PEG-400) and administered to the animals via a PE catheter inserted into the jugular vein. The control animals receive the same volume of solvent without test substance. The vein is then tied off and the wound closed.

The administration of the test substances can also p.o. done by putting the substances in DMSO dissolved and 0.5% tylose suspended orally administered by gavage become. The control animals receive identical volumes of solvent without test substance.  

At various times - up to 24 hours after application - blood is drawn from the animals by puncturing the retro-orbital venous plexus (approx. 250 ml). The coagulation is terminated by incubation at 4 ° C. overnight, followed by centrifugation at 6000 × g for 10 minutes. In the serum obtained in this way, the CETP activity is determined by the modified CETP test. The transfer of ³ H-cholesterol esters from HD lipoproteins to bio-vinylated LD lipoproteins is measured as described for the CETP test above.

The reaction is ended by adding streptavidin-SPA®beads (from Amersham) and the transmitted radioactivity is determined directly in the Liquid Scintlation Counter.

The test batch is carried out as described under "CETP test". Only 10 ml CETP are used for testing the serum by 10 ml of the corresponding serum samples replaced. Corresponding incubations with sera from untreated serve as controls Animals.

The activity transferred in the control batches with control sera is rated as 100% transfer. The substance concentration at which this transfer is reduced to half is given as the ED ₅₀ value.

Table B

In vivo activity of the compounds according to the invention

When trying to determine the oral effect on lipoproteins and triglyce ride becomes Syrian golden hamster from the company's own breeding test substance in DMSO dissolved and 0.5% tylose suspended orally administered by gavage. For The CETP activity is determined before the start of the experiment by retro-orbital Puncture blood drawn (approx. 250 ml). Then the test substances administered orally using a pharyngeal tube. The control animals receive identical ones Volume of solvent without test substance. Then the feed is removed from the animals moved and at different times - up to 24 hours after substance application cation - blood drawn by puncturing the retroorbital venous plexus.

The coagulation is terminated by incubating at 4 ° C. overnight the mixture is then centrifuged at 6000 × g for 10 minutes. In the serum thus obtained the content of cholesterol and triglycerides using modified commercial available enzyme tests determined (cholesterol enzymatically 14366 Merck, triglycerides 14364 Merck). Serum is appropriately mixed with physiological saline diluted.

100 ml of serum dilution are mixed with 100 ml of test substance in 96-well plates added and incubated for 10 minutes at room temperature. Then the optical density at a wavelength of 492 nm with an automatic plate Reader determined. The triglyceride or cholesterol contained in the samples concentration is determined using a standard curve measured in parallel.

The HDL cholesterol content is determined after the precipitation ApoB-containing lipoproteins using a reagent mixture (Sigma 352-4 HDL Cholesterol reagent) carried out according to the manufacturer's instructions.  

Table C.

Efficacy in vivo in transgenic hCETP mice

Transgenic mice from our own breeding (Dinchuck, Hart, Gonzalez, Karmann, Schmidt, Wirak; BBA (1995), 1295, 301) the substances to be tested in Feed administered. Before the start of the experiment, the mice were given retroorbital blood taken to determine cholesterol and triglycerides in serum. The serum was as described above for hamsters by incubation at 4 ° C. overnight and on closing centrifugation at 6000 × g. After a week the Blood was drawn again from mice to determine lipoproteins and triglycerides. The change in the measured parameters is called a percentage change expressed in relation to the initial value.  

Table D

The invention also relates to the combination of substituted tetrahydro naphthalenes of the general formula (I) with a glucosidase and / or amylase inhibitors for the treatment of familial hyperlipidaemia, obesity and diabetes mellitus. Glucosidase and / or amylase inhibitors in the context of Examples include acarbose, adiposins, Voglibose, Miglitol, Emiglitate, MDL-25 637, Camiglibose (MDL-73945), Tendamistate, AI-3688, Trestatin, Pradi micin-Q and salbostatin.

The combination of acarbose, miglitol, emiglitate or voglibose is preferred one of the above-listed compounds of the general for meln (I).

The compounds according to the invention can furthermore be used in combination with choles sterin-lowering Vastatinen or ApoB-lowering principles can be combined to Dyslipidemics, combined hyperlipidemics, hypercholesterolemics or hypertri treat glyceridemics.

The combinations mentioned are also for primary or secondary prevention coronary heart diseases (e.g. myocardial infarction) can be used.

Vastatins within the scope of the invention are, for example, lovastatin, simvastatin, Pravastatin, Fluvastatin, Atorvastatin and Cerivastatin. ApoB are reducing agents for example MTP inhibitors.  

The combination of cerivastatin or ApoB inhibitors with one of the Compounds according to the invention of the general formulas (I) and listed above (Ia).

The new active ingredients can be introduced into the usual formulations in a known manner are transferred, such as tablets, dragees, pills, granules, aerosols, syrups, emuls ions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carriers or solvents. Thera peutically active compound in a concentration of about 0.5 to 90 % By weight of the total mixture is present, d. H. in amounts that are sufficient to achieve the specified dosage range.

The formulations are prepared, for example, by stretching the active ingredients substances with solvents and / or carriers, optionally using Emulsifiers and / or dispersants, z. B. in the case of using Water as a diluent, optionally organic solvents as auxiliary solvents means can be used.

The application takes place in the usual way intravenously, orally, parenterally or perlingually, especially oral.

In the case of parenteral use, solutions of the active ingredient can be found below Use of suitable liquid carrier materials can be used.

In general, it has proven to be advantageous for intravenous administration Amounts from about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight to give effective results, and oral appli cation, the dosage is about 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg Body weight.

Nevertheless, it may be necessary to deviate from the quantities mentioned give way, depending on the body weight or the type of appli  cation path, from individual behavior towards the drug, the type of its formulation and the time or interval at which the administration is done. So in some cases it may be sufficient with less than the previous one mentioned minimum quantity, while in other cases the mentioned upper limit must be exceeded. In the case of application of larger quantities it may be advisable to mix these in several single doses throughout the day divide.  

Output connections

Example I

Methyl 8-hydroxy-7- (methoxycarbonyl) -3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-3-naphthyl acetate

48.48 g of sodium hydride in 1200 ml of THF are introduced under argon and, with ice cooling at 8-10 ° C., within 35-40 min. 139.92 g of methyl acetoacetate, dissolved in 375 ml of THF, are added dropwise and the mixture is stirred in an ice bath for 1 h. Then again at 8-10 ° C within 35-40 min. 761.2 ml of n-BuLi added dropwise in hexane and stirred again in an ice bath for 1 h. Then 27 g of dimethyl 2-dimethylglutarate, dissolved in 210 ml of THF within 15 min. added dropwise at 5-7 ° C and stirred for 2 h, while allowing the internal temperature to rise to room temperature. For working up, the reaction solution is transferred to a stirred mixture of 7.2 liters of 10% ammonium chloride solution. and 3.6 liters of toluene and stirred for a further 10 min. The organic phase is separated off and the aqueous phase is extracted again with 1.8 l of toluene. The united org. Phases are washed neutral twice with 1.8 liters of water each time, dried over sodium sulfate and concentrated in vacuo. 30 ml of toluene are added to the residue (approx. 60 g), and 60 ml of petroleum ether are slowly added while stirring. After inoculation with product, the product crystallizes out and, after cooling to 10-15 ° C., is filtered off with suction over 1 h and dried at 50 ° C. under vacuum (Frakt. 1). The mother liquor was concentrated and placed on a column of 600 g of silica gel (9.5 × 15 cm), and eluted first with pure toluene and later with an increasing proportion of ethyl acetate (95: 5 90: 10, 80: 20). The main fraction was concentrated and 7.5 ml of toluene were added to the residue (15 g) and 30 ml of petroleum ether were added with stirring, the product crystallizing out. The new mother liquor was combined with a contaminated fraction from the chromatography, concentrated (10 g) and crystallized as above with 5 ml of toluene and 45 ml of petroleum ether (fraction 3).
Yield: 24.9 g (54% of theory)
R _f = 0.15 (Cy: EE 8: 2).

Example II

Methyl 7- (methoxycarbonyl) -3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-8-trifluoromethyl sulfonyl-3-naphthyl acetate

21 g of the compound from Example I are dissolved in 328 ml of pyridine and 21.52 ml of trifluoromethanesulfonic anhydride with ice cooling at max. 5 ° C within 30 min. dripped. Stirred for 18 h while allowing the temperature to rise to room temperature. The reaction solution was worked up. transferred to a stirred mixture of 1.6 liters of water and 0.8 liters of toluene (PH = 6) and by adding 325 ml of conc. Hydrochloric acid set to PH = 2. The aq. Phase was extracted again with 0.4 l of toluene and the combined org. Phases with 0.4 liters of water, 2.5% sodium bicarbonate solution. and washed twice with water until neutral, dried over sodium sulfate and filtered through a layer of silica gel. The filtrate was concentrated to about 100 ml in vacuo and 100 ml of petroleum ether were added dropwise with stirring, the product crystallizing out. After cooling to 10-15 ° C. for 2 hours, the product was filtered off with suction and dried at 50 ° C. under vacuum.
Yield: 16.6 g (56% of theory)
R _f = 0.32 (Cy: EE 6: 4).

Example III

Methyl 8- (4-fluorophenyl) -7- (methoxycarbonyl) -3,3-dimethyl-1-oxo-1,2,3,4-tetra hydro-3-naphthyl acetate

Reaction with extreme exclusion of moisture and atmospheric oxygen! 16.5 g of the compound from Example II, 6.63 g of 4-fluorobenzeneboronic acid, 13.16 g of tripotassium phosphate and 4.76 g of tetrakis (triphenylphosphine) palladium (0) are placed in the heated reaction vessel and the apparatus is rinsed by repeated evacuation and venting with argon. The air-degassed dioxane was then added and the mixture was boiled under reflux for 12 h. After cooling, the reaction solution. Filtered through a layer of silica (40 g) and the filtrate was concentrated in vacuo. The residue was dissolved in 600 ml of toluene (PH 3) and with 200 ml of water, 5% sodium bicarbonate solution. and washed twice with water until neutral, dried over sodium sulfate and filtered again through a layer of silica gel. After concentration to about 50 ml and dropwise addition of about 100 ml of petroleum ether with stirring, the product crystallized out and, after cooling to 10-15 ° C. (1 h), was filtered off with suction and dried at 50 ° C. under vacuum (Fract. 1). The last layer of silica gel was again eluted with 200 ml of toluene / ethyl acetate 90:10 and 80:20, and the residue obtained after concentration of the solution and the residue of the mother liquor from Fract. 1 (2.3 g) by column chromatography on 250 g of silica gel 60 / 0.04-0.063 mm (column 5 × 25 cm) cleaned with cyclohexane / ethyl acetate 80:20.
Yield: 12.8 g (87% of theory)
R _f = 0.35 (Cy: EE 6: 4).

Example IV

Methyl 8- (4-fluorophenyl) -7- (methoxycarbonyl) -3,3-dimethyl-1-hydroxy-1,2,3,4-tetra hydro-3-naphthyl acetate

14.1 g of the compound from Example III in methanol is dissolved with gentle heating and added at 25 ° C sodium hydroxide solution. Then 5.36 g of sodium borohydride added and 1.5 h at max. 30 ° C with gentle water cooling stirred until the reaction is complete. Then adjusted by dropwise addition of 150 ml of 1N hydrochloric acid to pH 3, 15 min. stirred, the reaction solution. stirred into a mixture of 2.4 liters of water and 12 liters of toluene, and the aqueous phase extracted again with 0.6 liters of toluene. The united org. Phases were each with 0.6 liter 5% sodium bicarbonate solution. and washed twice with water until neutral, dried over sodium sulfate and concentrated under vacuum to approx. 50 ml. After dropwise addition of 100 ml of petroleum ether with stirring, the product crystallizes out and, after cooling to 10-15 ° C., is filtered off with suction and dried. The crystals and mother liquor were combined again and chromatographed on 870 g of silica gel 60 / 0.04-0.063 mm (column 6.5 × 52 cm) with toluene / ethyl acetate 90:10. The main fractions were concentrated in vacuo and finally crystallized from toluene. The solids were dried under vacuum at 50 ° C.
Yield: 11.5 g (73% of theory)
R _f = 0.20 (toluene: EE 9: 1).

Example V

Methyl 8- (4-fluorophenyl) -7- (methoxycarbonyl) -3,3-dimethyl-1- (tert-butyldimethyl silyloxy) -1,2,3,4-tetrahydro-3-naphthyl acetate

9.9 g of the compound from Example IV are made under argon in dry dichloromethane dissolved and cooled to -20 ° C. Then 7.20 ml of 2,6-lutidine are added dropwise and then 7.38 ml of t-butyldimethylsilyl trifluoromethanesulfonate. The following is 1 h at Touched -20 to -15 ° C until the reaction is complete.

For working up 100 ml sat. Ammonium chloride solution added dropwise, 10 min. stirred at room temperature and the phases separated. The aqueous phase was extracted once more with 100 ml of dichloromethane, and the combined organic phases were washed neutral twice with 100 ml of water each time, dried over sodium sulfate and concentrated. The crude product was chromatographed on 480 g of silica gel 60 / 0.04-0.063 mm (column 5 × 50 cm) with cyclohexane / ethyl acetate 90:10.
Yield: 10.5 g (83% of theory)
R _f = 0.48 (toluene: EE 9: 1).

Example VI

8- (tert-Butyl-dimethylsilyloxy) -1- (4-fluoro-phenyl) -3- (1-methoxycarbonyl-ethyl) - 5,6,7,8-tetrahydronaphtaline-2-carboxylic acid methyl ester

10.3 g of the compound from Example V are dissolved under argon in 200 ml of dry THF and cooled to -70 ° C. Then 13.98 ml of 2 molar LDA solution. within 30 min. at max. -60 ° C added dropwise, stirred for 1 h while allowing the internal temperature to rise to -20 ° C. Then again cooled to -70 ° C, and first 2.12 ml of methyl iodide, dissolved in 20 ml of THF, at max. -60 ° C within 30 min. dripped. After another 30 min. DC control. The reaction solution was worked up. in a mixture of 1 liter of 10% ammonium chloride solution. and 0.5 liter of toluene are stirred and the phases are separated. The aqueous phase was extracted once more with 0.25 liters of toluene and the purified organic phases were washed neutral twice with 0.25 liters of water each time, dried over sodium sulfate and concentrated under vacuum at 50 ° C. The crude product was chromatographed on 870 g of silica gel 60 / 0.04-0.063 mm (column 8 × 52 cm) with cyclohexane / ethyl acetate 90:10. The main fraction was concentrated under vacuum at 50 ° C. and finally crystallized from the cyclohexane after inoculation. The solid was dried at 50 ° C under vacuum.
Yield: 9.4 g (85% of theory)
R _f = 0.27 (Cy: EE 9: 1).

Example VII

8- (tert-Butyl-dimethylsilyloxy) -1- (4-fluoro-phenyl) -3- (2-hydroxy-1-methyl-ethyl) - 5,6,7,8-tetrahydronaphtaline-2-carboxylic acid methyl ester

5.24 g of the compound from Example VI is initially dissolved in argon in dry THF and cooled to -70 ° C. Then 79.26 ml of 1 molar diisobutyl aluminum hydride solution. within 45 min. at max. -65 ° C added dropwise and 90 min. stirred. Then 393 ml of a 20% potassium sodium tartrate solution. added dropwise, allowing the internal temperature to rise to room temperature. After 60 min. With stirring, the mixture was diluted with 1050 ml of water and 525 ml of toluene and the phases were separated. The aqueous phase was extracted once more with 250 ml of toluene, and the combined organic phases were washed twice with 250 ml of water until neutral, dried over sodium sulfate and concentrated under vacuum at 50 ° C.
Yield: 4.25 g (85% of theory)
R _f = 0.17 (Cy: EE 8: 2).

Example VIII

8- (tert-Butyl-dimethylsilyloxy) -1- (4-fluoro-phenyl) -3- (2-methylsulfonyloxy-1-methyl ethyl) -5,6,7,8-tetrahydronaphtaline-2-carboxylic acid methyl ester

4.25 g of the compound from Example VII are dissolved in diethyl ether under argon, 3.29 ml of triethylamine are added and the mixture is cooled to -20.degree. Then within 30 min. 1.71 ml of mesyl chloride were added dropwise at -25 to -20 ° C., and the mixture was stirred at the same temperature for 3 h. Then 31 ml sat. Ammonium chloride solution added dropwise and let the batch come to room temperature (pH 4). The phases are then separated and the aqueous phase is extracted once more with 31 ml of ether. The united org. Phases were with 31 ml of water, 1% sodium bicarbonate solution. (pH 8) and washed twice with water, dried over sodium sulfate and concentrated under vacuum at 50 ° C.
Yield: 4.77 g (85% of theory)
R _f = 0.28 (Cy: EE 8: 2).

Example IX

Methyl 5- (tert-butyldimethylsilyloxy) -7,7-dimethyl-4- (4-fluorophenyl) -2-isopropyl-5,6,7,8-tetrahydronaphtaline-3-carboxylate

4.7 g of the compound from Example VIII are dissolved in 69 ml of DMSO under argon and then added 0.78 g of sodium borohydride. Then stirred for 5 h at 85 ° C until the educt is largely implemented.

The reaction solution was worked up. in a mixture of 350 ml of 10% sodium chloride solution. and 175 ml of toluene were stirred in, slowly added dropwise to approx. 14 ml of 1 M hydrochloric acid to pH 5 and the phases were separated. The aqueous phase was extracted again with 90 ml of toluene, and the combined org. Phases with 90 ml 5% sodium bicarbonate solution each. and wash twice with water until neutral, dried over sodium sulfate and concentrated. The crude product was dissolved in a little toluene and placed on a short layer of silica gel (60 g) and eluted with toluene. The main fraction was concentrated and crystallized by inoculating with product from a little toluene and dried under vacuum to constant weight.
Yield: 2.61 g (78% of theory)
R _f = 0.30 (Cy: EE 95: 5).

Example X

5- (tert-Butyldimethylsilyloxy) -7,7-dimethyl-4- (4-fluorophenyl) -3-hydroxymethyl-2-isopropyl-5,6,7,8-tetrahydronaphthalene

Under argon, 2.57 g of the compound from Example IX are dissolved in dry toluene and cooled to -70 ° C. Then within 20 min. 15.9 ml of 1 molar diisobutylaluminium hydride solution. at max. -65 ° C added dropwise and stirred for 1 h at the same temperature. For working up, 2.0 ml of methanol were first carefully added dropwise, and after the evolution of hydrogen had ended, 158 ml of a 20% potassium sodium tartrate solution, the mixture being allowed to come to room temperature. After another 30 min. was stirred, the phases are separated and the aq. extracted. Phase once more with 30 ml of toluene. The united org. Phases were washed neutral twice with 30 ml of water, dried over sodium sulfate and concentrated at 50 ° C. under vacuum, the product crystallizing. The solid was dried at 50 ° C under vacuum to constant weight.
Yield: 2.30 g (82% of theory)
R _f = 0.25 (Cy: EE 9: 1).

Example XI

5- (tert-Butyldimethylsilyloxy) -7,7-dimethyl-4- (4-fluorophenyl) -2-isopropyl-5,6,7,8-tetra hydro-naphthalene-3-carbaldehyde

2.32 g of the compound from Ex. X are dissolved in dichloromethane under argon, 6.13 ml of DMSO and 3.52 ml of triethylamine are added and the mixture is cooled to 5 ° C. Then 3.23 g of sulfur trioxide-pyridine complex within 10 min. Entered in small portions at 5-10 ° C and stirred for 1 h. For working up, 12 ml of water are stirred in and the phases are separated. Then the org. Phase washed twice more with 12 ml of water each, dried over sodium sulfate and concentrated under vacuum at 50 ° C to about 3 ml. The product crystallizes out by rubbing and cooling, and the crystal slurry is now completely concentrated and dried under vacuum (0.2 mb) at room temperature to constant weight.
Yield: 2.28 g (79% of theory)
R _f = 0.57 (Cy: EE 9: 1).

Example XII

1- (4-Fluoro-phenyl) -6,6-dimethyl-8-oxo-3-pyrrolidin-1-yl-1,2,5,6,7,8-hexahydro-naphthalene-2-carboxylic acid, methyl ester

A solution of 1.69 g (10 mmol) of 3-pyrrolidin-1-yl-but-2-enoic acid methyl ester, 1.40 g (10 mmol) of dimedone and 1.24 g (10 mmol) of 4-fluorobenzaldehyde in 30 ml of cyclohexane is added overnight refluxed at the water separator. The mixture is cooled, the solvent is removed in vacuo and the residue is purified on silica gel 60 (elution with EtOAc / toluene 1: 4).
Yield: 0.90 g (23%)
R _f = 0.38 (EtOAc / toluene 1: 4).

Example XIII

1- (4-Fluoro-phenyl-3-hydroxy-6,6-dimethyl-8-oxo-1,4,5,6,7,8-hexahydro-naphthalene-2-carboxylic acid, methyl ester

A suspension of 13.0 g (32.7 mmol) of the compound from Example XII in 1100 ml sat. Citric acid solution is stirred at 60 ° C for 16 h. The mixture is allowed to cool and extracted with ethyl acetate (3 × 600 ml). After washing the combined organic phases with sat. NaCl solution and drying over Na ₂ SO ₄ gives a yellow residue, which is purified by flash filtration over 450 g of silica gel 60 with EtOAc / cyclohexane 1:20 to 20: 1.
Yield: 8.97 g (80%)
R _f = 0.32 (EtOAc / petroleum ether 1: 5).

Example XIV

1- (4-Fluorophenyl) -3-hydroxy-6,6-dimethyl-8-oxo-5,6,7,8-tetrahydro-naphthalene-2-carbonic acid methyl ester

A solution of 4.0 g (11.6 mmol) of the compound from Example XIII and 13.2 g (58.1 mmol) of DDQ in 400 ml of toluene is stirred at 80 ° C. for 24 h. The mixture is filtered through diatomaceous earth and washed with toluene. The filtrate is concentrated in vacuo and chromatographed over 300 g of silica gel 60 (CH ₂ Cl ₂ ).
Yield: 2.62 g (64%)
R _f = 0.35 (CH ₂ Cl ₂ ).

Example XV

1- (4-Fluoro-phenyl) -6,6-dimethyl-8-oxo-3-trifluoromethanesulfonyloxy-5,6,7,8-tetra hydro-naphthalene-2-carboxylic acid, methyl ester

4.66 g (16.5 mmol) of trifluoromethanesulfonic anhydride are added dropwise over 5 minutes to a solution of 3.14 g (9.17 mmol) of the compound from Example XIV in 20 ml of pyridine at 0 ° C. The mixture is allowed to warm to room temperature and stirred at this temperature for 16 h. The reaction mixture is poured onto ice water and extracted with EtOAc (3 ×). The combined organic phases are dried over Na ₂ SO _4, concentrated in vacuo and purified on 500 g of silica gel 60 (CH ₂ Cl ₂ ).
Yield: 3.43 g (79%)
R _f = 0.50 (CH ₂ Cl ₂ ).

Example XVI

3-Cyclopent-2-enyl-1- (4-fluorophenyl) -6,6-dimethyl-8-oxo-5,6,7,8-tetrahydro naphthalene-2-carboxylic acid, methyl ester

A mixture of 3.43 g (7.22 mmol) of the compound from Example 4, 1.24 g (2.16 mmol) of Pd (dba) ₂ , 1.29 g (3.24 mmol) of 1,2-bis (diphenylphosphino) is heated in a sealed autoclave. -ethane, 2.5 ml ethyldiisopropylamine, 6.4 ml cyclopentene and 65 ml dry toluene under a nitrogen atmosphere over 16 h at 100 ° C. It is filtered through a glass frit with a mixture of 5 g of silica gel 60 and 5 g of diatomaceous earth and concentrated. The crude product is chromatographed on 500 g of silica gel 60 (elution with CH ₂ Cl ₂ ).
Yield: 1.48 g (52%)
R _f = 0.36 (CH ₂ Cl ₂ ).

Example XVII

3-Cyclopentyl-1- (4-fluorophenyl) -6,6-dimethyl-8-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester

A mixture of 1.17 g (2.98 mmol) of the compound from Example XVI and 150 mg Pd / C (10%) in 80 ml EtOAc is hydrogenated for 5 h under a hydrogen atmosphere (1 atm). It is filtered through kieselguhr, concentrated and purified on silica gel 60 (EtOAc / petroleum ether 1:10).
Yield: 1.01 g (86%)
R _f = 0.23 (EtOAc / petroleum ether 1:10).

Example XVII

(8S) -3-Cyclopentyl-1- (4-fluorophenyl) -8-hydroxy-6,6-dimethyl-5,6,7,8-tetrahydro naphthalene-2-carboxylic acid, methyl ester

1.75 ml (3.5 mmol) of 2.0 M borane-dimethylsulfide solution in THF are added dropwise to a solution of 59 mg (0.40 mmol) of (1R, 2S) -aminoindanol in 8 ml of dry THF and the mixture is subsequently stirred at room temperature for 1 h. A solution of 783 mg (1.98 mmol) of the compound from Example XVII in 16 ml of dry THF is slowly added dropwise at 0-5 ° C. After 5 minutes, the mixture is allowed to warm to room temperature and stirred for 1 h. The reaction is stopped at 0 ° C. by adding 1.5 ml of methanol, water is added and the mixture is extracted with toluene. The combined organic phases are washed with sat. NaCl solution, dries with Na ₂ SO ₄ and concentrated. The crude product is chromatographed on 75 g of silica gel 60 (elution: EtOAc / petroleum ether / triethylamine 1: 10: 0.1).
Yield: 769 mg (97%), ee = 89.7% (Chiralcel AD, heptane / ethanol 90:10)
R _f = 0.33 (ether / petroleum ether 1: 5).

Example XIX

(8S) -8- (tert-Butyl-dimethyl-silanyloxy) -3-cyclopentyl-1- (4-fluorophenyl) -6,6-dimethyl-5,6,7,8-tetrahydro-naphthalene-2 -carboxylic acid methyl ester

A solution of 1.70 g (6.43 mmol) is added dropwise at -16 ° C. to a solution of 850 mg (2.14 mmol) of the compound from Example XVIII and 1.84 g (17.1 mmol) of 2,6-lutidine in 10 ml of dry toluene. tert-Butyl-dimethylsilyl triflate, stirred for 30 minutes at this temperature and for a further 30 minutes at 0 ° C. It is quenched with 5 ml of water and extracted with EtOAc. The combined organic phases are saturated with sat. NaHCO ₃ solution and sat. Washed NaCl solution, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product is purified on silica gel 60 (elution: EtOAc / cyclohexane / triethylamine 1: 10: 0.1).
Yield: 1.05 g (96%)
R _f = 0.63 (EtOAc / petroleum ether 1:10).

Example XX

(8S) - [8- (tert-Butyl-dimethyl-silanyloxy) -3-cyclopentyl-1- (4-fluorophenyl) -6,6-dimethyl-5,6,7,8-tetrahydro-naphthalene 2-yl] methanol

6.2 ml (9.28 mmol) of a 1.5 M solution of diisobutylaluminum hydride (DIBAH) in toluene are slowly added to a solution of 1.13 g (2.21 mmol) of the compound from Example XIX in 25 ml of dry toluene at -78 ° C. and the mixture is stirred 1 h at this temperature. After a further 30 minutes at -40 ° C, the mixture is allowed to warm to 0 ° C and hydrolyzed with 20 ml of a 20% K⁺ / Na⁺ tatrat solution. The mixture is filtered through diatomaceous earth and washed with EtOAc and water. After the aqueous phase has been separated off, it is re-extracted with EtOAc and the combined organic phases are washed with sat. Washed NaCl solution. It is dried over Na ₂ SO ₄ and concentrated. The raw product is directly implemented further.
Yield: 1.01 g (94%)
R _f = 0.42 (EtOAc / petroleum ether 1:10).

Example XXI

(8S) - (tert-Butyl-dimethyl-silanyloxy) -3-cyclopentyl-1- (4-fluorophenyl) -6,6-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-carbaldehyde

To a solution of 972 mg (2.01 mmol) of the compound from Example XX, 1.40 ml (10.1 mmol) of triethylamine and 2.5 ml of dimethyl sulfoxide in 10 ml of dry dichloromethane, 1.28 g (8.05 mmol) of sulfur trioxide-pyridine are added at 0 ° C. in an argon countercurrent -Complex in portions over 5 minutes. The mixture is stirred at 0-5 ° C. for 1 h, 20 ml of 5% NaHCO ₃ solution are added and the mixture is extracted with EtOAc. The combined organic phases are washed with 5% NaHCO ₃ solution and especially NaCl solution, dried over Na ₂ SO ₄ and concentrated. It is purified by flash chromatography on 100 g of silica gel 60 (elution: EtOAc / cyclohexane / triethylamine 1: 10: 0.1).
Yield: 840 mg (87%)
R _f = 0.60 (EtOAc / petroleum ether 1:10).

Manufacturing examples

Example 1 and Example 2

5- (tert-butyldimethylsilyloxy) -7,7-dimethyl-4- (4-fluorophenyl) -3- [hydroxy- (4-trifluoromethylphenyl) methyl] -2-isopropyl-5,6,7, 8-tetrahydronaphthalene

2.28 g of the compound from Ex. XI are dissolved in THF under argon and cooled to 5 ° C. Then 59.85 ml of a THF solution. The 3 eq 4-trifluoromethylphenyl magnesium bromide contains within 30 min. added dropwise at 5-10 ° C and stirred 1 h after. For working up, 30 ml of a sat. Ammonium chloride solution added dropwise, 10 min. stirred, then the mixture is stirred into a mixture of 500 ml of water and 250 ml of toluene, and the phases are separated. The aqueous phase was extracted again with 125 ml of toluene and the combined org. Phases washed twice with 125 ml of water until neutral, dried over sodium sulfate and at max. Concentrated 50 ° C under vacuum. The crude product was chromatographed on 250 g of silica gel 60 / 0.04-0.063 mm (column 5 × 25 cm) with cyclohexane / ethyl acetate 95: 5 and the main fractions were concentrated almost completely. The two diastereomers (diastereomers A and B) crystallize from the cyclo hexane residues after rubbing and cooling and are then dried in vacuo to constant weight.
Yield: 1.29 g of diastereomer A (52% of theory) (Example 1);
Yield: 1.01 g of diastereomer B (42% of theory) (Example 2);
R _f = 0.40 diastereomer A (Cy: EE 9: 1) (Example 1);
R _f = 0.33 diastereomer B (Cy: EE 9: 1) (Example 2).

Example 3

5- (tert-butyldimethylsilyloxy) -7,7-dimethyl-4- (4-fluorophenyl) -3- [fluoro- (4-trifluoromethylphenyl) methyl] -2-isopropyl-5,6,7, 8-tetrahydronaphthalene

Under argon, 0.8 g of the compound from Example XII (diastereomer B) is dissolved in toluene and cooled to -70 ° C. Then 0.26 ml of diethylamino sulfur trifluoride within 5 min. added dropwise and 60 min. stirred, allowing the internal temperature to rise to -60 ° C. For working up 5 ml of sat. Sodium bicarbonate solution. added dropwise, 10 min. stirred and the phases separated. The org. The phase was washed twice more with 5 ml of water until neutral, dried over sodium sulfate and concentrated at 50 ° C. under vacuum. The crude product crystallized, was dried to constant weight under vacuum and used in the next step without purification.
Yield: 0.78 g (83% of theory)
R _f = 0.65 (Cy: EE 9: 1).

Example 4 and Example 5

[1S, 7 (1RS)] - 1- (tert-butyldimethylsilanyloxy) -6-cyclopentyl-8- (4-fluorophenyl) -7- [hydroxy- (4-trifluoromethylphenyl) methyl] -3,3-dimethyl-1,2,3,4-tetrahydro naphthalene

To a solution of 830 mg (1.73 mmol) of the compound from Example XXII in 10 ml of dry THF, 33.5 ml of a 0.224 M solution of 4-trifluoromethyl-phenyl-magnesium bromide (prepared by refluxing 3.02 g.) Are added under argon at -25 ° C. Bromine-4-trifluoromethyl-benzene with 324 mg magnesium shavings in 60 ml dry THF) was added over 15 minutes. The mixture is stirred for 40 minutes at -20 ° C. and hydrolyzed at 0 ° C. by adding 20 ml of 5% NaHCO ₃ solution. The mixture is extracted with EtOAc and the combined organic phases are washed with 5% NaHCO ₃ solution and NaCl solution, dried over Na ₂ SO ₄ and concentrated. It is purified on 170 g of silica gel (elution EtOAc / petroleum ether / triethylamine 1: 10: 0.1).
Yield: 972 mg (90%) of a 1: 1 mixture of two diastereomers
R _f = 0.32 (diastereomer 1) (EtOAc / petroleum ether 1:10) (example 4) and
R _f = 0.24 (diastereomer 2) (EtOAc / petroleum ether 1:10). (Example 5).

Example 6

[1S, 7 (1RS)] - 1- (tert-butyldimethylsilanyloxy) -6-cyclopentyl-8- (4-fluorophenyl) -7- [fluoro- (4-trifluoromethylphenyl) methyl] -3,3-dimethyl-1,2,3,4-tetrahydro-naphthalene

407 mg (2.53 mmol) of DAST are added to a solution of 960 mg (1.53 mmol) of the compound from Examples 4 and 5 at -78 ° C. After 5 minutes, the mixture is allowed to warm to room temperature and stirred for a further 30 minutes. At 0 ° C is hydrolyzed with 15 ml of a 5% NaHCO ₃ solution. The mixture is extracted with EtOAc, the combined organic phases are washed with sat. NaCl solution, dries over Na ₂ SO ₄ and concentrated. The product is then purified on silica gel 60 (elution: EtOAc / petroleum ether / triethylamine 1: 20: 0.1).
Yield: 874 mg (91%) of a 1: 1 mixture of two diastereomers
R _f = 0.68 (EtOAc / petroleum ether 1:20).

Example 7

7,7-dimethyl-4- (4-fluorophenyl] -3- [fluoro- (4-trifluoromethylphenyl) methyl] -2-isopropyl-5,6,7,8-tetrahydronaphtaline-5-ol

At room temperature, 778 mg of the compound from Example XI are dissolved in 12.9 ml of THF and 12.9 ml of 1 molar tetrabutylammonium fluoride solution. within 5 min. added dropwise, and stirred for 3 h. The reaction solution was worked up. stirred into a mixture of 130 ml of water and 65 ml of toluene and the aq. Phase extracted again with 30 ml of toluene. The united org. Phases were washed twice with 30 ml of water, dried over sodium sulfate and under vacuum at max. Concentrated at 50 ° C. The crude product was chromatographed on 90 g of silica gel 60 / 0.04-0.063 mm (column 3 × 25 cm) with cyclohexane / diethyl ether 90:10, the main fraction was concentrated and crystallized from cyclohexane.
Yield: 0.45 g (66% of theory)
R _f = 0.27 (Cy: EE 9: 1).

Example 8 and Example 9

[1S, 7 (1S)] - 6-cyclopentyl-8- (4-fluorophenyl) -7- [fluoro- (4-trifluoromethyl-phenyl) methyl] -3,3-dimethyl-1,2, 3,4-tetrahydro-naphthalene-1-ol

A solution of 865 mg (1.38 mmol) of the compound from Example XXIII in 30 ml of THF is mixed with 12.5 ml of a 1.1 M solution of tetrabutylammonium fluoride in THF and stirred at room temperature for 16 h. Water is added and the mixture is extracted with EtOAc. The combined organic phases are saturated with sat. Wash the NaCl solution, dry over Na ₂ SO ₄ and concentrate. The diastereomers are separated on 140 g of silica gel 60 (elution: toluene / cyclohexane 8: 2).

Example 8

Yield: 236 mg (33%) diastereomer 2 (title compound, R _f = 0.38, toluene / cyclohexane 8: 2).

Example 9

Yield: 77 mg (11%) diastereomer 1 (R _f = 0.29, toluene / cyclohexane 8: 2).

In analogy to the manufacturing instructions shown, the table 1 Connections listed:

Table 1

Claims (10)

1. Substituted tetrahydro-naphthalenes of the general formula (I),
in which
A represents cycloalkyl having 3 to 8 carbon atoms or
represents aryl having 6 to 10 carbon atoms, or
represents a 5- to 7-membered, saturated, partially unsaturated or unsaturated, optionally benzocondensed heterocycle having up to 4 carbon atoms from the series S, N and / or O,
where aryl and the heterocyclic ring systems listed above, if appropriate, up to 5 times the same or different by cyano, halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy, each with up to 7 carbon atoms, or substituted by a group of the formula -NR ³ R ⁴ ,
wherein
R ³ and R ^{4 are the} same or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms
D for a residue of the formula
R ⁵ -L-,
or
R ⁹ -TVX-
stands,
wherein
R ⁵ , R ⁶ and R ⁹ independently of one another are cycloalkyl having 3 to 6 carbon atoms, or
Aryl having 6 to 10 carbon atoms or a 5- to 7-membered, optionally benzocondensed, saturated or unsaturated, mono-, bi- or tricyclic heterocycle having up to 4 heteroatoms from the series S, N and / or O,
where the cycles optionally, in the case of the nitrogen-containing rings also via the N function, up to 5 times the same or different by halogen, trifluoromethyl, nitro, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, Alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, aryl or trifluoromethyl-substituted aryl each having 6 to 10 carbon atoms or an optionally benzo-fused aromatic 5- to 7-membered heterocycle having up to 3 heteroatoms from the series S, N and / or O substituted are,
and / or are substituted by a group of the formula -OR ¹⁰ , -SR ¹¹ , -SO ₂ R ¹² or -NR ¹³ R ¹⁴ ,
wherein
R ¹⁰ R ¹¹ and R ¹² independently of one another are aryl having 6 to 10 carbon atoms, which in turn is substituted up to twice the same or different by phenyl, halogen or by straight-chain or branched alkyl having up to 6 carbon atoms,
R ¹³ and R ^{14 are the} same or different and have the meaning of R ³ and R ⁴ given above,
or
R ⁵ and / or R ^{6 is} a radical of the formula
mean,
R ^{7 represents} hydrogen, halogen or methyl,
and
R ^{8 is} hydrogen, halogen, azido, trifluoromethyl, hydroxy, trifluoromoxy, straight-chain or branched alkoxy or alkyl each having up to 6 carbon atoms or a radical of the formula -NR ¹⁵ R ¹⁶ ,
wherein
R ¹⁵ and R ^{16 are} identical or different and have the meaning of R ³ and R ⁴ given above,
or
R ⁷ and R ⁸ together form a radical of the formula = O or = NR ¹⁷ ,
wherein
R ¹⁷ denotes hydrogen or straight-chain or branched alkyl, alkoxy or acyl each having up to 6 carbon atoms,
L denotes a straight-chain or branched alkylene or alkenylene chain each having up to 8 carbon atoms, which are optionally substituted up to twice by hydroxy,
T and X are the same or different and represent a straight-chain or branched alkylene chain with up to 8 carbon atoms,
or
T or X represents a bond,
V represents an oxygen or sulfur atom or an -NR ¹⁸ group,
wherein
R ¹⁸ denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,
E represents cycloalkyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or hydroxy, or represents phenyl which is optionally substituted by halogen or trifluoromethyl is substituted,
R ¹ and R ² together form a straight-chain or branched alkylene chain with up to 7 carbon atoms, which is represented by a carbonyl group and / or by a radical of the formula
must be substituted
wherein
a and b are the same or different and represent a number 1, 2 or 3,
R ^{19 is} hydrogen, cycloalkyl having 3 to 7 carbon atoms, straight-chain or branched silylalkyl having up to 8 carbon atoms or straight-chain or branched alkyl having up to 8 carbon atoms, which may be by hydroxyl, straight-chain or branched alkoxy having up to 6 carbon atoms or is substituted by phenyl, which in turn can be substituted by halogen, nitro, trifluoromethyl, trifluoromethoxy or phenyl substituted by phenyl or tetrazole,
and alkyl is optionally substituted by a group of the formula -OR ²² ,
wherein
R ²² denotes straight-chain or branched acyl with up to 4 carbon atoms or benzyl,
or
R ¹⁹ straight-chain or branched acyl with up to 20 carbon atoms or benzoyl means that this is optionally substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or straight-chain or branched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,
R ²⁰ and R ² , which are the same or different, denote hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,
or
R ²⁰ and R ²¹ together form a 3 to 6-membered carbocycle,
and, optionally also geminal, the carbocycles formed, if appropriate up to 6 times, identically or differently, by trifluoromethyl, hydroxyl, nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy each having 3 to 7 carbon atoms, by straight-chain or branched alkoxycarbonyl, Alkoxy or alkylthio, each having up to 6 carbon atoms or substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which in turn is up to 2 times the same or different by hydroxyl, benzyloxy, trifluoromethyl, benzoyl, straight-chain or branched alkoxy, oxyacyl or carboxyl, each with up to 4 carbon atoms and / or phenyl is substituted, which in turn can be substituted by halogen, trifluoromethyl or trifluoromethoxy,
and / or the carbocycles formed are also geminal, optionally up to 5-fold identical or different substituted by phenyl, benzoyl, thiophenyl or sulfonylbenzyl, which in turn are optionally substituted by halo, trifluoromethyl, trifluoromethoxy or nitro,
and / or optionally by a radical of the formula
-SO ₂ -C ₆ H ₅ , - (CO) _d -NR ²³ R ²⁴ or = O
are substituted,
wherein
c represents a number 1, 2, 3 or 4,
d represents a number 0 or 1,
R ²³ and R ^{24 are the} same or different and are hydrogen, cycloalkyl having 3 to 6 carbon atoms, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, which may optionally be identical or different up to 2 times by halogen, trifluoromethyl, cyano, Phenyl or nitro is substituted,
and / or the carbocycles formed, if appropriate by a spiro-linked radical of the formula
are substituted,
wherein
W represents either an oxygen or a sulfur atom,
Y and Y 'together form a 2- to 6-membered straight-chain or branched alkylene chain,
e represents a number 1, 2, 3, 4, 5, 6 or 7,
f represents a number 1 or 2,
R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ and R ^{31 are the} same or different and are hydrogen, trifluoromethyl, phenyl, halogen or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
or
R ²⁵ and R ²⁶ or R ²⁷ and R ²⁸ each together form a straight-chain or branched alkyl chain with up to 6 carbon atoms,
or
R ²⁵ and R ²⁶ or R ²⁷ and R ²⁸ each together represent a radical of the formula
form,
wherein
W has the meaning given above,
g represents a number 1, 2, 3, 4, 5, 6 or 7,
R ³² and R ³³ together form a 3- to 7-membered heterocycle which contains an oxygen or sulfur atom or a group of the formula SO, SO ₂ or -NR ³⁴ ,
wherein
R ³⁴ denotes hydrogen, phenyl, benzyl or straight-chain or branched alkyl having up to 4 carbon atoms,
and their salts. 2. Substituted tetrahydro-naphthalenes of the formula according to claim 1, in which
A represents cyclopentyl or cyclohexyl, or
represents naphthyl, phenyl, pyridyl, thienyl, imidazolyl, pyrryl or morpholine, which may optionally be up to 2 times identical or different by fluorine, chlorine, bromine, amino, hydroxy, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl, or alkoxy, each with up to 6 carbon atoms are substituted,
D for a residue of the formula
R ⁵ -L-,
or
R ⁹ -TVX-
stands,
wherein
R ⁵ , R ⁶ and R ⁹ independently of one another are cyclopropyl, cyclopentyl or cyclohexyl, or
Phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl, where the cycles, optionally up to Triple in the case of nitrogen-containing rings also via the N function, identical or different by fluorine, chlorine, bromine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxy carbonyl, each having up to 4 carbon atoms, triazolyl, tetrazolyl, benzoxathiazolyl, or trifluoromethyl-substituted phenyl or phenyl,
and / or are substituted by a group of the formula -OR ¹⁰ , -SR ¹¹ or -SO ₂ R ¹² ,
wherein
R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are phenyl, which in turn is substituted up to 2 times the same or different by phenyl, fluorine, chlorine or by straight-chain or branched alkyl having up to 4 carbon atoms,
or
R ⁵ and / or R ^{6 is} a radical of the formula
mean,
R ⁷ denotes hydrogen, fluorine, chlorine or bromine,
and
R ^{8 is} hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkyl each having up to 5 carbon atoms or a radical of the formula -NR ¹⁵ R ¹⁶ ,
wherein
R ¹⁵ and R ^{16 are} identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms,
or
R ⁷ and R ⁸ together form a radical of the formula = O or = NR ¹⁷ ,
wherein
R ¹⁷ denotes hydrogen or straight-chain or branched alkyl, alkoxy or acyl each having up to 4 carbon atoms,
L denotes a straight-chain or branched alkylene or alkenylene chain each having up to 6 carbon atoms, which are optionally substituted up to twice by hydroxy,
T and X are identical or different and represent a straight-chain or branched alkylene chain with up to 6 carbon atoms,
or
T or X represents a bond,
V represents an oxygen or sulfur atom or a group of the formula -NR ¹⁸ -,
wherein
R ¹⁸ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or phenyl,
E stands for cyclopropyl, butyl, pentyl, hexyl or heptyl, or for straight-chain or branched alkyl having up to 6 carbon atoms, optionally by cyclopropyl, butyl, hexyl, pentyl, heptyl or by hydroxy is substituted, or represents phenyl which is optionally substituted by fluorine, chlorine or trifluoromethyl,
R ¹ and R ² together form a straight-chain or branched alkylene chain with up to 6 carbon atoms, which is represented by a carboxyl group and / or by a radical of the formula
must be substituted
wherein
b represents a number 1, 2 or 3,
R ^{19 is} hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, straight-chain or branched silylalkyl having up to 7 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl, straight-chain or branched alkoxy having up to 4 carbon atoms or by phenyl which in turn can be substituted by fluorine, chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy or phenyl substituted by phenyl or tetrazole,
and alkyl is optionally substituted by a group of the formula -OR ²² ,
wherein
R ²² denotes straight-chain or branched acyl with up to 3 carbon atoms or benzyl,
or
R ¹⁹ denotes straight-chain or branched acyl with up to 18 carbon atoms or benzoyl, which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or trifluoromethoxy, or
straight-chain or branched fluoroacyl with up to 6 carbon atoms means
R ²⁰ and R ^{21 are the} same or different, are hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms,
or
R ²⁰ and R ²¹ together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring,
and the carbocycles formed optionally up to 5 times the same or different, optionally also geminal, by trifluoromethyl, hydroxy, carboxyl, azido, fluorine, chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy , are substituted by straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio each having up to about 5 carbon atoms or straight-chain or branched alkyl having up to 5 carbon atoms, which in turn is up to 2 times the same or different by hydroxyl, benzyloxy, benzoyl, straight-chain or branched alkoxy or Oxyacyl is substituted with up to 3 carbon atoms, trifluoromethyl and / or phenyl, which in turn can be substituted by fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy,
and / or the carbocycles formed, also geminal, optionally up to 4-fold identical or different substituted by phenyl, benzoyl, thiophenyl or sulfonylbenzyl, which in turn are optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or nitro,
and / or optionally by a radical of the formula
-SO ₂ -C ₆ H ₅ , - (CO) _d -NR ²³ R ²⁴ or = O
are substituted,
wherein
c represents a number 1 2 3 or 4,
d represents a number 0 or 1,
R ²³ and R ^{24 are the} same or different and are hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, straight-chain or branched alkyl having up to 5 carbon atoms, benzyl or phenyl, which is optionally substituted by fluorine, chlorine, bromine, phenyl or trifluoromethyl ,
and / or the carbocycles formed, optionally by a spiro-linked radical of the formula
are substituted,
wherein
W represents either an oxygen or a sulfur atom,
Y and Y 'together form a 2- to 5-membered straight-chain or branched alkyl chain,
e represents a number 1, 2, 3, 4, 5 or 6,
f represents a number 1 or 2,
R ²⁵ , R ²⁶ , R ²⁷ and R ^{28 are the} same or different and are hydrogen trifluoromethyl, phenyl, fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms,
or
R ²⁵ and R ²⁶ or R ²⁷ and R ²⁸ each together form a straight-chain or branched alkyl chain with up to 5 carbon atoms or
R ²⁵ and R ²⁶ or R ²⁷ and R ²⁸ each together represent a radical of the formula
form,
wherein
W has the meaning given above,
g represents a number 1 2 3 4 5 or 6,
R ³² and R ³³ together form a 5- to 6-membered heterocycle which contains an oxygen or sulfur atom or a group of the formula NH or NCH ₃ ,
and their salts. 3. Substituted tetrahydro-naphthalenes of the formula according to claim 1, in which
A represents phenyl, pyridyl or thienyl, which are optionally substituted up to twice in the same or different manner by fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms,
D for a residue of the formula
or
R ⁹ -TVX-
stands,
wherein
R ⁶ and R ⁹ independently of one another are cyclopropyl, cyclopentyl or cyclohexyl, or
Phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8-yl mean
the cycles, optionally up to 3 times, in the case of nitrogen-containing rings also via the N function, the same or different by fluorine, chlorine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched alkyl, alkylthio, Alkylalkoxy, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, triazolyl, tetrazolyl, benzothiazolyl, trifluoromethyl substituted phenyl or phenyl and / or substituted by a group of the formula -OR ¹⁰ , -SR ¹¹ or -SO ₂ R ¹² ,
wherein
R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are phenyl, which in turn is substituted up to 2 times the same or different by phenyl, fluorine, chlorine or by straight-chain or branched alkyl having up to 3 carbon atoms,
or
R ^{6 is} a radical of the formula
means
R ^{7 represents} hydrogen or fluorine,
and
R ^{8 is} hydrogen, fluorine, chlorine, azido, trifluoromethyl, hydroxy, trifluoromethoxy or straight-chain or branched alkoxy or alkyl each having up to 4 carbon atoms or a radical of the formula -NR ¹⁵ R ¹⁶ ,
wherein
R ¹⁵ and R ^{16 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
or
R ⁷ and R ⁸ together form a radical of the formula = O or = NR ¹⁷ ,
wherein
R ¹⁷ denotes hydrogen or straight-chain or branched alkyl, alkoxy or acyl each having up to 4 carbon atoms,
L denotes a straight-chain or branched alkylene or alkenylene chain each having up to 5 carbon atoms, which are optionally substituted up to twice by hydroxy,
T and X are the same or different and represent a straight-chain or branched alkylene chain with up to 3 carbon atoms,
or
T or X represents a bond,
V represents an oxygen or sulfur atom or a group of the formula -NR ¹⁸ ,
wherein
R ¹⁸ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
E represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl, which is optionally substituted by fluorine or trifluoromethyl, or
represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxy,
R ¹ and R ² together form a straight-chain or branched alkylene chain with up to 5 carbon atoms, which is represented by a carbonyl group and / or a radical of the formula
must be substituted
wherein
R ^{19 is} hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, straight-chain or branched silylalkyl having up to 6 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which may be by hydroxyl, straight-chain or branched alkoxy having up to 3 carbon atoms or by phenyl is substituted, which in turn can be substituted by fluorine, chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy or phenyl substituted by phenyl or tetrazole,
and alkyl is optionally substituted by a group of the formula -OR ²² ,
wherein
R ²² denotes straight-chain or branched acyl with up to 3 carbon atoms or benzyl,
or
R ¹⁹ denotes straight-chain or branched acyl with up to 15 carbon atoms or benzoyl, which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or trifluoromethoxy, or
straight-chain or branched fluoroacyl with up to 4 carbon atoms means
and the carbocycles formed optionally up to 4 times the same or different, optionally also geminal, by fluorine, hydroxyl, trifluoromethyl, carboxyl, azido, chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, are substituted by straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio, each having up to 4 carbon atoms or straight-chain or branched alkyl, each having up to 4 carbon atoms, which in turn is up to 2 times the same or different by hydroxyl, benzyloxy, trifluoromethyl, benzoyl, methoxy, oxyacetyl and / or phenyl, which in turn can be substituted by fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy,
and / or the carbocycles formed, also geminal, optionally up to 4 times the same or different, are substituted by phenyl, benzoyl, thiophenyl or sulfonylbenzyl, which in turn are optionally substituted by fluorine, trifluoromethyl, trifluoromethoxy or nitro,
and / or optionally by a radical of the formula
-SO ₂ -C ₆ H ₅ , - (CO) _d -NR ²³ R ²⁴ or = O
are substituted,
wherein
c represents a number 1, 2, 3 or 4,
d represents a number 0 or 1,
R ²³ and R ^{24 are} identical or different and are hydrogen, cyclopropyl, cyclopentyl, benzyl, straight-chain or branched alkyl having up to 4 carbon atoms or phenyl which is optionally substituted by fluorine, chlorine or bromine,
and / or the carbocycles formed, optionally by a spiro-linked radical of the formula
are substituted,
wherein
W represents either an oxygen or a sulfur atom,
Y and Y 'together form a 2- to 6-membered straight-chain or branched alkylene chain,
e represents a number 1, 2, 3, 4 or 5,
f represents a number 1 or 2,
R ²⁵ , R ²⁶ , R ²⁷ and R ^{28 are the} same or different and are hydrogen, trifluoromethyl, phenyl, fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
or
R ²⁵ and R ²⁶ or R ²⁷ and R ²⁸ each together form a straight-chain or branched alkyl chain with up to 4 carbon atoms,
or
R ²⁵ and R ²⁶ or R ²⁷ and R ²⁸ each together represent a radical of the formula
form,
wherein
W has the meaning given above,
g represents a number 1, 2, 3, 4, 5, 6 or 7,
and their salts. 4. Substituted tetrahydro-naphthalenes according to Claims 1 to 3 as medicaments. 5. Process for the preparation of substituted tetrahydro-naphthalenes according to claim 1 to 3, characterized in that
[A] compounds of the general formula (II)
in which
A has the meaning given above,
R ³⁵ and R ^{36 are} identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{1 '} and R ^2' together represent the straight-chain or branched alkylene chain with up to 7 carbon atoms specified under R ¹ and R ² above, which is substituted by tert-butyl-dimethyl-silanyloxy (OTBS),
and
E 'and E "together with the carbon atom bound to them comprise the scope of E given above,
first by selective reduction of the aliphatic ester and subsequent reaction with compounds of the general formula (III)
R ³⁷ halogen (III)
in which
R ^{37 represents} mesyl, tosyl or sulfonyl,
and
Halogen is chlorine, bromine or iodine, preferably chlorine,
in inert solvents in the presence of a base,
into the compounds of the general formula (IV)
in which
A, E ', E'', R ^1' , R ^{2 '} , R ³⁵ and R ^{37 have} the meaning given above,
convicted,
in a further step depending on the above definitions of E '/ E''either by a double reduction or by saponification, Barton reaction and a reduction in the compounds of the general formula (V)
in which
A, E, R ^{1 '} and R ^{2' have} the meaning given above,
convicted,
then by oxidation into the aldehydes of the general formula (VI)
in which
A, E, R ^{1 '} and R ^{2' have} the meaning given above,
manufactures,
and finally introducing the residue D by a Grignard reaction and splitting off the TBS group using customary methods,
or
[B] Compounds of the general formula (VI)
in which
A, E, R ^{1 '} and R ^{2' have} the meaning given above,
initially as described under [A] in a Grignard reaction with compounds of the general formula (VII)
R ³⁸ -MgBr (VII)
in which
R ^{38 has} the meaning of R ⁵ and R ⁶ given above,
in inert solvents and under a protective gas atmosphere into the compounds of the general formula (VIII)
in which
A, D, E, R ³⁸ , R ^{1 '} and R ^{2' have} the meaning given above,
convicted,
optionally introducing the substituents R ⁷ / R ⁸ indicated under D at this stage, starting from the hydroxyl function, using customary methods,
and finally cleaves the TBS group with tetrabutylammonium fluoride in inert solvents,
or
[C] compounds of the general formula (IX)
in which
A, E, R ^{1 '} , R ^2' and R ^{38 have} the meaning given above
and
R ^{7 '} and R ^8' together represent the carbonyl group,
first reduced to the compounds of the general formula (VIII) and finally reacted as described under [A],
and separates in the case of the enantiomers / racemates by customary methods. 6. Medicament containing at least one substituted tetrahydro-naphtahlin Claims 1 to 3 and pharmacologically acceptable formulation auxiliaries. 7. Medicament according to claim 6 for the treatment of hyperlipoproteinemia. 8. Medicament according to claim 6 and 7 for the treatment of arteriosclerosis.   9. Use of substituted tetrahydro-naphthalenes according to Claims 1 to 3 for the manufacture of pharmaceuticals. 10. Use according to claim 9 for the manufacture of medicaments for treatment of arteriosclerosis, especially dyslipidemia.