JP2008534462A - 6,7,8,9-Tetrahydro-5-amino-5H-benzocyclohepten-6-ol derivatives and related compounds used as anti-inflammatory agents - Google Patents

Abstract

The present invention provides the following formula I: [wherein R ³ is an arbitrary group selected from _{1 to} 3 hydroxy groups, halogen atoms, or 1 to 3 (C ₁ -C ₅ ) -alkoxy groups. A C ₁ -C ₁₀ -alkyl group, an optionally substituted (C ₃ -C ₇ ) -cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, or other substitution Represents a group, A represents a —CR ⁶ R ⁷ —CH ₂ — group or —CH ₂ —CR ⁶ R ⁷ — group, and D represents a —CR ⁴ R ⁵ —CH ₂ — group or —CH ₂ —CR ⁴ represents a R ⁵ -group, R ⁴ represents a hydroxy group, an OR ¹⁰ group or an O (CO) R ¹⁰ group, R ⁵ represents a (C ₁ -C ₅ ) -alkyl group or optionally partially Or a fully fluorinated (C ₁ -C ₅ ) -alkyl group, (C ₃ -C ₇ ) cycloalkyl group, (C ₁ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, (C ₂ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl, heterocyclyl, (C ₁ -C ₈₎ heterocyclyl groups alkylene, (C ₂ -C ₈₎ alkenylene heterocyclyl group, an aryl group, (C ₁ -C ₈₎ alkylene aryl group, (C ₂ -C ₈₎ alkenylene aryl group, (C ₂ -C ₈₎ Represents an alkynylene aryl group or other substituent]] and relates to a polysubstituted 5H benzocycloheptene derivative. Said other substituents are specified in the claims. The invention also relates to a method for producing said derivatives and their use in anti-inflammatory agents.

Description

The present invention relates to 5H-benzocycloheptene derivatives, methods for their production and their use as anti-inflammatory agents.
Ring-opening non-steroidal anti-inflammatory agents are known from the prior art (WO 00/32584, DE 100 38 639 and WO 02/10143). In experiments, these compounds show a separation of action between anti-inflammatory and undesired metabolic effects and are superior or at least better than the non-steroidal glucocorticoids described so far Indicates.

However, obtaining non-steroidal anti-inflammatory drugs with improved profiles over prior art compounds, as prior art compounds do not necessarily have undesirable side effects or are not sufficiently selective. Is a further objective.
This object is achieved by the compounds of the invention described in the claims.

Accordingly, the present invention provides the following general formula (I):

[Wherein, R ¹ and R ² , independently of one another, are a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, an optionally substituted (C _1- C ₁₀ ) -alkoxy group, (C ₁ -C ₁₀ ) -alkylthio group, (C ₁ -C ₅ ) -perfluoroalkyl group, cyano group or nitro group, or
R ¹ and R ² together represent a group -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH-,-(CH ₂ ) _{n + 2-} , -NH- (CH ₂ ) _{n + 1-} , N (C ₁ -C ₃ -alkyl)-(CH ₂ ) _{n + 1} -and -NH-N = CH- (where n Is a group selected from 1 or 2, and the terminal atom is directly bonded to the adjacent ring-carbon atom, or NR ⁸ R ^9, where R ⁸ and R ⁹ are independent of each other Can be hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl),

R ¹¹ is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, (C ₁ -C ₁₀ ) -alkoxy group, (C ₁ -C ₁₀ ) -Alkylthio group or (C ₁ -C ₅ ) -perfluoroalkyl group,
R ¹² represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group or (C ₁ -C ₁₀ ) -alkoxy group,

R ³ is optionally substituted with a group selected from _{1 to} 3 hydroxy groups, halogen atoms, or 1 to 3 (C ₁ -C ₅ ) -alkoxy groups) C ₁ -C _10- An alkyl group, an optionally substituted (C ₃ -C ₇ ) -cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, ((C ₁ -C ₅ ) -alkyl group (1- They can optionally be substituted by 3 hydroxy groups or 1 to 3 COOR ¹⁰ groups, where R ¹⁰ represents any hydroxy protecting group, benzyl group or C ₁ -C ₁₀ -alkyl group Optionally substituted by one or more groups selected from (C ₁ -C ₅ ) -alkoxy groups, halogen atoms or exomethylene groups, and 1-3 nitrogen atoms and / or 1-2 Optionally containing oxygen atoms and / or 1 to 2 sulfur atoms and / or 1 to 2 keto groups Means a monocyclic or bicyclic heteroaryl group, wherein these groups can be attached to the 5H-benzocycloheptene-based amine through any position, and optionally one or more sites Can be hydrogenated at

A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group,
R ⁴ means a hydroxy group, an OR ¹⁰ group or an O (CO) R ¹⁰ group,

R ⁵ is a (C ₁ -C ₅ ) -alkyl group or an optionally partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group, (C ₃ -C ₇ ) cycloalkyl group, (C ₁ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, (C ₂ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, heterocyclyl group, (C ₁ -C ₈ ) alkylene Telocyclyl group, (C ₂ -C ₈ ) alkenylene heterocyclyl group, aryl group, (C ₁ -C ₈ ) alkylene aryl group, (C ₂ -C ₈ ) alkenylene aryl group, (C ₂ -C ₈ ) alkynylene aryl group (1-2 keto groups, 1-2 (C ₁ -C ₅ ) -alkyl groups, 1-2 (C ₁ -C ₅ ) -alkoxy groups, 1 to 3 halogen atoms, Or optionally substituted by 1 to 2 exomethylene groups and 1 to 3 nitrogen atoms and / or 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms The included) monocyclic or bicyclic heteroaryl group formulas; means (C ₁ -C ₈₎ alkyl heteroaryl, or (C ₂ -C ₈₎ heteroaryl group alkenylene, wherein these groups, 5H Can be attached to the benzocycloheptene system through any position and optionally hydrogenated at one or more sites;

R ⁶ and R ⁷ independently of one another represent a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a 5H-benzocycloheptene-based carbon atom]
It is related with the compound represented by these.

The subject of the present invention is
R ¹ and R ² are each independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, an optionally substituted (C ₁ -C ₁₀ ) — Means an alkoxy group, a (C ₁ -C ₁₀ ) -alkylthio group, a (C ₁ -C ₅ ) -perfluoroalkyl group, a cyano group or a nitro group, or
R ¹ and R ² together represent a group -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH-,-(CH ₂ ) _{n + 2-} , -NH- (CH ₂ ) _{n + 1-} , N (C ₁ -C ₃ -alkyl)-(CH ₂ ) _{n + 1} -and -NH-N = CH- (where n Is a group selected from 1 or 2, and the terminal atom is directly bonded to the adjacent ring-carbon atom, or NR ⁸ R ^9, where R ⁸ and R ⁹ are independent of each other Can be hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl),

R ¹¹ is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, (C ₁ -C ₁₀ ) -alkoxy group, (C ₁ -C ₁₀ ) -Alkylthio group or (C ₁ -C ₅ ) -perfluoroalkyl group,
R ¹² represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group or (C ₁ -C ₁₀ ) -alkoxy group,

R ³ is optionally substituted with a group selected from _{1 to} 3 hydroxy groups, halogen atoms, or 1 to 3 (C ₁ -C ₅ ) -alkoxy groups) C ₁ -C _10- An alkyl group, an optionally substituted (C ₃ -C ₇ ) -cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, ((C ₁ -C ₅ ) -alkyl group (1- They can optionally be substituted by 3 hydroxy groups or 1 to 3 COOR ¹⁰ groups, where R ¹⁰ represents any hydroxy protecting group, benzyl group or C ₁ -C ₁₀ -alkyl group Optionally substituted with one or more groups selected from (C ₁ -C ₅ ) -alkoxy groups, halogen atoms or exomethylene groups, and 1-3 nitrogen atoms and / or 1-2 Optionally oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 keto groups Means a monocyclic or bicyclic heteroaryl group, wherein these groups can be attached to the 5H-benzocycloheptene-based amine through any position, and optionally one or more Can be hydrogenated at the site of

A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group,
R ⁴ means a hydroxy group, an OR ¹⁰ group or an O (CO) R ¹⁰ group,

R ⁵ is a (C ₁ -C ₅ ) -alkyl group or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group, (C ₃ -C ₇ ) cycloalkyl group, (C ₁ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, (C ₂ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, heterocyclyl group, (C ₁ -C ₈ ) alkylene Telocyclyl group, (C ₂ -C ₈ ) alkenylene heterocyclyl group, aryl group, (C ₁ -C ₈ ) alkylene aryl group, (C ₂ -C ₈ ) alkenylene aryl group, (C ₂ -C ₈ ) alkynylene aryl group (1-2 keto groups, 1-2 (C ₁ -C ₅₎ - alkyl groups, 1-2 (C ₁ -C ₅₎ - alkoxy groups, 1-3 halogen atoms, Or optionally substituted with 1 to 2 exomethylene groups and 1 to 3 nitrogen atoms and / or 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms No) monocyclic or bicyclic heteroaryl group; means a (C ₁ -C ₈₎ alkyl heteroaryl, or (C ₂ -C ₈₎ heteroaryl group alkenylene, wherein these groups, 5H benzo Attached to the cycloheptene system through any position, and optionally hydrogenated at one or more sites;

R ⁶ and R ^7, independently of one another, represent a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a 5H-benzocycloheptene-based carbon atom, ) Stereoisomers.

R ¹ and R ² are each independently a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₁₀ ) -alkyl group, a (C ₁ -C ₁₀ ) -alkoxy group, or (C ₁ -C ₁₀ ) Means -alkylthio group, (C ₁ -C ₅ ) -perfluoroalkyl group, cyano group or nitro group, or
R ¹ and R ² together represent a group -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH-, or-(CH ₂ ) a group selected from _{n + 2-} (where n is 1 or 2 and the terminal atom is directly bonded to the adjacent ring-carbon atom), or NR ⁸ R ⁹ (where , R ⁸ and R ⁹ independently of one another represent hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl)

R ³ is a C ₁ -C ₁₀ -alkyl group (which may be substituted by a group selected from _{1 to} 3 hydroxy groups, halogen atoms, 1 to 3 (C ₁ -C ₅ ) -alkoxy groups), Optionally substituted phenyl or naphthyl group, (1-2 keto groups, 1-2 (C ₁ -C ₅ ) -alkyl groups, 1-2 (C ₁ -C ₅ ) -alkoxy Optionally substituted by a group, 1 to 3 halogen atoms, or 1 to 2 exomethylene groups, and 1 to 3 nitrogen atoms and / or 1 to 2 oxygen atoms and / or 1 to 2 Means a monocyclic or bicyclic heteroaryl group (containing a sulfur atom), wherein these groups can be attached to the benzocycloheptene-based amine through any position, and optionally 1 Or may be hydrogenated at multiple sites,

A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group,
R ⁴ represents a hydroxy group,

R ⁵ is a (C ₁ -C ₅ ) -alkyl group or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group, an aryl group, (C ₁ -C ₈ ) alkylene An aryl group, a (C ₂ -C ₈ ) alkenylene aryl group, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₁ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, or a (C ₂ -C) ₈₎ alkenylene (C ₃ -C ₇₎ means a cycloalkyl group,
R ⁶ and R ⁷ , independently of one another, denote a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a benzocycloheptene-based carbon atom,
The compounds of general formula (I) are a subgroup of the compounds of the invention.

R ¹ and R ² are each independently a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₁₀ ) -alkyl group, a (C ₁ -C ₁₀ ) -alkoxy group, or (C ₁ -C ₁₀ ) Means -alkylthio group, (C ₁ -C ₅ ) -perfluoroalkyl group, cyano group or nitro group, or
R ¹ and R ² together represent a group -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH-, and-(CH ₂ ) a group selected from _{n + 2-} (where n is 1 or 2 and the terminal atom is directly bonded to the adjacent ring-carbon atom), or NR ⁸ R ⁹ (where , R ⁸ and R ⁹ independently of one another represent hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl)

R ³ is a C ₁ -C ₁₀ -alkyl group (which may be substituted by a group selected from _{1 to} 3 hydroxy groups, halogen atoms, 1 to 3 (C ₁ -C ₅ ) -alkoxy groups), Optionally substituted phenyl group, (1-2 keto groups, 1-2 (C ₁ -C ₅ ) -alkyl groups, 1-2 (C ₁ -C ₅ ) -alkoxy groups, 1 Optionally substituted by ˜3 halogen atoms, or 1-2 exomethylene groups, and 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms Means a monocyclic or bicyclic heteroaryl group, wherein the group can be attached to the benzocycloheptene-based amine through any position, and optionally one or more Can be hydrogenated at the site,

A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group,
R ⁴ represents a hydroxy group,

R ⁵ is a (C ₁ -C ₅ ) -alkyl group or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group, aryl group, (C ₁ -C ₈ ) alkylene An aryl group, a (C ₂ -C ₈ ) alkenylene aryl group, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₁ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, or a (C ₂ -C) ₈₎ alkenylene (C ₃ -C ₇₎ means a cycloalkyl group,
R ⁶ and R ⁷ , independently of one another, denote a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a benzocycloheptene-based carbon atom,
Compounds of general formula (I) are preferred.

R ¹ and R ² are each independently a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₅ ) -alkyl group, a (C ₁ -C ₅ ) -alkoxy group, (C ₁ -C ₅ ) -Means a perfluoroalkyl group or a cyano group, or
R ¹ and R ² together represent a group -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH-, or-(CH ₂ ) means a group selected from _{n + 2-} (where n is 1 or 2 and the terminal atom is directly bonded to the adjacent ring-carbon atom);

R ³ is a C ₁ -C ₁₀ -alkyl group (optionally substituted with 1 to 3 hydroxy groups, halogen atoms), (C ₁ -C ₅ -alkyl, halogen, hydroxy or C ₁ -C _5- Optionally substituted by alkoxy, where the groups can be attached through any position to 5H-benzocycloheptene-based amines and 1-2 keto groups, 1-2 (C ₁ -C ₃ ) -alkyl group, 1 to 2 (C ₁ -C ₃ ) -alkoxy groups, 1 to 3 halogen atoms or 1 to 2 exomethylene groups, optionally at one or more positions Substituted, and optionally halogenated at one or more sites), phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinoli , Isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindononyl, dihydroisoindronyl, benzimidazolyl or indolyl group ,

A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group,
R ⁴ represents a hydroxy group,
R ⁵ means a (C ₁ -C ₅ ) -alkyl group, or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group,
R ⁶ and R ⁷ , independently of one another, denote a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a benzocycloheptene-based carbon atom,
The compounds of general formula (I) represent a specific subgroup.

R ¹ and R ² are each independently a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₅ ) -alkyl group, a (C ₁ -C ₅ ) -alkoxy group, (C ₁ -C ₅ ) -Means a perfluoroalkyl group or a cyano group, or
R ¹ and R ² together represent a group -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH-, and-(CH ₂ ) means a group selected from _{n + 2-} , where n is 1 or 2 and the terminal oxygen atom and / or carbon atom is directly bonded to the adjacent ring-carbon atom. ,

R ³ is a C ₁ -C ₁₀ -alkyl group (optionally substituted with 1 to 3 hydroxy groups, halogen atoms), (C ₁ -C ₅ -alkyl, halogen, hydroxy or C ₁ -C _5- Optionally substituted by alkoxy, where the groups can be attached through any position to 5H-benzocycloheptene-based amines and 1-2 keto groups, 1-2 (C ₁ -C ₃ ) -alkyl group, 1 to 2 (C ₁ -C ₃ ) -alkoxy groups, 1 to 3 halogen atoms or 1 to 2 exomethylene groups, optionally at one or more positions Substituted, and optionally hydrogenated at one or more sites), phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinyl, quinolinyl Means isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7 or 1,8-naphthyridinyl, dihydroindolo sulfonyl, dihydroisoquinoline indolocarbazole, cycloalkenyl, benzimidazolyl or indolyl group,

A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group,
R ⁴ represents a hydroxy group,
R ⁵ means a (C ₁ -C ₅ ) -alkyl group, or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group,
R ⁶ and R ⁷ , independently of one another, represent a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a benzocycloheptene-based carbon atom. The stereoisomer of (I) is another subject of the present invention.

R ¹ and R ² are each independently a hydrogen atom, hydroxy group, halogen atom, (C ₁ -C ₅ ) -alkyl group, (C ₁ -C ₅ ) -perfluoroalkyl group, cyano group, (C _1- C ₅ ) -alkoxy group, or together, means (C ₁ -C ₂ ) -alkylenedioxy group, and R ¹ and R ² should be directly adjacent;

R ³ is (optionally substituted by C ₁ -C ₅ -alkyl, halogen, hydroxy or C ₁ -C ₅ -alkoxy), phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoxyl. Nolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindronyl Means indolonyl, benzimidazolyl or indolyl groups, wherein these groups can be attached to the benzocycloheptene-based amines through any position and are 1 to 2 keto groups, 1 to 2 of (C ₁ -C ₃₎ - alkyl Group, a 1-2 exomethylene groups, optionally substituted with one or more positions, and 1 or obtained optionally is at multiple sites are hydrogenated,

A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group,
R ⁴ represents a hydroxy group,
R ⁵ means a (C ₁ -C ₅ ) -alkyl group, or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group,
R ⁶ and R ⁷ , independently of one another, represent a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a benzocycloheptene-based carbon atom. The stereoisomer (I) is particularly preferred.

R ¹ and R ² are each independently a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₁₀ ) -alkyl group, a (C ₁ -C ₁₀ ) -alkoxy group, or (C ₁ -C ₁₀ ) Means -alkylthio group, (C ₁ -C ₅ ) -perfluoroalkyl group, cyano group or nitro group, or
R ¹ and R ² together represent a group -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH-, or-(CH ₂ ) a group selected from _{n + 2-} (where n is 1 or 2 and the terminal atom is directly bonded to the adjacent ring-carbon atom), or NR ⁸ R ⁹ (where , R ⁸ and R ⁹ independently of one another represent hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl)
R ¹¹ and R ¹² represent a hydrogen atom,

R ³ is a C ₁ -C ₁₀ -alkyl group (which may be substituted by a group selected from _{1 to} 3 hydroxy groups, halogen atoms, 1 to 3 (C ₁ -C ₅ ) -alkoxy groups), Optionally substituted phenyl or naphthyl group, (1-2 keto groups, 1-2 (C ₁ -C ₅ ) -alkyl groups, 1-2 (C ₁ -C ₅ ) -alkoxy Optionally substituted by a group, 1 to 3 halogen atoms, or 1 to 2 exomethylene groups, and 1 to 3 nitrogen atoms and / or 1 to 2 oxygen atoms and / or 1 to 2 Means a monocyclic or bicyclic heteroaryl group (containing a sulfur atom), wherein these groups can be attached to the benzocycloheptene-based amine through any position, and optionally 1 Or may be hydrogenated at multiple sites,

A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group,
R ⁴ represents a hydroxy group,

R ⁵ is a (C ₁ -C ₅ ) -alkyl group or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group, aryl group, (C ₁ -C ₈ ) alkylene An aryl group, a (C ₂ -C ₈ ) alkenylene aryl group, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₁ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, or a (C ₂ -C) ₈₎ alkenylene (C ₃ -C ₇₎ means a cycloalkyl group,
R ⁶ and R ⁷ , independently of one another, represent a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a benzocycloheptene-based carbon atom. The compound (I) is the subject of the present invention.

R ¹ and R ² are each independently a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₁₀ ) -alkyl group, a (C ₁ -C ₁₀ ) -alkoxy group, or (C ₁ -C ₁₀ ) Means -alkylthio group, (C ₁ -C ₅ ) -perfluoroalkyl group, cyano group or nitro group, or
R ¹ and R ² together represent a group -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH-, and-(CH ₂ ) a group selected from _{n + 2-} (where n is 1 or 2 and the terminal atom is directly bonded to the adjacent ring-carbon atom), or NR ⁸ R ⁹ (where , R ⁸ and R ⁹ independently of one another represent hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl)
R ¹¹ and R ¹² represent a hydrogen atom,

R ³ is a C ₁ -C ₁₀ -alkyl group (which may be substituted by a group selected from _{1 to} 3 hydroxy groups, halogen atoms, 1 to 3 (C ₁ -C ₅ ) -alkoxy groups), Optionally substituted phenyl group, (1-2 keto groups, 1-2 (C ₁ -C ₅ ) -alkyl groups, 1-2 (C ₁ -C ₅ ) -alkoxy groups, 1 Optionally substituted by ˜3 halogen atoms, or 1-2 exomethylene groups, and 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms Means a monocyclic or bicyclic heteroaryl group, wherein the group can be attached to the benzocycloheptene-based amine through any position, and optionally one or more Can be hydrogenated at the site,

A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group;
R ⁴ represents a hydroxy group,
R ⁵ is a (C ₁ -C ₅ ) -alkyl group or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group, aryl group, (C ₁ -C ₈ ) alkylene An aryl group, a (C ₂ -C ₈ ) alkenylene aryl group, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₁ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, or a (C ₂ -C) ₈₎ alkenylene (C ₃ -C ₇₎ means a cycloalkyl group,

R ⁶ and R ⁷ , independently of one another, denote a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a benzocycloheptene-based carbon atom,
Stereoisomers of general formula (I) are preferred.

R ¹ and R ² are each independently a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₅ ) -alkyl group, a (C ₁ -C ₅ ) -alkoxy group, (C ₁ -C ₅ ) -Means a perfluoroalkyl group or a cyano group, or
R ¹ and R ² together represent a group -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH-, or-(CH ₂ ) means a group selected from _{n + 2-} (where n is 1 or 2 and the terminal atom is directly bonded to the adjacent ring-carbon atom);
R ¹¹ and R ¹² represent a hydrogen atom,

R ³ is a C ₁ -C ₁₀ -alkyl group (optionally substituted with 1 to 3 hydroxy groups, halogen atoms), (C ₁ -C ₅ -alkyl, halogen, hydroxy or C ₁ -C _5- Optionally substituted by alkoxy, where the groups can be attached through any position to 5H-benzocycloheptene-based amines and 1-2 keto groups, 1-2 (C ₁ -C ₃ ) -alkyl group, 1 to 2 (C ₁ -C ₃ ) -alkoxy groups, 1 to 3 halogen atoms or 1 to 2 exomethylene groups, optionally at one or more positions Substituted, and optionally hydrogenated at one or more sites), phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinyl, quinolinyl Means isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7 or 1,8-naphthyridinyl, dihydroindolo sulfonyl, dihydroisoquinoline indolocarbazole, cycloalkenyl, benzimidazolyl or indolyl group,

A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group,
R ⁴ represents a hydroxy group,
R ⁵ means a (C ₁ -C ₅ ) -alkyl group, or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group,
R ⁶ and R ⁷ , independently of one another, denote a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a benzocycloheptene-based carbon atom,
Stereoisomers of general formula (I) are a particular subject of the present invention.

R ¹ and R ² are each independently a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₅ ) -alkyl group, a (C ₁ -C ₅ ) -perfluoroalkyl group, a cyano group, or (C Means a ₁ -C ₅ ) -alkoxy group, or
R ¹ and R ² together represent a group -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH-, or-(CH ₂ ) means a group selected from _{n + 2-} (where n is 1 or 2 and the terminal atom is directly bonded to the adjacent ring-carbon atom);
R ¹¹ and R ¹² represent a hydrogen atom,

R ³ is (optionally substituted by C ₁ -C ₅ -alkyl, halogen, hydroxy or C ₁ -C ₅ -alkoxy), phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoxyl. Nolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindronyl Means indolonyl, benzimidazolyl or indolyl groups, wherein these groups can be attached to the benzocycloheptene-based amines through any position and are 1 to 2 keto groups, 1 to 2 of (C ₁ -C ₃₎ - alkyl Group, a 1-2 exomethylene groups, optionally substituted with one or more positions, and 1 or obtained optionally is at multiple sites are hydrogenated,

A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group,
R ⁴ represents a hydroxy group,
R ⁵ means a (C ₁ -C ₅ ) -alkyl group, or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group,
R ⁶ and R ⁷ , independently of one another, represent a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a benzocycloheptene-based carbon atom. The stereoisomer of (I) is preferred.

R ¹ and R ² are each independently a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₅ ) -alkyl group, a (C ₁ -C ₅ ) -perfluoroalkyl group, a cyano group, (C ₁ -C ₅₎ - alkoxy group, or together, (C ₁ -C ₂₎ - means alkylenedioxy group, and R ¹ and R ² should be directly adjacent,
R ¹¹ and R ¹² are hydrogen atoms,

R ³ is phenyl, furanyl, thienyl, pyrazolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, azaindridinyl, phthalidyl, thiofuraridyl , Indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, benzothiazolyl, indronyl, dihydroindolonyl, isoindolonyl, dihydroisoindolonyl, benzofuranyl, benzimidazolyl, indolizinyl, isobenzofuranyl, azaindolyl, azaisoin Drill, furanopyridyl, furanopyrimidinyl, furanopyrazinyl, furanopyridazini , Dihydrobenzofuranyl, dihydrofuranopyridyl, dihydrofuranopyrimidinyl, dihydrofuranopyrazinyl, dihydrofuranopyridazinyl, dihydrobenzofuranyl, coumarinyl, isocoumarinyl, dihydroisoquinolinyl, dihydroquinolinyl, benzoxazi Nonyl, phthalazinyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl group, tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidyl, tetrahydropyridyl, dihydro Pyridyl, 1H-pyridin-2-onyl, 1H-pyridine-4-onyl, 4-aminopyridyl, 1H-pyridin-4-ylidenaminyl, chromanyl, isochromanyl, chromeni , Isochromenyl, thiochromanyl, decahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, 5,6,7,8-tetrahydro-1H-quinolin-4-onyl, decahydroisoquinolinyl, tetrahydroisoquinolinyl , Dihydroisoquinolinyl, 3,4-dihydro-2H-benz [1,4] oxazinyl, 1,2-dihydro [1,3] benzoxazine-4-onyl, 3,4-dihydrobenz [1,4] Oxazine-4-onyl, 3,4-dihydro-2H-benzo [1,4] thiazinyl, 4H-benzo [1,4] thiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1H-cinnoline- 4-onyl, 3H-quinazoline-4-onyl, 1H-quinazoline-4-onyl, 3,4-dihydro-1H-quinoxalin-2-onyl, 2,3-1,2,3,4-tetra Hydro [1,5] naphthyridinyl, dihydro-1H- [1,5] naphthyridyl, 1H- [1,5] naphthylid-4-onyl, 5,6,7,8-tetrahydro-1H-naphthyridin-4-onyl, 1,2-dihydropyrido [3,2-d] [1,3] oxazine-4-onyl, octahydro-1H-indolyl, 2,3-dihydro-1H-indolyl, octahydro-2H-isoindolyl, 1,3-dihydro -2H-isoindolyl, 1,2-dihydroindazolyl, 1H-pyrrolo [2,3-b] pyridyl, 2,3-dihydro-1H-pyrrolo [2,3-b] pyridyl, or 2,2-dihydro -1H-pyrrolo [2,3-b] pyridin-3-onyl groups, where these groups can be attached to amines of the benzocycloheptene system through any position and 1-2 Of keto groups, 1-2 (C _1- C ₃₎ - alkyl group, a 1-2 exomethylene groups, optionally substituted with one or more positions, and 1 or obtained optionally is at multiple sites are hydrogenated,

A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group,
R ⁴ represents a hydroxy group,
R ⁵ means a (C ₁ -C ₅ ) -alkyl group, or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group,
R ⁶ and R ⁷ , independently of one another, represent a (C ₃ -C ₆ ) -cycloalkyl ring together with a hydrogen atom, a methyl or ethyl group, or a benzocycloheptene-based carbon atom. The stereoisomer is particularly preferred.

R ¹ and R ² are each independently a hydrogen atom, hydroxy group, halogen atom, (C ₁ -C ₅ ) -alkyl group, (C ₁ -C ₅ ) -perfluoroalkyl group, cyano group, (C _1- C ₅ ) -alkoxy group, or together, means a (C ₁ -C ₂ ) -alkylenedioxy group, and R ¹ and R ² should be directly adjacent;
R ¹¹ and R ¹² represent a hydrogen atom,

R ³ is (optionally substituted by C ₁ -C ₅ -alkyl, halogen, hydroxy or C ₁ -C ₅ -alkoxy), phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoxyl. Nolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindronyl Means indolonyl, benzimidazolyl or indolyl groups, wherein these groups can be attached to the benzocycloheptene-based amines through any position and are 1 to 2 keto groups, 1 to 2 of (C ₁ -C ₃₎ - alkyl Group, a 1-2 exomethylene groups, optionally substituted with one or more positions, and 1 or obtained optionally is at multiple sites are hydrogenated,

A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group,
R ⁴ represents a hydroxy group,
R ⁵ means a (C ₁ -C ₅ ) -alkyl group, or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group,
R ⁶ and R ⁷ , independently of one another, denote a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a benzocycloheptene-based carbon atom,
The stereoisomers of general formula (I) are particularly preferred.

R ¹ and R ² are each independently a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₃ ) -alkyl group, a (C ₁ -C ₃ ) -perfluoroalkyl group, a cyano group, or (C ₁ -C ₃₎ - means an alkoxy group,
R ¹¹ and R ¹² represent a hydrogen atom,

R ³ is (optionally substituted by C ₁ -C ₃ -alkyl, halogen, hydroxy or C ₁ -C ₃ -alkoxy), phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoxyl. Nolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindronyl Means indolonyl, benzimidazolyl or indolyl groups, wherein these groups can be attached to the benzocycloheptene-based amines through any position and are 1 to 2 keto groups, 1 to 2 of (C ₁ -C ₃₎ - alkyl Group, a 1-2 exomethylene groups, optionally substituted with one or more positions, and 1 or obtained optionally is at multiple sites are hydrogenated,

A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group,
R ⁴ represents a hydroxy group,
R ⁵ means a fully fluorinated (C ₁ -C ₃ ) -alkyl group,
R ⁶ and R ⁷ , independently of one another, denote a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a benzocycloheptene-based carbon atom,
The stereoisomers of general formula (I) are particularly preferred.

R ¹ and R ² each independently represent a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₃ ) -alkyl group, a CF ₃ group, a cyano group or a methoxy group,
R ¹¹ and R ¹² represent a hydrogen atom,

R ³ is optionally substituted by C ₁ -C ₃ -alkyl, halogen, hydroxy, C ₁ -C ₃ -alkoxy or methylpyrrolidin-on-5-yl) isoindolyl, dihydroindolyl, dihydroisoindolyl , Dihydroisoquinolinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinolonyl, isoquinolonyl, indazolyl, dihydroindolonyl, or dihydroisoindolonyl group, where these groups are benzocycloheptene based amines, Can be attached through any position and can be linked to one or more positions by 1-2 keto groups, 1-2 (C ₁ -C ₃ ) -alkyl groups, or 1-2 exomethylene groups Optionally substituted with and optionally hydrogenated at one or more sites,

A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group,
R ⁴ represents a hydroxy group,
R ⁵ means a fully fluorinated (C ₁ -C ₃ ) -alkyl group,
R ⁶ and R ⁷ independently of each other represent a hydrogen atom or a methyl or ethyl group,
The stereoisomers of general formula (I) are particularly preferred.

Groups C ₁ -C ₅ -alkyl, C ₁ -C ₅ -alkoxy, C ₁ -C ₅ -perfluoroalkyl, halogen, hydroxy, nitro, -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH-,-(CH ₂ ) _{n + 2-} , -NH- (CH ₂ ) _{n + 1} , N (C ₁ -C ₃ -alkyl)-(CH ₂ ) from _{n + 1} and —NH—N═CH—, where n is 1 or 2 and the terminal atom of the divalent substituent is bound directly to the adjacent ring-carbon atom. Compounds carrying selected 1 or 2 substituents on the 5H-benzocycloheptene-based aromatic ring are a particular subject of the present invention.

The compound of general formula I according to claim 1, wherein R ¹ and R ² independently of one another represent a hydrogen atom, a halogen atom or a cyano group, and R ¹¹ and R ¹² represent a hydrogen atom. It is a target.

R ¹ and R ² independently of each other represent a hydrogen atom, a halogen atom, or a cyano group,
R ¹¹ and R ¹² represent a hydrogen atom,
R ³ represents an indazolyl, dihydroindronyl or quinolinyl group (which may be optionally substituted by a halogen atom or methylpyrrolidin-2-one-5-yl);
A means -CH ₂ -CR ⁶ R ⁷ or CR ⁶ R ⁷ -CH _2-
D means -CH ₂ -CR ⁴ (R ⁵ )
R ⁴ represents a hydroxy group,
R ⁵ means a C ₁ -C ₃ -perfluoroalkyl group,
R ⁶ and R ⁷ represent a methyl or ethyl group,
Stereoisomers of general formula I are a further particularly preferred subject of the present invention.

R ¹ and R ² independently of each other represent a hydrogen atom, a bromine or chlorine atom, or a cyano group,
R ¹¹ and R ¹² represent a hydrogen atom,
R ³ means (optionally substituted by a bromine atom or methylpyrrolidin-2-one-5-yl), an indazolyl, dihydroindronyl or quinolonyl group;
A _{is, -CH 2 -C (CH 3)} 2 or C (CH ₃₎ -CH ₂ - means,
D means a _{-CH 2 -C (CF 3) (} OH),
R ⁴ represents a hydroxy group,
R ⁵ means a CF ₃ group,
R ⁶ and R ⁷ are particularly preferably compounds of the general formula I meaning a methyl group.

The following compounds,
1-bromo-6,7,8,9-tetrahydro-5-[(1H-indazol-4-yl) amino] -8,8-dimethyl-6- (trifluoromethyl) -5H-benzocycloheptene- 6-ol ,
4-{[1-Bromo-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino}- 1,3-dihydro-2H-indol-2-one and 4-{[1-bromo-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl)- 5H-benzocyclohepten-5-yl] amino} -7-bromo-1,3-dihydro-2H-indol-2-one ,
2-Chloro-6,7,8,9-tetrahydro-5- (1H-indazol-4-ylamino) -8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-6-ol ,
4-{[2-Chloro-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino}- 1,3-dihydro-2H-indol-2-one ,
6,7,8,9-Tetrahydro-6-hydroxy-8,8-dimethyl-5-{[7- (1-methyl-5-oxopyrrolidin-2-yl) -1H-indazol-4-yl] amino } -6- (trifluoromethyl) -5H-benzocycloheptene-2-carbonitrile ,
(5R * -cis) -5-{[6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] Amino} quinolin-2 (1H) -one ,
In particular (5R * -cis) -5-{[6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl Amino} quinolin-2 (1H) -one is particularly preferred.

R ¹ and R ² together represent a group -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH-,-(CH ₂ ) _{n + 2-} , -NH- (CH ₂ ) _{n + 1} , N (C ₁ -C ₃ -alkyl)-(CH ₂ ) _{n + 1} and -NH-N = CH- It is a subgroup.
Compounds in which the alkyl groups R ¹ and R ² have — (CH ₂ ) _{n + 2} — and thus together with the chain carbon atoms form a 5- to 6-membered ring are in another subgroup. To express.

R ³ is a C ₁ -C ₁₀ -alkyl group (optionally substituted with _{1 to} 3 hydroxy groups, halogen atoms, or 1 to 3 (C ₁ -C ₅ ) -alkoxy groups), optionally Substituted (C ₃ -C ₇ ) -cycloalkyl group, optionally substituted heterocyclyl group, ((C ₁ -C ₅ ) -alkyl group, (C ₁ -C ₅ ) -alkoxy group, halogen atom or exo Optionally substituted by one or more groups selected from methylene groups, and 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1- Means a monocyclic or bicyclic heteroaryl group (optionally containing two keto groups), wherein these groups can be attached to the 5H-benzocycloheptene-based amine through any position. , And optionally, can be hydrogenated at one or more sites. Compounds of general formula I of the mounting is another object of the present invention.

R ³ is a C ₁ -C ₁₀ -alkyl group (1 to 3 hydroxy groups, optionally substituted by a halogen atom), an optionally substituted phenyl group, (1 to 2 keto groups, 1 to 2 Optionally substituted by (C ₁ -C ₅ ) -alkyl groups, 1 to 2 (C ₁ -C ₅ ) -alkoxy groups, 1 to 3 halogen atoms, or 1 to 2 exomethylene groups. , And 1 to 3 nitrogen atoms and / or 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms). Are compounds of general formula I, which can be bonded to the nitrogen atom through any position and optionally hydrogenated at one or more sites, are another subject of the present invention.

R ³ optionally substituted phenyl or naphthyl group, phthalidyl, thiophthalidyl, benzoxazinonyl, phthalazinyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1 Another object is the compound of general formula I, which means 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group.

R ³ is a C ₁ -C ₁₀ -alkyl group (optionally substituted with ₁ to 3 hydroxy groups, halogen atoms), an optionally substituted phenyl group, phthalidyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, Means quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindronyl, dihydroisoindolonyl, benzimidazolyl or indolyl group The compounds of general formula I are a preferred subject of the present invention.

R ³ is indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, quinolonyl, isoquinolonyl, dihydroquinolonyl, dihydroisoquinolonyl, indazolyl, indronyl, Stereoisomers of the general formula I, meaning an isoindolonyl, dihydroindolonyl or dihydroisoindolonyl group, are another preferred subject of the present invention.
Particular preference is given to stereoisomers of the general formula I in which R ³ represents an indazolyl, dihydroindolonyl, dihydroisoindolonyl, quinolonyl or isoquinolonyl group.

Compounds of the general formula I meaning indazolyl, dihydroindolonyl and quinolonyl, wherein R ³ can be optionally substituted by a halogen atom or methylpyrrolidone are particularly preferred subjects of the invention.
The claimed group A is —CH ₂ —CR ⁶ R ⁷ — or —CR ⁶ R ⁷ —CH ₂ —, preferably —CH ₂ —C (CH ₃ ) ₂ or —C (CH ₃ ) ₂ —CH _2- , particularly preferably -CR ⁶ R ⁷ -CH ₂ , and more particularly preferably -C (CH ₃ ) ₂ -CH _2- .

The group D means a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group; a —CH ₂ —CR ⁴ (R ⁵ ) group is preferred; and —CH ₂ —C ( CF ₃ ) (OH) is particularly preferred.
Group _{^{-A-D-preferably, -CH 2 -CR 6 R 7 -CH}} 2 -CR 4 (R 5) -, - CR 6 R 7 -CH 2 -CH 2 -CR 4 (R 5) - and particularly preferably _{-CH 2 -C (CH 3) 2} -CH 2 -C (CF 3) (OH) - or _{-C (CH 3) 2 -CH 2} -CH 2 -C (CF 3) (OH) - Means.
The hydroxy group in R ⁴ is present in protected form and can particularly preferably be represented by one of the usual hydroxy protecting groups or as C ₁ -C ₅ ether or ester (CO) R ¹⁰ .
A hydroxy group is preferred as the group R ⁴ .

R ⁵ is a (C ₁ -C ₅ ) -alkyl group or an optionally partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group, (C ₃ -C ₇ ) cycloalkyl group, ( C ₁ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, (C ₂ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, heterocyclyl group, (C ₁ -C ₈ ) alkylene heterocyclyl Group, (C ₂ -C ₈ ) alkenylene heterocyclyl group, aryl group, (C ₁ -C ₈ ) alkylenearyl group, (C ₂ -C ₈ ) alkylenearyl group, or (C ₂ -C ₈ ) alkenylenearyl group Meaning, compounds of the general formula I are another subject of the present invention.

R ⁵ is a (C ₁ -C ₅ ) -alkyl group or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group, aryl group, (C ₁ -C ₈ ) alkylenearyl Group, (C ₂ -C ₈ ) alkenylene aryl group, (C ₃ -C ₇ ) cycloalkyl group, (C ₁ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, or (C ₂ -C ₈₎ The stereoisomers of general formula I, meaning alkenylene (C ₃ -C ₇ ) cycloalkyl radicals, are a particular subject of the present invention.

R ⁵ is a (C ₁ -C ₃ ) -alkyl group or optionally a partially or fully fluorinated (C ₁ -C ₃ ) -alkyl group, particularly preferably fully fluorinated (C ₁ Stereoisomers of the general formula I, which represent —C ₃ ) alkyl groups, or particularly preferably CF ₃ groups, are another subject of the present invention.
R ⁶ and R ⁷ , independently of one another, denote a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a 5H-benzocycloheptene-based carbon atom. A hydrogen atom or a methyl or ethyl group is preferred; a methyl or ethyl group is particularly preferred; and a methyl group is particularly preferred.
All combinations of groups disclosed in the examples are a particular subject of the present invention.

Definition :
C ₁ -C ₁₀ -or C ₁ -C ₅ -alkyl groups can be straight-chain or branched and are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl-, tert- Represents a butyl-, or n-pentyl-, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group. A methyl or ethyl group is preferred.
They can optionally be substituted by 1 to 3 hydroxy groups and / or 1 to 3 COOR ¹⁰ groups. A hydroxy group is preferred.

For partially or fully fluorinated (C ₁ -C ₅ ) -alkyl groups, the following partially or fully fluorinated groups are considered: fluoromethyl, difluoromethyl, trifluoromethyl , Fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl, and pentafluoroethyl. A trifluoromethyl or pentafluoroethyl group is preferred. Fully fluorinated alkyl groups are also referred to as perfluoroalkyl groups, as is known to those skilled in the art.

C ₁ -C ₁₀ -or C ₁ -C ₅ -alkoxy groups are linear or branched and are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy, or 3-methylbutoxy group is represented. A methoxy or ethoxy group is preferred.
C ₁ -C ₅ -alkylthio groups are straight-chain or branched and are methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, tert-butylthio or n-pentylthio, 2,2 -Represents a dimethylpropylthio, 2-methylbutylthio, or 3-methylbutylthio group. A methylthio or ethylthio group is preferred.

The term halogen atom or halogen means a fluorine, chlorine, bromine or iodine atom. A fluorine, chlorine or bromine atom is preferred.
The (C ₃ -C ₇ ) -cycloalkyl group is optionally a hydroxy group, a halogen atom (C ₁ -C ₅ ) -alkyl group, a (C ₁ -C ₅ ) -alkoxy group, an NR ⁸ R ⁹ group, COOR ¹⁰ groups, CHO, cyano, or substituted saturated cyclic groups having 3-7 ring-carbon atoms such as cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cyclo Defined by one or more groups selected from heptyl or methylcycloheptyl.

(C ₁ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl groups include, for example, — (CH ₂ ) cycloalkyl, — (C ₂ H ₄ ) -cycloalkyl, —C (C ₃ H ₆ ) -cyclo Alkyl, — (C ₄ H ₈ ) -cycloalkyl, (C ₅ H ₁₀ ) -cycloalkyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylenecyclohexyl or methylenecycloheptyl.

(C ₂ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl groups include, for example, — (CH═CH) -cycloalkyl, — [C (CH ₃ ) ═CH] -cycloalkyl, — [CH═C (CH ₃ )]-cycloalkyl,-(CH = CH-CH ₂ ) -cycloalkyl,-(CH ₂ -CH = CH) -cycloalkyl,-(CH = CH-CH ₂ -CH ₂ ) -cycloalkyl _{, - (CH 2 -CH = CH} -CH 2) - _{cycloalkyl, - (CH 2 -CH 2 -CH} = CH) - _{cycloalkyl, - (C (CH 3)} = CH-CH 2) - cycloalkyl, _{- (CH = C (CH 3} ) -CH 2) - means a cycloalkyl.

  The heterocyclyl group is a 5- to 7-membered non-aromatic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur as ring members, and at the same time, 1 or less oxygen or sulfur atoms. Exists as a ring member. It can be, for example, pyrrolidine, imidazolidine, pyrazolidine or piperidine.

An alkylene heterocyclyl group is defined as a heterocyclyl group attached to the backbone through a C ₁ -C ₈ -alkylene group, where the alkylene group can be straight or branched.
When the backbone is mentioned, it means a bicyclic bicycloheptene ring system of the general formula I.
An alkenylene heterocyclyl group is a heterocyclyl group attached to the backbone through an unsaturated C ₂ -C ₈ -alkylene group, where the alkylene group can be straight or branched.

In the present invention, an aryl group is an aromatic or partially aromatic carbocyclic of 6 to 14 carbon atoms having a ring such as phenyl or phenylene, or several fused rings such as naphthyl or anthranyl. It is a group. By way of illustration, mention may be made of phenyl, naphthyl, tetranyl, anthranyl, indanyl and indenyl.
Aryl groups can be any suitable group resulting from one or more groups from hydroxy, halogen, C ₁ -C ₅ -alkyl, C ₁ -C ₅ -alkoxy, cyano, CF ₃ or nitro groups to provide the appropriate compound. Can be substituted at the site.

As substituents, mention may be made, for example, of methoxy, ethoxy, propoxy, iso-propoxy, hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, iso-propyl or trifluoromethyl groups.
Optionally substituted phenyl and naphthyl groups are preferred.
An alkylenearyl group is an aryl group supplied to the ring system through a C ₁ -C ₈ -alkylene group, where the alkylene group is straight or branched, and optionally also some double Bonds can be carried.

An alkenylene aryl group is an aryl group bonded to the backbone through a C ₂ -C ₈ -alkenylene group, wherein the alkenylene group can be straight or branched.
An alkynylene aryl group is an aryl group bonded to the backbone through a C ₂ -C ₈ -alkynylene group, where the alkynylene group can be straight or branched.

  A monocyclic or bicyclic heteroaryl group that can be hydrogenated at one or more sites is any monocyclic or bicyclic aromatic ring system containing at least one heteroatom and at most 7 heteroatoms. Defined. A ring system having 1 to 5 heteroatoms is suitable. 1 to 4 nitrogens that can exist under all sub-combinations in the ring system as long as the heteroatoms do not exceed the number specified for each heteroatom and the combined maximum of 7 heteroatoms Atoms, 1-2 oxygen atoms and 1-2 sulfur atoms are suitable as heteroatoms; ring systems containing 1-3 nitrogen atoms and / or oxygen or sulfur atoms are particularly preferred.

For example, R ³ or R ⁵ is furanyl, thienyl, pyrazolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, azaindridinyl, phthalidyl , Thiofuraridyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, benzothiazolyl, indronyl, dihydroindolonyl, isoindronyl, dihydroisoindolonyl, benzofuranyl, benzimidazolyl, indolidinyl, isobenzofuranyl, azaindolyl, aza Isoindolyl, furanopyridyl, furanopyrimidinyl, furanopyrazinyl, furanopyridazi Dihydrobenzofuranyl, dihydrofuranopyridyl, dihydrofuranopyrimidinyl, dihydrofuranopyrazinyl, dihydrofuranopyridazinyl, dihydrobenzofuranyl, coumarinyl, isocoumarinyl, dihydroisoquinolinyl, dihydroquinolinyl, benzox Compounds of formula I meaning dinonyl, phthalazinyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl are part of the present invention and It represents a particular embodiment of the invention.

When the heteroaryl group is partially or fully hydrogenated, R ³ or R ⁵ is tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidyl, tetrahydropyridyl, dihydropyridyl, 1H-pyridin-2-onyl, 1H-pyridine-4-onyl, 4-aminopyridyl, 1H pyridine-4-onyl, 4-aminopyridyl, 1H pyridine-4-ylidenaminyl, chromanyl, isochromanyl, chromenyl, isochromenyl, thiochromanyl, decahydroquinolinyl, tetrahydroquinolinyl Nyl, dihydroquinolinyl, 5,6,7,8-tetrahydro-1H-quinolin-4-onyl, decahydroisoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl, 3,4-dihydro- 2H-Benz [1,4] oxazinyl, 1,2-dihydro [1,3] benzoxazi -4-onyl, 3,4-dihydrobenz [1,4] oxazin-4-onyl, 3,4-dihydro-2H-benzo [1,4] thiazinyl, 4H-benzo [1,4] thiazinyl, 1, 2,3,4-tetrahydroquinoxalinyl, 1H-cinnoline-4-onyl, 3H-quinazoline-4-onyl, 1H-quinazoline-4-onyl, 3,4-dihydro-1H-quinoxalin-2-onyl, 2,3-1,2,3,4-tetrahydro [1,5] naphthyridinyl, dihydro-1H- [1,5] naphthyridyl, 1H- [1,5] naphthylid-4-onyl, 5,6,7, 8-tetrahydro-1H-naphthyridine-4-onyl, 1,2-dihydropyrido [3,2-d] [1,3] oxazine-4-onyl, octahydro-1H-indolyl, 2,3-dihydro-1H-indolyl , Octahydro-2H-dihydro-1H-pyro [2,3-b] pyridyl, it means 2,2-dihydro -1H- pyrrolo [2,3-b] pyridine-3-onyl, compounds of formula I are part of the present invention.

The compounds according to the invention are also in the form of salts with physiologically compatible anions, for example hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoic acid It can also be present in the form of a salt, mesylate, citrate or oxalate.
Similar compounds that are metabolized in an organism to form a compound of general formula I according to claim 1 are part of the subject of the present invention.

  The compounds of the present invention are produced according to methods known in the prior art and then inorganic or organic acids or Lewis acids at temperatures ranging from −30 ° C. to + 80 ° C. to form compounds of general formula I Produced by an open-chain precursor of general formula II that is cyclized by adding an acid:

When a compound of general formula I [wherein R ¹ means a (C ₁ -C ₅ ) alkoxy group] is produced, a halogen compound is first produced, and then the halogen atom is known to those skilled in the art. In accordance with known methods, a substitution reaction on an aromatic compound can be substituted with a hydroxy group, which can optionally be converted to an alkoxy group according to methods known to those skilled in the art.
Compounds of general formula II are produced based on the meaning of A according to various methods:

I. Formation of a compound of general formula I (= compound of general formula Ia) in which A represents —CH ₂ — (CR ⁶ R ⁷ ) :
A compound of the general formula III (where LG means any leaving group known to those skilled in the art, eg chloride, bromide, iodide, sulfate or sulfonate, eg tosylate, mesylate) is an organic solvent, eg benzene Phase transfer catalysts with aldehydes of the general formula IV under basic conditions in toluene, for example aqueous NaOH or KOH, and commonly used phase transfer catalysts, for example quaternary ammonium salts, for example tetrabutylammonium iodide, benzyltrimethylammonium chloride Reacted below to form a compound of general formula V,

Next, the aldehyde V is reacted with a reagent VI (where R ^x means a (C ₁ -C ₃ ) -alkyl group or a benzyl group) under Horner-Wittig conditions, and the general formula VII After the ester has been saponified according to methods known to those skilled in the art,

The enol ether is decomposed under acidic conditions, such as glacial acetic acid / HOAc / H ₂ SO ₄ conditions, and the resulting α-keto acid is converted to the alcohol R ^y —OH (where R ^y Is esterified by (C ₁ -C ₅ ) -alkyl), reacted with Ruppert's reagent CF ₃ Si (CH ₃ ) ₃ , CF ₃ group is introduced,

The ester is reduced to form aldehyde X with a reducing agent such as diisobutylaluminum hydride (DIBAH = DIBAL) or lithium aluminum hydride (LAH = LiAlH ₄ ). The aldehyde is then reacted with an amine of the general formula R ³ —NH ₂ (R ³ has the meaning given in the claims) as already described in the prior art.

  The imine IIa thus obtained is then cyclized by the addition of Lewis acid at a temperature of -70 ° C to + 80 ° C (preferably in the range of -30 ° C to + 80 ° C) for up to 14 days. A compound of general formula Ia is formed.

II. Production of a compound of general formula I (= compound of general formula Ib ) in which A represents — (CR ⁶ R ⁷ ) —CH ₂ — :
A nitrile of the general formula XI is optionally continuously with sodium hydride and the corresponding alkyl halide R ⁶ -Hal and / or R ⁷ -Hal or Hal-[(C ₂ -C ₅ ) -alkylene] -Hal. Reacted to form a compound of general formula XII:

  The resulting compound of general formula XII is reduced under normal conditions with an inhibited hydride such as diisobutylaluminum hydride (DIBAH, DIBAL) to form an aldehyde,

And then, optionally with zinc addition, is reacted with CBr ₄ / triphenylphosphine to form a compound of general formula XIII:

Butyllithium converts the compound of general formula XIII to acetylene and CF _3- (CO) COOR ^y to ester XIV. The ester is hydrogenated according to methods known to those skilled in the art to form an ester of general formula VIIIb:

Then reduced analogously to Method I, an aldehyde is formed, reacted with an amine R ³ —NH ₂ to form an imine, and then cyclized to a compound of general formula Ib:

As the Lewis _{acid, BBr3, TiCl 4, Ti (} OR 3) 4, TiCl 2 (OR 3) 2, TiBr 2 (OR 3) 2, PdCl 4, Pd (OR 3) 4, PdCl 2 (OR 3) 2) , PdBr ₂ (OR ³ ) ₂ , ZnCl ₂ , ZnBr ₂ , AICl ₃ , AlBr ₃ , AIEtCl ₂ , Al Me ₂ Cl, Cu-salts such as Cu (OTf) ₂ , CuCl ₂ , CuBr ₂ , Yb (OTf) ₃ is appropriate.

When using chiral Lewis acids, the following Lewis acids are suitable: (R)-or (S) -SEGPHOS-PdCl ₂ (Mikami et al. Tetrah. Asymm. 2004, 15, 3885-89), (R)- Or (S) -BIN all-Ti (OiPr) ₂ (Ding etc. Tetrah. Lett. 2004, 45, 2009-12), (R)-or (S) -Cu ⁱ BuBOX,), (R)-or (S) -Cu ⁱ PrBOX, (R)-or (S) -Cu PhBOX, (R)-or (S)-Cu AdaBOX (Evans, etc. J. Am. Chem. Soc. 2000, 122, 7936-43 ), (R)-or (S) -Ph-pybox Sc (OTf) ₃ (Evans et al. J. Am. Chem. Soc. 2005, 127, 8006-7), (R)-or (S) ^-i Pr-pybox Yb (OTf) ₃ , (R)-or (S) ^-i Bu-pybox Yb (OTf) ₃ , (R)-or (S) -Ph-pybox Yb (OTf) ₃ (Qian etc. Asymm. 2000, 11, 2347-57).
The novel synthetic intermediate products cited are also the subject of the present invention.

The binding of substances to glucocorticoid receptor (GR) and other steroid hormone receptors (mineral corticoid receptor (MR), progesterone receptor (PR) and androgen receptor (AR)) is produced recombinantly. Tested with the help of different receptors. A cytosolic preparation of Sf9 cells infected with a recombinant baculovirus encoding GR is used for binding studies. Compared to the control substance [ ³ H] -dexamethasone, the substance shows a very high affinity for GR.

GR-mediated inhibition of transcription of cytokines, adhesion molecules, enzymes and other pro-inflammatory factors is regarded as an essential molecular mechanism for the anti-inflammatory action of glucocorticoids. This inhibition is generated by the interaction of GR with other transcription factors such as AP-1 and NF-κ-B (for an overview see Cato, ACB and Wade E, BioEssays 18,371-378 1996 ).
The compounds of general formula I according to the invention inhibit the secretion of cytokine IL-8 induced by lipopolysaccharide (LPS) in the human monocyte cell line THP-1. Cytokine concentrations were determined in the supernatant by a commercially available ELISA kit.

  The anti-inflammatory effect of the compounds of general formula I has been tested in animal experiments, with tests on haze oil-induced inflammation in rats and mice (J. Exp. Med. (1995), 182, 99-108). For this purpose, a haze oil solution in ethanol was administered locally to the animal's ear. Test substances were also administered locally or systemically at the same time as or after 2 hours of administration of the haze oil. After 16-24 hours, ear weight was measured as a dose for inflammatory edema, peroxidase activity as a dose for granulocyte infiltration, and elastase activity as a dose for neutrophil granulocyte infiltration. In this test, the compounds of general formula I inhibit three of the above inflammatory parameters after local and systemic and systemic administration.

  One of the most undesirable effects of glucocorticoid treatment is the so-called “steroid diabetes” (see Hatz, HJ, Glucocorticoide: Immun allogische Grundlagen, Pharmak all ogie und Therapierichtlinien, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998) . The reason for this is the stimulation of gluconeogenesis in the liver by induction of the enzymes responsible for this and by free amino acids produced from protein degradation (glucocorticoid catabolism). The key enzyme of catabolism in the liver is tyrosine aminotransferase (TAT). The activity of this enzyme is determined spectrophotometrically from liver homogenates and provides a good measure for the undesired metabolic effects of glucocorticoids. For measurement of TAT induction, animals are sacrificed 8 hours after administration of the test substance, the liver is removed, and TAT activity in the homogenate is measured. In this test, at doses where they have an anti-inflammatory effect, the compounds of general formula I induce no or an insignificant degree of tyrosine aminotransferase.

Based on their anti-inflammatory action and, in addition, anti-allergic immunosuppression and anti-proliferative action, the stereoisomers of general formula I according to the invention are for the treatment or prevention of the following pathological conditions in mammals and humans: Can be used as a medicament: in this case, the term “disease” refers to the following symptoms:
(I) Lung diseases associated with inflammation, allergies and / or proliferative processes:
-Chronic obstructive pulmonary disease of any origin, mainly bronchial asthma;
-Bronchitis of different origin;
-Adult Respiratory Syndrome (ARDS);
-Bronchiectasis;
-All forms of restrictive lung disease, mainly allergic alveolitis;
-All forms of pulmonary edema, mainly toxic pulmonary edema, eg radioactive pneumonia;
-Sarcoidosis and granulomatosis, especially Beck's disease;

(Ii) rheumatic diseases / autoimmune diseases / joint diseases associated with inflammation, allergies and / or proliferative processes:
-All forms of rheumatic disease, in particular rheumatoid arthritis, acute rheumatic fever, rheumatic polymyalgia;
-Reactive arthritis;
-Inflammatory parenchyma disease of other origins;
-Joint inflammation symptoms in the case of osteoarthritis (arthropathy);
-Traumatic arthritis;
-Vitiligo;
-Collagen disease of any origin, such as systemic extematodes, scleroderma, polymyositis, dermatomyositis, Sjogren's syndrome, Still's syndrome, Felty syndrome;
-Sarcosis and granulomatosis;
-Soft tissue rheumatism;

(Iii) Allergic or pseudoallergic diseases associated with inflammatory and / or proliferative processes:
-All forms of allergic reactions such as quinque edema, hay fever, insect bites, pharmaceutical agents, blood derivatives, contrast media, etc., hypersensitivity shock, urticaria, allergies and irritant contact dermatitis, allergies Vascular disease;
-Allergic vasculitis;

(Iv) Vascular inflammation (vasculitis):
-Panarteritis nodules, temporal arteritis, erythematous erythema;
-Nodular polyarteritis;
-Wege granulomatosis;
-Giant cell arthritis;

(V) Dermatological disorders associated with inflammation, allergies and / or proliferative processes:
-Atopic dermatitis (mainly in children);
-All forms of eczema, eg atopic eczema (mainly in children);
-A rash or dermatitis of any origin;
-Psoriasis and psoriasis groups;
-Pore red rash;
-Erythematous diseases induced by different toxicities such as radiation, chemicals, burns, etc .;
Bullous skin diseases such as autoimmune pemphigus vulgaris, bullous pemphigus-diseases of the lichenoid group;
-Itching (eg of allergic origin);
-Seborrheic edema;
-Shusa;
-Pemphigus vulgaris;
-Erythematous exudative polymorphs;
-Balanitis;
-Vulvitis;
-The development of vascular disease;
-Hair loss, eg alopecia area;
-Alopecia areata;
-Cutaneous T-cell lymphoma;
-Psoriasis;

(Vi) renal disease associated with inflammation, allergies and / or proliferative processes:
-Nephrotic syndrome;
-All nephritis, eg glomerulonephritis;
(Vii) Liver disease associated with inflammation, allergies and / or proliferative processes:
-Acute hepatocyte degradation;
-Different origins such as viruses, toxicity, pharmaceutical agents-induced acute hepatitis;
-Chronic aggressive hepatitis and / or chronic intermittent hepatitis;

(Viii) Gastrointestinal diseases associated with inflammation, allergies and / or proliferative processes:
-Localized enteritis (Crohn's disease);
-Ulcerative colitis;
-Gastritis;
-Reflux esophagitis;
-Ulcerative colitis of other origin, eg sprue origin;

(Ix) Rectal diseases attached by inflammation, allergy and / or proliferative processes:
-Anal edema;
-Cracks;
− 痔 痔;
-Idiopathic proctitis;

(X) Ocular diseases associated with inflammation, allergies and / or proliferative processes:
-Allergic keratitis, uveitis, iritis;
-Conjunctivitis;
-Blepharitis;
-Optic neuritis;
-Choroiditis;
-Sympathetic ophthalmitis;

(Xi) diseases of the ear-nose-throat region associated with inflammation, allergies and / or proliferative processes:
-Allergic rhinitis, hay fever;
-Otitis externa caused by contact dermatitis, infection, etc .;
-Otitis media;

(Xii) neurological diseases associated with inflammation, allergies and / or proliferative processes;
-Cerebral edema, mainly tumor-induced cerebral edema;
-Multiple sclerosis;
-Acute meningitis;
-Meningitis;
-Various forms of convulsions, such as infantile occipital convulsions;
-Acute spinal cord injury;
-Seizures;

(Xiii) blood diseases associated with inflammation, allergies and / or proliferative processes:
-Acquired hemolytic anemia;
-Idiopathic thrombocytopenia;

(Xiv) tumor diseases associated with inflammation, allergies and / or proliferation processes:
-Acute lymphoblastic leukemia;
-Malignant lymphoma;
-Lymphogranulomatosis;
-Lymphosarcoma;
-Intensive metastases mainly in breast, bronchial and prostate cancer;

(Xv) Endocrine diseases associated with inflammation, allergies and / or proliferative processes:
-Endocrine orbital disease;
-Thyroid crisis;
-De Kervan thyroiditis;
-Hashimoto thyroiditis;
-Basedow's disease;
-Endocrine eye disorders;
-Granulomatous thyroiditis;
-Lymph node-like goiter;
-Graves'disease;

(Xvi) organ and tissue transplantation, versus host graft disease;
(Xvii) Severe shock conditions such as hypersensitivity shock, systemic inflammatory response syndrome (SIRS);

(Xviii) Replacement therapy in:
Congenital-secondary adrenal insufficiency, eg congenital adrenal syndrome;
-Acquired-secondary adrenal dysfunction, such as Addison's disease, autoimmune adrenalitis, post-infectious tumor, metastasis, etc.
Congenital secondary adrenal insufficiency, eg congenital hypopituitarism;
-Acquired secondary adrenal insufficiency, eg after-infectious tumors, etc .:
(Xix) vomiting associated with inflammation, allergies and / or proliferative processes:
-In combination with a 5-HT3 antagonist in vomiting e.g. induced by cell growth inhibition;

(Xx) pain of inflammatory origin, eg back pain;
(Xxi) Various diseases.
Items (i), (ii), (iii), (v), (viii), (ix), (x), (xi), (xv), (xx), (xxi), especially (i), Local administration of the compounds of the invention for the treatment of the diseases indicated under (ii), (iii), (v), (x), (xi) and (xv) is preferred.

  Furthermore, the compounds of general formula I according to the invention can be used for the treatment and prevention of additional pathological conditions not mentioned above, where synthetic glucocorticoids are used (in this regard, Hatz, HJ , Glucocorticoide: see Immun allogische Grundlagen, Pharmak all ogie und Therapierichtlinien, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998).

  All the above mentioned indications (i) to (xx) are described in more detail in Hatz, HJ, Glucocorticoide: Immun Allogische Grundlagen, Pharmak All ogie und Therapierichtlinien, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998 .

  The invention also relates to a combination therapy or a combined composition, wherein a glucocorticoid receptor (GR) agonist of formula (I) or a pharmaceutically acceptable salt thereof, or a GR agonist of formula (I) or A pharmaceutical composition comprising a pharmaceutically acceptable salt thereof is used simultaneously with one or more pharmaceutical agents (optionally in the same composition) to treat one of the above pathological conditions, or the medical It is administered continuously with the drug. For example, with respect to the treatment of rheumatoid arthritis, osteoarthritis, CPOD (chronic obstructive pulmonary disease), asthma or allergic rhinitis, the GR agonist of the present invention may be used by one or more physicians for the treatment of such conditions. Can be combined with drugs. When such a combination is administered by inhalation, the pharmaceutical agents to be combined can be selected from the following list:

PDE4 inhibitors, including inhibitors of PDE4D isoforms;
A selective β.

Muscari receptor antagonists (eg M1, M2 or M3 antagonists, eg more selective M3 antagonists), eg ipratropium bromide, tiotripium bromide, oxitropium bromide, pirenzepine or telenzepine:
• A chemokine receptor function modulator (eg, a CCR1 receptor antagonist); or • An inhibitor of p38 kinase function.

With respect to another subject of the present invention, such a combination with a GR agonist of formula (I) or a pharmaceutically acceptable salt thereof is used to treat COPD, asthma or allergic rhinitis and inhalation Alternatively, it can be administered by inhalation or orally in combination with xanthine (eg, aminophylline or theophylline), which can also be administered orally.
For therapeutic effects in the pathological conditions referred to above, the appropriate dose will vary and, for example, the activity intensity of the compound of general formula I, the host, the type of administration, and the type and severity of the condition being treated As well as use as a prophylactic or therapeutic agent.

The present invention further provides the following:
(I) one use of a compound of general formula I according to the invention for the production of a medicament for treating a disease;
(Ii) a method of treating a disease comprising the administration of an amount of a compound of the invention that inhibits the disease and is given to a patient in need of such a drug;
(Iii) A pharmaceutical composition for treating a disease, comprising one compound of the present invention or a mixture thereof and at least one pharmaceutical adjuvant and / or vehicle.

  In general, satisfactory results can be expected in animals if the daily dose comprises a compound of the invention in the range of 1 μg to 100,000 μg per kg body weight. For larger animals, such as humans, recommended daily doses range from 1 μg to 100,000 μg per kg body weight. A dose of 10-30,000 μg per kg body weight is preferred, and a dose of 10-10,000 μg per kg body weight is more preferred. For example, this dose is suitably administered several times daily. For the treatment of acute shock (eg hypersensitivity shock), a single dose can be given that is above the dose mentioned above.

  Formulation of pharmaceutical preparations based on new compounds along with vehicles, fillers, substances that affect degradation, moisturizers, lubricants, adsorbents, diluents, flavor modifiers, colorants, etc. Depending on the active ingredient being processed, it is carried out by means known in the art and converted into the desired dosage form. In this case, see Remingt on's Pharmaceutical Science, 15th ed. Mack Publishing Company, East Penns Il vania (1980).

For oral administration, tablets, coated tablets, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions are particularly suitable.
For parenteral administration, injection and infusion preparations are possible.
For intra-articular injection, correspondingly prepared crystalline suspensions can be used.
For intramuscular injection, aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.

For rectal administration, the novel compounds can be used in the form of suppositories, capsules, solutions (eg, in the form of enemas), and ointments for systemic and local treatment.
For new pulmonary administration of compounds, the compounds can be used in the form of aerosols and inhalants.
For topical administration to the eye, outer ear, middle ear, nasal cavity and sinuses, the novel compounds can be used as drops, ointments and tinctures in the corresponding pharmaceutical formulations.

For topical application, formulations in gels, ointments, fat ointments, creams, pastes, powders, milk and tinctures are possible. The dosage of the compounds of general formula I should be 0.01% to 20% in these formulations in order to achieve a sufficient pharmacological action.
The present invention also comprises a compound of general formula I according to the present invention as a therapeutically active ingredient. Furthermore, the compounds of general formula I according to the invention are part of the invention as therapeutically active ingredients together with pharmaceutically compatible and acceptable adjuvants and vehicles.

  The invention also comprises a pharmaceutical composition comprising one pharmaceutically active compound of the invention or a mixture thereof, or a pharmaceutically compatible salt thereof, and a pharmaceutically compatible adjuvant and vehicle.

Example 1 :

1-bromo-6,7,8,9-tetrahydro-5-[(1H-indazol-4-yl) amino] -8,8-dimethyl-6- (trifluoromethyl) -5H-benzocycloheptene- 6-ol :
3- (2-Bromophenyl) -2,2-dimethylpropanal :
1.63 g (40.81 mmol) of ground sodium hydroxide and 150.7 mg (0.41 mmol) of tetrabutylammonium iodide are introduced into 6 ml of benzene. A mixture consisting of 12.7 g (51 mmol) 2-bromobenzyl bromide and 2.94 g (40.81 mmol) isobutyraldehyde was added dropwise to the mixture at 60 ° C. and the batch was then allowed to remain at this temperature for 8 hours. , Stir. After 8 hours of stirring at room temperature, the reaction mixture is mixed with 40 ml of water and shaken with 400 ml of diethyl ether. The organic phase is washed with water and saturated sodium chloride solution. After drying over sodium sulfate, the solvent is spun off and the remaining residue is chromatographed on silica gel (mobile solvent, ethyl acetate / hexane). 6.6 g (67.1%) of the desired compound is isolated.
MS (El) m / e (relative intensity): 242 (M ⁺ , 3), 169/71 (100).

(E / Z) -Ethyl-5- (2-bromophenyl) -4,4-dimethyl-2-ethoxypent-2-enoate :
Slowly cool 14.75 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran / heptane / toluene to a solution of 7.34 g (23.371 mmol) of 2-diethylhostano-2-ethoxyacetic acid ethyl ester in 21 ml of tetrahydrofuran. While dropping, it is stirred at 0 ° C. for 30 minutes. 6.6 g (27.37 mmol) of 3- (2-bromophenyl) -2,2-dimethyl-propanal dissolved in 31.5 ml of anhydrous tetrahydrofuran is added dropwise at 0 ° C. to this yellow solution.

The cold bath is removed and the batch is stirred at room temperature for 22 hours. The reaction mixture is mixed with 60 ml of water and shaken twice with 300 ml of diethyl ether each time. The combined organic extracts are washed with water and saturated sodium chloride solution. After drying over sodium sulfate and after the solvent is spun off, the remaining residue is chromatographed on silica gel (mobile solvent, ethyl acetate / hexane). In particular, 6.63 g (68.2%) of the desired compound is isolated as an E / Z mixture.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.10-1.40 (12H), 2.95-3.08 (2H), 3.68-3.80 (2H), 4.13-4.32 (2H), 4.89 and 6.17 (1 H together ), 7.00-7.10 (1 H), 7.14-7.34 (2H), 7.55 (1H).

5- (2-Bromophenyl) -4,4-dimethyl-2-oxopentanoic acid :
6.63 g (18.66 mmol) of (E / Z) -ethyl-5- (2-bromophenyl) -4,4-dimethyl-2-ethoxypent-2-enoate in a 2: 1 mixture consisting of ethanol / water Medium is mixed with 186 ml of 1M sodium hydroxide solution and it is stirred at room temperature for 18 hours. After draining the ethanol, the residue is extracted with diethyl ether. Discard the organic phase. The aqueous phase is acidified with concentrated HCl until a pH of 3 is reached. After extraction with diethyl ether, the combined organic extracts are washed neutral, dried and the solvent is spun off. The resulting product (5.83 g = 95.6%) is used directly for enol ether decomposition.

Finally, the crude product is mixed with 108 ml of 1M sulfuric acid and stirred at 90 ° C. for 17 hours. The reaction mixture is mixed with solid sodium carbonate while cooling in an ice bath until the pH reaches 9 (strong foaming) and it is extracted with diethyl ether. The ether phase is discarded after monitoring by TLC. The aqueous phase is acidified with concentrated HCl until a pH of 4 is reached. After extraction with diethyl ether and after washing and drying of the organic phase, the solvent is spun off and the resulting residue (4.23 g = 79.8%) is introduced in crude form to the next stage.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.10 (6H), 2.94 (2H), 3.00 (2H), 7.05-7.14 (1 H), 7.18-7.29 (2H), 7.58 (1 H).

Methyl-5- (2-bromophenyl) -4,4-dimethyl-2-oxopentanoate :
2 g (6.685 mmol) 5- (2-bromophenyl) -4,4-dimethyl-2-oxopentanoic acid is dissolved in 11.6 ml acetone and room temperature with 1.108 g (8.022 mmol) sodium carbonate. Mix with. After the addition of 1.23 g (8.691 mmol) iodomethane, the batch is refluxed for 2 hours. Potassium carbonate is aspirated onto a G4 frit, washed with acetone, and the solvent is spun off. After chromatography of the residue on silica gel (mobile solvent, ethyl acetate / hexane), 1.1 g (52.6%) of the desired compound is obtained.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.10 (6H), 2.88 (2H), 2.93 (2H), 3.88 (3H), 7.03-7.11 (1 H), 7.18-7.25 (2H), 7.58 (1H).

5- (2-Bromophenyl) -4,4-dimethyl-2- (trifluoromethyl) -pentane-1,2-diol :
1.1 g (3.512 mmol) methyl-5- (2-bromophenyl) -4,4-dimethyl-2-oxopentanoate was dissolved in 5.7 ml THF and 599.2 mg (4.214 mmol) Mix at 0 ° C. with (trifluoromethyl) -trimethylsilane. After the addition of 8.6 mg tetrabutylammonium fluoride, the batch is stirred at 0-5 ° C. for 1.5 hours. The reaction mixture is poured into ice water and extracted twice with diethyl ether. The combined organic extracts are washed with water and brine and dried.

  After the solvent is spun off, the residue is chromatographed on silica gel (mobile solvent, ethyl acetate / hexane). 1.17 g (73.1%) of methyl-5- (2-bromophenyl) -4,4-dimethyl-2- (trimethylsilanyloxy) -2- (trifluoromethyl) -pentanoate is isolated. The ester is dissolved in 10.7 ml of toluene and mixed at −10 ° C. with 5.35 ml of 1.2 M DIBAH solution. After stirring for 1 hour or more at -10 to 0 ° C, first 1.77 ml isopropanol and then 2.67 ml water are carefully added dropwise at -10 ° C. After 2 hours of vigorous stirring, the precipitate is sucked onto a frit, washed with ethyl acetate, and the solvent is spun off on a rotary evaporator. 1.07 g of pentanediol is obtained as silyl ether, which is introduced into the next step without further purification.

Finally, the crude product (1.07 g = 2.503 mmol) is dissolved in 14 ml THF and mixed with 789.7 mg (2.503 mmol) tetrabutylammonium fluoride. After stirring for 20 minutes at room temperature, the batch is added to ice water and extracted twice with diethyl ether. The combined organic extract is washed with water and brine. After drying over sodium sulfate, the solvent is spun off and the residue is chromatographed on silica gel (mobile solvent, ethyl acetate / hexane). 582.5 mg (65.5%) of the desired diol is isolated.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 0.93-1.10 (6H), 1.63 (1 H), 1.79 (1 H), 2.82-2.98 (2H), 3.52-3.72 (2H), 5.13 (1 H), 5.59 (1 H), 7.10-7.19 (1 H), 7.25-7.40 (2H), 7.59 (1H).

5- (2-Bromophenyl) -2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) -pentanal :
5.6 ml dimethyl sulfoxide and 826.2 mg (8.165 mmol) triethylamine dissolved in 17 ml dichloromethane, 580 mg (1.633 mmol) 5- (2-bromophenyl) -4,4-dimethyl-2- ( Add to (trifluoromethyl) -pentane-1,2-diol. After the addition of 779.7 mg (4.899 mmol) of SO ₃ / pyridine complex, the batch is stirred for 17 hours at room temperature. After the dropwise addition of 6.5 ml of saturated ammonium chloride solution, the batch is stirred for 15 minutes at room temperature and then extracted twice with diethyl ether. The combined organic extract is washed with water and brine. After drying and spinning off the solvent, the residue is chromatographed on silica gel (mobile solvent, ethyl acetate / hexane). 480.5 mg (83.3%) of the desired compound is isolated.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 0.95 (3H), 1.02 (3H), 2.13-2.30 (2H), 2.80-2.93 (2H), 3.93 (1H), 7.02-7.13 (1 H) , 7.20-7.29 (2H), 7.58 (1H), 9.80 (1 H).

5- (2-Bromophenyl) -1,1,1-trifluoro-2-[(1H-indazol-4-ylimino) -methyl] -4,4-dimethylpentan-2-ol :
100 mg (0.283 mmol) of the above aldehyde and 37.7 mg (0.283 mmol) of 4-aminoindazole are mixed with 0.4 ml of glacial acetic acid and stirred at room temperature for 4 days. The reaction mixture is flushed with toluene three times by rotary evaporation and the residue is chromatographed on silica gel (mobile solvent, ethyl acetate / hexane). 101.8 mg (76.6%) of the desired compound is isolated.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.02 (3H), 1.18 (3H), 2.09 (1 H), 2.39 (1 H), 2.98 (2H), 5.10 (1 H), 6.82 (1 H), 7.00-7.10 (1 H), 7.15-7.32 (2H), 7.35-7.49 (2H), 7.56 (1 H), 8.15 (1 H), 8.23 (1 H).

1-bromo-6,7,8,9-tetrahydro-5-[(1H-indazol-4-yl) amino] -8,8-dimethyl-6- (trifluoromethyl) -5H-benzocycloheptene- 6-ol :
60 mg (0.128 mmol) of 5- (2-bromophenyl) -1,1,1-trifluoro-2-[(1H-indazol-4-ylimino) -methyl] -4,4-dimethylpentane-2- The oar is mixed with 2.5 ml boron tribromide (1M in dichloromethane) and then stirred at room temperature for 7 days. The reaction mixture is mixed in portions with saturated sodium hydrogen carbonate solution at −30 ° C. and stirred vigorously for 10 minutes at room temperature after the addition of ethyl acetate. After two extraction cycles with ethyl acetate, the combined organic extracts are washed with water and brine and dried. After rotational removal of the solvent, the residue is chromatographed in Flashaster. 43.3 mg (70.5%) of the desired compound is isolated.
¹ H-NMR (300 MHz, CD ₃ OD): δ = 1.00 (3H), 1.30 (3H), 1.40 (1 H), 1.96 (1 H), 3.09 (1 H), 3.40 (1 H), 5.30 (1 H), 5.76 (1 H), 6.79 (1 H), 7.00-7.10 (2H), 7.41 (1 H), 7.56 (1 H), 8.13 (1 H).

Example 2 :

4-{[1-Bromo-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] -amino} -1,3-dihydro-2H-indol-2-one and 4-{[1-bromo-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] -amino} -7-bromo-1,3-dihydro-2H-indol-2-one :
7-{[5- (2-Bromophenyl) -2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) pentylidene] amino} -1,3-dihydro-2H-indol-2-one :
73 mg (0.21 mmol) of 5- (2-bromophenyl) -2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) -pentanal as described in Example 1 was added to 30.62 mg (0.29 mmol). Stir with 4-amino-1,3-dihydro-2H-indol-2-one and 0.29 ml glacial acetic acid at room temperature for 5 days. The reaction mixture is flushed with toluene three times on a rotary evaporator and the remaining residue is chromatographed on silica gel (mobile solvent, ethyl acetate / hexane). 82.9 mg of the desired imine is isolated.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.00 (3H), 1.10 (3H), 2.02 (1 H), 2.33 (1 H), 2.95 (2H), 3.55 (2H), 4.90 (1 H ), 6.69 (1 H), 6.83 (1 H), 7.08 (1 H), 7.18-7.32 (3H), 7.55 (1H), 8.09 (1H), 8.32 (1H).

4-{[1-Bromo-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] -amino} -1,3-dihydro-2H-indol-2-one (I) and 4-{[1-bromo-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (tri Fluoromethyl) -5H-benzocyclohepten-5-yl] -amino} -7-bromo-1,3-dihydro-2H-indol-2-one (II) :
81 mg (0.17 mmol) of the above imine is mixed with 3.4 ml of 1M boron tribromide in dichloromethane at room temperature and stirred at this temperature for 13 days. For further work, the reaction mixture is added to a mixture consisting of saturated sodium hydrogen carbonate solution and ice. After dilution with 50 ml of ethyl acetate, the mixture is stirred vigorously for 20 minutes. The organic phase is separated and the aqueous phase is shaken once more with 50 ml of ethyl acetate.

  The combined organic extracts are washed with water and brine and dried over sodium sulfate. After filtration of the desiccant and after rotational removal of the solvent, the remaining residue is chromatographed several times on silica gel (amine phase). 21.5 mg (26.5%) of 4-{[1-bromo-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocycloheptene- 5-yl] -amino} -1,3-dihydro-2H-indol-2-one (I) and 7.9 mg (8.4%) of 4-{[1-bromo-6,7,8,9-tetrahydro- 6-Hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] -amino} -7-bromo-1,3-dihydro-2H-indol-2-one (II) is isolated.

(I): ¹ H-NMR (400 MHz, CD ₃ OD): δ = 0.92 (3H), 1.20 (3H), 1.30 (1 H), 1.88 (1 H), 2.98 (1H), 3.30 (2H, Signal is lower than methanol signal), 3.48 (1H), 5.15 (1 H), 5.87 (1 H), 6.23 (1H), 6.89 (1 H), 7.05 (1H), 7.31 (1 H), 7.50 ( 1H).
(II): ¹ H-NMR (300 MHz, CD ₃ OD): δ = 0.90 (3H), 1.20 (3H), 1.30 (1 H), 1.87 (1 H), 2.98 (1 H), 3.30 (2H , Signal is lower than methanol signal), 3.59 (1 H), 5.10 (1 H), 5.82 (1 H), 6.99 (1 H), 7.09 (1 H), 7.30 (1 H), 7.50 (1 H ).

Example 3 :

2-Chloro-6,7,8,9-tetrahydro-5- (1H-indazol-4-ylamino) -8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-6-ol :
3- (3-Chlorophenyl) -2,2-dimethylpropanol :
7.95 g (198.7 mmol) of ground sodium hydroxide and 734 mg (1.98 mmol) of tetrabutylammonium iodide are introduced into 38.2 ml of benzene. A mixture consisting of 40 g (248.4 mmol) 3-chlorobenzyl bromide and 14.33 g (198.7 mmol) isobutyraldehyde is added dropwise to this mixture at 60 ° C. (heating of the reaction mixture to 72 ° C.). The batch is then stirred at 60 ° C. for 60 hours. After 24 hours of stirring at room temperature, the reaction mixture is mixed with 200 ml of ice water and shaken 3 times with 200 ml of methyl-tert-butyl ether each time. The combined organic phase is washed with water and saturated sodium chloride solution. After drying over sodium sulfate, the solvent is spun off and the remaining residue is chromatographed on silica gel (mobile solvent, ethyl acetate / hexane). 31.74 g (81.2%) of the desired compound (about 50% purity) is isolated.
MS (Cl) m / e (relative strength): 214 (100%).

(E / Z) -Ethyl-5- (3-chlorophenyl) -4,4-dimethyl-2-ethoxypent-2-enoate :
Slowly cool 85.2 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran / heptane / toluene to a solution of 21.36 g (79.62 mmol) of 2-diethylhostano-2-ethoxyacetic acid ethyl ester in 100 ml of tetrahydrofuran. While dropping, it is stirred at 0 ° C. for 30 minutes. 28.46 g (15.66 g = 79.62 mmol) of 3- (3-chlorophenyl) -2,2-dimethyl-propanal dissolved in 100 ml of anhydrous tetrahydrofuran are added dropwise at 0 ° C. to this yellow solution. The cold bath is removed and the batch is stirred overnight at room temperature. The reaction mixture is poured into 400 ml of water and shaken 3 times with 200 ml of methyl-tert-butyl ether each time. The combined organic extracts are washed with water and saturated sodium chloride solution. After drying over sodium sulfate and after the solvent is spun off, the remaining residue is chromatographed on silica gel (mobile solvent, ethyl acetate / hexane). In particular, 25.76 g (> 100%) of the desired compound is isolated as an E / Z mixture.
MS (Cl) m / e (relative strength): 330 (35%), 328 (100%), 185 (53%).

5- (3-Chlorophenyl) -4,4-dimethyl-2-oxopentanoic acid :
28.47 g (91.58 mmol) of (E / Z) -ethyl-5- (3-chlorophenyl) -4,4-dimethyl-2-ethoxypent-2-enoate in a 2: 1 mixture consisting of ethanol / water , Mixed with 751 ml of 1M sodium hydroxide solution and it is stirred overnight at room temperature. After draining the ethanol, the residue is diluted with 200 ml of water and extracted three times with 200 ml of methyl-tert-butyl ether each time. Discard the organic phase. The aqueous phase is acidified with concentrated HCl until a pH of 3 is reached. After extraction with methyl-tert-butyl ether (3 times), the combined organic extracts are washed neutral, dried and the solvent is spun off. The resulting product (15.82 g = 61.1%) is used directly for enol ether decomposition.

For this, the crude product is mixed with 330 ml of 1M sulfuric acid and 87 ml of glacial acetic acid and stirred at 90 ° C. for 2 days. The reaction is still not complete after 2 days, so an additional 44 ml of glacial acetic acid is added. After a total of 6 days of stirring, the reaction mixture is basified with solid potassium carbonate (pH 9, strong effervescence) while cooling in an ice bath and it is extracted 3 times with methyl-tert-butyl ether. The aqueous phase is acidified to pH 4 with concentrated HCl. After extraction with methyl tert-butyl ether, washing and drying of the organic phase, the solvent is spun off and the resulting residue (11.9 g = 83.8%) is used as crude in the next step.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.09 (6H), 2.69 (2H), 2.84 (2H), 7.00 (1 H), 7.13 (1 H), 7.22 (2H).

Ethyl-5- (3-chlorophenyl) -4,4-dimethyl-2-oxopentanoate :
10.61 g (41.65 mmol) of 5- (3-chlorophenyl) -4,4-dimethyl-2-oxopentanoic acid is added to 259 ml of ethanol, mixed with 4.7 ml of concentrated sulfuric acid and refluxed for 6.5 hours. To do. After cooling, the reaction mixture is poured into 500 ml of saturated sodium bicarbonate solution and extracted three times with 200 ml of ethyl acetate each time. The combined extracts are washed with saturated sodium bicarbonate solution and brine. After drying over sodium sulfate, the solvent is spun off and the residue is chromatographed on silica gel (mobile solvent, ethyl acetate / hexane). 5.26 g (44.6%) of the desired ester is isolated.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.05 (6H), 1.38 (3H), 2.68 (2H), 2.73 (2H), 4.30 (2H), 7.00 (1 H), 7.12 (1 H) , 7.20 (2H).

Ethyl-5- (3-chlorophenyl) -4,4-dimethyl-2-hydroxy-2- (trifluoromethyl) pentanoate :
5.26 g (18.59 mmol) ethyl-5- (3-chlorophenyl) -4,4-dimethyl-2-oxopentanoate was dissolved in 26.8 ml THF and 3.17 g (22.3 mmol) ( Mix with (trifluoromethyl) trimethylsilane. After the addition of 43 mg tetrabutylammonium fluoride, the batch is stirred overnight at room temperature. 5.36 g of tetrabutylammonium fluoride are added and the reaction mixture is stirred for another 2 hours at room temperature. The reaction mixture is diluted with methyl tert-butyl ether and the layers are separated. After further shaking with methyl-tert-butyl ether, the combined organic extracts are washed with water and brine and dried. After the solvent is spun off, the residue is chromatographed on silica gel (mobile solvent, ethyl acetate / hexane). 4.34 g (66.2%) of the desired product is isolated.
¹ H-NMR (400 MHz, CDCl ₃ ): δ = 0.89 (3H), 1.00 (3H), 1.35 (3H), 1.90-2.06 (2H), 2.50 (1 H), 2.80 (1 H), 3.92 ( 1 H), 4.27-4.45 (2H), 7.09 (1 H), 7.20 (3H).

5- (3-Chlorophenyl) -2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) pentanal :
2 g (5.67 mmol) of ethyl-5- (3-chlorophenyl) -4,4-dimethyl-2-hydroxy-2- (trifluoromethyl) pentanoate is dissolved in 74.1 ml of diethyl ether. At 0 ° C., 161.4 mg (4.25 mmol) of lithium hydride is added in small portions. After stirring for 1 hour at 0 ° C., 12 ml of saturated sodium bicarbonate are added and the batch is stirred vigorously for another 2 hours at room temperature. After adding some silica gel, it is stirred for another 10 minutes and the reaction mixture is aspirated through a glass fiber filter. The ether phase is washed with brine, dried over sodium sulfate and the solvent is spun off. The crude product is chromatographed on the Flashmaster. 1.43 g (81.6%) of a 9: 7 mixture is obtained consisting of the desired aldehyde and starting material. This mixture is introduced into the next step without further purification.

5- (3-Chlorophenyl) -1,1,1-trifluoro-2-[(1H-indazol-4-ylimino) -methyl] -4,4-dimethylpentan-2-ol :
300 mg (0.97 mmol) and 129.39 mg (0.97 mmol) of 4-aminoindazole of the above mixture consisting of aldehyde and ester are mixed with 1.4 ml of glacial acetic acid and stirred at room temperature for 4 days. The reaction mixture is flushed with toluene three times by rotary evaporation and the residue is chromatographed on silica gel (mobile solvent, ethyl acetate / hexane). 117.4 mg (28.5%) of the desired compound is isolated.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 0.95 (3H), 1.09 (3H), 1.90 (1 H), 2.24 (1 H), 2.59 (1 H), 2.85 (1 H), 6.82 ( 1 H), 7.09 (1 H), 7.15-7.32 (3H), 7.38- 7.52 (2H), 8.13 (1 H), 8.20 (1 H).

2-Chloro-6,7,8,9-tetrahydro-5- (1H-indazol-4-ylamino) -8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-6-ol :
116 mg (0.27 mmol) of 5- (3-chlorophenyl) -1,1,1-trifluoro-2-[(1H-indazol-4-ylimino) -methyl] -4,4-dimethylpentan-2-ol Are mixed with 5.47 ml of boron tribromide (1M in dichloromethane) and then stirred at room temperature for 7 days. The reaction mixture is poured into a mixture consisting of saturated sodium hydrogen carbonate solution and ice and after the addition of ethyl acetate it is stirred vigorously for 20 minutes at room temperature.

The ethyl acetate phase is separated and the aqueous phase is further extracted with ethyl acetate. The combined organic extracts are washed with water and brine and dried. After rotary removal of the solvent, the residue is chromatographed on silica gel (mobile solvent, dichloromethane / methanol). 67.9 mg (58.5%) of the desired compound is isolated.
¹ H-NMR (300 MHz, CD ₃ OD): δ = 0.88 (3H), 1.19 (3H), 1.42 (1H), 1.90 (1 H), 2.60 (1 H), 3.11 (1 H), 5.23 ( 1 H), 5.73 (1 H), 6.73 (1 H), 7.00 (1 H), 7.10 (1 H), 7.18 (1 H), 7.30 (1 H), 8.09 (1 H).

Example 4 :

4-{[2-Chloro-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] -amino} -1,3-dihydro-2H-indol-2-one :
7-{[5- (3-Chlorophenyl) -2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) pentylidene] amino} -1,3-dihydro-2H-indol-2-one :
450 mg (1.46 mmol) of the mixture described in Example 3, consisting of 5- (3-chlorophenyl) -2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) -pentanal and the corresponding ester, Stir with (1.46 mmol) of 4-amino-1,3-dihydro-2H-indol-2-one and 2.1 ml of glacial acetic acid at room temperature for 4 days. The reaction mixture is flushed 3 times with toluene in a rotary evaporator and the remaining residue is chromatographed on silica gel (mobile solvent, hexane / ethyl acetate). 307.1 (48%) mg of the desired imine is isolated.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 0.90 (3H), 1.02 (3H), 1.85 (1 H), 2.20 (1 H), 2.52 (1 H), 2.81 (1 H), 3.54 ( 2H), 4.90 (1 H), 6.69 (1 H), 6.86 (1 H), 7.08 (1 H), 7.15-7.32 (4H), 8.04 (1 H), 8.50 (1 H).

4-{[2-Chloro-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] -amino} -1,3-dihydro-2H-indol-2-one :
305 mg (0.69 mmol) of the above imine is mixed at room temperature with 13.9 ml of 1M boron tribromide in dichloromethane and stirred at this temperature for 5 days. For further work, the reaction mixture is poured into a mixture consisting of saturated sodium hydrogen carbonate solution and ice. After dilution with 50 ml of ethyl acetate, the mixture is stirred vigorously for 20 minutes. The organic phase is separated and the aqueous phase is shaken once more with 50 ml of ethyl acetate. The combined organic extracts are washed with water and brine and dried over sodium sulfate. After filtration of the desiccant and after rotational removal of the solvent, the remaining residue is chromatographed several times on silica gel (dichloromethane / methanol). 175.5 mg (57.5%) of 4-{[2-chloro-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocycloheptene- 5-yl] -amino} -1,3-dihydro-2H-indol-2-one is isolated.
¹ H-NMR (300 MHz, CD ₃ OD): δ = 0.84 (3H), 1.15 (3H), 1.40 (1 H), 1.85 (1 H), 2.58 (1 H), 3.06 (1 H), 3.25 (1 H, signal is lower than methanol signal), 3.45 (1 H), 5.10 (1 H), 5.90 (1 H), 6.23 (1 H), 6.89 (1 H), 7.15 (2H), 7.28 ( 1 H).

Example 5 :

6,7,8,9-Tetrahydro-6-hydroxy-8,8-dimethyl-5-{[7- (1-methyl-5-oxopyrrolidin-2-yl) -1H-indazol-4-yl] amino } -6- (Trifluoromethyl) -5H-benzocycloheptene-2-carbonitrile :
2-Chloro-6,7,8,9-tetrahydro-5- (1H-indazol-4-ylamino) -8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclo described in Example 3 Mixing 35 mg (0.083 mmol) of hepten-6-ol with 8.09 mg (0.17 mmol) of sodium cyanide and 18.04 mg (0.083 mmol) of nickel bromide in 1 ml of 1-methyl-2-pyrrolidinone And the reaction is placed in a microwave (20 bar, 200 ° C., 20 minutes). For further work, the reaction mixture is mixed with 5 ml of ethyl acetate. After the addition of 2 ml of water, the mixture is stirred vigorously for 15 minutes at room temperature.

It is shaken once more with ethyl acetate. The combined organic extract is washed with water and bralin. After drying of the organic phase, the solvent is spun off and the residue is chromatographed on a Flashmaster (amine phase, mobile solvent, methanol / dichloromethane). 16.4 mg (38.8%) 6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-5-{[7- (1-methyl-5-oxopyrrolidin-2-yl) -1H- Indazol-4-yl] amino} -6- (trifluoromethyl) -5H-benzocycloheptene-2-carbonitrile (80%) is obtained.
¹ H-NMR (300 MHz, CD ₃ OD): δ = 0.85 (3H), 1.20 (3H), 1.45 (1H), 1.90-2.08 (2H), 2.32-2.60 (6H), 2.69 (1H), 3.22 (1H), 5.34 (1H), 5.75 (1H), 6.83 (1H), 7.45-7.59 (3H), 8.20 (1 H).

Example 6 :

(5R * -cis) -5-{[6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] -Amino} -quinolin-2 (1H) -one :

2- (2-Chlorophenyl) -2-methylpropanenitrile :
25 g (164.92 mmol) 2-chlorobenzyl cyanide is dissolved in 250 ml dimethylformamide and the solution is mixed with 68 g (346.33 mmol) iodomethane. At 0 ° C., 13.9 g (346.33 mmol) of sodium hydride suspension (W = 55-60%) are added in small portions. After overnight stirring at room temperature, the reaction mixture is poured into ice water and shaken 3 times with methyl-tert-butyl ether. The combined organic extracts are washed with water and then brine. After drying over sodium sulfate, the solvent is spun off and the residue is chromatographed on silica gel (mobile solvent, methyl-tert-butyl ether / hexane). 27.25 g (91.8%) of the desired compound is isolated.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.99 (6H), 7.24-7.33 (2H), 7.40-7.50 (2H).

2- (2-Chlorophenyl) -2-methylpropanal :
27.25 g (151.69 mmol) of the above nitrile is dissolved in 510 ml of toluene. At -70 ° C., 186.9 ml of a 1.2M solution of DIBAH in toluene is added dropwise. After 2.5 hours of stirring at this temperature, 26.1 ml of isopropanol and then 1.72 ml of 10% L-(+)-tartaric acid solution are added dropwise. In this case, the temperature rises. Stir the batch vigorously at room temperature for 1 hour. After 3 cycles of extraction with methyl-tert-butyl ether, the combined organic extracts are washed with brine, dried and the solvent is spun off. The residue obtained (27.5 g = 100%) is further introduced in crude form.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.50 (6H), 7.21-7.46 (4H), 9.72 (1 H).

1-chloro-2- (3,3-dibromo-1,1-dimethylprop-2-enyl) benzene :
29.5 g (112.31 mmol) of triphenylphosphine is dissolved in 350 ml of dichloromethane. After the addition of 7.34 g (112.31 mmol) of zinc dust, the batch is cooled to 0 ° C. and then 37.2 g (112.31 mmol) of tetrabromomethane are added in portions. After 16 hours of stirring at room temperature, 10 g (54.75 mmol) of 2- (2-chlorophenyl) -2-methylpropanal dissolved in 140 ml of dichloromethane are added dropwise. After 2 hours of stirring, the reaction mixture is mixed with 350 ml of hexane, stirred vigorously and sucked through a frit packed with silica gel. After washing the residue with 600 ml hexane / dichloromethane (1: 1), the filtrate is evaporated to dryness. The residue is chromatographed on silica gel (mobile solvent, ethyl acetate / hexane). 6.31 g found to be the starting material was isolated and therefore used again in the reaction to form a double bond.

In this regard, in a modified variant, 34.3 g (103.46 mmol) of tetrabromomethane are dissolved in 414 ml of dichloromethane and mixed in portions with 54.4 g (207.41 mmol) of triphenylphosphine at 0 ° C. To do. After stirring for 1 hour at 0 ° C., 6.31 g (34.55 mmol) of recovered 2- (2-chlorophenyl) -2-methylpropanol, dissolved in 80 ml of dichloromethane, are added dropwise. The batch is stirred overnight at room temperature. The reaction mixture is poured into 1.3 L of hexane. After 1 hour of vigorous stirring, it is sucked through celite and the solvent is spun off. The residue is chromatographed on silica gel (mobile solvent, ethyl acetate / hexane). 4.67 g (41.4%) of the desired product (still containing some starting material) is isolated.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.60 (6H), 6.93 (1 H), 7.16-7.25 (2H), 7.38 (1 H), 7.43 (1 H).

1-chloro-2- (1,1-dimethylprop-2-ynyl) benzene :
4.46 g (13.66 mmol) of the above dibromoalkene is dissolved in 180 ml of tetrahydrofuran and mixed in portions with 16.1 ml (26.8 mmol) of butyllithium solution (15% in hexane) at -70 ° C. After 2 hours of stirring at this temperature, 2.7 ml of water are carefully added dropwise and then the mixture is stirred vigorously at room temperature for 2 hours. After mixing the reaction mixture with methyl-tert-butyl ether, the organic phase is washed with water and then with brine. After drying of the organic phase, the solvent is spun off and the residue (2.83 g> 100%) is introduced in crude form to the next stage.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 1.71 (6H), 2.30 (1 H), 7.16-7.20 (2H), 7.30 (1H), 7.63 (1H).

Ethyl-5- (2-chlorophenyl) -2-hydroxy-5-methyl-2- (trifluoromethyl) hex-3-inoate :
2.83 g (15.84 mmol) of 1-chloro-2- (1,1-dimethylprop-2-ynyl) benzene is dissolved in 150 ml of tetrahydrofuran and the mixture is cooled to -60 °. At this temperature, 9.8 ml (15.84 mmol) of n-butyllithium solution (15% in hexane) are added dropwise and then the batch is stirred at 0 ° C. for 2 hours. After repeated cooling to −60 ° C., 1.9 ml (15.84 mmol) of ethyl trifluoropyruvate is added dropwise. After stirring for 24 hours at room temperature, the reaction mixture is poured into saturated ammonium chloride solution. After 3 cycles of extraction with methyl tert-butyl ether, the combined organic extracts are washed with brine. After drying with sodium sulfate and after spin-off of the solvent, the residue is chromatographed on the Flashmaster. 2.4 g (43.6%) of the desired compound is isolated.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.49 (3H), 1.79 (6H), 4.12 (1 H), 4.41 (2H), 7.17-7.25 (2H), 7.39 (1H), 7.58 (1H ).

Ethyl-2-hydroxy-5-methyl-5-phenyl-2- (trifluoromethyl) hexanoate :
2.3 g (6.59 mmol) are mixed with 231 mg Pd / C (10%) and 16 ml ethanol and stirred at room temperature overnight under a hydrogen atmosphere. The catalyst is sucked through a glass-pleated filter and the filtrate is rotated. 2.14 g of a mixture consisting of the desired saturated product and the corresponding alkene compound is isolated.

The mixture is again subjected to hydrogenation (15 ml of ethanol, 214 mg of Pd / C, hydrogen atmosphere, 24 hours of stirring at room temperature). The catalyst is aspirated through a glass-fiber filter, the filtrate is spun and the residue is chromatographed on the Flashmaster. 995.2 mg (46.2%) of product containing mainly dechlorinated compounds is isolated.
MS (Cl) m / e (relative strength); 336 (100%).

2-hydroxy-5-methyl-5-phenyl-2- (trifluoromethyl) hexanal :
995.2 mg (2.82 mmol) ethyl-2-hydroxy-5-methyl-5-phenyl-2- (trifluoromethyl) hexanoate was dissolved in 11.5 ml diethyl ether and with 82.79 mg lithium aluminum hydride Mix little by little at 0 ° C. After 1 hour of stirring at this temperature, 10 ml of saturated sodium bicarbonate are carefully added dropwise and then the batch is stirred vigorously for 1 hour. After 3 cycles of extraction with methyl-tert-butyl ether, the combined organic extracts are washed with brine, and after 3 cycles of extraction with sodium sulfate, the combined organic extracts are washed with brine and washed with sodium sulfate. Dry and spin off the solvent. The remaining residue is chromatographed on the Flashmaster. 211.3 mg of the desired aldehyde are obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.25-1.38 (1 H), 1.32 (6H), 1.60-1.85 (3H), 3.71 (1 H), 7.15-7.40 (5H), 9.49 (1 H).

5-{[4- (2-hydroxy-5-methyl-5-phenyl-2- (trifluoromethyl) hexylidene] amino} quinolin-2 (1H) -one :
211 mg (0.684 mmol) of the above aldehyde and 109.8 mg (0.684 mmol) of 5-amino-quinolin-2 (1H) -one are stirred in 2.6 ml of glacial acetic acid at room temperature for 3 days. The batch is rotated until dryness is reached, and the residue is chromatographed on the Flashmaster. 177.9 mg (57.7%) of the desired imine is isolated.
¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.30-1.40 (6H), 1.41-2.00 (4H), 4.70 (1H), 6.68-6.80 (2H), 7.13-7.25 (1H), 7.25-7.35 (4H), 7.40 (1 H), 7.52 (1 H), 7.82 (1 H), 8.11 (1 H).

(5R * -cis) -5-{[6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] -Amino} -quinolin-2 (1H) -one :
83.85 mg (0.19 mmol) of the above imine is dissolved in 1 ml of dichloromethane. After cooling to 0 ° C., 1.9 ml of a 1M solution of boron tribromide in dichloromethane is added dropwise. The batch is then stirred at room temperature for 14 days. The reaction mixture is poured into a mixture consisting of saturated sodium bicarbonate solution and ice and extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried over sodium sulfate and the solvent is spun off. The remaining residue is chromatographed on the Flashmaster. 10.8 mg (13%) of the desired compound is isolated.
¹ H-NMR (400 MHz, DMSO [d6]): δ = 1.28-1.50 (7H), 1.73-1.87 (1H), 1.89-2.01 (1H), 2.10-2.23 (1H), 5.14 (1H), 5.72 (1H), 6.20-6.55 (3H), 7.00-7.12 (2H), 7.20 (1 H), 7.30 (1H), 7.40 (1H), 8.19 (1H), 11.5 (1H).

By using the corresponding imine, the following compounds can be synthesized analogously:
5-{[6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} isoquinoline-1 (2H )-on;
5-{[6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} 1,3-dihydro -2H-indol-2-one;
5-{[6,7,8,9-Tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} 2,3-dihydro -Isoindole-1-one;
5-{[6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} isochromen-1-one ;
9,9-Dimethyl-5-[(7,8-difluoro-2-methylquinazolin-5-yl) amino] -6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H-benzocyclo Heptene-6-ol;

9,9-Dimethyl-5-[(2-methylquinazolin-5-yl) amino] -6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol ;
9,9-Dimethyl-5-[(2-methylquinolin-5-yl) amino] -6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol ;
5-{[1-Chloro-6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} quinoline -2 (1H) -on;
1-Chloro-9,9-dimethyl-5-[(2-methylquinazolin-5-yl) amino] -6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H-benzocycloheptene -6-ol;
5-{[2-Chloro-6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} quinoline -2 (1H) -on;

2-Chloro-9,9-dimethyl-5-[(2-methylquinazolin-5-yl) amino] -6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H-benzocycloheptene -6-ol;
5-{[1-Chloro-2-fluoro-6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl Amino} quinolin-2 (1H) -one;
1-Chloro-2-fluoro-9,9-dimethyl-5-[(2-methylquinazolin-5-yl) amino] -6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H- Benzocyclohepten-6-ol;
5-{[2-Chloro-1-fluoro-6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl Amino} quinolin-2 (1 H) -one;
2-Chloro-1-fluoro-9,9-dimethyl-5-[(2-methylquinazolin-5-yl) amino] -6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H- Benzocyclohepten-6-ol;

5-{[1-Bromo-6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} quinoline -2 (1 H) -on;
1-Bromo-9,9-dimethyl-5-[(2-methylquinazolin-5-yl) amino] -6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H-benzocycloheptene -6-ol;
5-{[2-Bromo-6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} quinoline -2 (1 H) -on;
2-Bromo-9,9-dimethyl-5-[(2-methylquinazolin-5-yl) amino] -6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H-benzocycloheptene -6-ol;
5-{[1-Bromo-2-chloro-6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl Amino} quinolin-2 (1 H) -one;

1-Bromo-2-chloro-9,9-dimethyl-5-[(2-methylquinazolin-5-yl) amino] -6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H- Benzocyclohepten-6-ol;
5-{[2-Bromo-1-chloro-6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl Amino} quinolin-2 (1 H) -one;
2-Bromo-1-chloro-9,9-dimethyl-5-[(2-methylquinazolin-5-yl) amino] -6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H- Benzocyclohepten-6-ol;
5-{[1,2-dichloro-6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino } Quinoline-2 (1 H) -one;
1,2-dichloro-9,9-dimethyl-5-[(2-methylquinazolin-5-yl) amino] -6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H-benzocyclo Hepten-6-ol.

Without further effort, one of ordinary skill in the art would be able to utilize the invention to its full extent using the foregoing description. Accordingly, the following preferred specific embodiments are merely exemplary and do not limit the remainder of the disclosure.
In the foregoing and following examples, all temperatures are given without correction in ° C., and all parts and percentages are by weight unless otherwise indicated.

All applications, patents and publications cited herein, and the corresponding German application number 102005014090.4 filed on March 22, 2005 and the US provisional application number filed on April 11, 2005 The entire disclosure of 60 / 669,885 is incorporated herein by reference.
The foregoing examples can be repeated with similar success by substituting the reactions and / or operating conditions generally or specifically described in the present invention with those used in the preceding examples. .
From the foregoing description, those skilled in the art can readily ascertain the essential features of the present invention and make various changes and modifications to the present invention within the scope of the invention.

Claims (15)

The following general formula (I):

[Wherein, R ¹ and R ² , independently of one another, are a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, an optionally substituted (C _1- C ₁₀ ) -alkoxy group, (C ₁ -C ₁₀ ) -alkylthio group, (C ₁ -C ₅ ) -perfluoroalkyl group, cyano group or nitro group, or
R ¹ and R ² together represent a group -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH-,-(CH ₂ ) _{n + 2-} , -NH- (CH ₂ ) _{n + 1-} , N (C ₁ -C ₃ -alkyl)-(CH ₂ ) _{n + 1} -and -NH-N = CH- (where n Is a group selected from 1 or 2, and the terminal atom is directly bonded to the adjacent ring-carbon atom, or NR ⁸ R ^9, where R ⁸ and R ⁹ are independent of each other Can be hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl),
R ¹¹ is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, (C ₁ -C ₁₀ ) -alkoxy group, (C ₁ -C ₁₀ ) -Alkylthio group or (C ₁ -C ₅ ) -perfluoroalkyl group,
R ¹² represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group or (C ₁ -C ₁₀ ) -alkoxy group,
R ³ is optionally substituted with a group selected from _{1 to} 3 hydroxy groups, halogen atoms, or 1 to 3 (C ₁ -C ₅ ) -alkoxy groups) C ₁ -C _10- An alkyl group, an optionally substituted (C ₃ -C ₇ ) -cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, ((C ₁ -C ₅ ) -alkyl group (1- They can optionally be substituted by 3 hydroxy groups or 1 to 3 COOR ¹⁰ groups, where R ¹⁰ represents any hydroxy protecting group, benzyl group or C ₁ -C ₁₀ -alkyl group Optionally substituted by one or more groups selected from (C ₁ -C ₅ ) -alkoxy groups, halogen atoms or exomethylene groups, and 1-3 nitrogen atoms and / or 1-2 Optionally containing oxygen atoms and / or 1 to 2 sulfur atoms and / or 1 to 2 keto groups Means a monocyclic or bicyclic heteroaryl group, wherein these groups can be attached to the 5H-benzocycloheptene-based amine through any position, and optionally one or more sites Can be hydrogenated at
A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group;
R ⁴ means a hydroxy group, an OR ¹⁰ group or an O (CO) R ¹⁰ group,
R ⁵ is a (C ₁ -C ₅ ) -alkyl group or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group, (C ₃ -C ₇ ) cycloalkyl group, (C ₁ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, (C ₂ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, heterocyclyl group, (C ₁ -C ₈ ) alkylene Telocyclyl group, (C ₂ -C ₈ ) alkenylene heterocyclyl group, aryl group, (C ₁ -C ₈ ) alkylene aryl group, (C ₂ -C ₈ ) alkenylene aryl group, (C ₂ -C ₈ ) alkynylene aryl group (1-2 keto groups, 1-2 (C ₁ -C ₅₎ - alkyl groups, 1-2 (C ₁ -C ₅₎ - alkoxy groups, 1-3 halogen atoms, Or optionally substituted with 1 to 2 exomethylene groups and 1 to 3 nitrogen atoms and / or 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms No) monocyclic or bicyclic heteroaryl group; means (C ₁ -C ₈₎ alkylene heteroaryl group, or a (C ₂ -C ₈₎ heteroaryl group alkenylene, wherein these groups, 5H benzo Attached to the cycloheptene system through any position, and optionally hydrogenated at one or more sites;
R ⁶ and R ⁷ independently of one another represent a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a 5H-benzocycloheptene-based carbon atom]
A compound represented by The following general formula (I):

[Wherein, R ¹ and R ² are each independently a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₁₀ ) -alkyl group, a (C ₁ -C ₁₀ ) -alkoxy group, (C ₁ -C ₁₀₎ - alkylthio groups, (C ₁ -C ₅₎ - means a perfluoroalkyl group, a cyano group or a nitro group, or
R ¹ and R ² together represent a group -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH-, or-(CH ₂ ) a group selected from _{n + 2-} (where n is 1 or 2 and the terminal atom is directly bonded to the adjacent ring-carbon atom), or NR ⁸ R ⁹ (where , R ⁸ and R ⁹ independently of one another represent hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl)
R ¹¹ and R ¹² represent a hydrogen atom,
R ³ is a C ₁ -C ₁₀ -alkyl group (which may be substituted by a group selected from _{1 to} 3 hydroxy groups, halogen atoms, 1 to 3 (C ₁ -C ₅ ) -alkoxy groups), Optionally substituted phenyl or naphthyl group, (1-2 keto groups, 1-2 (C ₁ -C ₅ ) -alkyl groups, 1-2 (C ₁ -C ₅ ) -alkoxy Optionally substituted by a group, 1 to 3 halogen atoms, or 1 to 2 exomethylene groups, and 1 to 3 nitrogen atoms and / or 1 to 2 oxygen atoms and / or 1 to 2 Means a monocyclic or bicyclic heteroaryl group (containing a sulfur atom), wherein these groups can be attached to the benzocycloheptene-based amine through any position, and optionally 1 Or may be hydrogenated at multiple sites,
A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group;
R ⁴ represents a hydroxy group,
R ⁵ is a (C ₁ -C ₅ ) -alkyl group or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group, an aryl group, (C ₁ -C ₈ ) alkylene An aryl group, a (C ₂ -C ₈ ) alkenylene aryl group, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₁ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, or a (C ₂ -C) ₈₎ alkenylene (C ₃ -C ₇₎ means a cycloalkyl group,
R ⁶ and R ⁷ independently of one another represent a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring with a benzocycloheptene-based carbon atom]
The stereoisomer of Claim 1 represented by these. The following general formula (I):

[Wherein, R ¹ and R ² are each independently a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₁₀ ) -alkyl group, a (C ₁ -C ₁₀ ) -alkoxy group, (C ₁ -C ₁₀₎ - alkylthio groups, (C ₁ -C ₅₎ - means a perfluoroalkyl group, a cyano group or a nitro group, or
R ¹ and R ² together represent a group -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH-, and-(CH ₂ ) a group selected from _{n + 2-} (where n is 1 or 2 and the terminal atom is directly bonded to the adjacent ring-carbon atom), or NR ⁸ R ⁹ (where , R ⁸ and R ⁹ independently of one another represent hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl)
R ¹¹ and R ¹² represent a hydrogen atom,
R ³ is a C ₁ -C ₁₀ -alkyl group (which may be substituted by _{1 to} 3 hydroxy groups, halogen atoms, or groups selected from _{1 to} 3 (C ₁ -C ₅ ) -alkoxy groups) An optionally substituted phenyl group, (1-2 keto groups, 1-2 (C ₁ -C ₅ ) -alkyl groups, 1-2 (C ₁ -C ₅ ) -alkoxy groups, Optionally substituted by 1 to 3 halogen atoms, or 1 to 2 exomethylene groups, and 1 to 3 nitrogen atoms and / or 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms Monocyclic or bicyclic heteroaryl groups, wherein the groups can be attached to the benzocycloheptene-based amine through any position, and optionally one or more Can be hydrogenated at the site of
A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group;
R ⁴ represents a hydroxy group,
R ⁵ is a (C ₁ -C ₅ ) -alkyl group or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group, an aryl group, (C ₁ -C ₈ ) alkylene An aryl group, a (C ₂ -C ₈ ) alkenylene aryl group, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₁ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, or a (C ₂ -C) ₈₎ alkenylene (C ₃ -C ₇₎ means a cycloalkyl group,
R ⁶ and R ⁷ , independently of one another, represent a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a 5H benzocycloheptene-based carbon atom]
The stereoisomer of Claim 1 represented by these. The following general formula (I):

[Wherein, R ¹ and R ² are each independently a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₅ ) -alkyl group, a (C ₁ -C ₅ ) -alkoxy group, (C ₁ -C ₅₎ - means a perfluoroalkyl group, or a cyano group, or
R ¹ and R ² together represent a group -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH-, or-(CH ₂ ) means a group selected from _{n + 2-} (where n is 1 or 2 and the terminal atom is directly bonded to the adjacent ring-carbon atom);
R ¹¹ and R ¹² represent a hydrogen atom,
R ³ is a C ₁ -C ₁₀ -alkyl group (optionally substituted with 1 to 3 hydroxy groups, halogen atoms), (C ₁ -C ₅ -alkyl, halogen, hydroxy or C ₁ -C _5- Optionally substituted by alkoxy, where the groups can be attached to the 5H benzocycloheptene-based amine through any position, and 1-2 keto groups, 1-2 (C _1- C ₃₎ - alkyl group, one to two (C ₁ -C ₃₎ - alkoxy groups, by 1 to 3 halogen atoms or one to two exomethylene group, optionally substituted with one or more positions And optionally hydrogenated at one or more sites), phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, Means Sokinoriniru, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7 or 1,8-naphthyridinyl, dihydroindolo sulfonyl, dihydroisoquinoline indolocarbazole, cycloalkenyl, benzimidazolyl or indolyl group,
A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group;
R ⁴ represents a hydroxy group,
R ⁵ means a (C ₁ -C ₅ ) -alkyl group, or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group,
R ⁶ and R ⁷ each independently represent a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring together with a benzocycloheptene-based carbon atom]
The stereoisomer of Claim 1 represented by these. The following general formula (I):

[Wherein, R ¹ and R ² are each independently a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₅ ) -alkyl group, a (C ₁ -C ₅ ) -perfluoroalkyl group, a cyano group, (C ₁ -C ₅ ) -alkoxy group, or taken together means (C ₁ -C ₂ ) -alkylenedioxy group, and R ¹ and R ² should be directly adjacent;
R ³ is (optionally substituted by C ₁ -C ₅ -alkyl, halogen, hydroxy or C ₁ -C ₅ -alkoxy), phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoxyl. Nolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindronyl Means indolonyl, benzimidazolyl or indolyl groups, wherein these groups can be attached to the benzocycloheptene-based amines through any position and are 1 to 2 keto groups, 1 to 2 of (C ₁ -C ₃₎ - alkyl Group, a 1-2 exomethylene groups, obtained is optionally substituted with one or more positions and 1 or obtained optionally is at multiple sites are hydrogenated,
A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group;
R ⁴ represents a hydroxy group,
R ⁵ means a (C ₁ -C ₅ ) -alkyl group, or optionally a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group,
R ⁶ and R ⁷ independently of one another represent a hydrogen atom, a methyl or ethyl group, or a (C ₃ -C ₆ ) -cycloalkyl ring with a benzocycloheptene-based carbon atom]
The stereoisomer of Claim 1 represented by these. R ¹ and R ² each independently represent a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₃ ) -alkyl group, a CF ₃ group, a cyano group or a methoxy group,
R ¹¹ and R ¹² represent a hydrogen atom,
R ³ is (optionally substituted by C ₁ -C ₃ -alkyl, halogen, hydroxy, C ₁ -C ₃ -alkoxy or methylpyrrolidin-2-one-5-yl), isoindolyl, dihydroindolyl, dihydro Means isoindolyl, dihydroisoquinolinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinolonyl, isoquinolonyl, indazolyl, dihydroindolonyl, or dihydroisoindolonyl group, where these groups are of benzocycloheptene type It can be attached to the amine through any position and is 1 or 2 by 1 to 2 keto groups, 1 to 2 (C ₁ -C ₃ ) -alkyl groups, or 1 to 2 exomethylene groups. Optionally substituted at multiple positions, and optionally hydrogenated at one or more sites,
A represents a —CR ⁶ R ⁷ —CH ₂ — group or a —CH ₂ —CR ⁶ R ⁷ — group,
D represents a —CR ⁴ R ⁵ —CH ₂ — group or a —CH ₂ —CR ⁴ R ⁵ — group;
R ⁴ represents a hydroxy group,
R ⁵ means a fully fluorinated (C ₁ -C ₃ ) -alkyl group,
R ⁶ and R ⁷ independently of each other represent a hydrogen atom or a methyl or ethyl group,
Stereoisomers of general formula (I) according to claim 1.   Use of the stereoisomer according to any one of claims 1 to 6 for producing a pharmaceutical agent.   Use of a stereoisomer according to any one of claims 1 to 5 for the manufacture of a pharmaceutical agent for the treatment of inflammatory diseases. -Lung disease associated with inflammation, allergies and / or proliferative processes,
-Rheumatic / autoimmune / joint diseases associated with inflammation, allergies and / or proliferative processes,
Allergies or pseudoallergic diseases associated with inflammatory and / or proliferative processes,
-Dermatological diseases associated with inflammation, allergies and / or proliferative processes,
-Eye diseases associated with inflammation, allergies and / or proliferative processes,
-For the production of a pharmaceutical agent for the treatment of diseases of the ear-nose-throat region associated with inflammation, allergies and / or proliferation processes, or endocrine diseases associated with inflammation, allergies and / or proliferation processes. Use as described in.   A pharmaceutical formulation comprising at least one stereoisomer according to any one of claims 1 to 5 or a mixture thereof and a pharmaceutically compatible vehicle. A method for producing stereoisomers of general formula I, comprising:
The following general formula II:

[Wherein the groups have the meanings indicated above]
The stereoisomer represented by these is cyclized by addition of an inorganic or organic acid, or a Lewis acid. 12. The general formula II according to claim 11, wherein AD means —CH ₂ — (CR ⁶ R ⁷ ) — (CH ₂ ) —C (OH) (CF ₃ ) — (compound of general formula IIa) A compound of the general formula III (where LG means chloride, bromide, iodide, sulfate or sulfonate) with an aldehyde of the general formula IV under basic conditions in an organic solvent, Reaction under a phase transfer catalyst with a commonly used phase transfer catalyst to form a compound of general formula V,

Next, the aldehyde V is reacted with a reagent VI (where R ^x means a (C ₁ -C ₃ ) -alkyl group or a benzyl group) under Horner-Wittig conditions and of the general formula VII After obtaining the compound and saponifying the ester according to methods known to those skilled in the art,

The enol ether is decomposed under acidic conditions, and the resulting α-keto acid is converted into an alcohol R ^y —OH (where R ^y means (C ₁ -C ₅ ) -alkyl under commonly used acidic conditions). To form an α-ketoester of the general formula VIII, reacted with Ruppert's reagent CF ₃ Si (CH ₃ ) ₃ ,

It is then reduced under conditions known to those skilled in the art to form aldehyde X and then reacted with an amine of the general formula R ³ —NH ₂ as already described in the prior art to give the general formula IIa ( Wherein R ³ has the meaning indicated in the claims, and AD represents —CH ₂ —C (CR ⁶ R ⁷ ) — (CH ₂ ) —C (OH) (CF) ₃ —. Imine) is formed,

Furthermore, the method which can be made to react according to claim 11. 12. General formula II according to claim 11, wherein AD represents — (CR ⁶ R ⁷ ) — (CH ₂ ) ₂ —C (OH) (CF ₃ ) — (compound of general formula IIb) A process for the production of a compound, wherein the nitrile of the general formula XI is converted to sodium hydride and the corresponding alkyl halide R ⁶ -Hal and / or R ⁷ -Hal or Hal-[(C ₂ -C ₅ ) -alkylene]- Reacting with Hal, optionally continuously, to form a compound of general formula XII,

The compound is reduced under normal conditions to form an aldehyde and then reacted with CBr ₄ / triphenylphosphine, optionally with the addition of zinc, to form a compound of general formula XIII;

The compound is converted to acetylene with butyllithium and converted to ester XIV with CF _3- (CO) COOR ^y , and the ester XIV is hydrogenated according to methods known to those skilled in the art to obtain a compound of general formula VIII b Forming an ester and reducing to an aldehyde, analogous to the method of claim 12,

It is then reacted with an amine R ³ —NH ₂ to give a compound of the general formula IIb (where R ³ has the meaning indicated in the above claims and AD is — (CR ⁶ R ⁷ ) — (CH ₂ ) ₂ -C (OH) (CF ₃ )-))

Furthermore, a process which can be reacted according to claim 11.   6. Stereoisomers of the general formula I according to any one of claims 1 to 5, in the form of salts with physiologically compatible anions.   Claims that exist in the form of their hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or oxalate Item 15. A stereoisomer according to Item 14.