TW201326179A - Furo[3,4-c]quinoline derivatives, medicaments containing such compounds, their use and process for their preparation - Google Patents

Abstract

The present invention relates to compounds defined by formula I wherein the variables R1-R8 are defined as in the description, possessing valuable pharmacological activity. Particularly, the compounds are inhibitors of cholesterol ester transfer protein (CETP) and thus are suitable for treatment and prevention of diseases which can be influenced by inhibition of this protein.

Description

Furan [3,4-C]quinoline derivative, medicament containing the same, use and preparation method thereof

The present invention relates to a 1,3,6,7,8,9-hexahydro-furan[3,4-c]quinoline derivative having the following chemical skeleton, which is structurally defined by Formula I, Wherein the radicals R ¹ to R ⁸ are as defined below, including tautomers, stereoisomers, mixtures thereof and salts thereof. The compounds according to the invention have useful pharmacological properties and are useful in the pharmaceutical field for the preparation of pharmaceutical compositions for human and/or veterinary medical use. The invention further relates to the use of a pharmaceutical composition comprising one or more compounds according to the invention and a compound according to the invention as a medicament, in particular for the preparation of a pharmaceutical combination for the treatment and/or prevention of a cardiac metabolic disorder or cardiovascular disorder Things. Furthermore, the invention relates to a process for the preparation of the compounds and pharmaceutical compositions according to the invention. Moreover, the present invention relates to a compound according to the present invention and a pharmaceutical composition for use in a method for inhibiting CETP and treating and/or preventing cardiovascular disorders or related diseases.

In the literature, compounds having an inhibitory effect on cholesterol ester transfer protein (CETP) have been proposed for the treatment of cardiovascular disorders, in particular hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, High cholesterol Blood and atherosclerosis.

Compounds from various chemical classes are described in the literature as inhibitors of CETP (WO 98/35937, WO 00/017164, WO 05/100298, US 2002120011, US 2002177708, WO 00/18724). Moreover, the substituted tetrahydroquinoline salt organism (WO 06/063828) has been described, however, the substituted 1,3,6,7,8,9--defined by formula I for inhibiting CETP has not been described. Hexahydro-furan[3,4-c]quinoline derivatives.

International Patent Application No. PCT/EP2011052376 discloses that a hexahydrofuran [3,4-c]quinoline derivative, a process for its preparation and its treatment and/or prevention can be inhibited by inhibiting cholesterol ester transfer protein transfer protein (CETP) Use of a pharmaceutical composition that affects abnormalities, such as cardiac metabolic disorders or cardiovascular disorders.

The object of the present invention is to find novel compounds, especially those having useful pharmacological properties, especially those which are active in terms of CETP, such as 1,3,6,7,8,9-hexahydro-furan [3,4 -c] Quinoline derivative. Another object of the present invention is to find 1,3,6,7,8,9-hexahydro-furan [3,4-] which has an inhibitory effect on CETP in vitro and in vivo and has suitable pharmacological and pharmacokinetic properties. c] Quinoline derivative to use it as a drug.

Another object of the present invention is to provide a novel pharmaceutical composition suitable for preventing and/or treating cardiac metabolic disorders or cardiovascular disorders, particularly hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, Hypercholesterolemia and atherosclerosis.

Other objects of the present invention will become apparent from the above and the following description.

In a first aspect, the invention relates to a compound structurally defined by formula I, Wherein R ¹ is a mono or bicyclic 5 to 10 membered aryl or heteroaryl group, wherein the heteroaryl group comprises from 1 to 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl group thereof is visible Requires substitution with R ⁹ , R ¹⁰ and/or R ¹¹ wherein R ⁹ is hydrogen, halogen, cyano, 1-4C-alkyl, 2-4C-alkenyl, 3-6C-cycloalkyl, 1-4C - alkoxy, fully or partially fluoro-substituted 1-4C-alkyl, fully or partially fluoro-substituted 1-4C-alkoxy, pentafluorothio, cyano-1-4C-alkyl, 1 -2C-alkyl-3-6C-cycloalkyl, cyano-3-6C-cycloalkyl, 1-2C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl or -(1-2C-alkyl)-oxetan-3-yl, R ¹⁰ is hydrogen, halogen, cyano, 1-4C-alkyl, 2-4C-alkenyl, 3-6C-cycloalkyl , 1-4C-alkoxy, fully or partially fluoro-substituted 1-4C-alkyl, fully or partially fluoro-substituted 1-4C-alkoxy, cyano-1-4C-alkyl, methyl 3-6C-cycloalkyl, cyano-3-6C-cycloalkyl, methoxy-1-4C-alkyl, hydroxy-1-4C-alkyl or 3-(1-2C-alkyl) - oxetan-3-yl, R ¹¹ is hydrogen or halogen, or R ⁹ and R ¹⁰ and together form a 5-6C- comprises a cycloalkane ring which is attached the carbon atom, One of the methylene groups may be replaced by oxygen, wherein for the case of a 6-membered ring system, the ring may optionally comprise a double bond, and/or wherein the ring may optionally be mono- or di-substituted with methyl, wherein, for two In the case where a methyl group is bonded to the same carbon, the methyl group may form a cyclopropyl ring together with the carbon to which it is attached, and R ² is a 1-6C-alkyl group, a 1-3C-perfluoroalkyl group, a 1-4C-alkane. Oxy-1-4C-alkyl or 4-7C-cycloalkyl, wherein 4-7C-cycloalkyl may be mono- or disubstituted by fluorine, hydroxy, methoxy and/or 1-2C-alkyl, as desired Wherein, in the case of a 5-7C-cycloalkyl system, one methylene group may optionally be replaced by oxygen, and R ³ and R ⁴ together with a carbon atom to which it is bonded form a 3-7C-cycloalkane ring, especially a cyclopropane ring. R ⁵ is hydrogen or 1-4C-alkyl, R ⁶ is 1-4C-alkyl, R ⁷ is hydrogen or 1-4C-alkyl, or R ⁶ and R ⁷ together and including the carbon atom to which they are bonded Forming a 5-7C-cycloalkane ring wherein one methylene group may optionally be replaced by oxygen, wherein the ring may optionally comprise a double bond, and/or wherein the ring may optionally be fluoro, hydroxy, 1-2C-alkoxy and/or Or 1-2C-alkyl mono or disubstituted R ⁸ is hydrogen, acetyl group, propionyl acyl group, a methoxy group or a hydroxyl group, its tautomers, their stereoisomers, mixtures and salts thereof.

The compounds of the formula I according to the invention and their pharmaceutically acceptable salts have useful pharmacological properties, in particular the inhibitory effect on cholesterol ester transfer protein (CETP).

The invention also relates to pharmaceutically acceptable salts of the compounds of the formula I according to the invention which are composed of inorganic or organic acids.

The invention also relates to a pharmaceutical composition comprising at least one compound of the formula I according to the invention or a pharmaceutically acceptable salt thereof, optionally together with one or more inert carriers and/or diluents.

The invention also relates to the preparation or preparation (for example by combination or mixing) of at least one compound according to the invention, including pharmaceutically acceptable salts thereof, and one or more excipients, carriers and/or diluents. Pharmaceutical composition.

The invention also relates to the use of at least one compound of the formula I according to the invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament suitable for the treatment and/or prophylaxis which can be effected by inhibition of cholesterol ester transfer protein (CETP) Pharmaceutical compositions of diseases, disorders or conditions, such as their cardiac metabolic disorders or cardiovascular disorders as described herein.

The invention also relates to the use of at least one compound of the formula I according to the invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prevention of cardiovascular disorders and related diseases such as hypolipoproteinemia, A pharmaceutical composition of dyslipidemia, hypertriglyceridemia, hyperlipidemia, hypercholesterolemia or atherosclerosis.

The invention also relates to at least one compound of the formula I according to the invention or A use of a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for inhibiting cholesterol ester transfer protein (CETP).

The invention also relates to a compound according to the invention, which is suitable for use in therapy and/or prevention, for example for the treatment and/or prevention of diseases or conditions which may be affected by inhibition of cholesterol ester transfer protein (CETP), For example, cardiovascular disorders, cardiac metabolic disorders, and related disorders, such as any of the diseases, disorders, and conditions described herein.

The invention also relates to a compound according to the invention which is suitable for inhibiting cholesterol ester transfer protein (CETP).

The invention further relates to a process for the preparation of a pharmaceutical composition according to the invention which comprises, preferably by non-chemically incorporating a compound of the formula I according to the invention or a pharmaceutically acceptable salt thereof into one or more In an inert carrier and / or diluent.

The present invention also relates to a disease or condition which can be affected by inhibition of cholesterol ester transfer protein (CETP) in a mammal (especially human) patient in need thereof (for example, cardiovascular disorders, cardiac metabolic disorders) Or a related disease, such as any of the diseases and conditions described herein, comprising administering to the patient a therapeutically effective amount of a compound of formula I according to the invention or a pharmaceutically acceptable salt thereof.

The invention also relates to a condition for the treatment and/or prevention of a condition which can be affected by inhibition of cholesterol ester transfer protein (CETP), such as a cardiovascular disorder, a cardiac metabolic disorder or a related disorder, such as any of the diseases described herein. And a pharmaceutical compound or composition according to the invention for use in a method of the invention, comprising, if desired, alone or in combination with one or more other therapeutic agents The compound or composition is administered (such as selected from the ones described herein) in combination (such as separate, sequential, simultaneous, combined or timed interleaved).

The invention also relates to a compound of the formula I according to the invention or a pharmaceutically acceptable salt thereof for use in a method of treating and/or preventing a cardiovascular disorder, a cardiac metabolic disorder or a related disorder selected from the group consisting of: an artery Atherosclerosis, dyslipidemia (eg mixed dyslipidemia), β-lipidemia, alpha liplipemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypolipoproteinemia, high Lipoprotein blood, low HDL cholesterol, high LDL cholesterol, familial hypercholesterolemia, peripheral vascular disease, hypertension, endothelial disorder, sore throat, ischemia, cardiac ischemia, stroke, myocardial infarction , reperfusion injury, angioplasty restenosis, arteriosclerosis, coronary heart disease, coronary artery disease, coronary vascular disease or congestive heart failure, diabetic vascular complications, insulin resistance, obesity, metabolic syndrome, diabetes (especially type 2 Diabetes) or endotoxemia, the method comprising, as needed, monotherapy or with one or more other therapeutic agents (such as selected from those described herein, such as HMG-CoA reductase) The combination therapy (such as separate, sequential, simultaneous, combined or timed interleaved) of the formulation (e.g., statin) is administered to the compound or a pharmaceutically acceptable salt thereof.

The invention also relates to a compound of the formula I according to the invention or a pharmaceutically acceptable salt thereof for use in a method of increasing HDL cholesterol levels in a patient and/or reducing VLDL cholesterol and/or LDL cholesterol levels in a patient, Optionally, in combination with one or more other therapeutic agents, such as those selected from the text (such as HMG-CoA reductase inhibitors (eg, statins)).

The invention also relates to a primary or secondary prevention of cardiovascular disease, in particular A compound of formula I according to the invention, or a pharmaceutically acceptable salt thereof, for use in a method of a severe cardiovascular event, optionally with one or more other therapeutic agents, such as those selected from the text (such as HMG-) A combination of a CoA reductase inhibitor (eg, statin).

The invention also relates to a process and an intermediate product for the preparation of a compound of the formula I according to the invention, its tautomers, stereoisomers thereof, mixtures thereof and salts thereof (see the general synthesis section method a and b).

Among the synthetic methods according to the invention, particular mention is made of a process for the preparation of a compound of formula VII (for example as an intermediate product of a compound of formula I) from a compound of formula IX and VIII, Wherein the variable groups R ² , R ³ , R ⁴ , R ⁶ and R ⁷ are as defined above and below and R ⁸ represents hydrogen, the method comprising, inter alia, a compound of formula IX and a compound of formula VIII, eg The reaction is carried out under reduced pressure at a temperature between 150 ° C and 250 ° C or in a suitable solvent such as acetic acid at a temperature between 100 ° C and 150 ° C to yield a compound of formula VII.

Among the intermediates according to the invention, it is particularly worth mentioning that the use of a compound of formula VI in the synthesis of a compound of formula I, Wherein the variable groups R ² , R ³ , R ⁴ , R ⁶ and R ⁷ are as defined above and below and R ⁸ represents hydrogen.

Other aspects of the invention will be apparent from the above and the following (including examples) and claims.

Unless otherwise stated, such groups, residues and substituents, especially R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are As defined above and below. If a residue, substituent or group occurs multiple times in a compound, it may have the same or different meanings. Some preferred meanings of the groups and substituents of the compounds according to the invention are given below.

A preferred embodiment of the invention is characterized by the following definitions:

a) for the definition of R ¹ ( a ⁱ ) in the order of preferred ( a ¹ ) to better ( a ² ) to most ( a ⁵ ):

( a ¹ ): Preferably, R ¹ represents thienyl, thiazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which may be via R ⁹ , R ¹⁰ and/or R ¹¹ substituted, or 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl, 3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5' -yl, 3,3-dimethyl-2,3-dihydrobenzofuran-6-yl or 2H-spiro[benzofuran-3,1'-cyclopropane]-6-yl, wherein R ⁹ is Hydrogen, halogen, cyano, 1-4C-alkyl, 2-4C-alkenyl, 3- 4C-cycloalkyl, 1-3C-alkoxy, 1-3C-alkyl substituted completely or predominantly with fluorine 1-3C-alkoxy, pentafluorothio, cyano-1-3C-alkyl, 1-2C-alkyl-3-4C-cycloalkyl, cyano-3, completely or predominantly substituted by fluorine -4C-cycloalkyl, 1-2C-alkoxy-1-3C-alkyl, hydroxy 1-3C-alkyl or 3-(1-2C-alkyl)-oxetan-3-yl, R ¹⁰ is hydrogen, halogen, cyano, 1-4C-alkyl, 1-3C-alkoxy, 1-3C-alkyl completely or predominantly substituted by fluorine, 1-3C- completely or predominantly substituted by fluorine. Alkoxy, cyano-1-3C-alkyl or methoxy-1-3C-alkyl, R ¹¹ is hydrogen or halogen.

( a ² ): More preferably, R ¹ represents 2-(R ⁹ )-3-(R ¹⁰ )-thiophen-5-yl, 5-(R ⁹ )-4-(R ¹⁰ )-thiazole-2 -yl, 1-(R ¹⁰ )-2-(R ⁹ )-3-(R ¹¹ )-phenyl-5-yl, 1-(R ¹⁰ )-2-(R ⁹ )-4-(R ¹¹ ) -Benz-5-yl, 5-(R ⁹ )-4-(R ¹⁰ )-pyridin-2-yl, 2-(R ⁹ )-3-(R ¹⁰ )-pyridin-5-yl, 5-( R ⁹ )-3-(R ¹⁰ )-pyridin-2-yl, 5-(R ⁹ )-4-(R ¹⁰ )-pyrimidin-2-yl, 2-(R ⁹ )-pyrimidin-5-yl, 3-(R ⁹ )-4-(R ¹⁰ )-pyridazine-6-yl, 2-(R ⁹ )-3-(R ¹⁰ )-pyrazine-5-yl, 1,1-dimethyl- 1,3-Dihydroisobenzofuran-5-yl, 3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl, 3,3-dimethyl-2, 3-Dihydrobenzofuran-6-yl or 2H-spiro[benzofuran-3,1'-cyclopropane]-6-yl, wherein R ⁹ is hydrogen, halogen, cyano, isopropyl, isobutyl Base, tert-butyl, isopropenyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, pentafluoroethyl, difluoro Methyl, 1,1-difluoroethyl-1-yl, trifluoromethoxy, difluoromethoxy, pentafluorothio, 2-cyano-propan-2-yl, 1-methyl-cyclopropane -1-yl, 1-methyl-cyclobut-1-yl, 1-cyano-cycloprop-1-yl, 1-cyano-cyclobutene-1- , 1-methoxy-ethyl-1-yl, 2-methoxy-propan-2-yl, 1-methoxy-ethyl-1-yl, 2-hydroxy-propan-2-yl or 3-( 1-2C-alkyl)-oxetan-3-yl, R ¹⁰ is hydrogen, halogen, cyano, methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluoromethyl , trifluoromethoxy or methoxymethyl, R ¹¹ is hydrogen, fluorine or chlorine.

( a ³ ): Even better, R ¹ represents 2-(R ⁹ )-thiophen-5-yl, 1-(R ⁹ )-2-(R ¹⁰ )-phenyl-4-yl, 1-( R ⁹ )-3-(R ¹⁰ )-phenyl-4-yl, 4-(R ⁹ )-phenyl-1-yl, 3-tert-butylphenyl, 3-trifluoromethylphenyl, 1, 2,3-Trifluoro-phenyl-5-yl, 1,3-difluoro-phenyl-5-yl, 5-(R ⁹ )-pyridin-2-yl, 2-(R ⁹ )-pyridine-5- , 5-(R ⁹ )-3-(R ¹⁰ )-pyridin-2-yl, 2-(R ⁹ )-pyrimidin-5-yl, 5-(R ⁹ )-4-(R ¹⁰ )-thiazole -2-yl, 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl or 3,3-dimethyl-2,3-dihydrobenzofuran-6-yl, Wherein R ⁹ is fluorine, chlorine, bromine, cyano, isopropyl, isobutyl, isopropenyl, tert-butyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, isopropoxy , tert-butoxy, trifluoromethyl, pentafluoroethyl, difluoromethyl, 1,1-difluoroethyl-1-yl, trifluoromethoxy, difluoromethoxy, pentafluorothio , 2-cyano-propan-2-yl, 1-methyl-cycloprop-1-yl, 1-methyl-cyclobut-1-yl, 1-cyano-cycloprop-1-yl, 1- Cyano-cyclobutan-1-yl, 2-methoxy-propan-2-yl, 2-hydroxy-propan-2-yl or 3-methyl-oxetan-3-yl, R ¹⁰ is hydrogen Methyl, cyano, methoxy Fluoro or chloro.

( a ⁴ ): Even more preferably, R ¹ represents 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-(1,1-difluoro-eth-1-yl)- Phenyl, 4-methylphenyl, 4-isopropylphenyl, 4-isobutylphenyl, 4-tert-butylphenyl, 3-tert-butylphenyl, 4-isopropenylbenzene Base, 4-cyanophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4- Tributyloxyphenyl, 4-trifluoromethoxyphenyl, 4-pentafluorothiophenyl, 4-pentafluoroethylphenyl, 2-trifluoromethyl-pyridin-5-yl, 5- Trifluoromethyl-pyridin-2-yl, 3-fluoro-4-trifluoromethyl-phenyl, 2-fluoro-4-trifluoromethylphenyl, 3-fluoro-5-trifluoromethyl-pyridine -2-yl, 3-cyano-4-trifluoromethylphenyl, 3-methoxy-4-trifluoromethylphenyl, 4-(2-cyano-propan-2-yl)-benzene , 4-(2-hydroxy-propan-2-yl)-phenyl, 4-cyclopropylphenyl, 4-(1-methylcyclopropyl-1-yl)-phenyl, 4-(1 -cyanocyclopropyl-1-yl)-phenyl, 2-trifluoromethyl-thiophen-5-yl, 4-(3-methyl-oxetan-3-yl)-phenyl, 5 - tert-butyl-4-methyl-thiazol-2-yl or 2-tert-butyl-pyrimidin-5-yl.

( a ⁵ ): Best, R ¹ represents 4-trifluoromethylphenyl, 4-tert-butylphenyl, 4-pentafluorothiophenyl, 4-pentafluoroethylphenyl, 2 -trifluoromethyl-pyridin-5-yl, 3-fluoro-4-trifluoromethyl-phenyl, 2-fluoro-4-trifluoromethylphenyl, 3-cyano-4-trifluoromethyl Phenyl or 3-methoxy-4-trifluoromethylphenyl.

b) for the definition of R ² ( b ⁱ ) in the order of preferred ( b ¹ ) to better ( b ² ) to optimal ( b ⁶ ):

( b ¹ ): preferably, R ² represents 1-5C-alkyl, trifluoromethyl, pentafluoroethyl, 1-3C-alkoxy-1-2C-alkyl, 1-3C-alkane Oxy-3C-alkyl or 4-7C-cycloalkyl, wherein 4-7C-cycloalkyl may be mono- or disubstituted by fluorine, hydroxy, methoxy and/or methyl as desired, and for 5-7C In the case of a cycloalkyl system, a methylene group may optionally be replaced by oxygen.

( b ² ): More preferably, R ² represents 1-5C-alkyl, trifluoromethyl, 1-3C-alkoxy-1-2C-alkyl, 1-3C-alkoxy-3C- Alkyl, cyclobutyl, methylcyclobutyl, dimethylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, fluorocyclohexyl, difluoro Cyclohexyl, hydroxycyclohexyl, methoxycyclohexyl, tetrahydrofuranyl or tetrahydropyranyl.

( b ³ ): Even better, R ² represents ethyl, isopropyl, 2-butyl, isobutyl, tert-butyl, 3-pentyl, cyclobutyl, cyclopentyl, cyclohexyl , methoxymethyl, 1-methoxyethyl, 2-methoxy-propan-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydrogen Piperan-3-yl or tetrahydropyran-2-yl.

( b ⁴ ): Even more preferably, R ² represents ethyl, isopropyl, tert-butyl, methoxymethyl, 1-methoxyethyl, 2-methoxy-propan-2 -yl, cyclobutyl, cyclopentyl or tetrahydropyran-4-yl.

( b ⁵ ): Even more preferably, R ² represents an isopropyl group, a tert-butyl group or a tetrahydropyran-4-yl group.

( b ⁶ ): Best, R ² represents an isopropyl group.

c) for the definition of R ³ and R ⁴ ( c ⁱ ) in the order of preferred ( c ¹ ) to better ( c ² ) to optimal ( c ³ ):

( c ¹ ) Preferably, R ³ and R ⁴ together with a carbon atom to which they are bonded form a cyclopropane, cyclobutane or cyclopentane ring.

( c ² ) More preferably, R ³ and R ⁴ together with a carbon atom to which they are bonded form a cyclopropane or cyclobutane ring.

(C ³⁾ the best words, R ³ and R ⁴ together and including the carbon atoms bonded thereto form a cyclopropane ring.

d) for the definition of R ⁵ ( d ⁱ ) in the order of preferred ( d ¹ ) to better ( d ² ) to optimal ( d ³ ):

( d ¹ ) Preferably, R ⁵ represents hydrogen, methyl or ethyl.

( d ² ) More preferably, R ⁵ represents hydrogen or methyl.

( d ³ ) Best, R ⁵ represents hydrogen.

e) for the definition of R ⁶ and R ⁷ ( e ⁱ ) in the order of preferred ( e ¹ ) to better ( e ² ) to best ( e ⁵ ):

( e ¹ ) Preferably, R ⁶ represents methyl, ethyl, propyl or isopropyl and R ⁷ represents hydrogen, methyl or ethyl, or R ⁶ and R ⁷ together and including carbon bonded thereto The atom forms a 5-6C-cycloalkane ring, wherein one methylene group may optionally be replaced by oxygen, and the ring may optionally contain a double bond and/or ring, optionally via fluorine, hydroxyl, 1-2C-alkoxy and/or 1-2C-alkyl is mono- or disubstituted.

( e ² ) More preferably, R ⁶ represents methyl, ethyl, propyl or isopropyl and R ⁷ represents hydrogen, methyl or ethyl, or R ⁶ and R ⁷ together and include carbon bonded thereto The atom forms a cyclopentane ring, a cyclopentene ring, a cyclohexane ring or a tetrahydropyran ring.

( e ³ ) Even better, R ⁶ and R ⁷ independently represent a methyl group or an ethyl group, or R ⁶ and R ⁷ together and including a carbon atom bonded thereto form a cyclopentane ring, cyclopentan-2- Alkene-1,1-diyl ring, cyclohexane ring, 4,4-difluorocyclohexane-1,1-diyl ring or tetrahydropyran-4,4-diyl ring.

( e ⁴ ) Even more preferably, R ⁶ represents a methyl group and R ⁷ represents a methyl group, or R ⁶ and R ⁷ together and including a carbon atom bonded thereto form a cyclopentane ring or a cyclopent-2-ene a 1,1-diyl ring, a cyclohexane ring or a tetrahydropyran-4,4-diyl ring.

( e ⁵ ) Preferably, R ⁶ and R ⁷ together with a carbon atom to which they are bonded form a tetrahydropyran-4,4-diyl ring.

f) for the definition of R ⁸ ( f ⁱ ) in the order of preferred ( f ¹ ) to better ( f ² ) to optimal ( f ³ ):

( f ¹ ) Preferably, R ⁸ represents hydrogen, ethoxylated or hydroxy.

( f ² ) More preferably, R ⁸ represents hydrogen or a hydroxyl group.

( f ³ ) Best, R ⁸ represents hydrogen.

Any one of the above definitions a) (a ¹ ) to f) (f ³ ) and each of them may be combined with each other.

Each of a ⁾ , b ⁱ , c ⁱ , d ⁱ , e ⁱ , and f ^{i of} a) to f) represents a characteristic and individual embodiment of the above-described corresponding substituent. Thus, due to the above definition, the compounds of formula I according to the invention (including their tautomers, stereoisomers, mixtures and salts) can be sufficiently characterized by the term (a ⁱ b ⁱ c ⁱ d ⁱ e ⁱ f ⁱ ) Preferred individual embodiments of the class, wherein for each index i, a single number is given and i varies between 1 and the maximum number given above; the index 0 of each letter indicates the beginning of the "invention" section Individual embodiments are given. The indices i vary independently of each other. The invention should include all individual embodiments described by the terms in parentheses having all the permutations of the index i (including i equal to 0) defined above.

Tables 1 below show, by way of example and in the preferred order of increasing the first row to the last row, such embodiments E-1 to E-16 which are considered to be preferred compounds according to the invention. This means that the embodiment E-16 represented by the entry of the last row of Table 1 is the preferred embodiment.

Each includes its tautomers, stereoisomers, mixtures and salts.

Another preferred embodiment of the compound of formula I according to the invention refers to a compound of formula I*, Wherein the variable groups R ¹ to R ⁸ are as defined above and below, their tautomers, stereoisomers thereof, mixtures thereof and salts thereof.

This example also includes a compound of formula I*, wherein the variable groups R ¹ to R ^{8 are} selected from the above definitions a) (a ¹ ) to f) (f ³ ) , tautomers thereof, stereoisomers thereof Constructs, mixtures thereof and salts thereof.

This example refers in particular to Examples E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9 in Table 1. a compound of the formula I* and a salt thereof as defined by E-10, E-11, E-12, E-13, E-14, E-15 or E-16.

An embodiment of a compound of formula I according to the invention refers to a compound of formula I**, Wherein the variable groups R ¹ to R ⁸ are as defined above and below, their tautomers, stereoisomers thereof, mixtures thereof and salts thereof.

This example also includes a compound of formula I** wherein the variable groups R ¹ to R ^{8 are} selected from the above definitions a) (a ¹ ) to f) (f ³ ) , tautomers thereof, stereo Isomers, mixtures thereof and salts thereof.

This example is particularly shown by the examples E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9 in Table 1, A compound of the formula I** and a salt thereof as defined by E-10, E-11, E-12, E-13, E-14, E-15 or E-16.

Another preferred embodiment of the compound of formula I according to the invention refers to a compound of formula I***, Wherein the variable groups R ¹ to R ⁸ are as defined above and below, their tautomers, stereoisomers thereof, mixtures thereof and salts thereof.

This example also includes a compound of formula I***, wherein the variable groups R ¹ to R ^{8 are} selected from the above definitions a) (a ¹ ) to f) (f ³ ) , tautomers thereof, Stereoisomers, mixtures thereof and salts thereof.

This example is particularly shown by the examples E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9 in Table 1, a compound of the formula I*** and a salt thereof as defined by E-10, E-11, E-12, E-13, E-14, E-15 or E-16 class.

Another embodiment of a compound of formula I according to the invention represents a compound of formula I****, Wherein the variable groups R ¹ to R ⁸ are as defined above and below, their tautomers, stereoisomers thereof, mixtures thereof and salts thereof.

This example also includes a compound of formula I****, wherein the variable groups R ¹ to R ^{8 are} selected from the above definitions a) (a ¹ ) to f) (f ³ ) , tautomers thereof, Its stereoisomers, mixtures thereof and salts thereof.

This example is particularly shown by the examples E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9 in Table 1, A compound of the formula I**** and a salt thereof as defined by E-10, E-11, E-12, E-13, E-14, E-15 or E-16.

A preferred embodiment of one of the compounds of formula I according to the invention is a compound of formula I***** Wherein the variable groups R ¹ to R ⁸ are as defined above and below, their tautomers, stereoisomers thereof, mixtures thereof and salts thereof.

This example also includes compounds of the formula I*****, wherein the variable groups R ¹ to R ^{8 are} selected from the above definitions a) (a ¹ ) to f) (f ³ ) , tautomers thereof , stereoisomers thereof, mixtures thereof and salts thereof.

This example is particularly shown by the examples E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9 in Table 1, A compound of the formula I***** and a salt thereof as defined by E-10, E-11, E-12, E-13, E-14, E-15 or E-16.

The invention further includes all mixtures (including racemates) of the stereoisomers described herein, which are independent of the ratio.

In a particular embodiment, the invention refers to compounds according to the invention wherein R ³ and R ⁴ together and including a carbon atom to which they are bonded form a cyclopentane ring.

A particularly preferred compound according to the invention is a compound selected from the group consisting of:

(3R,9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(4-(trifluoromethyl)phenyl)-2',3',5 ',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyranyl]-9-ol

̇5-((3R,9S)-9-Hydroxy-4-isopropyl-7,7-(ethyl-1,2-diyl)-2',3',5',6,6',7 ,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline Porphyrin-1,4'-piperidin-3-yl)-2-(trifluoromethyl)benzonitrile

(3R,9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(3-methoxy-4-(trifluoromethyl)phenyl)-2 ',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyranyl]-9-ol

(3R,9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(6-(trifluoromethyl)pyridin-3-yl)-2',3 ',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyranyl]-9-ol

̇(3R,6R,9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(4-(trifluoromethyl)phenyl)-2',3' ,5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-piperane-6,9-diol

̇5-((3R,6R,9S)-6,9-dihydroxy-4-isopropyl-7,7-(B -1,2-diyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4 '-Pyloryl-3-yl)-2-(trifluoromethyl)benzonitrile

(3R,6R,9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(3-methoxy-4-(trifluoromethyl)phenyl) -2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyrano]-6, 9-diol

and

(3R,6R,9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(6-(trifluoromethyl)pyridin-3-yl)-2' ,3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyrano]-6,9-di alcohol

Or its salt.

Some terms used above and below in relation to the compounds according to the invention will now be more precisely defined: the term "substituted" as used herein means the substitution of one or more hydrogens on a given atom by one of the specified groups. The restriction is that the normal valence of the specified atom is not exceeded and the substitution produces a stable compound.

The term 1-nC-alkyl, alone or as part of another group, wherein n may have a number from 1 to 6, denotes a saturated, branched or unbranched aliphatic, acyclic hydrocarbon radical having from 1 to n carbon atoms. . Examples of such groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, t-butyl, n-pentyl, isopentyl, Neopentyl, third amyl, n-hexyl, isohexyl and the like.

The term 2-nC-alkenyl, wherein n may have a value from 2 to 4, alone or as part of another group, means an unsaturated, branched or unbranched aliphatic having 2 to n carbon atoms, acyclic Hydrocarbyl group. Examples of such groups may include, but are not limited to, ethenyl, prop-1-en-1-yl, prop-1-en-2-yl, but-1-en-1-yl, but-1-ene- 2-Based, but-2-en-2-yl and the like.

The term halogen in the meaning of the present invention means fluorine, chlorine, bromine and iodine, of which fluorine, chlorine and bromine are more worth mentioning.

The term 1-nC-alkoxy, alone or as part of another group, denotes a 1-nC-alkyl-O- group, wherein 1-nC-alkyl is as defined above. Examples of such groups may include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy, third butoxy , n-pentyloxy, isopentyloxy, neopentyloxy, third pentyloxy, n-hexyloxy, isohexyloxy and the like.

The term 1-nC-alkoxy-1-nC-alkyl denotes 1-nC-alkyl as defined herein, substituted by 1-nC-alkoxy as defined herein.

The term cyano-1-nC-alkyl denotes 1-nC-alkyl as defined herein by cyano.

The term hydroxy-1-nC-alkyl denotes 1-nC- as defined in the context of hydroxy substitution. alkyl.

Mono or bicyclic 5 to 10 membered aryl or heteroaryl (wherein the heteroaryl group comprises from 1 to 4 heteroatoms selected from the group consisting of N, O and S) is meant to include from 0 to 4, optionally selected from N, A single or fused bicyclic 5 to 10 membered (completely or partially) aromatic or heteroaromatic ring system of heteroatoms of the group consisting of O and S.

An aryl group as used herein, alone or as part of another group, refers to a carbocyclic, mono- or fused bicyclic (complete or partial) aromatic ring system comprising a specified number of ring members. Representative 6 or 10 membered mono or fused bicyclic aryl groups include, but are not limited to, phenyl and naphthyl.

A heteroaryl group as used herein, alone or as part of another group, refers to a heterocyclic, mono- or fused bicyclic (complete or partial) heteroaromatic ring system comprising a specified number of ring members and comprising from 1 to 4 A hetero atom selected from the group consisting of nitrogen, oxygen and sulfur.

Representative 5-membered monocyclic heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, and Oxadiazole.

Representative 6 membered monocyclic heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl.

Representative 9-membered fused bicyclic groups include, but are not limited to, fluorenyl, benzothienyl, benzofuranyl, benzimidazolyl, benzopyrazolyl (carbazolyl), benzothiazolyl, benzo Oxazolyl, benzisothiazolyl, and benzisoxazole.

Representative 10-membered fused bicyclic heteroaryl groups include, but are not limited to, quinolinyl, isoquinolinyl, and quinazolyl.

Among the above 5- to 10-membered aryl or heteroaryl groups, more preferred are thienyl, thiazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and naphthyl groups.

The term 3-nC-cycloalkyl, alone or as part of another group, wherein n may have a value from 4 to 7, denotes a saturated, monocyclic, aliphatic hydrocarbon ring group having from 3 to n ring carbon atoms. . Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, with cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl being more notable. .

The term 3-nC-cycloalkane, wherein n may have a value from 4 to 7, alone or as part of another group, denotes a saturated, monocyclic, aliphatic hydrocarbon ring having from 3 to n ring carbon atoms. Examples of such rings may include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane rings, of which cyclopropane, cyclobutane, cyclopentane, and more Cyclohexane.

The term 1-nC-alkyl-3-nC-cycloalkyl denotes 3-nC-cycloalkyl as defined herein, substituted by 1-nC-alkyl as defined herein.

The term cyano-3-nC-cycloalkyl denotes a 3-nC-cycloalkyl group as defined herein substituted by cyano.

The completely or partially fluorine-substituted 1-nC-alkyl group is, for example, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1-Difluoro-1-ethyl or 1,1,1,3,3,3-hexafluoroisopropyl, especially trifluoromethyl. In one embodiment, a portion of the fluorine-substituted 1-nC-alkyl group represents a 1-nC-alkyl group substituted primarily with fluorine. This "mainly" means that more than half of the hydrogen atoms of the 1-nC-alkyl group are replaced by fluorine atoms.

a completely or partially fluorine-substituted 1-nC-alkoxy group such as difluoromethoxy Base, trifluoromethoxy, pentafluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy or 1,1,1,3,3,3-hexafluoro Isopropoxy group. In one embodiment, a portion of the fluorine-substituted 1-nC-alkoxy group represents a 1-nC-alkoxy group substituted primarily with fluorine. This "mainly" means that more than half of the hydrogen atoms of the 1-nC-alkoxy group are replaced by fluorine atoms.

In general, unless otherwise stated, a heterocyclic group as used herein includes all possible isomeric forms thereof, such as tautomers and/or positional isomers thereof. Thus, for example, the term pyridyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.

Substituted components as described herein may be substituted at any possible position unless otherwise indicated.

Moreover, unless otherwise stated, a carbocyclic group may be substituted at any possible position by a given substituent or parent molecular group in a manner as described herein.

Moreover, unless otherwise stated, a heterocyclic group as described herein may be substituted at any possible position (such as at any substitutable ring carbon or ring nitrogen atom) by a given substituent or parent molecular group thereof. .

Moreover, unless otherwise stated, a ring comprising a quaternary ammonium or amine group type ring nitrogen atom (-N=) may preferably not be present in such amine or imido type ring nitrogen atom. The upper four grades are ammonium.

If such residues, substituents or groups occur multiple times in a compound, they may have the same or different meanings.

In general, for a group comprising two or more subgroups, the last named subgroup is a group attachment point, for example the substituent "1-nC-alkoxy-1-nC- "Alkyl" means a 1-nC-alkoxy group bonded to a 1-nC-alkyl group, the former being bonded to the core or group to which the substituent will be bonded.

All atoms/elements described herein that include atoms that are part of a group include all stable isotopic forms of the respective elements. For example, whenever hydrogen is described explicitly or as part of a group such as a methyl group, this includes hydrogen and helium in the form of isotopes of the stable hydrogen of elemental hydrogen.

Unless otherwise stated, such groups, residues and substituents, in particular R ¹ to R ⁸ , R ^{7 '} , PG, R ^a , R ^b , R ⁹ to R ¹¹ are as defined above and below.

If not otherwise stated, the substituents R ⁹ , R ¹⁰ and/or R ¹¹ may be bonded to the ortho, meta or para position where the aromatic ring is bonded to the binding site of the backbone ring system, especially in the meta or pair Bit key.

Depending on their nature, the salts of the compounds of the formula I according to the invention include all acid addition salts and all base salts, in particular all pharmaceutically acceptable acid addition salts and base salts. Particular mention is made of physiologically tolerable salts of inorganic or organic acids or bases conventionally used in pharmacy. Such salts include water insoluble and especially water soluble salts.

Inorganic acids suitable for use in forming pharmaceutically or physiologically acceptable acid addition salts include, for example but are not limited to, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and the like. Organic acids suitable for use in forming pharmaceutically or physiologically acceptable acid addition salts include, for example, but are not limited to, citric acid, maleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid, methanesulfonic acid, and the like.

Thus, pharmaceutically or physiologically acceptable acid addition salts of inorganic or organic acids include, for example, but are not limited to, hydrochloride, hydrobromide, phosphate, sulfate, citrate, maleate, fumar Acid salt, succinate, lactic acid Salt, tartrate, methanesulfonate, etc.

Also included are salts which are unsuitable for pharmaceutical use but which are useful, for example, as free compounds of the isolated or purified form or pharmaceutically acceptable salts thereof.

The pharmaceutically unacceptable salts obtainable, for example, as a process product for the preparation of a compound according to the invention, for example on an industrial scale, can be converted into a pharmaceutically acceptable compound by methods known to those skilled in the art. Salt.

All isomeric forms of the compounds of formula I (especially all regioisomers and stereoisomeric forms, such as all palmar, enantiomerically, diastereomeric, unless expressly indicated to the particular isomeric form Constructs, racemic forms, tautomers, and all geometric isoforms are contemplated to be within the scope of the invention. Obviously, the most effective isomers with the least side effects in medicine are preferred.

It will be understood that the compounds of the invention comprise at least two asymmetrically substituted carbon atoms and may be isolated as a pure diastereomer or as a mixture of diastereomers in optically active or racemic form.

The compound of formula I is at least at positions 3 and 9 and depends on the meaning of R ³ and R ⁴ at position 7, depending on the meaning of R ⁸ at position 6 and depending on the meaning of R ⁶ and R ⁷ at position 1 The palm of the sex center.

The labels are as follows:

The present invention contemplates all conceivable stereoisomers, especially the diastereomers and enantiomers described herein, for example in substantially pure form, in an enriched form (eg, substantially free of any or All other undesired diastereomers and/or enantiomers and/or in any mixing ratio, including racemic forms and salts thereof.

In general, substantially pure stereo can be obtained according to the synthetic principles commonly used by those skilled in the art, for example by separating the corresponding mixtures, by using stereochemically pure starting materials and/or by stereoselective synthesis. isomer.

It is known in the related art how to prepare optically active forms, such as by resolution of racemic forms, or by, for example, synthesis from optically active starting materials and/or by the use of antagonistic agents.

Suitable diastereomeric compounds/intermediaries which can be separated by asymmetric synthesis, for example by preparation and isolation, by known methods, for example by chromatography or by crystallization from a suitable solvent (stepwise). And/or by using a palmitic reaction component (eg, a palmitic reagent, a palmitic catalyst, a palmitic ligand, a palmitic synthon, a palmitic building block, etc.), the invention is prepared An enantiomerically pure compound.

Moreover, it is known to those skilled in the art how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, such as by separation of the corresponding racemic mixture by chromatography on a palm separation column; or by utilizing Resolution of a racemic compound by a suitable resolving agent; for example, by formation of a racemic compound with a diastereomeric salt of an optically active acid or base, followed by resolution of the salt and release of the desired compound from the salt Or by using the palmar auxiliary reagent Derivatization of the corresponding racemic compound followed by enantiomeric separation and removal of the palmitic auxiliary group; by kinetic resolution of the racemate (eg by enzymatic resolution); by appropriate conditions, Enantioselective (preferred) crystallization from the agglomerates of the enantiomeric crystals (or crystallization by entrainment); or by (stepwise) crystallization from a suitable solvent in the presence of a palmitic auxiliary.

Biological test

The biological properties of the novel compounds can be studied as follows:

CETP in vitro assay

The CETP inhibitory activity of the compounds of the invention can be determined in a fluorescent assay purchased from Roar Biomedical, Inc. (New York, NY, USA). As described herein, the compounds of the invention inhibit the conversion of CETP-dependent cholesteryl esters from HDL to LDL. Recombinant human CETP was partially purified by medium conditioned by CHO cells expressing CETP. In a 384-well plate, combine 2.5 μl of the compound solution in DMSO with 2 μl of donor solution, 2 μl of receptor solution, and 0.8 μl of recombinant human CETP solution (to achieve a total volume of 100 μl using assay buffer) and at 37 Incubate for 3 hours at °C. Fluorescence intensity was measured at an excitation wavelength of 485 nm and an emission wavelength of 535 nm. Between 1 nM and the compound concentration dose-effect between the curve 30 μM, ₅₀ values _are calculated IC.

The compounds of the formula I according to the invention have, for example, less than 10000 nM, preferably less than 2000 nM, more preferably less than 400 nM, even more preferably less than 100 nM and most preferably less than 50 nM or less than 20 nM IC ₅₀ value. The IC ₅₀ values for the examples edited in the experimental section are provided in Table 2 below.

Metabolic degradation test

The metabolic degradation of the test compound was analyzed at 37 ° C using the collected human liver microsomes. The final culture volume of 100 μl per time point consisted of TRIS buffer (0.1 M), magnesium chloride (5 mM), microsomal protein (1 mg/ml) and test compound at a final concentration of 1 μM at room temperature, pH 7.6. .

After a brief pre-incubation period of 37 ° C, the reaction was initiated by the addition of a reduced form of β-nicotine indoleamine adenine dinucleotide phosphate (NADPH, 1 mM) and by aliquoting the test solution after different time points Terminated in the solvent. In addition, degradation unrelated to NADPH was monitored in cultures without NADPH and terminated at the last time point. The stopped culture formed cell pellets by centrifugation (10000 g, 5 min). An aliquot of the supernatant was analyzed by LC-MS/MS for the amount of the parent compound. The half-life (t 1/2) was determined by the slope of the semi-log plot of the concentration-time spectrum.

For example, a compound of formula I according to the invention is generally in human liver microparticles The body has a metabolic half-life of more than 50 min, preferably more than 100 min, more preferably more than 130 min.

Therefore, the compound of the present invention has a good inhibitory activity against CETP and has an extended metabolic stability particularly in human liver microsomes.

Indication

The compounds of formula I according to the invention and their physiologically tolerable salts have useful pharmacological properties for their commercial use. Thus, for example, such compounds are useful as inhibitors of CETP and are expected to be commercially useful in the treatment of diseases responsive to inhibition of CETP, such as any of the diseases described herein.

In view of its ability to inhibit cholesterol ester transfer protein (CETP), the compounds of formula I according to the invention and the corresponding pharmaceutically acceptable salts thereof are theoretically suitable for the treatment and/or prophylaxis by inhibiting cholesterol ester transfer proteins ( CETP) All of the conditions or diseases that are affected by the activity. Thus, the compounds according to the invention are particularly suitable for the treatment and/or prevention of cardiovascular disorders and/or cardiac metabolic disorders and related diseases, in particular atherosclerosis, surrounding Vascular disease, dyslipidemia (including, for example, mixed dyslipidemia), β-lipidemia, alpha lipoemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypolipoproteinemia, Hyperlipoproteinemia, low HDL cholesterol, high LDL cholesterol, familial hypercholesterolemia, sore throat, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplasty restenosis , hypertension, endothelial dysfunction, vascular complications of diabetes, prevention of diabetes, insulin resistance, obesity, metabolic syndrome, diabetes (especially type 2 diabetes) or endotoxemia, or arteriosclerosis, coronary heart disease, coronary artery disease , coronary vascular disease or congestive heart failure.

Application form and dosage

The compounds of formula I and their pharmaceutically acceptable salts can be used, for example, in the form of a pharmaceutical composition for enteral, parenteral or topical administration. It can be administered in any generally acceptable mode of administration, such as in the form of a lozenge, a coated lozenge, a dragee, a hard and soft gelatin capsule, a solution, an emulsion or a suspension, The rectum, for example in the form of a suppository, parenteral (including intravenously), for example in the form of an injection or infusion, or topically, for example in the form of an ointment, cream or oil. In a possible mode of administration, oral and intravenous delivery is preferred.

The pharmaceutical composition according to the invention comprises, for example, at least one compound of the invention (=active substance) in a total amount of from 0.1 to 99.9% by weight, from 5 to 95% by weight or from 20 to 80% by weight, optionally together with pharmaceutically acceptable Excipients.

Those skilled in the art are familiar with pharmaceutically acceptable excipients such as diluents, carriers, binders, disintegrants, interfacial activity by virtue of their expertise. Agents, lubricants, vehicles, adjuvants, adjuvants and/or other additives known to be suitable for the preparation of pharmaceutical compositions.

As pharmaceutically acceptable excipients, any excipient known to be suitable for use in pharmaceutical compositions is generally contemplated. Examples thereof include, but are not limited to, diluents, fillers, binders, disintegrants, lubricants, glidants, solvents, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants, preservatives, Stabilizer, carrier, thickener, complexing agent, buffer, pH adjuster (for example to obtain neutral, alkaline or acidic formulations), penetration enhancer, polymer, coating agent, propellant, tension modifier , surfactants, colorants, flavoring agents, sweeteners and dyes.

In general, suitable carrier materials are not only inorganic carrier materials but also organic carrier materials. Thus, for example, lactose, starch (for example, corn starch) or a derivative thereof, talc, vermiculite, polyvinylpyrrolidone, stearic acid or a salt thereof can be used for tablets, coated tablets, dragees and hard Carrier material of gelatin capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols. Carrier materials suitable for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Carrier materials suitable for injectable solutions or infusion solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols or polyethylene glycols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

In particular, the use of the desired pharmaceutical composition, formulation or formulation and Excipients, carriers and/or diluents of the type suitable for the mode are to be administered.

By the method known per se and familiar to the person skilled in the art, for example by combining the compound of the formula I or a pharmaceutically acceptable salt thereof (if necessary with other active substances), if necessary Or a variety of conventional carriers (such as solid or liquid carriers) and / or diluents, for example with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, Water/ethanol, water/glycerin, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or a fatty substance such as hard fat or a suitable mixture thereof, incorporated into A pharmaceutical composition according to the present invention is prepared in a gadolin formulation such as a troche or coated lozenge, capsule, powder, suspension or suppository.

Depending on the nature of the compound to be administered, the nature and severity of the disease to be treated or prevented, the age of the patient and the individual's condition and mode of administration and frequency, the dosage of the compound (=active compound) of the invention may be broadly restricted. Internal changes and, in each particular case, will of course be consistent with individual requirements. The dose of the compound of the invention (= active compound) conventionally used on the order of CETP inhibitors is generally considered. Conveniently, the dose by intravenous route may be from 0.1 ng/ml to 10 mg/ml, preferably from 1 ng/ml to 10 mg/ml, and the dose by the oral route is from 0.1 to 2000 mg, preferably 1 To 100 mg, 1 to 4 times per day in each case. Depending on the dosage, the daily dose can conveniently be administered in several dosage units.

combination

In addition to its use in monotherapy, the compounds according to the invention may also be used in combination with other active substances, especially for treatment and/or prevention. The above diseases, abnormalities and conditions.

Other active substances suitable for use in the combination include, for example, associated with one of the indications to enhance the therapeutic effect of a cholesterol ester transfer protein (CETP) inhibitor according to the invention and/or to reduce the cholesterol ester transfer protein according to the invention ( The doses of the CETP) inhibitors are the same.

Therapeutic agents suitable for use in the combination include, in particular, one or more lipid modulators. Lipid regulators include HMG CoA reductase inhibitors (eg, simvastatin, atorvastatin), fibrates (eg, bezafibrate, fenofibrate), Nicotinic acid and its derivatives, PPAR (α, γ or α/γ) agonists or modulators, ACAT inhibitors (such as avasimibe), MTP inhibitors, squalene cyclase and horns a squalene synthetase inhibitor, an LXR agonist or modulator, a bile acid binding substance (eg, cholestyramine, colesevelam), a cholesterol absorption inhibitor (eg, ezetimibe), Niacin, PCSK9 inhibitors, bile acid reuptake inhibitors, and lipase inhibitors.

Other therapeutic agents suitable for use in this combination include one or more anti-diabetic agents, such as metformin, alpha-glucosidase inhibitors (eg, acarbose, voglibose), PPAR (α, γ or α/γ) agonist or modulator, DPP-IV inhibitor (eg, sitagliptin, vildagliptin, saxagliptin, argrid) Alogliptin, Linagliptin, SGLT 2 inhibitors (eg dapagliflozin, sergliflozin), GLP-1 or GLP- 1 analog (such as exenatide, liraglutide), insulin or insulin analog, sulfonylurea (such as glibenclamide, tolbutamide, tolgbutamide) Glimepiride, thiazolidinediones (eg rosiglitazone, pioglitazone), nateglinide, repaglinide, 11-beta-HSD Inhibitor, glucose-6-phosphatase inhibitor, fructose-1,6-bisphosphatase inhibitor, glycogen phosphorylase inhibitor, glucagon receptor antagonist, phosphoenolpyruvate carboxykinase, liver An inhibitor of a sugar synthase kinase or pyruvate dehydrogenase and a glucokinase activator.

Also suitable for the combination are one or more anti-obesity drugs, including, for example, sibutramine, tetrahydrolipostatin, leptin, leptin mimetic, cannabinoid 1 receptor antagonist, MCH-1 receptor antagonist, MC4 receptor agonist, NPY5 or NPY2 antagonist or β3-agonist (such as SB-418790 or AD-9677) and 5HT2C receptor agonist.

Moreover, with drugs for influencing hypertension or chronic heart failure such as A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, beta blockers, calcium antagonists, central antihypertensive drugs, α-2- Combinations of adrenergic receptor antagonists, neutral endopeptidase inhibitors, platelet aggregation inhibitors, and others, or combinations thereof, are suitable. Examples of angiotensin II receptor antagonists are candesartan cilexetil, potassium losartan, eprosartan mesylate, valsartan (valsartan), telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, Austria Mesaltan ester (olmesartan medoxomil), tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701, and the like. Angiotensin II receptor antagonists are generally useful in combination with diuretics (such as hydrochlorothiazide) for the treatment or prevention of hypertension and diabetic complications.

The above therapeutic agents as a combination partner of the compound according to the present invention include pharmaceutically acceptable derivatives thereof such as pharmaceutically acceptable salts thereof. Those skilled in the art are aware of the types, total dosages, and forms of administration of other therapeutic agents that are co-administered based on their expertise. The total daily dose can vary over a wide range. The dosage of the above combination partner is usually from 1/5 of the generally recommended minimum dose to 1/1 of the generally recommended dosage.

In practicing the present invention, a compound according to the invention may be administered in combination, in a sequential, sequential, combined or sequential manner with one or more other active substances, such as any of the therapeutic agents described above as a combination partner.

In the present invention, the invention further relates to a combination comprising at least one first active ingredient of a compound according to the invention and a second active ingredient which is at least one of the above-mentioned active substances as a combination partner, in separate, sequential, Simultaneous, combined or time-staggered for use in therapy, especially for the treatment and/or prevention of cardiovascular disorders or related diseases such as those described herein.

Furthermore, the present invention relates to the use of a compound according to the invention in combination with at least one active substance as a combination partner as described above, which is suitable for the treatment or prevention which can be affected by inhibition of cholesterol ester transfer protein (CETP) activity. a disease or condition (especially a cardiac metabolic disorder and/or cardiovascular loss) A pharmaceutical composition, especially one of the diseases, disorders or conditions listed above.

Moreover, the invention relates to a pharmaceutical composition comprising a compound according to the invention and at least one active substance as a combination partner as described above, optionally with one or more inert carriers and/or diluents.

The term "combination" according to the invention may exist as a fixed combination, a non-fixed combination, a free combination or a part of a set.

A "fixed combination" is defined as a combination wherein the first active ingredient and the second active ingredient are present in a single unit dose or together as a single entity. An example of a "fixed combination" is a pharmaceutical composition in which the first active ingredient and the second active ingredient are present in a mixture for simultaneous administration. Another example of a "fixed combination" is a pharmaceutical composition in which the first active ingredient and the second active ingredient are present in one unit rather than in a mixture.

A "set of a portion" is defined as a combination in which the first active ingredient and the second active ingredient are present in more than one unit. An example of a "one part of a kit" is a combination in which the first active ingredient and the second active ingredient are present separately. The components of one of the sets can be dispensed separately, sequentially, simultaneously, simultaneously or sequentially.

The first and second active ingredients of a portion of the kit according to the present invention may be provided as separate formulations (i.e., independent of one another), which are then placed together for simultaneous, combined, sequential, separate or sequential interleaving In combination therapy; or as separate components of a combination package, packaged and present for simultaneous, combined, sequential, separate or sequential interleaving in combination therapy.

Medical treatment of the first and second active ingredients of a portion of the kit according to the invention The type of pharmaceutical formulation may be similar, ie the two components may be formulated in separate tablets or capsules or may be different, ie suitable for use in different administration forms, such as one active ingredient formulated into tablets or capsules and the other One is formulated, for example, for intravenous administration.

The amounts of the first and second active ingredients of the combination, composition or kit according to the invention may together comprise a therapeutically effective amount, especially for the treatment and/or prevention of the above mentioned diseases, disorders and conditions.

General synthesis

The compounds according to the invention can be obtained by synthetic methods known in principle. These compounds are preferably obtained by the following method according to the invention as described in more detail below.

Wherein R ¹ to R ⁷ as hereinbefore defined lines, R ⁸ represents hydrogen synthesis of compounds of the formula I can be carried out according to the method of the present invention is related to a reaction shown in FIG.).

In the first step of the route, a ketoester of formula XI (wherein R ^a represents a methyl or ethyl group) in a suitable solvent such as methanol or ethanol utilizes a suitable base such as sodium ethoxide or sodium methoxide. Deprotonation and treatment with an epoxide of formula XII at a temperature between -10 ° C and 80 ° C to produce ketolide X.

Using a suitable oxidizing agent (such as 2-iodooxybenzoic acid and 4-methoxypyridine-N-oxide) in a suitable solvent (such as dimethyl hydrazine) between 0 ° C and 50 ° C The ketone lactone X is oxidized at a temperature to form furanone IX.

The furanone of the formula IX and the enaminone of the formula VIII, for example, at a temperature between 150 ° C and 250 ° C, under a reduced pressure, or at a temperature between 100 ° C and 150 ° C, Condensation in a suitable solvent such as acetic acid yields the tricyclic dihydropyridine of formula VII.

Using an oxidizing agent such as 2,3-dichloro-5,6-dicyano-1,4-benzoxanthene (DDQ) in a suitable solvent such as dichloromethane at between 0 ° C and 50 ° C The dihydropyridine VII is oxidized at a temperature to form a tricyclic pyridine of the corresponding formula VI. Use of a suitable hydrogenating agent (such as borane-tetrahydrofuran-complex, borane-dimethyl sulfide-complex, borane-dimethylaniline-complex, borane-diethylaniline- a complex, sodium borohydride, lithium borohydride, lithium aluminum hydride) in a suitable solvent (such as diethyl ether, tetrahydrofuran, 1,4-dioxane or toluene) between -78 ° C and 100 ° C, However, it is preferably at a temperature between -50 ° C and 80 ° C, if necessary in the palm ligand (such as (1R, 2S) - (+) - cis-1-amino-2-indanol (1S,2R)-(-)-cis-1-amino-2-indanyl, (R)-1-methyl-3,3-biphenyl-tetrahydro-pyrrolo[1, 2-c][1,3,2]oxazolane or (S)-1-methyl-3,3-biphenyl-tetrahydro-pyrrolo[1,2-c][1 , the 3,2] oxazine N and B dioxole) is present, for reduction of ketone of formula VI group of the tricyclic pyridine, to produce an alcohol of formula V, wherein R ⁵ represents hydrogen. Reduction in the presence of a palm ligand results in a compound of formula V enriched in enantiomers. For example, using a borane reagent (such as borane-tetrahydrofuran-complex, borane-dimethyl sulfide-complex, borane-dimethylaniline-complex or borane-diethylaniline- a complex, each reduced in the presence of (1R,2S)-(+)-cis-1-amino-2-indanol to give a compound of formula V having a S configuration in a newly formed stereocenter As is known from the literature (see Tetrahedron: Asymmetry 1995, 6, 301-306; Synthesis 1998, 937-961 or Angew. Chem. 1999, 111, 3574-3576). Similarly, a compound of formula V with a suitable alkyl metal compound (such as 1-4C-dialkylzinc-, 1-4C-alkylmagnesium halide- or 1-4C-alkyllithium-reagent, especially 1-2C) -dialkylzinc-, 1-2C-alkylmagnesium halide- or 1-2C-alkyllithium-reagent) in a suitable solvent such as n-hexane, cyclohexane, toluene, diethyl ether, tetrahydrofuran or 1,4 -dioxane), as needed in the palm ligand (such as (R)-1-methyl-3,3-biphenyl-tetrahydro-pyrrolo[1,2-c][1, 3,2]oxazolidine, (R)-1-methyl-3,3-biphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxine Boron heterocycle, (-)-3-exo-dimethylamino-isobornyl, (+)-3-exo-dimethylamino-isobornyl or as in J. Am. Chem. Soc. In the presence of a ligand described in 2002, 124, 10970-10971 or Tetrahedron 1998, 54, 5651-5666, between -50 ° C and 100 ° C, but preferably between -20 ° C Alkylation at a temperature between 70 ° C produces the corresponding compound of formula V wherein R ⁵ represents a 1-4C-alkyl group, especially a 1-2C-alkyl group.

The alcohol group of the compound of formula V can be temporarily protected with a suitable protecting group, for example, as a third butyl dimethylformamidine ether, with a third butyl dimethylformamidine alkyl chloride Reacting in a solvent such as dimethylformamide or acetonitrile in the presence of imidazole at a temperature between -20 ° C and 120 ° C to produce a protected derivative of formula IV (where PG Indicates this appropriate protecting group). Alternatively, by reacting a compound of formula V with a third butyldimethylformamidinium-triflate in the presence of a base such as pyridine or 2,6-lutidine in a solvent such as In methylene chloride, diethyl ether, tetrahydrofuran, 1,4-dioxane or toluene, the reaction is carried out at a temperature between -50 ° C and 100 ° C, but preferably between -30 ° C and 50 ° C. This protection. Alternatively, it can be used, for example, in "Protective Groups in Organic Synthesis", Second Edition, Greene TW, Wuts PGM; Wiley-Interscience: New York, 1991 or in "Protective Groups", Kocienski PJ; Thieme: New York, 1994. Any other suitable protecting group as described.

By using a lactone of formula IV with a suitable R ¹ -metal reagent (such as R ¹ -magnesium halide- or R ¹ -lithium-reagent) in an aprotic solvent (such as diethyl ether, tetrahydrofuran, 1,4-two) In methane or toluene), it is converted to the formula III at a temperature between -78 ° C and room temperature for the lithium reagent or at a temperature between -50 ° C and room temperature for the magnesium reagent. Lactic acid naphthol.

Use a suitable acid (such as titanium tetrachloride or boron trifluoride-diethyl ether complex) with a suitable hydrogenating agent (such as sodium borohydride, sodium cyanoborohydride or sodium triethoxy borohydride, but preferably with three a combination of sodium acetoxyborohydride) in a suitable solvent (such as diethyl ether, dichloromethane, toluene or tetrahydrofuran, but preferably tetrahydrofuran) at a temperature between -50 ° C and room temperature Reduction of the lactate naphthol of III to the corresponding compound of formula II. Reduction under the preferred conditions yields a compound of formula II enriched in diastereomers. For example, reduction with a borane reagent such as sodium triethoxysulfonate in the presence of titanium tetrachloride can produce a compound of formula II wherein the newly formed stereocenter is better as evidenced by extensive NMR analysis. The ground has an R configuration.

Preferably, a fluoride reagent such as tetrabutylammonium fluoride or cesium fluoride is used or with an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid in a suitable solvent such as dichloromethane, 1,2-di In ethyl chloride, diethyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile or toluene, at a temperature between -50 ° C and 120 ° C, but preferably between -20 ° C and 80 ° C, Deprotection of a compound of formula II wherein PG represents a third butyldimethylformamidinyl group produces a compound of formula I.

Alternatively, by the literature, for example, in "Protective Groups in Organic Synthesis", Second Edition, Greene TW, Wuts PGM; Wiley-Interscience: New York, 1991 or in "Protective Groups", Kocienski PJ; Thieme: New York, 1994 The appropriate method described in the above removes any other protecting groups previously introduced.

The compound of formula II can also be converted to a compound of formula I (wherein R ⁸ represents ethyl ethoxy, propenyloxy or hydroxy) according to method b) of the invention shown in Figure 2.

The compound of formula I (wherein R ¹ to R ⁷ are as defined above and R ⁸ represents ethyl ethoxy, propyloxy or hydroxy) can be synthesized according to the method b) of the present invention shown in Figure 2. Wherein PG represents the appropriate protecting group which is initiated by a compound of formula XIII corresponding to compound II wherein R ⁸ represents hydrogen.

The first step is the formation of an N-oxide of formula XIV. The reaction is carried out by using a suitable oxidizing agent such as m-chloroperbenzoic acid (MCPBA) in a suitable solvent such as dichloromethane, 1,2-dichloroethane, chloroform or tetrachloromethane. The compound of formula XIII is treated at a temperature between 10 ° C and 60 ° C. The compound of formula XIV is then reacted with acetic anhydride or propionic anhydride at a temperature between 90 ° C and 180 ° C to yield a compound of formula II wherein R ⁸ represents an ethoxylated or propyloxy group. Preferably, a fluoride reagent such as tetrabutylammonium fluoride or cesium fluoride or an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is used in a suitable solvent such as dichloromethane, 1,2-dichloro Ethane, diethyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile or toluene, or methanol or water or a mixture thereof, between -50 ° C and 120 ° C, but preferably between -20 ° C and 80 The compound of formula II (wherein PG represents a third butyldimethylformamidinyl group) is deprotected at a temperature between ° C to give a compound of formula I wherein R ⁸ represents ethoxylated or propyloxy. Alternatively, by the literature, for example, in "Protective Groups in Organic Synthesis", Second Edition, Greene TW, Wuts PGM; Wiley-Interscience: New York, 1991 or in "Protective Groups", Kocienski PJ; Thieme: New York, 1994 The appropriate method described in the above removes any other protecting groups previously introduced. Using a suitable base such as sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as methanol, ethanol, tetrahydrofuran, water or a mixture of water and methanol or ethanol , wherein the processing of at a temperature of between 80 deg.] C under 0 ℃ and R ⁸ represents acetyl compound acyl group or a propoxy group of formula I, wherein R ⁸ can produce the compound of formula I of the hydroxyl groups represented. Alternatively, a suitable base such as sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide can be used in a suitable solvent such as methanol, ethanol or water or a mixture of water and methanol or ethanol. Wherein the compound of the formula II wherein the -OPG group and the R ⁸ residue are in the cis configuration are treated at a temperature between 0 ° C and 80 ° C, directly yielding the formula I wherein R ⁸ represents a hydroxyl group Compound.

The starting compounds of formula VIII, XI, XII are known or can be obtained in a similar or analogous manner to known procedures. A compound of formula VIII can be similar to its corresponding cyclohexa-1,3-dione, for example as described in Synthesis 1983, 902-903 Prepared as a substance. The cyclohexanedione can be prepared similarly to the procedure described in Angew. Chem. 1999, 111, 3574-3576.

In addition to the methods listed, a host of other methods are envisioned. Thus, the prior methods are in no way meant to limit the possible synthetic routes to which the compounds of the invention may be obtained, but are presented by way of example only to show some routes.

In addition to the above methods for the synthesis of compounds of formula I, it is conceivable to be familiar with such techniques if such transformations are compatible with other functional groups and if the functional groups so loaded are stable in subsequent conversions in the synthesis. Other functional group transformations at any stage of the synthesis are known.

For example, an aromatic hydroxy group can be converted to an aromatic sulfomethoxy group (such as methylsulfonyloxy, toluenesulfonyloxy or trifluoromethylsulfonyloxy). By using a compound having an aromatic hydroxy group with a sulfonic anhydride, a sulfonium chloride or a sulfonimide in a solvent such as dichloromethane, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, 1,4- In dioxane, acetonitrile or toluene) at a temperature between -78 ° C and 40 ° C in a base such as triethylamine, N,N-diisopropyl-N-ethylamine, pyridine or The conversion is carried out in the presence of a ruthenium catalyst such as 4-dimethylamino-pyridine (DMAP) in the presence of 6,6-lutidine.

By reacting a compound having an aromatic sulfomethoxy group with an alkenyl trifluoroborate, an alkenyl boronic acid, an alkenyl-boronic acid Alcohol ester, optionally substituted cyclopropylboronic acid or optionally substituted cyclopropylboronic acid An alcohol ester in a mixture of toluene, N,N-dimethylformamide, isopropanol, acetonitrile, 1,4-dioxane or tetrahydrofuran or toluene and tetrahydrofuran in a base such as aqueous sodium carbonate, aqueous carbonate In the presence of potassium, aqueous cesium carbonate, silver carbonate, cesium fluoride, triethylamine or N,N-diisopropyl-N-ethylamine, and in a catalyst such as ruthenium-triphenylphosphine-palladium- (0) , bis-tris-tert-butylphosphine-palladium-(0), 1,1'-bis-(biphenylphosphino)-ferrocene-dichloro-palladium-(II) or bis-[1 , in the presence of 2-bis-(biphenylphosphino)-ethane]-palladium-(0)), or in a palladium source (such as palladium diacetate or hydrazine-(diphenylmethyleneacetone)-dipalladium- (0) and a suitable ligand (such as tri-tert-butylphosphine, tri-cyclohexylphosphine, diadamantyl-1-yl-butylphosphine, 2-dicyclohexylphosphino-2',6 '-Diisopropoxy-1,1'-biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl or 2- In the presence of dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl), between 0 ° C and 180 ° C, but preferably between room temperature and 120 ° C Reacting at a temperature between the two, the aromatic sulfonyloxy group can be further converted into an alkenyl group or taken as needed a cyclopropyl group. The alkenyl group can be converted to an optionally substituted cyclopropyl group by a Simmons-Smith reaction, by using bromine-iodo-methane or diiodomethane and diethylzinc. , if necessary in the presence of trifluoroacetic acid in a solvent such as dichloromethane, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, 1,4-dioxane or toluene, at -50 ° C The reaction is carried out at a temperature between 80 ° C, but preferably between -10 ° C and room temperature.

The alkoxycarbonyl group can be converted to a dialkylmethanol group. By using an alkyl lithium reagent or an alkyl-Grignard reagent in a solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane or toluene, between -50 ° C and 80 ° C However, it is preferred to carry out the conversion by reacting at a temperature between -20 ° C and room temperature. Alternatively, the alkoxycarbonyl group can be converted to the hydroxymethyl group of the compound. By means of a reducing agent such as lithium aluminum hydride in a solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane or toluene, between -50 ° C and 80 ° C, but preferably between - React at a temperature between 20 ° C and 40 ° C to carry out the transfer Chemical. The hydroxyl group can be further converted to an alkoxy group by an alkylation reaction. May with an alkylating agent (such as an alkyl halide, methanesulfonic acid-alkyl-ester, p-toluenesulfonic acid-alkyl-ester or trifluoromethanesulfonate-alkyl-ester), in a base such as sodium hydride In the presence of potassium hydride, sodium hexamethyldiazide or potassium hexamethyldiazide, in a solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, N,N-dimethyl The conversion is carried out in methotrexate, acetonitrile or toluene at a temperature between -50 ° C and 80 ° C, but preferably between -20 ° C and 50 ° C.

Moreover, those skilled in the art know that if multiple reaction centers are present in the starting or intermediate compound, one or more reaction centers need to be temporarily blocked by the protecting group to allow the reaction to be specifically at the desired reaction center. keep going. For example, "Protecting Groups in Organic Synthesis" by T. Greene and P. Wuts (John Wiley & Sons, Inc. 1999, Third Edition) or P. Kocienski's "Protecting Groups (Thieme Foundations Organic Chemistry Series N Group" (Thieme) A detailed description of the use of a large number of proven protecting groups can be found in Medical Publishers, 2000).

In the foregoing reaction, any reactive group present, such as a carboxyl group, a carbonyl group, a hydroxyl group, an amine group, or an alkylamine group, may be protected during the reaction by a conventional protecting group which is removed again after the reaction. - or an imido group.

For example, the protecting group for the carboxyl group can be methyl-, ethyl-, tert-butyl- or benzyl.

For example, the protecting group for the carbonyl group can be an acetal or a ketal such as 1,3-dioxolan- or 1,3-dioxanyl.

For example, the protecting group for the hydroxy group may be trimethylmethane alkyl-, tert-butyldimethylformamidin-, ethenyl-, trityl-, benzyl- or tetrahydroper喃基.

The protecting group for an amine group, an alkylamino group or an imido group may be, for example, a decyl group, an ethyl fluorenyl group, a trifluoroethyl fluorenyl group, an ethoxycarbonyl group, a third butoxycarbonyl group, a benzyloxycarbonyl group. , benzyl, methoxybenzyl or 2,4-dimethoxybenzyl.

For example, in an aqueous solvent such as water, methanol/water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or 1,4-dioxane/water, in an acid such as trifluoroacetic acid or hydrochloric acid. Or in the presence of sulfuric acid or in the presence of a basic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, but preferably sodium hydroxide, or aprotic in the presence of, for example, iodotrimethylnonane, The removal of the carboxymethyl or carboxyethyl group is carried out in a hydrolytical manner at a temperature between 0 and 120 ° C, preferably between 10 and 100 ° C.

A mixture of acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid or pyridine-p-toluenesulfonate with water or in an organic solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4- can be used. In dioxane, toluene or acetone, the acetal or ketal is removed at a temperature between -20 ° C and 150 ° C, but preferably between 0 ° C and 120 ° C.

Preferably, by hydrogenolysis, for example using hydrogen, in the presence of a catalyst such as palladium/activated carbon in a suitable solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane or glacial acetic acid, Adding an acid (such as hydrochloric acid) or adding a base (such as triethylamine) as needed, at a temperature between 0 and 100 ° C, but preferably at an ambient temperature between 20 and 60 ° C, and 1 to 7 Bar, but preferably from 3 to 5 bar under hydrogen pressure, removes benzyl, methoxybenzyl or benzyloxycarbonyl. However, it is preferred to remove the 2,4-dimethoxybenzyl group in the presence of anisole in trifluoroacetic acid.

It is preferably treated by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by using iodine trimethyl decane, if necessary using a solvent such as dichloromethane, 1,4-dioxane, methanol or diethyl ether. The third butyl or third butoxycarbonyl group is removed.

Fluoride reagents (such as tetrabutylammonium fluoride or cesium fluoride) or acids (such as trifluoroacetic acid, hydrochloric acid or sulfuric acid) in solvents such as dichloromethane, 1,2-dichloroethane , in diethyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile or toluene, at a temperature between -50 ° C and 120 ° C, but preferably between -20 ° C and 80 ° C, remove the top three Mercaptoalkyl- or tert-butyldimethylformamidinyl.

The present invention is also directed to intermediates (including salts, stereoisomers, and salts of such stereoisomers), methods, and processes disclosed herein and useful in the synthesis of the final compounds according to the present invention. Accordingly, the invention is also directed to a process for the preparation of a compound according to the invention as disclosed herein, which can be carried out as described herein. Such methods can include one or more steps of conversion and/or reaction with the intermediate product, suitably under the conditions disclosed herein, using the appropriate reaction partner.

Furthermore, the compounds of the formula I or the intermediates obtained in the synthesis of the compounds of the formula I can be resolved into the enantiomers and/or diastereomers thereof as described above. Thus, for example, a cis/trans mixture can be resolved into its cis and trans isomers and the racemic compound can be separated into its enantiomers. body.

Thus, for example, the cis/trans mixture can be resolved into its cis and trans isomers by chromatography. The compound of the formula I in the presence of a racemate or the intermediate obtained in the synthesis of the compound of the formula I can be obtained by a method known per se (refer to "Topics in Stereochemistry" by Allinger NL and Eliel EL, sixth Vol., Wiley Interscience, 1971) An intermediate of the compound of Formula I isolated having its optical enantiomer and having at least 2 asymmetric carbon atoms or in the synthesis of a compound of Formula I, based on its physico-chemical differences , which can be resolved into the above by a method known per se, for example, by chromatography and/or fractional crystallization to form its diastereomers, and if such compounds are obtained in a racemic form. Enantiomer.

Preferably, optical activity is carried out by columnar chromatography on the palm phase or by crystallization from an optically active solvent or by formation of a salt or derivative (such as an ester or guanamine) with a racemic compound. The substance reacts to resolve the racemate. The salt can be formed by using an enantiomerically pure acid for the basic compound and an enantiomerically pure base for the acidic compound. Diastereomeric derivatives are formed using enantiomerically pure auxiliary compounds such as acids, activated derivatives or alcohols thereof. Separation of a mixture of diastereomers of a salt or derivative can thus be achieved by utilizing its different physico-chemical properties (e.g., solubility differences); by the action of a suitable reagent, the free enantiomer can be pure non- Release by enantiomeric salts or derivatives. Optically active acids commonly used for this purpose are, for example, D- and L-forms of tartaric acid, benzhydryl tartaric acid, xylene tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamine. Acid, aspartic acid or quinic acid. The optically active alcohols which can be used as auxiliary residues can be, for example, (+) or (-)-methanol and guanamines. The optically active thiol group can be, for example, (+)- or (-)-methoxycarbonyl.

Moreover, the compound of formula I can be converted to its salt with an inorganic or organic acid, especially for medical use, to a pharmaceutically acceptable salt. Acids which can be used for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. Corresponding methods are known to those skilled in the art.

When one of the final steps (eg removal of an acid or base labile protecting group from a suitable precursor) or purification is carried out in the presence of an inorganic or organic acid (eg, hydrochloric acid, trifluoroacetic acid, acetic acid or formic acid, etc.) or a base The compound of formula I can be obtained as a free compound or comprises a stoichiometric or non-stoichiometric amount of the acid or base (e.g., as a salt) depending on the individual chemical nature and the individual nature of the acid or base employed. The acid/base contained may be removed according to procedures known in the art, such as by titration or NMR analysis, and as needed, according to procedures familiar to those skilled in the art.

The salt of the compound of formula I can be converted to a free compound, if desired. Corresponding methods are known to those skilled in the art, for example via neutralization.

The free compound can be combined or reacted with the desired acid or base, for example by dissolving or suspending the free compound in a suitable solvent containing the desired acid or base or subsequently adding the desired acid or base (eg ketone (such as acetone, methyl) Ethyl ketone or methyl isobutyl ketone), ether (such as diethyl ether, diisopropyl ether, tetrahydrofuran or 1,4-dioxane), chlorinated hydrocarbons (such as dichloromethane or chloroform), low molecular weight aliphatic Alcohol (such as methanol, ethanol or isopropanol) or ester (such as ethyl acetate), or water, Salt is obtained in or a mixture thereof. The salt can be obtained by filtration, reprecipitation, precipitation of the salt with a non-solvent, or by evaporation of the solvent. The salt obtained can be converted to the other, for example by reaction with a suitable acid or base or by a suitable ion exchanger. Likewise, the salt obtained can be converted into a free compound which in turn can be converted to a salt by alkalization or acidification. In this way, a pharmaceutically unacceptable salt can be converted into a pharmaceutically acceptable salt.

The residue obtained by distilling off the solvent under reduced pressure and recrystallizing from a suitable solvent or subjecting it to a conventional purification method (such as column chromatography on a suitable support material) can be carried out in a manner known per se. The substances according to the invention are isolated and purified.

The compounds according to the invention can advantageously be obtained by the methods described in the following examples, for which purpose they can also be combined with methods known to those skilled in the art by virtue of their expert knowledge. Likewise, other compounds according to the invention, which are not explicitly described in the following examples, can be prepared in a similar or analogous manner to the examples.

Any or all of the compounds according to the invention (including salts, stereoisomers and stereoisomers thereof) mentioned as the final compound in the following examples are of particular interest within the scope of the invention.

Other features and advantages of the present invention will be apparent from the following examples. The following examples are intended to illustrate the principles of the invention by way of example and not limitation.

Instance

The following examples are intended to further illustrate the invention without limiting it.

The compounds described below have been characterized by the characteristic mass after ionization in the mass spectrometer, its _Rf -value in thin layer chromatography and/or its residence time in analytical HPLC.

HPLC method:

Method 1: Column: Waters XBridge C18, 30 x 3, 0 mm, 2, 5 μm, 60 ° C; UV detection: 190-400 nm; eluent A: water (0.2% trifluoroacetic acid), eluent B :methanol

Method 2: Column: Waters XBridge C18, 30 x 3, 0 mm, 2, 5 μm, 60 ° C; UV detection: 190-400 nm; eluent A: water (0.2% trifluoroacetic acid), eluent B :methanol

Method 3: Column: Waters XBridge C18, 30 x 4, 6 mm, 3, 5 μm, 60 ° C; UV detection: 190-400 nm; eluent A: water (0.2% trifluoroacetic acid), eluent B :methanol

Method 4: Column: Merck Chromolith Flash RP18e, 25 x 4.6 mm, 2 μm, UV detection: 230 nm / 254 nm; eluent A: water (0.1% formic acid), eluent B: methanol

Method 5: Column: Agilent Stable Bond SB-C18, 30 x 4.6 mm, 1, 8 μm; UV detection: DAD 190-400 nm; eluent A: water (0.1% trifluoroacetic acid), eluent B: Methanol

Thin layer chromatography: Merck; TLC silicone 60 F ₂₅₄

Method for preparing starting compounds Intermediate 1:

7-Aminospiro[2.5]non-6-ene-5-one

Step 1:1 - cyclopropylpropan-2-one

219 g of 1-(triphenylphosphoraniliden)-2-propanone, 100 g of (1-ethoxy-cyclopropoxy)-trimethyl-decane and 13.1 g of p-toluenesulfonic acid in 280 ml The mixture in 2-dichlorobenzene was heated to 105 ° C in an autoclave for 5 hours. The mixture was cooled to room temperature and stirred for 18 hours. The product was purified by distillation. Yield: 350 g of a 7% solution of 1,2-dichlorobenzene (based on 1H-NMR) (44% of theory)

Step 2: 7-Hydroxyspiro[2.5]oct-6-en-5-one

5.75 g of sodium was added portionwise to 240 ml of methanol and the solution was heated to reflux for 1 hour. 28.4 ml of dimethyl malonate was added and the mixture was heated to reflux for a further 10 minutes. The mixture was cooled to 35 ° C, 350 g of 1-cyclobutylidene propan-2-one (7% solution of 1,2-dichlorobenzene) was added and the mixture was refluxed for 1 hour. After cooling again to room temperature, 28.0 g of a potassium hydroxide solution in 130 ml of water was added and the mixture was refluxed for 1 hour. The mixture was cooled to room temperature and the pH was adjusted to 1.5 and then refluxed for one hour by careful addition of half-saturated hydrochloric acid. The mixture was cooled to room temperature and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by gelatin chromatography (petroleum ether / ethyl acetate 50: 50).

Yield: 10.0 g (28% of theory)

Step 3: 7-Aminospiro[2.5]indole-6-en-5-one

15 g of 7-hydroxy-spiro[2.5]oct-6-en-5-one and 10.9 g of ammonium acetate were dissolved in 170 ml of toluene and 1.9 ml of acetic acid. The mixture was refluxed for 4 hours using a Dean Stark trap. After cooling to room temperature, 100 ml of tert-butyl methyl ether was added, and the precipitated product was collected by filtration and dried under vacuum at 50 °C.

Yield: 13.9 g (93% of theory)

Mass spectrometry (ESI ⁺ ): m/z = 138 [M+H] ⁺

HPLC (Method 1): residence time = 0.430 min.

Intermediate 2:

(S)-9-(Terbutylbutyldimethylformamidooxy)-4-isopropyl-9-hydroxy-7,7-(ethyl-1,2-diyl)-2',3 ',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyrano]-3-one

Step 1:1, 6-dioxaspiro[2.5]octane

Under nitrogen, 6.6 g of sodium hydride (60% in mineral oil) was suspended in 90 ml of tetrahydrofuran and cooled to 0 °C. 91.7 g of trimethylsulfide iodide was added in portions. A solution of 15 g of dihydro-2H-piperidin-4(3H)-one in 300 ml of dimethyl hydrazine and 60 ml of tetrahydrofuran was added dropwise to the mixture. The mixture was then warmed to room temperature and stirred for 18 hours. The mixture was then poured into 1.2 l of ice water and extracted three times with diethyl ether. The combined organic phases were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuo gave the product.

Yield: 10.15 g (59% of theory)

R _f -value: 0.47 (silicone, petroleum ether / ethyl acetate 1:1)

Step 2: 3-Isobutyl decyl-1,8-dioxaspiro[4.5]nonan-2-one

Dissolve 6.6 g of 1,6-dioxaspiro[2.5]octane and 8.2 ml of methyl 4-methyl-3-oxovalerate in 30 ml of ethanol, cool to 0 ° C and use 3.9 g of sodium ethoxide Batch processing. After the addition was completed, the mixture was warmed to room temperature and stirred for 18 hours. The mixture was then poured into 200 ml of ice water, acidified to pH 3 by addition of 1 M hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate 100:0 to 50:50).

Yield: 3.93 g (33% of theory)

Mass spectrometry (ESI ⁺ ): m/z = 227 [M+H] ⁺

HPLC (method 4): residence time = 0.952 min.

Step 3: 3-Isobutyl decyl-1,8-dioxaspiro[4.5]indole-3-en-2-one

2.16 g of 4-methoxypyridine-1-oxide hydrate and 5.57 g of 2-iodooxybenzoic acid (45% by weight) were suspended in 20 ml of dimethyl hydrazine and stirred for 20 minutes until all the material had dissolved. Next, 3.0 g of 3-isobutyl decyl-1,8-dioxaspiro[4.5]nonan-2-one was added and the mixture was stirred for 24 hours. The mixture was diluted with a saturated aqueous solution of sodium hydrogencarbonate and the formed precipitate was filtered. The mother liquor was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was chromatographed on silica gel (petroleum ether / ethyl acetate 100:0 to 40:60).

Yield: 1.0 g (34% of theory)

Mass spectrometry (ESI ⁺ ): m/z = 225 [M+H] ⁺

HPLC (method 4): residence time = 0.899 min.

Step 4: 4-isopropyl-7,7-(ethyl-1,2-diyl)-2',3',5',6',7,8-hexahydro-3H-spiro[furan[3 ,4-c]quinoline-1,4'-pyrano]-3,9(6H)-dione

Mixing 8.0 g of 3-isobutylindol-1,8-dioxaspiro[4.5]non-3-en-2-one and 7.4 g of 7-amino-spiro[2.5]oct-6-en-5-one and Heat to 200 ° C under vacuum of 20 mbar for 10 minutes. The mixture was cooled to room temperature, 50 ml of ethyl acetate was added, the mixture was stirred for 60 minutes and the precipitate was isolated by filtration. will The crude product was dissolved in 100 ml of dichloromethane and treated with 7.9 g of 2,3-dichloro-5,6-dicyano-p-benzopyrene and stirred for 4 hours. The precipitate was isolated by filtration, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The phases were separated and the organic phase was dried with sodium sulfate and evaporated in vacuo.

Yield: 6.7 g (58% of theory)

Mass spectrometry (ESI ⁺ ): m/z = 342 [M+H] ⁺

HPLC (Method 2): residence time = 1.234 min.

Step 5: (S)-4-Isopropyl-9-hydroxy-7,7-(ethyl-1,2-diyl)-2',3',5',6,6',7,8, 9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyrano]-3-one

132 mg of (1R,2S)-(+)-cis-1-amino-2-indanol was dissolved in 300 ml of tetrahydrofuran and 2.19 ml of borane-diethylaniline-complexed was added dropwise to the solution. Things. After the gas evolution was completed, the solution was cooled to 0 ° C and 2 g of 4-isopropyl-7,7-(ethyl-1,2-diyl)-2',3 contained in 10 ml of tetrahydrofuran was added dropwise. ',5',6',7,8-hexahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-piperan]-3,9(6H)-dione. During the 2 hour period, the temperature was allowed to warm to room temperature and the mixture was stirred for 18 hr, and 100 mg of (1R,2S)-(+)-cis-1-amino-2-indanol was added and stirring was continued for further 7 hours. 20 ml of methanol was added dropwise and the mixture was stirred for another 30 minutes. The solvent was evaporated in vacuo and chromatographed on silica gel eluted with petroleum ether / ethyl acetate 100:0 to 0:100.

Yield: 1.51 g (75% of theory)

Mass spectrometry (ESI ⁺ ): m/z = 344 [M+H] ⁺

HPLC (Method 1): residence time = 1.137 min.

Step 6: (S)-9-(Terbutylbutyldimethylformamidooxy)-4-isopropyl-9-hydroxy-7,7-(ethyl-1,2-diyl)-2 ',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-piperidone-3-one

1.50 g of (S)-4-isopropyl-9-hydroxy-7,7-(ethyl-1,2-diyl)-2',3',5',6,6',7,8, 9-octahydro-3H-spiro[furan[3,4-c]quinolin-1,4'-piperidone-3-one was dissolved in 15 ml of tetrahydrofuran, and 1.64 ml of 2,6-dimethyl was added dropwise. Pyridine and 3.07 ml of trifluoromethanesulfonic acid-t-butyldimethylformamidate and the mixture was stirred for 1 hour. The solvent was then evaporated in vacuo and chromatographed on EtOAc (EtOAc:EtOAc:EtOAc:EtOAc

Yield: 1.92 g (96% of theory)

Mass spectrometry (ESI ⁺ ): m/z = 458 [M+H] ⁺

HPLC (Method 1): residence time = 1.543 min.

Intermediate 3:

5-iodo-2-(trifluoromethyl)benzonitrile

2.24 g of 5-bromo-2-(trifluoromethyl)benzonitrile was dissolved in a microwave vial 10 ml of 1,4-dioxane. 90 mg of copper iodide-(I) and 2.7 g of sodium iodide were added and the mixture was purged with argon for 5 minutes. 142 μl of trans-N,N'-dimethylcyclohexane-1,2-diamine and 1.9 ml of hexamethyldioxane were added and the mixture was heated for 6 hours to 110 °C. The mixture was then diluted in 100 ml of 4 M hydrochloric acid and stirred for 10 minutes. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed eluted with EtOAc (EtOAc EtOAc

Yield: 2.35 g (88% of theory)

HPLC (Method 5): residence time = 1.288 min.

Intermediate 4:

(9S)-9-(Terbutylbutyldimethylformamidooxy)-4-isopropyl-9-hydroxy-7,7-(ethyl-1,2-diyl)-3-(4 -(trifluoromethyl)phenyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1 , 4'-piperidin-3-ol

3.66 g of 1-iodo-4-(trifluoromethyl)benzene was dissolved in 40 ml of tetrahydrofuran, cooled to -78 ° C and treated with dropwise addition of 15.6 ml of a 1.7 M solution of tributyllithium in n-pentane. The mixture was stirred for 5 minutes and then 4.00 g of (S)-4-isopropyl-9-hydroxy-7,7-(ethyl-1,2-diyl)-2' contained in 20 ml of tetrahydrofuran was added dropwise. A solution of 3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-piperidone-3-one. The mixture was stirred at -78 ° C for 45 minutes, then quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate. Dry with magnesium sulfate and combine The organic phase and the solvent were evaporated in vacuo. The residue was chromatographed on silica gel (petroleum ether / ethyl acetate 100:0 to 70:30).

Yield: 3.35 mg (63% of theory)

Mass spectrometry (ESI ⁺ ): m/z = 604 [M+H] ⁺

HPLC (Method 1): residence time = 1.466 and 1.505 min. (diastereomer)

Similar to the above intermediate product 4, the following intermediate product was obtained:

(1) 5-((9S)-9-(T-butyldimethylformyloxy)-3-hydroxy-4-isopropyl-7,7-(ethyl-1,2-diyl) -2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyrano]-3 -yl)-2-(trifluoromethyl)benzonitrile

Obtained starting from 5-iodo-2-trifluoromethyl-benzonitrile.

Mass spectrometry (ESI ⁺ ): m/z = 629 [M+H] ⁺

HPLC (Method 1): residence time = 1.492 and 1.519 min.

Rf-value: 0.23 and 0.46 (silicone, petroleum ether/ethyl acetate 8:2)

(2) (3R, 9S)-9-(T-butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-( 3-methoxy-4-(trifluoromethyl)phenyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4 -c]quinoline-1,4'-pyranose]

Obtained starting from 4-iodo-2-methoxy-1-trifluoromethyl-benzene.

Mass spectrometry (ESI ⁺ ): m/z = 618 [M+H] ⁺

HPLC (Method 1): residence time = 1.470 and 1.506 min.

(3) (3R,9S)-9-(Third butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-( 6-(Trifluoromethyl)pyridin-3-yl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c] Quinoline-1,4'-pyranose]

Obtained starting from 5-iodo-2-trifluoromethyl-pyridine.

Mass spectrometry (ESI ⁺ ): m/z = 605 [M+H] ⁺

HPLC (Method 1): residence time = 1.462 and 1.494 min.

Intermediate 5:

(3R,9S)-9-(Terbutylbutyldimethylformamidooxy)-4-isopropyl-9-hydroxy-7,7-(ethyl-1,2-diyl)-3- (4-(Trifluoromethyl)phenyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline -1,4'-pyranose]

And (3S,9S)-9-(t-butyldimethylmethylmethylalkyloxy)-4-isopropyl-9-hydroxy-7,7-(ethyl-1,2-diyl)-3 -(4-(Trifluoromethyl)phenyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quin Porphyrin-1,4'-pyranose]

3.35 g (9S)-9-(t-butyldimethylformyloxy)-4-isopropyl-9-hydroxy-7,7-(ethyl-1,2-diyl)-3 -(4-(Trifluoromethyl)phenyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quin The porphyrin-1,4'-piperidin-3-ol was dissolved in 100 ml of dichloromethane, cooled to 0 ° C and treated dropwise with 22.5 ml of 1 m of titanium-(IV)-chloride in dichloromethane. The mixture was stirred at room temperature for 30 minutes and 6.26 g of sodium triacetoxyborohydride was added. The mixture was stirred at room temperature for 2 hours and then quenched with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried over sodium sulfate. The solvent was evaporated in vacuo and chromatographed on silica gel eluting with petroleum ether/ethyl acetate (100:0 to 85:15).

(3R,9S)-9-(Terbutylbutyldimethylformamidooxy)-4-isopropyl-9-hydroxy-7,7-(ethyl-1,2-diyl)-3- (4-(Trifluoromethyl)phenyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline -1,4'-pyranose]: Yield: 1.77 g (54% of theory)

Mass spectrometry (ESI ⁺ ): m/z = 588 [M+H] ⁺

HPLC (method 1): residence time = 1.956 min.

R _f -value: 0.43 (silicone, petroleum ether / ethyl acetate 9:1)

(3S,9S)-9-(Third butyldimethylformyloxy)-4-isopropyl-9-hydroxy-7,7-(ethyl-1,2-diyl)-3- (4-(Trifluoromethyl)phenyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline -1,4'-pyranose]: Yield: 1.03 g (32% of theory)

Mass spectrometry (ESI ⁺ ): m/z = 588 [M+H] ⁺

HPLC (method 1): residence time = 1.956 min.

R _f - value: 0.28 (silicone, petroleum ether / ethyl acetate 9:1)

Similar to Intermediate 5, the following intermediates were obtained:

(1) 5-((3R,9S)-9-(T-butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)- 2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyrano]-3-yl )-2-(trifluoromethyl)benzonitrile

Mass spectrometry (ESI ⁺ ): m/z = 613 [M+H] ⁺

HPLC (Method 1): residence time = 1.528 min.

Rf-value: 0.20 (silicone, petroleum ether / ethyl acetate 9:1)

And 5-((3S,9S)-9-(t-butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)-2' ,3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-piperanyl-3-yl)- 2-(trifluoromethyl)benzonitrile

Mass spectrometry (ESI ⁺ ): m/z = 613 [M+H] ⁺

HPLC (Method 1): residence time = 1.528 min.

Rf-value: 0.32 (silicone, petroleum ether / ethyl acetate 9:1)

From 5-((9S)-9-(t-butyldimethylformyloxy)-3-hydroxy-4-isopropyl-7,7-(ethyl-1,2-diyl)- 2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyrano]-3-yl -2-(Trifluoromethyl)benzonitrile was obtained at the beginning.

(2) (3R, 9S)-9-(T-butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-( 3-methoxy-4-(trifluoromethyl)phenyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4 -c]quinoline-1,4'-pyranose]

Mass spectrometry (ESI ⁺ ): m/z = 618 [M+H] ⁺

HPLC (Method 1): residence time = 1.525 min.

Rf-value: 0.18 (silicone, petroleum ether / ethyl acetate 9:1)

And (3S,9S)-9-(t-butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(3- Methoxy-4-(trifluoromethyl)benzene -2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyran]

Mass spectrometry (ESI ⁺ ): m/z = 618 [M+H] ⁺

HPLC (Method 1): residence time = 1.525 min.

Rf-value: 0.31 (silicone, petroleum ether / ethyl acetate 9:1)

From (9S)-9-(t-butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(3-methoxy 4-(trifluoromethyl)phenyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quin The porphyrin-1,4'-piperidin-3-ol is obtained starting from the beginning.

(3) (3R,9S)-9-(Third butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-( 6-(Trifluoromethyl)pyridin-3-yl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c] Quinoline-1,4'-pyranose]

Mass spectrometry (ESI ⁺ ): m/z = 589 [M+H] ⁺

HPLC (Method 1): residence time = 1.598 min.

Rf-value: 0.12 (silicone, petroleum ether / ethyl acetate 9:1)

And (3S,9S)-9-(t-butyldimethylformyloxy)-4-isopropyl -7,7-(ethyl-1,2-diyl)-3-(6-(trifluoromethyl)pyridin-3-yl)-2',3',5',6,6',7, 8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyran]

Mass spectrometry (ESI ⁺ ): m/z = 589 [M+H] ⁺

HPLC (Method 1): residence time = 1.598 min.

Rf-value: 0.22 (silicone, petroleum ether / ethyl acetate 9:1)

From (9S)-9-(t-butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(6-(three Fluoromethyl)pyridin-3-yl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1 , 4'-piperidin-3-ol was obtained at the beginning.

Intermediate 6:

(3R,6RS,9S)-acetic acid 9-(t-butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-( 4-(Trifluoromethyl)phenyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline- 1,4'-piperidin-6-yl ester

70 mg (3R,9S)-9-(t-butyldimethylformyloxy)-4-isopropyl-9-hydroxy-7,7-(ethyl-1,2-diyl) -3-(4-(trifluoromethyl)phenyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c ] Quinoline-1,4'-pyranose] dissolved in 2 ml of dichloromethane and utilized 67.5 mg of m-chloroperbenzoic acid (MCPBA) (70%) processing. The mixture was stirred for 18 hours and then separated between dichloromethane and aqueous sodium hydroxide (1 M). The organic phase was dried over sodium sulfate and the solvent was evaporated.

The residue was dissolved in 2 ml of acetic anhydride and heated at 130 ° C for 2 hours. Excess acetic anhydride was removed under vacuum and the residue was diluted with diethyl ether. After washing with a saturated aqueous solution of sodium hydrogencarbonate, the organic phase was dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by reversed column chromatography (Xbridge <RTI ID=0.0># </RTI> </RTI> <RTIgt;

(Yield: 37 mg (49% of theory)

Mass spectrometry (ESI ⁺ ): m/z = 646 [M+H] ⁺

HPLC (Method 1): residence time = 1.584 min.

Similar to the intermediate product 6, the following intermediate product was obtained:

(1) (3R, 6RS, 9S)-acetic acid 9-(t-butyldimethylformyloxy)-3-(3-cyano-4-(trifluoromethyl)phenyl)-4 -isopropyl-7,7-(ethyl-1,3-diyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3 ,4-c]quinoline-1,4'-piperidin-6-yl ester

From (3R,9S)-9-(t-butyldimethylmethylmethylalkyloxy)-3-(3-cyano-4-(trifluoromethyl)phenyl)-4-isopropyl- 7,7-(B-1,2-diyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c] Quinoline-1,4'-pyranose] Get it at the beginning.

Mass spectrometry (ESI ⁺ ): m/z = 671 [M+H] ⁺

HPLC (method 3): residence time = 1.998 min.

(2) (3R, 6RS, 9S)-acetic acid 9-(t-butyldimethylformyloxy)-3-(3-methoxy-4-(trifluoromethyl)phenyl)- 4-isopropyl-7,7-(ethyl-1,3-diyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan [ 3,4-c]quinoline-1,4'-piperidin-6-yl ester

From (3R,9S)-9-(t-butyldimethylformyloxy)-3-(3-methoxy-4-(trifluoromethyl)phenyl)-4-isopropyl -7,7-(B-1,2-diyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c [Quinoline-1,4'-pyran] is obtained starting from .

Mass spectrometry (ESI ⁺ ): m/z = 676 [M+H] ⁺

HPLC (Method 1): residence time = 1.566 min.

(3) (3R, 6RS, 9S)-acetic acid 9-(t-butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)- 3-(6-(Trifluoromethyl)pyridin-3-yl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4 -c]quinoline-1,4'-piperidin-6-yl ester

From (3R,9S)-9-(t-butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(6- (trifluoromethyl)pyridin-3-yl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline -1,4'-Peme] was obtained at the beginning.

Mass spectrometry (ESI ⁺ ): m/z = 647 [M+H] ⁺

HPLC (Method 1): residence time = 1.528 min.

Method of preparing the final compound Examples 1 to 4

(1) (3R,9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(4-(trifluoromethyl)phenyl)-2',3' , 5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyrano]-9-ol (Example 1)

1.77 g of (3R,9S)-9-(t-butyldimethylformyloxy)-4-isopropyl-9-hydroxy-7,7-(B-) in 20 ml of tetrahydrofuran 1,2-diyl)-3-(4-(trifluoromethyl)phenyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro [ A solution of furan [3,4-c]quinoline-1,4'-pyran] was added to a solution of 3.41 ml of 1 M tetrabutylammonium fluoride in tetrahydrofuran. The solution was stirred at room temperature for 3 hours, then the solvent was evaporated in vacuo and purified eluting with EtOAc EtOAc EtOAc

Yield: 1.34 g (94% of theory)

Mass spectrometry (ESI ⁺ ): m/z = 474 [M+H] ⁺

HPLC (method 1): residence time = 1.160 min.

Similar to Example 1, the following examples were obtained:

(2) 5-((3R,9S)-9-hydroxy-4-isopropyl-7,7-dimethyl-2',3',5',6,6',7,8,9- Octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-piperanyl-3-yl)-2-(trifluoromethyl)benzonitrile (Example 2)

From 5-((3R,9S)-9-(t-butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)-2' ,3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-piperanyl-3-yl)- 2-(Trifluoromethyl)benzonitrile was obtained starting from the beginning.

Mass spectrometry (ESI ⁺ ): m/z = 499 [M+H] ⁺

HPLC (Method 1): residence time = 1.142 min.

(3) (3R,9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(3-methoxy-4-(trifluoromethyl)phenyl) -2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyran]-9- Alcohol (Example 3)

From (3R,9S)-9-(t-butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(3- Methoxy-4-(trifluoromethyl)phenyl) -2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyran] (Example 4 ) Get started.

Mass spectrometry (ESI ⁺ ): m/z = 504 [M+H] ⁺

HPLC (method 1): residence time = 1.160 min.

(4) (3R,9S)-4-isopropyl-7,7-dimethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-2',3',5', 6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyrano]-9-ol (Example 4)

From (3R,9S)-9-(t-butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(6- (trifluoromethyl)pyridin-3-yl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline -1,4'-Peme] was obtained at the beginning.

Mass spectrometry (ESI ⁺ ): m/z = 475 [M+H] ⁺

HPLC (Method 1): residence time = 1.0514 min.

Examples 5 through 8:

(3R,6R,9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(4-(trifluoromethyl)phenyl)-2',3', 5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyrano]-6,9-diol (Example 5 )

35 mg (3R, 6RS, 9S)-acetic acid 9-(t-butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)- 3-(6-(Trifluoromethyl)pyridin-3-yl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4 -c]quinoline-1,4'-piperidin-6-yl ester was dissolved in 0.5 ml of methanol and treated with 43 mg of potassium carbonate. The mixture was stirred at room temperature for 24 hours, diluted with ethyl acetate and washed with brine. The organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by reverse phase column chromatography (XBridge C18 10 μm, water (0.1% trifluoroacetic acid) / methanol 90:10 to 0:100).

Yield: 14 mg (53% of theory)

Mass spectrometry (ESI ⁺ ): m/z = 490 [M+H] ⁺

HPLC (Method 1): residence time = 1.291 min.

Similar to Example 5, the following examples were obtained:

(1) 5-((3R,6R,9S)-6,9-Dihydroxy-4-isopropyl-7,7-(ethyl-1,2-diyl)-2',3',5' ,6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-piperidin-3-yl)-2-(trifluoromethyl) Benzobenzonitrile (Example 6)

From (3R,6RS,9S)-acetic acid 9-(t-butyldimethylformyloxy)-3-(3-cyano-4-(trifluoromethyl)phenyl)-4-iso Propyl-7,7-(ethyl-1,2-diyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4 -c] Quinoline-1,4'-piperidin-6-yl ester was obtained initially.

Mass spectrometry (ESI ⁺ ): m/z = 515 [M+H] ⁺

HPLC (Method 2): residence time = 1.222 min.

(2) (3R,6R,9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(3-methoxy-4-(trifluoromethyl)benzene -2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyran]- 6,9-diol (Example 7)

From (3R,6RS,9S)-acetic acid 9-(t-butyldimethylformamidineoxy)-3-(3-methoxy-4-(trifluoromethyl)phenyl)-4- Isopropyl-7,7-(ethyl-1,2-diyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3, 4-c]quinoline-1,4'-piperidin-6-yl ester was obtained initially.

Mass spectrometry (ESI ⁺ ): m/z = 520 [M+H] ⁺

HPLC (method 1): residence time = 1.266 min.

(3) (3R,6R,9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(6-(trifluoromethyl)pyridin-3-yl)- 2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyrano]-6,9 -diol (Example 8)

From (3R,6RS,9S)-acetic acid 9-(t-butyldimethylformyloxy)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3- (6-(Trifluoromethyl)pyridin-3-yl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c Quinoline-1,4'-pyranose] The -6-yl ester was obtained at the beginning.

Mass spectrometry (ESI ⁺ ): m/z = 505 [M+H] ⁺

HPLC (Method 1): residence time = 1.03 min.

Some examples of formulations are now described, wherein "active material" means one or more compounds according to the invention, including salts thereof. In the case of combination with one of the other active substances mentioned above, the term "active substance" also includes other active substances.

Example A Lozenges containing 100 mg of active substance composition:

1 tablet contains:

Preparation

The active substance, lactose and starch are mixed together and the aqueous solution using polyvinylpyrrolidone is uniformly wetted. After the wet composition has been screened (2.0 mm mesh) and in a tray type dryer at 50 °C, the filter (1.5 mm mesh) is again screened and the lubricant is added. The final mixture is compressed to form a tablet.

Lozenge weight: 220 mg

Diameter: 10 mm, double plane, faceted on both sides and on one side There are notches.

Instance B Lozenges containing 150 mg of active substance composition:

1 tablet contains:

System of law:

The active material mixed with lactose, corn starch and vermiculite was wetted with a 20% aqueous solution of polyvinylpyrrolidone and passed through a sieve having a mesh of 1.5 mm. The granules dried at 45 ° C were again passed through the same screen and mixed with a defined amount of magnesium stearate. The tablet is compressed from the mixture.

Example C Hard gelatin capsule containing 150 mg of active substance composition:

1 capsule contains: active substance 150.0 mg

System of law:

The active substance is mixed with excipients, passed through a sieve having a mesh of 0.75 mm and homogeneously mixed using a suitable apparatus. The final mixture was packaged in a size 1 hard gelatin capsule.

Example D a suppository containing 150 mg of active substance composition:

1 suppository contains:

System of law:

After the suppository block has been melted, the active material is homogeneously distributed therein and the melt is poured into a cold mold.

Example E Ampoule containing 10 mg of active substance composition:

System of law:

The active substance is dissolved in the required amount of 0.01 N HCl, isotonic with common salts, sterile filtered and transferred to 2 ml ampoules.

Example F Ampoule containing 50 mg of active substance composition:

System of law:

The active substance was dissolved in the required amount of 0.01 N HCl, made isotonic using common salts, sterile filtered and transferred to 10 ml ampoules.

Claims (24)

a compound of formula I, Wherein R ¹ is a mono or bicyclic 5 to 10 membered aryl or heteroaryl group, wherein the heteroaryl group contains 1 to 4 hetero atoms selected from the group consisting of N, O and S, and the aryl or heteroaryl group thereof is visible Requires substitution with R ⁹ , R ¹⁰ and/or R ¹¹ wherein R ⁹ is hydrogen, halogen, cyano, 1-4C-alkyl, 2-4C-alkenyl, 3-6C-cycloalkyl, 1-4C - alkoxy, fully or partially fluoro-substituted 1-4C-alkyl, fully or partially fluoro-substituted 1-4C-alkoxy, pentafluorothio, cyano-1-4C-alkyl, 1 -2C-alkyl-3-6C-cycloalkyl, cyano-3-6C-cycloalkyl, 1-2C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl or -(1-2C-alkyl)-oxetan-3-yl, R ¹⁰ is hydrogen, halogen, cyano, 1-4C-alkyl, 2-4C-alkenyl, 3-6C-cycloalkyl , 1-4C-alkoxy, fully or partially fluoro-substituted 1-4C-alkyl, fully or partially fluoro-substituted 1-4C-alkoxy, cyano-1-4C-alkyl, methyl 3-6C-cycloalkyl, cyano-3-6C-cycloalkyl, methoxy-1-4C-alkyl, hydroxy-1-4C-alkyl or 3-(1-2C-alkyl) - oxetan-3-yl, R ¹¹ is hydrogen or halogen, or R ⁹ and R ¹⁰ together and including the carbon atoms bonded thereto form a 5-6C- cycloalkyl ring, One of the methylene groups may need to be replaced by oxygen. For the case of a 6-membered ring system, the ring may optionally contain a double bond, and/or the ring may optionally be mono- or di-substituted with methyl groups, wherein for two methyl groups In the case of the same carbon, these methyl groups, together with the carbon to which they are attached, may form a cyclopropyl ring, R ² is 1-6C-alkyl, 1-3C-perfluoroalkyl, 1-4C-alkoxy- 1-4C-alkyl or 4-7C-cycloalkyl, wherein 4-7C-cycloalkyl may be mono- or disubstituted by fluorine, hydroxy, methoxy and/or 1-2C-alkyl, optionally for 5 In the case of a -7C-cycloalkyl system, a methylene group may be replaced by oxygen as needed, and R ³ and R ⁴ together with a carbon atom to which it is bonded form a 3-7C-cycloalkane ring, and R ⁵ is hydrogen or 1 -4C-alkyl, R ⁶ is 1-4C-alkyl, R ⁷ is hydrogen or 1-4C-alkyl, or R ⁶ and R ⁷ together and including a carbon atom bonded thereto form a 5-7C-cycloalkane Ring, one of which may optionally be replaced by oxygen, the ring optionally containing a double bond, and/or the ring may optionally be fluoro, hydroxy, 1-2C-alkoxy and/or 1-2C-alkyl mono or di-substituted, R ⁸ is hydrogen, acetyl group, propoxy group XI A methoxy group or a hydroxyl group, a tautomer thereof, a stereoisomer thereof, mixtures thereof and salts thereof. A compound of formula I as claimed in claim 1, wherein one or each of the definitions a ⁱ , b ⁱ , c ⁱ , d ⁱ , e ⁱ and f ⁱ are combined to produce an embodiment, a ⁱ representing R ^significance of the specification as selected paragraphs a) of about ^{a 0, a 1, a 2} , a 3, a ⁴ a ⁵ and definitions as defined, b ⁱ represents the meaning of R ^2, is selected as the specification paragraphs b) as defined by the definitions of b ⁰ , b ¹ , b ² , b ³ , b ⁴ , b ⁵ and b ⁶ , where c ⁱ represents the meaning of R ³ and R ⁴ , as selected in paragraph c) of the specification Defined by the definitions of c ⁰ , c ¹ , c ² and c ³ , d ⁱ denotes the meaning of R ⁵ , as defined by the definitions of d ⁰ , d ¹ , d ² and d ³ in relation to paragraph d) in the specification, e ⁱ represents the meaning of R ⁶ and R ⁷ as defined by the definitions of e ⁰ , e ¹ , e ² , e ³ , e ⁴ and e ⁵ in paragraph e) of the specification, and f ⁱ represents the meaning of R ⁸ , as defined by the definitions of f ⁰ , f ¹ , f ² and f ³ in paragraphs f) of the specification; tautomers, stereoisomers, mixtures thereof and salts thereof. A compound of formula I according to claim 1 which is selected from the group consisting of E-1, E-2, E-3, E-4, E-5, E-6, E-7, E- in Table 1 of the specification. 8. Tautomers, stereoisomers, mixtures thereof, as defined in the examples of E-9, E-10, E-11, E-12, E-13, E-14, E15 and E-16 And its salt. A compound of formula I according to claim 1, 2 or 3, wherein R ¹ represents 2-(R ⁹ )-3-(R ¹⁰ )-thiophen-5-yl, 5-(R ⁹ )-4-(R ¹⁰ )-thiazol-2-yl, 1-(R ¹⁰ )-2-(R ⁹ )-3-(R ¹¹ )-phenyl-5-yl, 1-(R ¹⁰ )-2-(R ⁹ )-4 -(R ¹¹ )-phenyl-5-yl, 5-(R ⁹ )-4-(R ¹⁰ )-pyridin-2-yl, 2-(R ⁹ )-3-(R ¹⁰ )-pyridine-5- , 5-(R ⁹ )-3-(R ¹⁰ )-pyridin-2-yl, 5-(R ⁹ )-4-(R ¹⁰ )-pyrimidin-2-yl, 2-(R ⁹ )-pyrimidine -5-yl, 3-(R ⁹ )-4-(R ¹⁰ )-pyridazine-6-yl, 2-(R ⁹ )-3-(R ¹⁰ )-pyrazine-5-yl, 1,1 - dimethyl-1,3-dihydroisobenzofuran-5-yl, 3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl, 3,3-di Methyl-2,3-dihydrobenzofuran-6-yl or 2H-spiro[benzofuran-3,1'-cyclopropane]-6-yl, wherein R ⁹ is hydrogen, halogen, cyano, iso Propyl, isobutyl, tert-butyl, isopropenyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, pentafluoro Ethyl, difluoromethyl, 1,1-difluoroethyl-1-yl, trifluoromethoxy, difluoromethoxy, pentafluorothio, 2-cyano-propan-2-yl, 1- Methyl-cycloprop-1-yl, 1-methyl-cyclobutan-1-yl, 1-cyano-cycloprop-1- , 1-cyano-cyclobutan-1-yl, 1-methoxy-ethyl-1-yl, 2-methoxy-propan-2-yl, 1-hydroxy-eth-1-yl, 2-hydroxyl -prop-2-yl or 3-(1-2C-alkyl)-oxetan-3-yl, R ¹⁰ is hydrogen, halogen, cyano, methyl, ethyl, isopropyl, tert-butyl Base, methoxy, trifluoromethyl, trifluoromethoxy or methoxymethyl, R ¹¹ is hydrogen, fluorine or chlorine, and R ² represents 1-5C-alkyl, trifluoromethyl, pentafluoroethyl a group, a 1-3C-alkoxy-1-2C-alkyl group, a 1-3C-alkoxy-3C-alkyl group or a 4-7C-cycloalkyl group, wherein the 4-7C-cycloalkyl group may be subjected to fluorine , hydroxy, methoxy and/or methyl mono or disubstituted, and in the case of a 5-7C-cycloalkyl system, one methylene may optionally be replaced by oxygen, and R ³ and R ⁴ together and include a carbon atom to form a cyclopropane, cyclobutane or cyclopentane ring, R ⁵ represents hydrogen or methyl, R ⁶ represents methyl, ethyl, propyl or isopropyl, and R ⁷ represents hydrogen, methyl or Ethyl, or R ⁶ and R ⁷ together and including the carbon atom to which they are bonded form a 5-6C-cycloalkane ring, wherein one methylene group may optionally be replaced by oxygen, the ring optionally containing a double bond, and/or The ring Mono or disubstituted by fluorine, hydroxy, 1-2C-alkoxy and/or 1-2C-alkyl, R ⁸ represents hydrogen, ethoxylated or hydroxy, tautomers, stereoisomers thereof , mixtures thereof and salts thereof. A compound of formula I according to claim 1, 2, 3 or 4, wherein R ¹ represents 2-(R ⁹ )-thiophen-5-yl, 1-(R ⁹ )-2-(R ¹⁰ )-benzene-4 -yl, 1-(R ⁹ )-3-(R ¹⁰ )-phenyl-4-yl, 4-(R ⁹ )-phenyl-1-yl, 3-tert-butylphenyl, 3-trifluoromethyl Phenyl, 1,2,3-trifluoro-phenyl-5-yl, 1,3-difluoro-phenyl-5-yl, 5-(R ⁹ )-pyridin-2-yl, 2-(R ⁹ )-pyridin-5-yl, 5-(R ⁹ )-3-(R ¹⁰ )-pyridin-2-yl, 2-(R ⁹ )-pyrimidin-5-yl, 5-(R ⁹ )-4- (R ¹⁰ )-thiazol-2-yl, 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl or 3,3-dimethyl-2,3-dihydrobenzo Furan-6-yl, wherein R ⁹ is fluorine, chlorine, bromine, cyano, isopropyl, isobutyl, isopropenyl, tert-butyl, cyclopropyl, cyclobutyl, methoxy, ethoxy Base, isopropoxy, tert-butoxy, trifluoromethyl, pentafluoroethyl, difluoromethyl, 1,1-difluoroethyl-1-yl, trifluoromethoxy, difluoromethoxy , pentafluorothio, 2-cyano-propan-2-yl, 1-methyl-cycloprop-1-yl, 1-methyl-cyclobutan-1-yl, 1-cyano-cyclopropane- 1-yl, 1-cyano-cyclobut-1-yl, 2-methoxy-propan-2-yl, 2-hydroxy-propan-2-yl or 3-methyl-oxetan-3- group, R ¹⁰ is hydrogen, methyl Cyano, methoxy, fluorine or chlorine, R ² represents an ethyl, isopropyl, 2-butyl, isobutyl, tert-butyl, 3-pentyl, cyclobutyl, cyclopentyl, cyclohexyl , methoxymethyl, 1-methoxyethyl, 2-methoxy-propan-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydrogen Piperan-3-yl or tetrahydropyran-2-yl, R ³ and R ⁴ together and including a carbon atom bonded thereto form a cyclopropane or cyclobutane ring, R ⁵ represents hydrogen, and R ⁶ and R ^{7 are} independent Is a methyl or ethyl group, or R ⁶ and R ⁷ together and including a carbon atom bonded thereto to form a cyclopentane ring, a cyclopent-2-ene-1,1-diyl ring, a cyclohexane ring, 4 , 4-difluorocyclohexyl-1,1-diyl ring or tetrahydropyran-4,4-diyl ring, R ⁸ represents hydrogen or hydroxy, tautomers, stereoisomers, mixtures thereof and Its salt. A compound of formula I according to claim 1, 2, 3, 4 or 5, wherein R ¹ represents 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-(1,1-difluoro- Ethyl-1-yl)-phenyl, 4-methylphenyl, 4-isopropylphenyl, 4-isobutylphenyl, 4-tert-butylphenyl, 3-tert-butylphenyl , 4-isopropenylphenyl, 4-cyanophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-isopropoxy Phenylphenyl, 4-tert-butoxyphenyl, 4-trifluoromethoxyphenyl, 4-pentafluorothiophenyl, 4-perfluoroethyl-phenyl, 2-trifluoromethyl- Pyridin-5-yl, 5-trifluoromethyl-pyridin-2-yl, 3-fluoro-4-trifluoromethyl-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 3-fluoro 5-5-trifluoromethyl-pyridin-2-yl, 3-cyano-4-trifluoromethyl-phenyl, 3-methoxy-4-trifluoromethyl-phenyl, 4-(2- Cyano-propan-2-yl)-phenyl, 4-(2-hydroxy-propan-2-yl)-phenyl, 4-cyclopropylphenyl, 4-(1-methylcyclopropyl-1 -yl)-phenyl, 4-(1-cyanocyclopropyl-1-yl)-phenyl, 2-trifluoromethyl-thiophen-5-yl, 5-tert-butyl-4-methyl - thiazol-2-yl or 2-tert-butyl - pyrimidin-5-yl, R ² represents ethyl, isopropyl, tertiary butyl , Methoxymethyl, 1-methoxyethyl, 2-methoxy - propan-2-yl, cyclobutyl, cyclopentyl or tetrahydropyran-yl, R ³ and R ⁴ together And comprising a carbon atom bonded thereto to form a cyclopropane ring, R ⁵ represents hydrogen, R ⁶ represents a methyl group and R ⁷ represents a methyl group, or R ⁶ and R ⁷ together and a carbon atom bonded thereto form a cyclopentane ring , cyclopent-2-ene-1,1-diyl ring, cyclohexane ring or tetrahydropyran-4,4-diyl ring, R ⁸ represents hydrogen or hydroxy, tautomer, stereoisomer Body, mixtures thereof and salts thereof. A compound of formula I according to claim 1, 2, 3, 4 or 5, wherein R ¹ represents 4-trifluoromethylphenyl, 4-tert-butylphenyl, 4-pentafluorothiophenyl, 4 - pentafluoroethylphenyl, 2-trifluoromethyl-pyridin-5-yl, 3-fluoro-4-trifluoromethyl-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 3 -Cyano-4-trifluoromethyl-phenyl or 3-methoxy-4-trifluoromethyl-phenyl, R ² represents isopropyl, tert-butyl or tetrahydropyran-4-yl And R ³ and R ⁴ together and include a carbon atom bonded thereto to form a cyclopropane ring, R ⁵ represents hydrogen, and R ⁶ and R ⁷ together and including a carbon atom bonded thereto form tetrahydropyran-4,4-di The base ring, R ⁸ represents hydrogen or a hydroxyl group, its tautomers, stereoisomers, mixtures thereof and salts thereof. The compound of any one of claims 1 to 7, which has the formula I*, Wherein R ¹ to R ⁸ are as defined in any one of claims 1 to 7, which are tautomers, stereoisomers, mixtures thereof and salts thereof. The compound of any one of claims 1 to 7, which has the formula I**, Wherein R ¹ to R ⁸ are as defined in any one of claims 1 to 7, which are tautomers, stereoisomers, mixtures thereof and salts thereof. The compound of any one of claims 1 to 7, which has the formula I***, Wherein R ¹ to R ⁸ are as defined in any one of claims 1 to 7, which are tautomers, stereoisomers, mixtures thereof and salts thereof. The compound of any one of claims 1 to 7, which has the formula I****, Wherein R ¹ to R ⁸ are as defined in any one of claims 1 to 7, which are tautomers, stereoisomers, mixtures thereof and salts thereof. The compound of any one of claims 1 to 7, which has the formula I***** Wherein R ¹ to R ⁸ are as defined in any one of claims 1 to 7, which are tautomers, stereoisomers, mixtures thereof and salts thereof. The compound according to any one of claims 1 to 12, which comprises one or more of the following: R ² represents an isopropyl group, and R ³ and R ⁴ together and including a carbon atom bonded thereto form a cyclopropane ring, and R ⁵ represents hydrogen And R ⁶ and R ⁷ together with a carbon atom to which it is bonded form a tetrahydropyran-4,4-diyl ring, and R ⁸ represents hydrogen, a tautomer, a stereoisomer thereof, a mixture thereof, and salt. The compound according to any one of claims 1 to 12, which comprises one or more of the following: R ² represents an isopropyl group, and R ³ and R ⁴ together and including a carbon atom bonded thereto form a cyclopropane ring, and R ⁵ represents hydrogen And R ⁶ and R ⁷ together with a carbon atom to which it is bonded form a tetrahydropyran-4,4-diyl ring, and R ⁸ represents a hydroxyl group, tautomers, stereoisomers thereof, mixtures thereof and salt. The compound of any one of claims 1 to 14, wherein R ³ and R ⁴ together with and including a carbon atom to which they are bonded form a cyclopentane ring, tautomers, stereoisomers thereof, mixtures thereof and salts thereof . The compound of claim 1, which is selected from the group consisting of: (3R, 9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(4-(three Fluoromethyl)phenyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4' -pyrano]-9-ol 5-((3R,9S)-9-hydroxy-4-isopropyl-7,7-(ethyl-1,2-diyl)-2',3',5',6,6',7, 8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-piperanyl-3-yl)-2-(trifluoromethyl)benzonitrile (3R,6R,9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(3-methoxy-4-(trifluoromethyl)phenyl)- 2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyrano]-6,9 -diol (3R,9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(6-(trifluoromethyl)pyridin-3-yl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyranyl]-9-ol (3R,6R,9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(4-(trifluoromethyl)phenyl)-2',3', 5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyrano]-6,9-diol 5-((3R,6R,9S)-6,9-dihydroxy-4-isopropyl-7,7-(ethyl-1,2-diyl)-2',3',5',6, 6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinolin-1,4'-piperan-3-yl)-2-(trifluoromethyl)benzene Nitrile (3R,6R,9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(3-methoxy-4-(trifluoromethyl)phenyl)- 2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyrano]-6,9 -diol And (3R,6R,9S)-4-isopropyl-7,7-(ethyl-1,2-diyl)-3-(6-(trifluoromethyl)pyridin-3-yl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro[furan[3,4-c]quinoline-1,4'-pyrano]-6,9-di alcohol Or its salt. A pharmaceutically acceptable salt of a compound according to any one of claims 1 to 16 with an inorganic or organic acid or base. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt according to claim 17, optionally with one or more inert carriers and/or diluents. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt according to claim 17, for use in the treatment or prevention of a disease, disorder or condition which may be affected by inhibition of cholesterol ester transfer protein (CETP) (such as Cardiac metabolic disorder or cardiovascular disorder, such as dyslipidemia or atherosclerosis, Elevating HDL cholesterol and/or lowering LDL cholesterol, if desired in combination with one or more other therapeutic agents, such as including statins. A use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt according to claim 17, for the preparation of a disease suitable for the treatment or prevention of a disease which can be affected by inhibition of cholesterol ester transfer protein (CETP), A pharmaceutical composition of an abnormality or condition, such as a cardiovascular disorder or a cardiac metabolic disorder or related disorder. A method of preparing a pharmaceutical composition according to claim 18, which comprises a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt of claim 17 and one or more inert carriers and/or diluted The agents are combined or mixed. A process for the preparation of a compound of formula I according to any one of claims 1 to 16 or a pharmaceutically acceptable salt of claim 17, which comprises one or more of the methods shown in the section "General Synthesis" in the specification. And / or b. A process for the preparation of a compound of formula VII from a compound of formula IX and VIII, for example as an intermediate in the synthesis of a compound of formula I, Wherein the variables R ² , R ³ , R ⁴ , R ⁶ and R ⁷ are as defined in any one of claims 1 to 7 and R ⁸ represents hydrogen, the method comprising, inter alia, reacting a compound of formula IX with a compound of formula VIII For example, the reaction is carried out under reduced pressure at a temperature between 150 ° C and 250 ° C or in a suitable solvent such as acetic acid at a temperature between 100 ° C and 150 ° C to produce the compound of formula VII. a compound of formula VI, Wherein the variables R ² , R ³ , R ⁴ , R ⁶ and R ⁷ are as defined in any one of claims 1 to 7 and R ⁸ represents hydrogen, the tautomers, stereoisomers thereof, mixtures thereof and salt.