Substituted chromanol derivatives and their use

1. A compound of formula (I)

in which

A represents a group of the formula

in which

* represents the point of attachment to the CR 1 R 2 grouping,

R 6 represents a substituent selected from the group consisting of halogen, cyano, (C 1 -C 6 )-alkyl and (C 1 -C 6 )-alkoxy, where alkyl and alkoxy for their part may be substituted up to five times by fluorine,

and

n represents the number 0, 1, 2 or 3,

where, if the substituent R 6 is present more than once, its meanings may be identical or different,

D represents (C 3 -C 8 )-alkyl, (C 4 -C 8 )-cycloalkyl, (C 4 -C 8 )-cycloalkenyl, (C 6 -C 10 )-aryl, 5- or 6-membered heteroaryl, tetrahydrofuranyl or tetrahydropyranyl, where

aryl and heteroaryl for their part may be substituted by halogen, cyano, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, trifluoromethyl or trifluoromethoxy

and

cycloalkyl and cycloalkenyl for their part may be substituted by fluorine or (C 1 -C 6 )-alkyl,

R 1 represents hydrogen, fluorine, hydroxyl, methoxy, mercapto or methyl,

R 2 represents hydrogen

or

R 1 and R 2 together with the carbon atom to which they are attached form a carbonyl group,

R 3 represents (C 1 -C 6 )-alkyl or (C 3 -C 7 )-cycloalkyl

and

R 4 and R 5 independently of one another represent hydrogen or (C 1 -C 4 )-alkyl or together with the carbon atom to which they are attached form a spiro-linked 3- to 5-membered cycloalkyl ring,

or a salt.

2. The compound of claim 1 in which

A represents a group of the formula

in which

* represents the point of attachment to the CR 1 R 2 grouping,

R 6 represents a substituent selected from the group consisting of fluorine, chlorine, cyano, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy, where alkyl and alkoxy for their part may be substituted up to five times by fluorine,

and

n represents the number 0, 1, 2 or 3,

where, if the substituent R 6 is present more than once, its meanings may be identical or different,

D represents phenyl, thienyl, furyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl, where

phenyl, thienyl and furyl for their part may be substituted by fluorine, chlorine, cyano, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, trifluoromethyl or trifluoromethoxy

and

cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl for their part may be substituted by fluorine or (C 1 -C 4 )-alkyl,

R 1 represents hydrogen, fluorine, hydroxyl or methyl,

R 2 represents hydrogen

or

R 1 and R 2 together with the carbon atom to which they are attached form a carbonyl group,

R 3 represents (C 3 -C 6 )-alkyl or (C 3 -C 6 )-cycloalkyl

and

R 4 and R 5 independently of one another represent hydrogen or methyl or together with the carbon atom to which they are attached form a spiro-linked 3- to 5-membered cycloalkyl ring,

or a salt.

3. The compound of claim 1 in which

A represents a group of the formula

in which

* represents the point of attachment to the CR 1 R 2 grouping

and

R 6 represents trifluoromethyl, trifluoromethoxy or tert-butyl,

D represents phenyl, 4-fluorophenyl, cyclopentyl, cyclohexyl, cyclopent-1-en-1-yl or cyclohex-1-en-1-yl,

R 1 represents hydrogen, fluorine or hydroxyl,

R 2 represents hydrogen

or

R 1 and R 2 together with the carbon atom to which they are attached form a carbonyl group,

R 3 represents isopropyl or cyclopentyl

and

R 4 and R 5 represent methyl or together with the carbon atom to which they are attached form a spiro-linked cyclopropyl or cyclobutyl ring,

or a salt.

4. A method of making a compound of claim 1 , comprising

[A] coupling a compound of the formula (II)

in which R 3 , R 4 and R 5 are each as defined in claim 1

and

R 7 represents hydrogen, methyl or a hydroxyl protective group

in an inert solvent, if appropriate in the presence of a catalyst, with an organometallic compound of the formula (III)

A-Q  (III),

in which A is as defined in claim 1

and

Q represents Li, —MgBr, —ZnBr or —B(OH) 2 ,

to give a compound of the formula (IV)

in which A, R 3 , R 4 , R 5 and R 7 are each as defined above,

this compound is then oxidized to a compound of the formula (V)

in which A, R 3 , R 4 , R 5 and R 7 are each as defined above,

then if R 7 represents methyl or a hydroxyl protective group, removing the radical, to produce a compound of the formula (Va)

in which A, R 3 , R 4 and R 5 are each as defined above,

converting the resulting compound into a compound of the formula (VI)

in which A, R 3 , R 4 and R 5 are each as defined above

and

X represents a leaving group, such as, for example, chlorine, bromine, iodine, tosylate, mesylate or triflate,

coupling the compound of formula (VI) in an inert solvent in the presence of a base and a palladium catalyst, with a boronic acid derivative of the formula (VII)

in which D is as defined in claim 1

and

R 8 represents hydrogen or (C 1 -C 4 )-alkyl or both radicals together form a —C(CH 3 ) 2 —C(CH 3 ) 2 — bridge

to give a compound of the formula (VIII)

in which A, D, R 3 , R 4 and R 5 are each as defined above,

and converting the compound of formula (VIII) by asymmetric reduction into a compound of the formula (I-A)

in which A, D, R 3 , R 4 and R 5 are each as defined above

or

[B] converting a compound of the formula (IIa)

in which R 3 , R 4 and R 5 are each as defined above

is into a compound of the formula (IX)

in which X, R 3 , R 4 and R 5 are each as defined above,

coupling the compound of formula (IX) in an inert solvent in the presence of a base and a palladium catalyst, with a boronic acid derivative of the formula (VII) to give a compound of the formula (X)

in which D, R 3 , R 4 and R 5 are each as defined above,

reacting the compound of formula (X) in an inert solvent, if appropriate in the presence of a catalyst, with an organometallic compound of the formula (III) to give a compound of the formula (XI)

in which A, D, R 3 , R 4 and R 5 are each as defined above,

and converting the compound of formula (XI) by asymmetric reduction into a compound of the formula (I-B)

in which A, D, R 3 , R 4 and R 5 are each as defined above,

or converting the compound of the formula (XI) with the aid of a fluorinating agent into a compound of the formula (XII)

in which A, D, R 3 , R 4 and R 5 are each as defined above

and converting the compound of formula (XII) by asymmetric reduction, into a compound of the formula (I-C)

in which A, D, R 3 , R 4 and R 5 are each as defined above,

and optionally converting the compound of formula (I-A), (I-B) or (I-C) to the salt thereof.

5. A pharmaceutical composition comprising a compound of claim 1 in combination with an inert nontoxic pharmaceutically suitable auxiliary.

6. A pharmaceutical composition comprising a compound of claim 1 in combination with a further active compound selected from the group consisting of antidiabetics, substances having antithrombotic action, hypotensive substances, lipid metabolism-modifying substances, anti-inflammatory substances and substances which stabilize arteriosclerotic plaque, in combination with an inert nontoxic pharmaceutically suitable auxiliary.

7. The pharmaceutical composition of claim 6 wherein the further active compound is a HMG-CoA reductase inhibitor.