Substituted chromanol derivatives and their use
View Patent ↗The present invention relates to substituted chromanol derivatives, to processes for their preparation, to their use on their own or in combination for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular disorders.
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.