Method for controlling the plasma level of lipoproteins to treat alzheimeris disease
AssigneeNederlandse Organisatie voor toegepast-natuurweten schappelijk onderzoek TNO
InventorsJohannes Marinus Gerardus Princen, Take Kooistra
Life of this patent
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Abstract
A compound which is an antagonist of platelet activating factor (PAF-antagonist) or a structurally related compound thereof not having PAF-antagonistic activity can be used for decreasing the plasma level of lipoprotein(a) and/or increasing the plasma level of high-density lipoprotein. The compound may be an azepine derivative, especially a benzo- or thienotriazolo-diazepine derivative, a diphenyl-tetrahydrofuran or diphenyldioxolane derivative or a tetrahydrofuran phospholipid analogue.
Claims21
A method for treating or preventing atherosclerotic conditions comprising decreasing the synthesis of apolipoprotein(a) or decreasing the plasma level of lipoprotein(a) or increasing the synthesis of apolipoprotein A1 or increasing the plasma level of high-density lipoprotein by administering an effective amount of a compound selected from the group consisting of azepine derivatives having the following formula 1:
- and of benzoazepine derivatives having the following formula 1a:
- wherein, in formula 1, A is a group —CH═C(R2)—CH═CH—, —S—C(R2)═CH—, —CH═C(R2)—S— or an optionally substituted benzo or thieno ring having the following formula 1b:
- Q is a nitrogen atom (—N═), or an optionally substituted carbon atom (—CR4═), R4 being as defined below;
- X is a nitrogen, sulphur or oxygen atom, the neighboring bond optionally being a double bond if X is nitrogen;
- Y is a nitrogen atom (═N—) or an optionally substituted carbon atom (═CR—), having a substituent R wherein R is hydrogen, methyl, ethyl, methoxycarbonyl or ethoxycarbonyl;
- Z is a nitrogen atom (—N═) or an optionally methyl-substituted carbon atom (—CR1═) having a substituent R′ wherein R1is hydrogen, methyl or hydroxymethyl;
- at least one of Y and Z is a nitrogen atom;
- R1 is hydrogen, halogen, C1-C6 alkyl, cycloalkylalkyl or cycloalkylalkenyl, trifluoromethyl, hydroxymethyl or aminomethyl,
- R2 is hydrogen, halogen, trifluoromethyl, nitro, C1-C3 alkyl or the group —CH2—CH2R2, R2′ being an optionally substituted phenyl, C1-C3 alkoxycarbonyl, or an aminomethyl or carbamoyl group, the nitrogen atom of the aminomethyl or carbamoyl group optionally being substituted by one or two C1-C3 alkyl groups or optionally being part of a pyrrolidino, piperidino, or morpholino ring;
- R3 is hydrogen, hydroxyl, methyl or carboxyl;
- and
- R4 is hydrogen, halogen, hydroxyl, methyl or methoxy.
A method of treating or preventing atherosclerotic conditions, being non-thrombotic conditions, the method being effected via a mode of action selected from the group consisting of decreasing the synthesis of lipoprotein(a), decreasing the plasma level of lipoprotein(a), increasing the synthesis of apolipoprotein A1, increasing the plasma level of high-density lipoprotein and combinations of the foregoing modes, the method comprising administering to a patient in need thereof, an effective amount of a benzoazepine derivative having the following formula 1a:
- wherein
- Q is a nitrogen atom (—N═) or an optionally substituted carbon atom (—CR4═);
- X is a nitrogen, sulphur or oxygen atom, the neighboring bond optionally being a double bond if X is nitrogen;
- Y is a nitrogen atom (═N—) or an optionally substituted carbon atom (═CR—), wherein R is hydrogen, methyl, ethyl, methoxycarbonyl or ethoxycarbonyl;
- Z is a nitrogen atom (—N═) or an optionally methyl-substituted carbon atom (—CR1═) wherein R′ is hydrogen, methyl or hydroxymethyl;
- at least one of Y and Z being a nitrogen atom;
- R1 is hydrogen, halogen, C1-C6 alkyl, cycloalkylalkyl or cycloalkylalkenyl, trifluoromethyl, hydroxymethyl or aminomethyl;
- R2 is hydrogen, halogen, trifluoromethyl, nitro, C1-C3 alkyl or a group —CH2—CH2R2;
- R2′ is optionally a substituted phenyl, C1-C3 alkoxycarbonyl, or an aminomethyl or carbamoyl group, the nitrogen atom of the aminomethyl or carbamoyl group optionally being substituted by one or two C1-C3 alkyl groups or optionally being part of a pyrrolidino, piperidino, or morpholino ring;
- R3 is hydrogen, hydroxyl, methyl or carboxyl;
- and
- R4 is hydrogen, halogen, hydroxyl, methyl or methoxy.
Dependencies are inferred from the claim text.