Glycerin derivatives and inhibition of blood PAF
AssigneeHoffman-La Roche Inc.
InventorsRichard Barner, Kasper Burri, Jean-Marie Cassal, Paul Hadvary, Georges Hirth, Klaus Muller
Life of this patent
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Abstract
Glycerine derivatives of the formula ##STR1## wherein the residues R.sup.1, R.sup.2 and R.sup.3 have the significance given in the description, and their hydrates, which inhibit blood platelet activating factor (PAF), are descried.
Claims23
A compound of the formula ##STR8## wherein one of the residues R.sup.1, R.sup.2 and R.sup.3 is group U of the formula --X.sup.1 --C(O)--(A.sup.1).sub.n --Z.sup.1, another of the residues is group V of the formula --X.sup.2 --C(O)--A.sup.2 --Z.sup.2 and the remaining residue is group W of the formula --X.sup.3 T--(C.sub.2-6 -alkylene)--N.sup.+ (Het)Q.sup.- whereby one of --X.sup.1, --X.sup.2 and --X.sup.3 is oxygen or NH and the other two are oxygen, A.sup.1 and A.sup.2, independently, are oxygen or NH, n is the integer 1 or 0, Z.sup.1 is C.sub.9-25 -alkyl or C.sub.9-25 -alkenyl, Z.sup.2 is C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl, or phenyl-T is carbonyl, C(O)O or C(O)NH or, when X.sup.3 is oxygen, T is also methylene, -N.sup.+ (Het) is selected from the group consisting of oxazolium, isoxazolium, pyridazinium, quinolinium, isoquinolinium, N-methylimidazolium, pyridinium and thiazolium, and --Q.sup.- is the anion of a strong inorganic or organic acid, or its hydrate.
A compound selected from the group consisting of 3-[3-[[(S)-2-[(methoxycarbonyl)oxy]-3-[(octadecylcarbamoyl)oxy]propoxy]car bonyl]propyl]thiazolium iodide,
- 1-[3-[[(RS)-2-[(methoxycarbonyl)oxy[-3-(octadecylcarbamoyl)oxy]propoxy]carb onyl]propyl]pyridinium chloride,
- 1-[3[[(RS)-2-(1-methoxyformamido)-3-(octadecylcarbamoyloxy)propoxy]carbonyl ]propyl]thiazolium chloride,
- 1-[3-[[(S)-2-[(methoxycarbonyl)oxy]-3-[(octadecylcarbamoyl)oxy propoxy]carbonyl]propyl]pyridinium iodide, and
- 1-[3-[[(R)-2-[(methoxycarbonyl)oxy]-3-[(octadecylcarbamoyl)oxy propoxy]carbonyl]propyl]pyridinium chloride.
A compound of the formula ##STR9## wherein one of the residues R.sup.10, R.sup.20 and R.sup.30 is group U of the formula --X.sup.1 --C(O)--(A.sup.1).sub.n --Z.sup.1, another of the residues is group V of the formula --X.sup.2 --C(O)--(A.sup.2).sub.p --Z.sup.2, and the remaining residue is group W of the formula --X.sup.3 T--(C.sub.2-6 -alkylene)--N.sup.+ (Het)Q.sup.-, wherein one of --X.sup.1, --X.sup.2 and --X.sup.3 is oxygen or NH and the other two are oxygen, A.sup.1 and A.sup.2, independently, are oxygen or NH, n and p are the integer 1 or 0, Z.sup.1 is C.sub.9-25 -alkyl or C.sub.9-25 -alkenyl, Z.sup.2 is C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl, or phenyl, T is carbonyl, C(O)O or C(O)NH or, when X.sup.3 is oxygen, T is also methylene, --N.sup.+ (Het) is selected form the group consisting of oxazolium, isoxazolium, pyridazinium, quinolinium, isoquolinium, N-methylimidazolium, pyridinium and thiazolium and Q.sup.- is the anion of a strong inorganic or organic acid;
- provided that an amino group or an azido group is present in place of one of the groups U and V.
A pharmaceutical composition for inhibiting blood platelet activating factor comprising an effective amount of a compound of the formula ##STR10## wherein one of the residues R.sup.1, R.sup.2 and R.sup.3 is group U of the formula --OY.sup.1 or --X.sup.1 --C(O)--(A.sup.1).sub.n --Z.sup.1,
- another of the residues is group V of the formula --OY.sup.2 or --X.sup.2 --C(O)--(A.sup.2).sub.p --Z.sup.2,
- and the remaining residue is group W of the formula, --X.sup.3 T--(C.sub.2-6 -alkylene)--N.sup.+ (Het)Q.sup.-
- wherein one of X.sup.1, --X.sup.2 and X.sup.3 is oxygen or NH and the other two are oxygen,
- Y.sup.1 is C.sub.10-26 -alkyl or C.sub.10-26 -alkenyl,
- Y.sup.2 is C.sub.1-6 -alkyl, C.sub.2-6 -alkenyl,
- C.sub.3-6 -cycloalkyl, C.sub.5-6 -cycloalkenyl, phenyl, benzyl or 2-tetrahydropyranyl,
- A.sup.1 and A.sup.2, independently, are oxygen or NH,
- n and p are the integer 1 or 0,
- Z.sup.1 is C.sub.9-25 -alkyl or C.sub.9-25 -alkenyl,
- Z.sup.2 is C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl, phenyl or, when (A.sup.2).sub.p is not oxygen, Z.sup.2 is also hydrogen,
- T is carbonyl, C(O)O or C(O)NH or, when X.sup.3 is oxygen, T is also methylene,
- --N.sup.+ (Het) is selected from the group consisting of oxazolium, isoxazolium, pyridazinium, quinolinium, isoquinolinium, N-methylimidazolium, pyridinium and thiazolium, and
- Q.sup.- is the anion of a strong inorganic or organic acid, provided that when R.sup.1 is a group of the formula --OY.sup.1 or --OY.sup.2, R.sup.2 is a group V or OY.sup.1, and X.sup.3 is oxygen, then T is C(O)O or C(O)NH,
- or its hydrate.
A method of inhibiting blood platelet activating factor which comprises administering to a host requiring such treatment an effective amount of a compound of the formula ##STR11## wherein one of the residues R.sup.1, R.sup.2 and R.sup.3 is group U of the formula --OY.sup.1 or --X.sup.1 --C(O)--(A.sup.1).sub.n --Z.sup.1,
- another of the residues is group V of the formula --OY.sup.2 or --X.sup.2 --C(O)--(A.sup.2).sub.p --Z.sup.2,
- and the remaining residue is group W of the formula, --X.sup.3 T--(C.sub.2-6 -alkylene)--N.sup.+ (Het)Q.sup.-
- wherein one of X.sup.1, --X.sup.2 and X.sup.3 is oxygen or NH and the other two are oxygen,
- Y.sup.1 is C.sub.10-26 -alkyl or C.sub.10-26 -alkenyl,
- Y.sup.2 is C.sub.1-6 -alkyl, C.sub.2-6 -alkenyl,
- C.sub.3-6 -cycloalkyl, C.sub.5-6 -cycloalkenyl, phenyl, benzyl or 2-tetrahydropyranyl,
- A.sup.1 and A.sup.2, independently, are oxygen or NH,
- n and p are the integer 1 or 0,
- Z.sup.1 is C.sub.9-25 -alkyl or C.sub.9-25 -alkenyl,
- Z.sup.2 is C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl, phenyl or, when (A.sup.2).sub.p is not oxygen, Z.sup.2 is also hydrogen,
- T is carbonyl, C(O)O or C(O)NH or, when X.sup.3 is oxygen, T is also methylene,
- --N.sup.+ (Het) is selected from the group consisting of oxazolium, isoxazolium, pyridazinium, quinolinium, isoquinolinium, N-methylimidazolium, pyridinium and thiazolium, and
- Q.sup.- is the anion of a strong inorganic or organic acid, provided that when R.sup.1 is a group of the formula --OY.sup.1 or --OY.sup.2, R.sup.2 is a group V or OY.sup.1, and X.sup.3 is oxygen, then T is C(O)O or C(O)NH,
- or its hydrate.
Dependencies are inferred from the claim text.