Pharmaceutical compositions
View Patent ↗A compound comprising a cyclopentanone, cyclopentenone, cyclohexanone or cyclohexenone group, wherein a first ring carbon atom carries an —SR substituent, R is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, or aralkynyl group that, optionally, includes at least one heteroatom in its carbon skeleton, the remaining available ring carbon atoms are optionally substituted, and said compound either: —(a) is more soluble in water at a temperature of 20-40° C.; (b) is less lipophilic; and/or, (c) has a greater therapeutic index; or; (d) is less soluble in water at a temperature of 20-40° C.; (e) is more lipophilic; and/or, (f) has a greater therapeutic index; than an equivalent cyclohex-2-en-1-one or cyclopent-2-en-1-one derivative in which a hydrogen atom replaces said —SR group.
1. A pharmaceutical composition comprising a compound comprising a cyclopentanone group and having the formula:
(a) II or III
Wherein:—
R 1 and R 2 are, independently, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaromatic or heteroalicyclic;
R 3 and R 4 are hydrogen,
R 5 is —SR, and R is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, or aralkynyl group that, optionally, includes at least one heteroatom in its carbon skeleton;
R 6 is hydrogen or halogen,
and X is:—
wherein R 7 , R 8 and R 9 are, independently, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaromatic or heteroalicyclic, and “a” is absent or a hydrocarbyl linking group;
(b) VI:—
wherein:—
R 1 is H, or a substituted or unsubstituted alkyl or alkenyl group containing 1 to 3 carbon atoms;
R 2 is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl aralkenyl, or aralkynyl group, optionally including at least one heteroatom in its carbon skeleton, and containing 1-12 carbon atoms;
R 3 is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl aralkenyl, or aralkynyl group, optionally including at least one heteroatom in its carbon skeleton, and containing 1-12 carbon atoms, or a silyl group;
R 4 is hydrogen;
X is hydrogen, halogen or an alkyl group containing 1-3 carbon atoms;
Y is a group —SR; and
R is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, or aralkynyl group that, optionally, includes at least one heteroatom in its carbon skeleton;
(c) VII:—
wherein R 1 is a saturated or unsaturated, branched or straight alkyl chain terminated with a COOX group and includes 4 to 15 carbon atoms, X is H or a C 1 -C 6 alkyl group, R 2 is a straight chain C 1 -C 20 saturated alkyl group, R is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, or aralkynyl group that, optionally, includes at least one heteroatom in its carbon skeleton, and the ring carbon atoms are otherwise unsubstituted; or,
(d) VIII:—
wherein each of R 1 and R 2 is a saturated or unsaturated branched or straight chain alkyl group, both R 1 and R 2 together include between 4 and 12 carbon atoms, R 1 is unsubstituted, R is unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, or aralkynyl group that, optionally, includes at least one heteroatom in its carbon skeleton, and the ring carbon atoms are otherwise unsubstituted,
and a pharmaceutically acceptable carrier.
2. A pharmaceutical composition as in claim 1 , comprising a compound having a calculated or measured logP value that is at least 0.25, 0.5, 0.75, 1 or 1.25 higher or lower than the logP value for the equivalent cyclopent-2-en-1-one derivative in which a hydrogen atom replaces said —SR group, wherein the logP values for the compound and derivative are calculated or measured using the same technique.
3. A pharmaceutical composition as in claim 1 , comprising a compound comprising a substituted or unsubstituted 3-(RS)-cyclopentan-1-one or 4-(RS)-cyclopentan-1-one.
4. A pharmaceutical composition as in claim 1 comprising a compound that is transformable into the equivalent cyclopent-2-en-1-one derivative, in which a hydrogen atom replaces said —SR group, by a reverse Michael reaction, or that is a pro-drug for said equivalent.
5. A pharmaceutical composition as in claim 1 , comprising a compound comprising a plurality of —SR groups.
6. A pharmaceutical composition as in claim 5 , comprising a compound comprising an additional —SR group bound to a substituent, itself bound to the cyclopentanone group.
7. A pharmaceutical composition as in claim 6 comprising a compound comprising an additional group —SR bound to the first carbon atom in a side chain carried by the ring carbon atom adjacent (α) to the carbonyl ring carbon atom.
8. A pharmaceutical composition as in claim 1 , comprising a compound wherein R is an R X CH 2 -group and R X is hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, or aralkynyl group, that optionally includes at least one heteroatom in its carbon skeleton.
9. A pharmaceutical composition as in claim 1 or 8 , comprising a compound wherein R or R X includes at least one hydrophilic group.
10. A pharmaceutical composition as in claim 9 , comprising a compound wherein said hydrophilic group is or includes a hydroxyl, carbonyl, carboxyl, amino, amido, quaternary ammonium or thiolyl group.
11. A pharmaceutical composition as in claim 10 , comprising a compound wherein R or R X provides the functionality of an amine, amide, peptide, ester, carboxylic acid, carboxylic acid salt, alcohol, aldehyde, ketone or thiol to said compound.
12. A pharmaceutical composition as in claim 1 or 8 , comprising a compound wherein R or R X includes at least one lipophilic group and/or is lipophilic.
13. A pharmaceutical composition as in claim 12 , comprising a compound wherein said lipophilic group is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, or aralkynyl group that, optionally, includes at least one heteroatom in its carbon skeleton.
14. A pharmaceutical composition as in claim 13 , comprising a compound wherein said lipophilic group is a substituted or unsubstituted phenyl or napthyl group, or an N-tert-butoxycarbonyl S-cysteinyl ester.
15. A pharmaceutical composition as in claim 1 , comprising a compound wherein the group —SR is an S-cysteinyl or a substituted S-cysteinyl group.
16. A pharmaceutical composition as in claim 15 , comprising a compound wherein the substituted S-cysteinyl group is a di- or tri-peptide group that includes an S-cysteinyl moiety.
17. A pharmaceutical composition as in claim 16 , comprising a compound wherein the substituted S-cysteinyl group is an S-glutathionyl, an S-cysteinyl N-tert-butoxycarbonyl, an S-cysteinyl ester, an S-glutathionyl ester, or an S-cysteinyl N-tert-butoxycarbonyl group.
18. A pharmaceutical composition as in claim 1 comprising a compound having the formula (a) or (b):—
wherein: R is as defined in claim 1 .
19. A pharmaceutical composition as in claim 1 , said comprising a compound having the formula II or III, wherein R 1 and R 2 are hydrogen, or the formula IV, wherein X is hydrogen.