Substituted pyrazino[1,2-a]pyrimidines useful as CBP/catenin antagonists for enhancing asymmetric division of somatic stem cells
Provided are: composition and methods for: treating aging or an age-related condition, symptom or disease; stimulating hair growth, regrowth or pigmentation (or preventing hair loss); for increasing adenosine receptor expression in dermal cells (in combination with hair growth); for treating a condition or disease of the skin or at least one symptom thereof, including cosmetic treatment (e.g., wrinkles, hyperpigmentation, redness, rosacea, dryness, cracking, loss of firmness, loss of elasticity, thinning, and loss of vibrancy). The methods comprise administering a sufficient amount of the disclosed CBP/catenin (e.g., CBP/(β-catenin) antagonist compositions, and particularly wherein administration is in an amount and manner sufficient to provide for increasing the number of asymmetric renewing divisions relative to, or at the expense of symmetric divisions in relevant somatic stem cell population. In particular aspects, the CBP/catenin (e.g., CBP/(β-catenin) antagonist comprises an alkyl and/or fatty acid ester derivative of formula (I) as disclosed herein
1. A compound having the formula (I):
wherein R 1 is selected from hydrogen or C 1 -C 6 alkyl, and
wherein R 2 is selected from —OH or —O(CO)(CH 2 ) n CH 3 , wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34, and
provided that where R 1 is hydrogen, R 2 cannot be —OH; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 1 is selected from C 1 -C 6 alkyl.
3. The compound of claim 2 , wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14.
4. The compound of claim 2 , wherein the compound has formula (II):
5. The compound of claim 4 , wherein C 1 -C 6 alkyl is CH 3 , and R 2 is —OH.
6. The compound of claim 4 , wherein C 1 -C 6 alkyl is CH 3 , and R 2 is —O(CO)(CH 2 ) n CH 3 , wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34.
7. The compound of claim 6 , wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14.
8. The compound of claim 7 , where the compound is 4-(((6S,9S,9aS)-1-(benzylcarbamoyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl dodecanoate.
9. A compound of claim 1 selected from the group consisting of:
4-(((6S,9S,9aS)-1-(benzylcarbamoyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl acetate;
4-(((6S,9S,9aS)-1-(benzylcarbamoyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl hexanoate;
4-(((6S,9S,9aS)-1-(benzylcarbamoyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl dodecanoate;
4-(((6S,9S,9aS)-1-(benzylcarbamoyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl palmitate;
4-(((6S,9aS)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl acetate;
4-(((6S,9aS)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl pentanoate;
4-(((6S,9aS)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl nonanoate;
4-(((6S,9aS)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl dodecanoate;
4-(((6S,9aS)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl tridecanoate; and
4-(((6S,9aS)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl palmitate.
10. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition of claim 10 , comprising an effective amount of a compound according to claim 1 .
12. A compound selected from the group consisting of:
4-(((6S,9S)-1-(benzylcarbamoyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl acetate;
4-(((6S,9S)-1-(benzylcarbamoyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl hexanoate;
4-(((6S,9S)-1-(benzylcarbamoyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl dodecanoate;
4-(((6S,9S)-1-(benzylcarbamoyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl palmitate;
4-(((6S)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl acetate;
4-(((6S)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl pentanoate;
4-(((6S)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl nonanoate;
4-(((6S)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl dodecanoate;
4-(((6S)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl tridecanoate; and
4-(((6S)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl palmitate.