Tri-substituted 2-benzhydryl-5-benzylamino-tetrahydro-pyran-4-OL and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-OL analogues, and novel 3,6-disubstituted pyran derivatives
3,6-disubstituted pyrans, optionally with a further substituent at the 4-position, are monoamine reuptake inhibitors with activity profiles of anti-depressants.
1. A 3,6-substituted pyran group-containing compound having the structural formula:
wherein
A, A′, and B are individually selected from the group of optionally substituted C 4 -C 14 aryl and heteroaryl wherein heteroatoms of heteroaryl A and/or A′ are selected from the group consisting of O, N, and S;
Z is selected from the group consisting of a chemical bond and —Y—(CH 2 ) o — wherein Y is NH or O and o is 0, 1, 2, 3, or 4;
R is H or C 1-8 alkyl;
W is selected from the group consisting of hydrogen and —OH wherein when W is hydrogen, B is phenyl or a phenyl substituted with C 1-4 alkyl, C 2-6 alkenyl, C 2-6 optionally halogenated alkynyl, C 2-6 hydroxyalkynyl, COOR′, —OH, or —NH 2 ;
R′ is C 1-18 alkyl, C 5-10 cycloalkyl, or C 2-18 alkenyl;
R 2 is C 1-8 alkyl, C 5-6 cycloalkyl, or C 2-8 alkenyl; and
n and m individually are 0, 1, 2, 3, or 4, and wherein any carbon of —(CH 2 ) n may be substituted by OR 4 wherein R 4 is C 1-8 alkyl, C 2-18 alkylene, or —COOR 5 wherein R 5 is C 1-18 alkyl or C 2-18 alkylene, or a pharmaceutically acceptable salt, ester, ether or carbamate thereof.
2. The compound of claim 1 , wherein at least one of A and A′ is an optionally substituted phenyl, napthyl, anthryl, furanyl, thienyl, or pyridinyl group.
3. The compound of claim 1 , wherein W is —OH and B is an optionally substituted phenyl, napthyl, anthryl, furanyl, thienyl, pyridinyl group, or
where X is N, O, or S.
4. The compound of claim 1 , having the formula
or a pharmaceutically acceptable salt, ester, ether or carbamate thereof.
5. The compound of claim 2 , having the formula
or a pharmaceutically acceptable salt, ester, ether or carbamate thereof.
6. The compound of claim 3 , having the formula
or a pharmaceutically acceptable salt, ester, ether or carbamate thereof.
7. The compound of claim 1 , having the formula
or a pharmaceutically acceptable salt, ester, ether or carbamate thereof.
8. The compound of claim 2 , having the formula
or a pharmaceutically acceptable salt, ester, ether or carbamate thereof.
9. The compound of claim 3 , having the formula
or a pharmaceutically acceptable salt, ester, ether or carbamate thereof.
10. The compound of claim 1 , having a formula selected from the group consisting of:
or a pharmaceutically acceptable salt, ester, ether or carbamate thereof.
11. The compound of claim 2 , having a formula selected from the group consisting of:
or a pharmaceutically acceptable salt, ester, ether or carbamate thereof.
12. The compound of claim 3 , wherein A and A′ are both unsubstituted phenyl.
13. The compound of claim 3 , having a formula selected from the group consisting of:
or a pharmaceutically acceptable salt, ester, ether or carbamate thereof.
14. The compound of claim 12 , having a formula selected from the group consisting of:
or a pharmaceutically acceptable salt, ester, ether or carbamate thereof.
15. A compound selected from the group consisting of: Cis-(6-benzhydryl-tetrahydropyran-3-yl)-(4-hydroxy-benzyl)-amine (16h); Cis-(6-benzhydryl-tetrahydropyran-3-yl)-(1H-iodo-5-ylmethyl)-amine (16n); Cis-(6-benzhydryl-tetrahydropyran-3-yl)-(4-amino-benzyl)-amine (16o); Cis-(6-benzhydryl-tetrahydropyran-3-yl)-(3,4-dichloro-benzyl)-amine (16i); (2R,4R,5R)-2-benzhydryl-5-(4-methoxy-benzylamino)-tetrahydropyran-4-ol (−)29a; (2S,4R,5R)-2-benzhydryl-5-(4-fluoro-benzylamino)-tetrahydro-pyran-4-ol (−)29b; (2S,4R,5R)-2-benzhydryl-5-benzylamino-tetrahydro-pyran-4-ol (−)29d; (2S,4R,5R)-2-benzhydryl-5-(2,4-dimethoxy-benzylamino)-tetrahydropyran-4-ol (−)-29e; (2S,4R,5R)-2-benzhydryl-5-(3,5-dimethoxy-benzylamino)-tetrahydropyran-4-ol (−)-29f; (2S,4R,5R)-2-benzhydryl-5-(4-hydroxy-benzylamino)-tetrahydropyran-4-ol (−)32a; (2S,4R,5R)-2-benzhydryl-5-[(1H-indol-5-ylmethyl)-amino]-tetrahydropyran-4-ol (−)32b; (2R,4S,5S)-2-benzhydryl-5-(4-hydroxy-benzylamino)-tetrahydro-pyran-4-ol (+)32a; (2R,4S,5S)-2-benzhydryl-5-[(1H-indol-5-ylmethyl)-amino]-tetrahydropyran-4-ol (+)32b; cis-(3S,6S)-(6-benzhydryl-tetrahydropyran-3-yl)-(4-hydroxy-benzyl)-amine (−)37a; cis-(3R,6R)-(6-benzhydryl-tetrahydropyran-3-yl)-(4-hydroxy-benzyl)-amine (+)37a and pharmaceutically acceptable salts, esters, ethers and carbamates thereof.
16. A compound selected from the group consisting of: (2S,4R,5R)-2-benzhydryl-5-(4-methoxy-benzylamino)-tetrahydropyran-4-ol (−)29a; (2S,4R, 5R)-2-benzhydryl-5-(4-fluoro-benzylamino)-tetrahydro-pyran-4-ol (−)29b; (2S,4R,5R)-2-benzhydryl-5-benzylamino-tetrahydro-pyran-4-ol (−)29d; (2S,4R,5R)-2-benzhydryl-5-(2,4-dimethoxy-benzylamino)-tetrahydropyran-4-ol (−)-29e; (2S,4R,5R)-2-benzhydryl-5-(3,5-dimethoxy-benzylamino)-tetrahydropyran-4-ol (−)-29f; (2S,4R,5R)-2-benzhydryl-5-(4-hydroxy-benzylamino)-tetrahydropyran-4-ol (−)32a; (2S,4R,5R)-2-benzhydryl-5-[(1H-indol-5-ylmethyl)-amino]-tetrahydropyran-4-ol (−)32b; (2R,4S,5S)-2-benzhydryl-5-(4-hydroxy-benzylamino)-tetrahydro-pyran-4-ol (+)32a; (2R,4S,5S)-2-benzhydryl-5-[(1H-indol-5-ylmethyl)-amino]-tetrahydropyran-4-ol (+)32b; cis-(3S,6S)-(6-benzhydryl-tetrahydropyran-3-yl)-(4-hydroxy-benzyl)-amine (−)37a; cis-(3R, 6R)-(6-benzhydryl-tetrahydropyran-3-yl)-(4-hydroxy-benzyl)-amine (+)37a and pharmaceutically acceptable salts, esters, ethers and carbamates thereof.
17. A method of reducing monoamine reuptake in a mammalian species, comprising administering a binding amount of a monoamine receptor binder comprising the compound of claim 1 .
18. A method of reducing monoamine reuptake in a mammalian species, comprising administering a binding amount of a monoamine receptor binder comprising the compound of claim 2 .
19. A method of reducing monoamine reuptake in a mammalian species, comprising administering a binding amount of a monoamine receptor binder comprising the compound of claim 10 .
20. A method for treatment of depression, comprising administering to a patient exhibiting signs of depression, the compound of claim 1 in an amount effective to inhibit reuptake of serotonin at the SERT and norepinephrine at the NET.
21. The method of claim 20 wherein the compound exhibits greater inhibition of serotonin and norepinephrine reuptake than of dopamine reuptake.
22. A method for treatment of depression, comprising administering to a patient exhibiting signs of depression, the compound of claim 1 in an amount effective to inhibit norepinephrine reuptake at the NET.
23. The method of claim 22 wherein said compound exhibits higher norepinephrine reuptake inhibition than serotonin reuptake inhibition and dopamine reuptake inhibition.
24. The compound of claim 18 , wherein W is —OH and B is selected from the group consisting of an optionally substituted phenyl, napthyl, anthryl, furanyl, thienyl, pyridinyl group, or
where X is N, O, or S.