CA2373559A1 - Serotonin transport inhibitors - Google Patents

Serotonin transport inhibitors Download PDF

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Publication number
CA2373559A1
CA2373559A1 CA002373559A CA2373559A CA2373559A1 CA 2373559 A1 CA2373559 A1 CA 2373559A1 CA 002373559 A CA002373559 A CA 002373559A CA 2373559 A CA2373559 A CA 2373559A CA 2373559 A1 CA2373559 A1 CA 2373559A1
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beta
compound
lower alkyl
alpha
nhcoch3
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CA2373559C (en
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Bertha Kalifon Madras
Peter Claude Meltzer
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Harvard College
Organix Inc
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Organix Inc
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
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Abstract

The present invention relates to the therapeutic use of non-amine tropane analogues that bind to the SERT to treat neuropsychiatric disorders.

Claims (24)

1. A compound having the structural formula:
wherein:
R1 = COOCH3, COR3, lower alkyl, lower alkenyl, lower alkynyl, CONHR4, or COR6;
R2 = is a 6.alpha., 6.beta.; 7.alpha. or 7.beta. substituent, which can be selected from H, OH, OR3, F, Cl, Br, and NHR3;
X = CH2, CHY, CYY1, CO, O, S; SO, SO2, or C=CX1Y with the C, O or S
atom being a member of the ring;
X1 = NR3, CH2, CHY, CYY1, CO, O, S; SO, SO2, or NSO2R3;
R3= H, (CH2)n C6H4Y, C6H4Y, CHCH2, lower alkyl, lower,alkenyl or lower alkynyl;
Y and Y1 = H, Br, Cl, I, F, OH, OCH3, CF3, NO2, NH2, CN, NHCOCH3, N(CH3)2, (CH2)n CH3, COCH3, or C(CH3)3;
R4 = CH3, CH2CH3, Or CH3SO2;
R6 = morpholinyl or piperidinyl;

Ar = phenyl-R5, naphthyl-R5, anthracenyl-R5, phenanthrenyl-R5, or diphenylmethoxy-R5;
R5 = Br, Cl, I, F, OH, OCH3, CF3, NO2, NH2, CN, NHCOCH3, N(CH3)2, (CH2)n CH3, COCH3, C(CH3)3 where n= 0-6, 4-F, 4-Cl, 4-I, 2-F, 2-Cl, 2-I, 3-F, 3-CI, 3-I, 3,4-diCl, 3,4-diOH, 3,4-diOAc, 3,4-diOCH3, 3-OH-4-Cl, 3-OH-4-F, 3-Cl-4-OH, 3-F-4-OH, lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(lower alkoxy);
m = 0 or 1; and n=0, 1,2,3,4 or 5;
wherein the compound has a SERT/DAT selectivity ratio of at least 3.
2. The compound according to claim 1, wherein the SERT/DAT
selectivity ratio is at least about 8.
3. The compound according to claim 1, wherein the SERT/DAT
selectivity ratio is at least about 50.
4. The compound according to claim 1, wherein the C in the 3 position is in the a conformation.
5. A compound having the structural formula:
wherein:
R1 = COOCH3, COR3, lower alkyl, lower alkenyl, lower alkynyl, CONHR4, or COR6;
R2 = is a 6.alpha., 6.beta., 7.alpha. or 7.beta. substituent, which can be selected from H, OH, OR3, F, Cl, Br, and NHR3;
X = CH2, CHY, CYY1, CO, O, S; SO, SO2, or C=CX1Y with the C, O or S
atom being a member of the ring;
X1 = NR3, CH2, CHY, CYY1 CO, O, S; SO, SO2, or NSO2R3;
R3 = H, (CH2)n C6H4Y, C6H4Y, CHCH2, lower alkyl, lower alkenyl or lower alkynyl;
Y and Y1 = H, Br, Cl, I, F, OH, OCH3, CF3, NO2, NH2, CN, NHCOCH3, N(CH3)2, (CH2)n CH3, COCH3, or C(CH3)3;
R4 = CH3, CH2CH3, or CH3SO2;
R6 = morpholinyl or piperidinyl;
Ar = phenyl-R5, naphthyl-R5, anthracenyl-R5, phenanthrenyl-R5, or diphenylmethoxy-R5;
R5 = Br, Cl, I, F, OH, OCH3, CF3, NO2, NH2, CN, NHCOCH3, N(CH3)2, (CH2)n CH3, COCH3, C(CH3)3 where n= 0-6, 4-F, 4-CI, 4-I, 2-F, 2-Cl, 2-I, 3-F, 3-Cl, 3-I, 3,4-diCl, 3,4-diOH, 3,4-diOAc, 3,4-diOCH3, 3-OH-4-Cl, 3-OH-4-F, 3-Cl-4-OH, 3-F-4-OH, lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(lower alkoxy);
m = 0 or 1; and n = 0,1,2,3,4 or 5;
wherein the compound has an affinity (K i) for the SERT of less than about 500 nM.
6. The compound according to claim 5, wherein the compound has an IC50 at the SERT of less than about 50 nM.
7. The compound according to claim 5, wherein the compound has an IC50 at the SERT of less than about 25 nM.
8. The compound according to claim 5, wherein the compound has an IC50 at the SERT of less than about 15 nM.
9. The compound according to claim 5, wherein the C in the 3 position is in the .alpha. conformation.
10. The compound of claim 1, selected from the group consisting of:
a. 2.beta.-carbomethoxy-3.beta.-(4'-propynylphenyl))-8-oxabicyclo[3.2.1]octane;
b. (1R, IS)-2.beta.-carbomethoxy-3.alpha.-(4'- propynylphenyl)-8-oxabicyclo[3.2.1]octane;
c. 2.beta.-carbomethoxy-3.alpha.-(4-isopropenylphenyl)-8-oxabicyclo[3.2.1]octane;
d. 2 .beta.-carbomethoxy-3.beta.-(4-isopropenylphenyl)-8-oxabicyclo[3.2.1]octane;
e. 2.beta.-carbomethoxy-3.beta.-(4-isopropenylphenyl)-8-oxabicyclo[3.2.1]octane.
11. The compound of claim 5, selected from the group consisting of a. 2-.beta.-carbomethoxy-3-.beta.-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]octane;
b. 2.beta.-carbomethoxy-3-.beta.-(3,4-dichlorophenyl)bicyclo[3.2.1]octane;
c. 2.beta.-carbomethoxy-3.beta.-(4'-propynylphenyl))-8-oxabicyclo[3.2.1]octane;
d. 2.beta.-carbomethoxy-3.alpha.-(4'- propynylphenyl)-8-oxabicyclo[3.2.1]octane;
e. 2.beta.-carbomethoxy-3.beta.-(2-naphthyl)-8-bicyclo [3.2.1]octane;

f. 2.beta.-carbomethoxy-3.alpha.-(2-naphthyl)-8-bicyclo[3.2.1)octane;
g. 2.beta.-carbomethoxy-3.alpha.-(4-isopropenylphenyl)-8-oxabicyclo[3.2.1]octane;
h. 2.beta.-carbomethoxy-3.beta.-(4-isopropenylphenyl)-8-oxabicyclo[3.2.1]octane;
i. 2.beta.-carbomethoxy-3.beta.-(4-isopropenylphenyl)-8-oxabicyclo[3.2.1]octane.
12. The compound according to claim 1, wherein the compound has the structure:

wherein:
X = O, CH2, CHY, CYY1, CO, or C=CX1Y;
R7 = lower alkenyl or lower alkynyl group having from about 2 to about 8 carbon atoms: and, R8 = H or Br, Cl, I, F, OH, OCH3, CF3, NO2, NH2, CN, NHCOCH3, N(CH3)2, (CH2)n CH3, COCH3, C(CH3)3 where n= 0-6.
13. The compound according to claim 12, wherein R7 is selected from ethenyl, propenyl, butenyl, propynyl, butynyl and methylpropynyl.
14. The compound according to claim 5, wherein the compound has the structure:

wherein:
X = O, CH2, CHY, CYY1, CO, or C=CX1Y;
R7 = lower alkenyl or lower alkynyl group having from about 2 to about 8 carbon atoms: and, R8 = H or Br, Cl, I, F, OH, OCH3, CF3, NO2, NH2, CN, NHCOCH3, N(CH3)2, (CH2)n CH3, COCH3, C(CH3)3 where n= 0-6.
15. The compound according to claim 14; wherein R7 is selected from ethenyl, propenyl, butenyl, propynyl, butynyl and methylpropynyl.
16. A pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable carrier and an effective amount of a compound having the structural formula:

wherein:
R1 = COOCH3, COR3, lower alkyl, lower alkenyl, lower alkynyl, CONHR4, or COR6;
R2 = is a 6.alpha., 6.beta., 7.alpha. or 7.beta. substituent, which can be selected from H, OH, OR3, F, Cl, Br, and NHR3;
X = CH2, CHY, CYY1, CO, O, S; SO, SO2, or C=CX1Y with the C, O or S
atom being a member of the ring;
X1 = NR3, CH2, CHY, CYY1 CO, O, S; SO, SO2, or NSO2R3;
R3= H, (CH2)n C6H4Y, C6H4Y, CHCH2, lower alkyl, lower alkenyl or lower alkynyl;
Y and Y1 = H, Br, Cl, I, F, OH, OCH3, CF3, NO2, NH2, CN, NHCOCH3, N(CH3)2, (CH2)n CH3, COCH3, or C(CH3)3;
R4 = CH3, CH2CH3, or CH3SO2;
R6 = morpholinyl or piperidinyl;
Ar = phenyl-R5, naphthyl-R5, anthracenyl-R5, phenanthrenyl-R5, or diphenylmethoxy-R5;
R5 = Br; Cl, I, F, OH, OCH3, CF3, NO2, NH2, CN, NHCOCH3, N(CH3)2, (CH2)n CH3, COCH3, C(CH3)3 where n= 0-6, 4-F, 4-Cl, 4-I, 2-F, 2-Cl, 2-I, 3-F, 3-Cl, 3-1, 3,4-diCl, 3,4-diOH, 3;4-diOAc, 3,4-diOCH3, 3-OH-4-Cl, 3-OH-4-F; 3-Cl-4-OH, 3-F-4-OH, lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(lower alkoxy);
m = 0 or 1; and n = 0, 1, 2, 3, 4 or 5;
wherein the compound has a SERT/DAT selectivity ratio of at least 3.
17. A pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable carrier and an effective amount of a compound having the structural formula:

wherein:
R1 = COOCH3, COR3, lower alkyl, lower alkenyl, lower alkynyl, CONHR4, or CORE;
R2 = is a 6.alpha., 6.beta., 7.alpha. or 7.beta. substituent, which can be selected from H, OH, OR3, F, Cl, Br, and NHR3;
X = CH2, CHY, CYY1, CO, O, S; SO, SO2, or C=CX1Y with the C, O or S
atom being a member of the ring;

X1=NR3,CH2,CHY,CYY1CO,O,S;SO,SO2,or NSO2R3;
R3=H,(CH2)nC6H4Y,C6H4Y,CHCH2,lower alkyl,lower alkenyl or lower alkynyl;
Y and Y1=H,Br,C1,I,F,OH,OCH3,CF3,NO2,NH2,CN,NHCOCH3, N(CH3)2,(CH2)nCH3,COCH3,or C(CH3)3;
R4=CH3,CH2CH3,or CH3SO2;
R6=morpholinyl or piperidinyl;
Ar=phenyl-R5,naphthyl-R5,anthracenyl-R5,phenanthrenyl-R5,or diphenylmethoxy-R5;
R5=Br,C1,I,F,OH,OCH3,CF3,NO2,NH2,CN,NHCOCH3,N(CH3)2, (CH2)nCH3,COCH3,C(CH3)3 where n=0-6,4-F,4-C1,4-I,2-F,2-C1,2-I,3-F,3-C1, 3-I,3,4-diC1,3,4-diOH,3,4-diOAc,3,4-diOCH3,3-OH-4-C1,3-OH-4-F,3-C1-4-OH, 3-F-4-OH,lower alkyl,lower alkoxy,lower alkenyl,lower alkynyl,CO(lower alkyl), or CO(lower alkoxy);
m=0 or 1; and n=0,1,2,3,4 or 5;
wherein the compound has an affinity (K i) for the SERT of less than about 500 nM.
18. A method for inhibiting serotonin reuptake of a monoamine transporter in a mammal comprising administering to the mammal a serotonin reuptake inhibiting amount of a compound having the structural formula:

wherein:

R1=COOCH3,COR3,lower alkyl, lower alkenyl, lower alkynyl, CONHR4, or COR6;
R2=is a 6a, 6.beta.,7a or 7.beta.substituent, which can be selected from H, OH, OR3, F,C1,Br,and NHR3;
X=CH2,CHY,CYY1,CO,O,S;SO,SO2,or C=CX1Y with the C,O or S
atom being a member of the ring;
X1=NR3,CH2,CHY,CYY1CO,O,S;SO,SO2,or NSO2R3;
R3=H,(CH2)nC6H4Y,C6H4Y,CHCH2,lower alkyl, lower alkenyl or lower alkynyl;
Y and Y1=H,Br,C1,I,F,OH,OCH3,CF3,NO2,NH2,CN,NHCOCH3, N(CH3)2,(CH2)nCH3,COCH3,or C(CH3)3;
R4=CH3,CH2CH3,or CH3SO2;
R6=morpholinyl or piperidinyl;
Ar=phenyl-R5,naphthyl-R5,anthracenyl-R5,phenanthrenyl-R5, or diphenylmethoxy-R5;
R5=Br,Cl,I,F,OH,OCH3,CF3,NO2,NH2,CN,NHCOCH3,N(CH3)2, (CH2)nCH3,COCH3,C(CH3)3 where n=0-6,4-F,4-C1,4-I,2-F,2-C1,2-I;3-F,3-C1, 3-I,3,4-diC1,3,4-diOH,3,4-diOAc,3,4-diOCH3,3-OH-4-C1,3-OH-4-F,3-C1-4-OH, 3-F-4-OH,lower alkyl,lower alkoxy,lower alkenyl,lower alkynyl,CO(lower alkyl), or CO(lower alkoxy);
m=0 or 1; and n=0,1,2,3,4 or 5;
wherein the compound has a SERT/DAT selectivity ratio of at least 3.
19. A method for inhibiting serotonin reuptake of a monoamine transporter in a mammal comprising administering to the mammal a serotonin reuptake inhibiting amount of a compound having the structural formula:

wherein:

R1=COOCH3,COR3, lower alkyl, lower alkenyl, lower alkynyl, CONHR4, or COR6;
R2= is a 6.alpha., 6.beta., 7.alpha. or 7.beta. substituent, which can be selected from H,OH,OR3, F,C1,Br, and NHR3;
X=CH2,CHY,CYY1,CO,O;S;SO,SO2, or C=CX1Y with the C,O or S
atom being a member of the ring;
X1=NR3,CH2,CHY,CYY1CO,O,S;SO,SO2,or NSO2R3;
R3=H,(CH2)nC6H4Y,C6H4Y,CHCH2, lower alkyl, lower alkenyl or lower alkynyl;
Y and Y1=H,Br,C1,I,F,OH,OCH3,CF3,NO2,NH2,CN,NHCOCH3, N(CH3)2,(CH2)nCH3,COCH2,or C(CH3)3;
R4=CH3,CH2CH3, or CH3SO2;
R6=morpholinyl or piperidinyl;
Ar=phenyl-R5, naphthyl-R5, anthracenyl-R5, phenanthrenyl-R5, or diphenylmethoxy-R5;

R5=Br,C1,I,F,OH,OCH3,CF3,NO2,NH2,CN,NHCOCH3,N(CH3)2, (CH2)nCH3,COCH3,C(CH3)3 where n=0-6,4-F,4-C1,4-I,2-F,2-C1,2-I,3-F,3-C1, 3-I,3,4-diCl,3,4-diOH,3,4-diOAc,3,4-diOCH3,3-OH-4-C1,3-OH-4-F,3-C1-4-OH, 3-F-4-OH, lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(lower alkoxy);
m=0 or 1; and n=0,1,2,3,4 or 5;
wherein the compound has an affinity (K i) for the SERT of less than about 500 nM.
20. A method of treating a mammal suffering from a serotonin related disorder comprising administering to the mammal an effective amount of a compound having the structural formula:

wherein:

R1=COOCH3,COR3, lower alkyl, lower alkenyl, lower alkynyl, CONHR4, or COR6;
R2=is a 6.alpha., 6.beta., 7.alpha. or 7.beta. substituent, which can be selected from H,OH,OR3, F,C1,Br, and NHR3;

X=CH2,CHY,CYY1,CO,O,S;SO,SO2, or C=CX1Y with the C,O or S
atom being a member of the ring;
X1=NR3,CH2,CHY,CYY1CO,O,S;SO,SO2, or NSO2R3;
R3=H,(CH2)nC6H4Y;C6H4Y,CHCH2,lower alkyl,lower alkenyl or lower alkynyl;
Y and Y1=H,Br,C1,I,F,OH,OCH3,CF3,NO2,NH2,CN,NHCOCH3, N(CH3)2,(CH2)nCH3,COCH3, or C(CH3)3;
R4=CH3,CH2CH3,or CH3SO2;
R6=morpholinyl or piperidinyl;
Ar=phenyl-R5, naphthyl-R5, anthracenyl-R5, phenanthrenyl-R5, or diphenylmethoxy-R5;
R5=Br,C1,I,F,OH,OCH3,CF3,NO2,NH2,CN,NHCOCH3;,N(CH3)2, (CH2)nCH3,COCH3,C(CH3)3 where n=0-6,4-F,4-C1,4-I,2-F,2-C1,2-I,3-F,3-C1, 3-I,3,4-diC1,3,4-diOH,3,4-diOAc,3,4-diOCH3,3-OH-4-C1,3-OH-4-F,3-C1-4-OH, 3-F-4-OH,lower alkyl, lower alkoxy, lower alkenyl; lower alkynyl, CO(lower alkyl), or CO(lower alkoxy);
m=0or 1; and n=0,1,2,3,4 or 5;
wherein the compound has a SERT/DAT selectivity ratio of at least 3.
21. The method for treating according to claim 20, wherein the disorder is selected from depression, anxiety, eating disorders, and obsessive compulsive disorders.
22. A method of treating a mammal suffering from a serotonin related disorder comprising administering to the mammal an effective amount of a compound having the structural formula:

wherein:
R1=COOCH3,COR3, lower alkyl, lower alkenyl, lower alkynyl,,CONHR4, or COR6;
R2= is a 6.alpha.,6.beta.,7.alpha. or 7.beta. substituent, which can be selected from H,OH,OR3, F,C1,Br, and NHR3;
X=CH2,CHY,CYY1,CO,O,S;SO,SO2, or C=CX1Y with the C,O or S
atom being a member of the ring;
X1=NR3,CH2,CHY,CYY1CO,O,S;SO,SO2, or NSO2R3;
R3=H,(CH2)nC6Y,C6H4Y,CHCH2, lower alkyl, lower alkenyL or lower alkynyl;
Y and Y1=H,Br,C1,I,F,OH,OCH3,CF3,NO2,NH2,CN,NHCOCH3, N(CH3)2,(CH2)nCH3,COCH3, or C(CH3)3;
R4=CH3,CH2CH3, or CH3SO2;
R6=morpholinyl or piperidinyl;
Ar=phenyl-R5, naphthyl-R5, anthxacenyl-R5, phenanthrenyl-R5, or diphenylmethoxy-R5;
R5=Br,C1,I,F,OH,OCH3,CF3,NO2,NH2,CN,NHCOCH3,N(CH3)2, (CH2)nCH3,COCH3,C(CH3)3 where n=0-6,4-F,4-C1,4-I,2-F,2-C1,2-I,3-F,3-C1, 3-I,3,4-diC1,3,4-diOH,3,4-diOAc,3,4-diOCH3,3-OH-4-C1,3-OH-4-F,3-C1-4-OH, 3-F-4-OH, lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(lower alkoxy);
m=0 or 1 ;and n=0,1,2,3,4 or 5;
wherein the compound has an affinity (K i) for the SERT of less than about 500 nM.

22. The method for treating according to claim 21, wherein the disorder is selected from depression, anxiety, eating disorders, and obsessive compulsive disorders.
23. A method for treating a mammal suffering from depression comprising administering to the mammal an effective amount of a compound having the structural formula:

wherein:

R1=COOCH3, COR3, lower alkyl, lower alkenyl, lower alkynyl, CONHR4, or COR6;
R2 = is a 6.alpha., 6.beta., 7.alpha. or 7.beta. substituent, which can be selected from H,OH,OR3, F,C1,Br, and NHR3;
X=CH2,CHY,CYY1,CO,O,S;SO,SO2, or C=CX1Y with the C,O or S
atom being a member of the ring;
X1=NR3,CH2,CHY,CYY1CO,O,S;SO,SO2, or NSO2R3;
R3=H,(CH2)nC6H4Y,C6H4Y,CHCH2, lower alkyl, lower alkenyl or lower alkynyl;
Y and Y1=H,Br,C1,I,F,OH,OCH3,CF3,NO2,NH2,CN,NHCOCH3, N(CH3)2,(CH2)nCH3,COCH3, or C(CH3)3;
R4=CH3,CH2CH3, or CH3SO2;
R6= morpholinyl or piperidinyl;
Ar = phenyl-R5, naphthyl-R5, anthracenyl-R5, phenanthrenyl-R5, or diphenylmethoxy-R5;
R5=Br,C1,I,F,OH,OCH3,CF3,NO2,NH2,CN,NHCOCH3,N(CH3)2, (CH2)nCH3,COCH3,C(CH3)3 where n=0-6,4-F,4-C1,4-I,2-F,2-C1,2-I,3-F,3-C1, 3-I,3,4-diC1,3,4-diOH,3,4-diOAc,3,4-diOCH3,3-OH-4-C1,3-OH-4-F,3-C1-4-OH, 3-F-4-OH, lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(lower alkoxy);
m = 0 or 1; and n = 0,1,2,3,4 or 5;
wherein the compound has a SERT/DAT selectivity ratio of at least 3.
24. A method for treating a mammal suffering from depression comprising administering to the mammal an effective amount of a compound having the structural formula:

wherein:
R1=COOCH3,COR3, lower alkyl, lower alkenyl, lower alkynyl, CONHR4, or COR6;
R2 = is a 6.alpha., 6.beta., 7.alpha. or 7.beta. substituent, which can be selected from H, OH, OR3, F, C1, Br, and NHR3;
X=CH2,CHY,CYYI,CO,O,S;SO,SO2, or C=CX1Y with the C,O or S
atom being a member of the ring;
X1=NR3,CH2,CHY,CYY1CO,O,S;SO,SO2; or NSO2R3;
R3=H,(CH2)nC6H4Y,C6H4Y,CHCH2, lower alkyl, lower alkenyl or lower alkynyl;
Y and Y1=H,Br,C1,I,F,OH,OCH3,CFA,NO2;NH2,CN,NHCOCH3, N(CH3)2,(CH2)nCH3,COCH3, or C(CH3)3;
R4=CH3,CH2CH3, or CH3SO2;
R6=morpholinyl or piperidinyl;
Ar=phenyl-R5, naphthyl-R5, anthracenyl-R5, phenanthrenyl-R5, or diphenylmethoxy-R5;
R5=Br,C1,I,F,OH;OCH3,CF3,NO2,NH2,CN,NHCOCH3,N(CH3)2, (CH2)nCH3,COCH3,C(CH3)3 where n=0.6,4-F,4-C1,4-I,2-F,2-C1,2-I,3-F,3-C1, 3-1,3,4-diC1,3,4-diOH;3,4-diOAc,3,4-diOCH3,3-OH-4-C1,3-OH-4-F,3-C1-4-OH, 3-F-4-OH; lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(lower alkoxy);
m = 0 or 1; and n = 0,1,2,3,4 or 5;
wherein the compound has an affinity (K i) for the SERT of less than about 500 nM.
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