Compounds with high monoamine transporter affinity
View Patent ↗Featured compounds have high monoamine transport affinity and are characterized by one of the following two general formulas set out above. The compounds bind selectively or non-selectively to monoamine transporters. The compounds are useful to treat various medical indications including attention deficit hyperactivity disorder (ADHD), Parkinson's disease, cocaine addiction, smoking cessation, weight reduction, obsessive-compulsive disorder, various forms of depression, traumatic brain injury, stroke, and narcolepsy.
1. A compound having the formula:
WHERE:
* indicates a chiral center, and each chiral center, independently, may be R, S, or R/S;
—X=—CH 2 R 1 ; —CHR 1 R 5 ; —CR 1 ═O; —CR 6 ═O; —O—R 1 ; —SR 1 ; —SOR 6 ; —SO 2 R 6 ; —SO 2 NHR 1 ; or —CH═CR 1 R 5 and where:
a. —R 1 and —R 5 are independently selected from: —H; —CH 3 ; —CH 2 CH 3 ; or —CH 2 (CH 2 ) m CH 3 , where m=0, 1, 2, or 3;
PROVIDED THAT, when X=—O—R 1 , then R 1 ≠H; and
b. —R 6 is selected from: —OH; —OCH 3 ; —NHR 1 ; —O-alkyl; —O-alkenyl; —O-alkynyl; —O-allyl; —O-iodoallyl; -alkyl; -alkenyl; -alkynyl; -allyl; -isopropyl; and -isobutyl;
—Ar=
phenyl substituted at any two positions with R 3a and R 3b , where R 3a and R 3b are as defined in options “I.” or “II.”, below;
OPTION I. for R 3a , and R 3b
—R 3a and —R 3b are independently selected from: —H; —Br; —Cl; —I; —F; —OH; —OCH 3 ; —CF 3 ; —NO 2 ; —NH 2 ; —CN; —NHCOCH 3 , —C(CH 3 ) 3 , —(CH 2 ) q CH 3 where q=0–6; —COCH 3 ; —F (at the 2, 3 or 4 position), —Cl (at the 2, 3 or 4 position); —I (at the 2, 3 or 4 position); alkyl; alkenyl; alkynyl; allyl; iospropyl; isobutyl; alkyl; -alkylN 2 S 2 chelator; -alkylN 2 S 2 Tc chelator; or COR 7 , where R 7 is defined below; or
OPTION II. for R 3a and R 3b
—R 3a and —R 3b as a pair are independently selected from the following pairs: 3,4-diCl; 3,4, diOH; 3,4-diOAc; 3,4-diOCH 3 ; 3-OH, 4-Cl; 3-OH,4-F; 3-Cl,4-OH; or 3-F,4-OH;
n=0 or 1;
—R 2 =—H; —COOCH 3 ; —COR 7 ; -alkyl; -alkenyl; -allyl; -iodoallyl; -alkynyl; -alkylN 2 S 2 chelator-; —O-alkylN 2 S 2 chelator; -alkylN 2 S 2 Tc chelator;
—O-alkylN 2 S 2 Tc chelator; where,
—R 7 is=—NHR 8 ; morpholinyl; piperidinyl; —CH 3 ; —CH 2 CH 3 ; —CH 2 (CH 2 ) r CH 3 where r=0, 1, 2, or 3; alkyl; alkenyl; alkynyl; allyl; isopropyl; iodoallyl; O-iodoallyl; -isobutyl; —CH 2 SO 2 ; -alkylN 2 S 2 chelator; -alkylN 2 S 2 Tc chelator; O-alkylN 2 S 2 chelator; or —O-alkylN 2 S 2 Tc chelator; and
—R 8 is=-alkyl; -alkenyl; -allyl; -iodoallyl; -alkynyl; -isoxazole; -oxadiazole; -oxazole; -alkylN 2 S 2 chelator —O-alkylN 2 S 2 chelator; -alkylN 2 S 2 Tc chelator; or —O-alkylN 2 S 2 Tc chelator;
R4a and R4b are independently selected from:
—H; —Br; —Cl; —I; —F; —OH; —OCH 3 ; —CF 3 ; —NO 2 ; —NH 2 ; —CN; —NHCOCH 3 , —C(CH 3 ) 3 , —(CH 2 ) q CH 3 where q=0–6; —COCH 3 ; —F (at the 2, 3 or 4 position), —Cl (at the 2, 3 or 4 position); —I (at the 2, 3 or 4 position); alkyl; alkenyl; alkynyl; allyl; iospropyl; isobutyl; alkyl; -alkylN 2 S 2 ; -alkylN 2 S 2 Tc; and COR 7 , where R 7 is defined above; or
R4a and R4b are selected as a pair from the following pairs:
3,4-diCl; 3,4-diOH; 3,4-diOAc; 3,4-diOCH 3 ; 3-OH, 4-Cl; 3-OH,4-F; 3-Cl,4-OH; and 3-F, 4-OH.
2. The compound of claim 1 in which n=0.
3. The compound of claim 1 or claim 2 in which X=—O—R 1 .
4. The compound of claim 3 in which —R 1 =—CH 3 .
5. The compound of claim 1 in which Ar=phenyl substituted at any two positions with R 3a , and R 3b .
6. The compound of claim 5 in which R 3a , and R 3b are independently selected from —H and —Cl.
7. The compound of claim 6 in which R 3a , and R 3b are both —Cl.
8. A compound selected from the group consisting of
9. A pharmaceutical composition comprising a compound according to any one claims 1 – 4 , 5 – 7 or 8 mixed with a pharmaceutically acceptable carrier.