Thiophene-2-carboximidamide based selective neuronal nitric oxide synthase inhibitors
Selective neuronal nitric oxide synthase (nNOS) inhibitor compounds designed with one or more thiophene-2-carboximidamide substituents for improved bioavailability.
1. A compound of a formula
wherein n is an integer selected from 1 and 2; and R is a moiety selected from
where R′ is H or R′ is selected from
moieties; or a salt thereof.
2. The compound of claim 1 wherein said phenyl moiety is meta-substituted.
3. The compound of claim 2 selected from
4. A compound selected from compounds of a formula
wherein said phenyl moiety is meta-substituted, n is an integer selected from 1 and 2 and R is
where R′ is selected from H, alkyl, arylalkyl, alkenyl, arylalkenyl, alkynyl and arylalkynyl moieties, and X is selected from H, halogen, methyl, mono- and polyfluoro-substituted methyl moieties; and compounds of a formula
wherein R′ is selected from H, methylene, alkyl, arylalkyl, alkenyl, arylalkenyl, alkynyl, and arylalkynyl moieties, and R″ is selected from H, a valence bond and a methylene moiety, providing that where R″ is a valence bond or a methylene moiety, R′ is a methylene moiety whereby R′ and R″ taken together form a 5-6 member heterocyclic ring, and X is selected from H, halogen, methyl, mono- and polyfluorosubstituted methyl moieties; and salts thereof.
5. The compound of claim 4 wherein R″ is H, and said compound is of a formula
6. The compound of claim 4 wherein R″ is selected from a valence bond and a methylene moiety, said compound of a formula
wherein m is an integer selected from 0 and 1.
7. A compound selected from compounds of a formula
and compounds of a formula
wherein L is a linker moiety selected from divalent CH═CH, CH 2 CH 2 , CH 2 (OH)CH 2 (OH), OCH 2 CH(OH), O(CH 2 ) 2 O, O(CH 2 ) 3 O, (CH 2 ) 2 NH, (CH 2 ) 2 NHCH 2 , CH 2 CH(CH 2 NH 2 )CH 2 CH 2 , CH 2 CH(CH 2 NH 2 )NHCH 2 and OCH(CH 2 NH 2 )CH 2 O moieties; and salts thereof.
8. The compound of claim 7 wherein L is selected from said CH 2 CH 2 and CH 2 (OH)CH 2 (OH) moieties.
9. A compound of a formula
wherein n and n′ are integers independently selected from 0 and 1; or a salt thereof.
10. A compound selected from compounds of a formula
and compounds of a formula
wherein n and n′ are integers independently selected from 0 and 1; X is selected from O and NH; and R is selected from phenyl, fluoro-, chloro-, bromo- and thiophene-2-carboximidamide-substituted phenyl moieties, said substituent with a relationship selected from ortho-, meta- and para- to said prolinyl linker moiety, and salts thereof.
11. The compound of claim 10 wherein each said X is O.
12. The compound of claim 11 wherein each said n and n′ is 0.
13. The compound of claim 12 wherein each said R is a thiophene-2-carboximidamide-substituted phenyl moiety.
14. The compound of claim 13 wherein each said compound is a trans stereoisomer.
15. The compound of claim 11 wherein each said n and n′ is 1.
16. The compound of claim 15 wherein each said R is a thiophene-2-carboximidamide-substituted phenyl moiety.
17. The compound of claim 16 selected from cis and trans stereoisomers.