Arylvinylazacycloalkane compounds and methods of preparation and use thereof
Novel vinylazacycloalkane compounds of Formula (I) are disclosed. The compounds are ligands of various nAChRs. The compounds and their pharmaceutically acceptable salts can be used to prepare pharmaceutical compositions and/or medicaments intended to prevent or treat disorders associated with dysfunction of nAChRs, especially within the central nervous system or the gastrointestinal system. Examples of types of disorders that can be treated include neurodegenerative disorders, including central nervous system disorders such as Alzheimer's disease, cognitive disorders, motor disorders such as Parkinson's disease, drug addiction, behavioral disorders and inflammatory disorders within the gastrointestinal system. The compounds can also serve as analgesics in the treatment of acute, chronic or recurrent pain.
1. A vinylazacycloalkane compound of Formula (I):
wherein:
the wavy line represents E geometry about the double bond;
X is CR 2 ;
R 1 is hydrogen, C 1-6 -alkyl, halogen, —OR 4 , —NR 4 R 5 , or —SR 4 ;
R 2 is hydrogen, C 1-6 -alkyl, aryl, aryl-C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, cycloalkyl, polycycloalkyl, —OR 6 , —NR 6 R 7 ,
—SR 6 , —SOR 6 , or —SO 2 R 6 ,
wherein the C 1-6 -alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl groups may be substituted with one or more substituents selected from the group consisting of F, CI, Br, I, —R 8 , —OR 8 , —NR 8 R 9 , —CF 3 , —OCF 3 , —CN, —NO 2 , —SR 8 , —S(O)R 8 , —SO 2 R 8 , —O—SO 2 R 8 , —C(═O)NR 8 R 9 , —NR 8 C(═O)R 9 , —C(═O)OR 8 , —OC(═O)R 8 , —NHSO 2 R 8 , —SO 2 NR 8 R 9 , —C(S)NR 8 R 9 , and —NHC(S)R 8 ;
R 3 is hydrogen or methyl;
R 4 and R 5 are, independently, hydrogen or C 1-6 -alkyl;
R 6 and R 7 are, independently, hydrogen, C 1-6 -alkyl, aryl, aryl-C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or polycycloalkyl,
wherein the C 1-6 -alkyl, cycloalkyl, heterocyclyl, heteroaryl and aryl groups can be substituted with one or more substituents selected from the group consisting of F, CI, Br, I, —R 8 , —NR 8 R 9 , —CF 3 , —CN, —NO 2 , —C 2 R 8 , —N 3 , —SO 2 CH 3 , —OR 8 , —SR 8 , —C(═O)NR 8 R 9 , —NR 8 C(═O)R 8 , —C(═O)R 8 , —C(═O)OR 8 , —(CH 2 ) q OR 8 , —OC(═O)R 8 , —OC(═O)NR 8 R 9 , and —NR 8 C(═O)OR 8 ;
R 8 and R 9 are, independently, hydrogen, C 1-6 -alkyl, or an aromatic group-containing species, wherein the aromatic group-containing species can be substituted with one or more of C 1-6 -alkyl, halogen, or amino; or
either R 6 and R 7 together or R 8 and R 9 together with the atoms to which they are attached form a 3- to 10-membered ring;
m is 1, 2, 3, or 4; and
n is 1, 2, or 3;
or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein the wavy line represents variable geometry (E or Z) about the double bond;
provided that when R 1 and R 2 each are hydrogen, then R 3 is hydrogen;
provided that when R 1 is hydrogen, R 2 is —OR 6 , and R 6 is phenyl, then R 3 is hydrogen;
provided that when R 1 is hydrogen, R 2 is —OR 6 , and R 6 is ethyl, then R 3 is hydrogen;
and provided that when R 2 is —OR 6 , R 6 is isopropyl, and R 3 is either hydrogen or methyl, then R 1 is other than hydrogen.
3. The compound of claim 1 wherein the wavy line represents variable geometry (E or Z) about the double bond;
X is CR 2 ;
R 1 is hydrogen, C 1-6 -alkyl, halogen, —OR 4 , —NR 4 R 5 , or —SR 4 ;
R 2 is —OR 6 ;
R 3 is hydrogen or methyl;
R 4 and R 5 are, independently, hydrogen or C 1-6 -alkyl;
R 6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, hexyl, phenyl, naphthyl, indenyl, phenyl-C 1-6 -alkyl, naphthyl-C 1-6 -alkyl, indenyl-C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or polycycloalkyl,
wherein the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, hexyl, phenyl, naphthyl, indenyl, cycloalkyl, heterocyclyl, and heteroaryl groups can be substituted with one or more substituents selected from the group consisting of F, CI, Br, I, —R 8 , —NR 8 R 9 , —CF 3 , —CN, —NO 2 , —C 2 R 8 , —N 3 , —SO 2 CH 3 , —OR 8 , —SR 8 , —C(═O)NR 8 R 9 , —NR 8 C(═O)R 8 , —C(═O)R 8 , —C(═O)OR 8 , —(CH 2 ) q OR 8 , —OC(═O)R 8 , —OC(═O)NR 8 R 9 , and —NR 8 C(═O)OR 8 ;
R 8 and R 9 are, independently, hydrogen, C 1-6 -alkyl, or an aromatic group-containing species, wherein the aromatic group-containing species can be substituted with one or more of C 1-6 -alkyl, halogen, or amino; or
R 8 and R 9 together with the atoms to which they are attached form a 3- to 10-membered ring;
m is 1,2,3, or 4; and
n is 1, 2, or 3;
or an isomer, mixture, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof;
provided that when R 1 and R 2 each are hydrogen, then R 3 is hydrogen;
provided that when R 1 is hydrogen and R 6 is phenyl, then R 3 is hydrogen;
provided that when R 1 is hydrogen and R 6 is ethyl, then R 3 is hydrogen;
provided that when R 6 is isopropyl, and R 3 is either hydrogen or methyl, then R 1 is other than hydrogen.
4. The compound of claim 3 wherein the wavy line represents E geometry.
5. The compound of claim 1 , wherein the aromatic group-containing species is pyridyl, quinolinyl, pyrimidinyl, phenyl, or benzyl.
6. The compound of claim 1 , wherein R 1 is H.
7. The compound of claim 1 , wherein R 2 is —OR 6 .
8. The compound of claim 1 , wherein n is 1.
9. The compound of claim 1 , wherein m is 2.
10. The compound of claim 1 , wherein R 6 is heterocyclyl.
11. The compound of claim 1 , wherein
R 1 is H;
R 2 is —OR 6 ;
n is 1;
m is 2;
R 6 is heterocyclyl; and
the wavy line represents E geometry.
12. A compound selected from the group consisting of:
(R)- and (S)-2-chloro-5-((E)-2-pyrrolidin-3-ylvinyl)pyridine;
(R)- and (S)-3-cyclopropylmethoxy-5-((E)-2-pyrrolidin-3-ylvinyl)pyridine;
(R)- and (S)-2-chloro-5-((E)-2-piperidin-3-ylvinyly pyridine;
(R)- and (S)-3-cyclopropylmethoxy-5-((E)-2-piperidin-3-ylvinyl)pyridine; and
2-chloro-5-((E)-2-piperidin-4-ylvinyl)pyridine;
or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable carrier.
14. The pharmaceutical composition of claim 13 , further comprising an additional active component.
15. A process for preparing arylvinylazacycloalkane compounds of formula
wherein:
the wavy line represents variable geometry (E or Z) about the double bond;
X is CR 2 ;
R 1 is hydrogen, C 1-6 -alkyl, halogen, —OR 4, —NR 4 R 5 , or —SR 4 ;
R 2 is hydrogen, C 1-6 -alkyl, aryl, aryl-C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, cycloalkyl, polycycloalkyl, —OR 6 , —NR 6 R 7 , —SR 6 , —SOR 6 , or —SO 2 R 6 ,
wherein the C 1-6 -alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl groups may be substituted with one or more substituents selected from the group consisting of F, CI, Br, I, —R 8 , —OR 8 , —NR 8 R 9 , —CF 3 , —OCF 3 , —CN, —NO 2 , —SR 8 , —S(O)R 8 , —SO 2 R 8 , —O—SO 2 R 8 , —C(═O)NR 8 R 9 , —NR 8 C(═O)R 9 , —C(═O)OR 8 , —OC(═O)R 8 , —NHSO 2 R 8 , —SO 2 NR 8 R 9 , —C(S)NR 8 R 9 , and -NHC(S)R 8 ;
R 3 is hydrogen or methyl;
R 4 and R 5 are, independently, hydrogen or C 1-6 -alkyl;
R 6 and R 7 are, independently, hydrogen, C 1-6 -alkyl, aryl, aryl-C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or polycycloalkyl,
wherein the C 1-6 -alkyl, cycloalkyl, heterocyclyl, heteroaryl and aryl groups can be substituted with one or more substituents selected from the group consisting of F, CI, Br, I, —R 8 , —NR 8 R 9 , —CF 3 , —CN, —NO 2 , —C 2 R 8 , —N 3 , —SO 2 CH 3 , —OR 8 , —SR 8 , —C(═O)NR 8 R 9 , —NR 8 C(═O)R 8 , —C(═O)R 8 , —C(═O)OR 8 , —(CH 2 ) q OR 8 , —OC(═O)R 8 , —OC(═O)NR 8 R 9 , and —NR 8 C(═O)OR 8 ;
R 8 and R 9 are, independently, hydrogen, C 1-6 -alkyl, or an aromatic group-containing species, wherein the aromatic group-containing species can be substituted with one or more of C 1-6 -alkyl, halogen, or amino; or
either R 6 and R 7 together or R 8 and R 9 together with the atoms to which they are attached form a 3- to 10-membered ring;
m is 1, 2, 3, or 4; and
n is 1, 2, or 3;
or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, comprising:
a) reacting an aldehyde of formula
wherein m is 1, 2, or 3, and n is 1, 2, or 3;
with a phosphorane ylide of the formula
PPh 3 ═CH 2
to yield a vinylazacycloalkane of the formula
b) reacting the resulting vinylazacycloalkane with a heteroaryl halide of the formula
wherein X and R 1 are as defined above, and Y is halogen; and
c) removing any remaining protecting groups.