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 method for the treatment of one or more of pre-senile dementia, early onset Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, Lewy Body dementia, micro-infarct dementia, AIDS-related dementia, HIV-dementia, mild cognitive impairment, age-associated memory impairment, premature amnesic disorder, age-related cognitive disorders, substance-related cognitive disorders, cognitive disorders related to immunodeficiency syndrome, cognitive disorders associated with vascular disorders, schizophrenia, cognitive dysfunction in schizophrenia, attention deficit disorder, attention deficit hyperactivity disorder, attention deficiencies, or learning deficiencies comprising:
administering to a patient in need thereof an effective amount of 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, Cl, 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, Cl, 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 method of claim 1 , wherein R 1 is H.
3. The method of claim 1 , wherein R 2 is —OR 6 .
4. The method of claim 1 , wherein n is 1.
5. The method of claim 1 , wherein m is 2.
6. The method of claim 1 , wherein R 8 is heterocycle.
7. The method of claim 1 , wherein the geometry about the double bond is E.
8. The method of claim 1 , wherein the aromatic group-containing species is pyridyl, quinolinyl, pyrimidinyl, phenyl, or benzyl.
9. The method of claim 1 , wherein the disorder is selected from one or more of pre-senile dementia, early onset Alzheimer's Disease, senile dementia, dementia of the Alzheimer's type, attention deficit disorder, attention deficit hyperactivity disorder, mild cognitive impairment, age-associated memory impairment, schizophrenia, and cognitive dysfunction in schizophrenia.
10. The method of claim 1 , wherein the compound is 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-ylvinyl)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.