Compounds, their preparation and use
The present invention relates to novel compounds that are found to be cholinergic ligands at the nicotinic acetylcholine receptors and modulators of the monoamine receptors and transporters. Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.
1. A chemical substance represented by Formula I
any of its enantiomers or any mixture of enantiomers, or a pharmaceutically-acceptable addition salt thereof, wherein
A, B, D, E and G, independently of each another, represent a carbon (C) or a nitrogen (N) atom, constituting an aromatic ring system; and
X represents a group of Formula III
wherein ═ represents a single or a double bond; n is 0, 1, 2 or 3; and R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl.
2. The chemical substance of claim 1 , which substance is
a benzo[b]thiophene of Formula IA
a benzo[b]thiazole of Formula IB
a thienopyridine of Formula IC
a thienopyridine of Formula ID
a thienopyridine of Formula IE
or a thienopyridine of Formula IF
wherein A and X are as defined in claim 1 .
3. The chemical substance of claim 1 , which is a benzo[b]thiophene of Fonnula IA, wherein
X represents a group of Formula III, wherein
═ represents a double bond;
n is 0 or 1; and
R represents hydrogen, alkyl or aralkyl.
4. The chemical substance of claim 1 , which is
(±) 3-(2-Benzo[b]thiophenyl-1,1-dioxide)-8-H-8-azabicyclo[3.2.1]oct-2-ene;
(±) 3-(2-Benzo[b]thiophenyl-1,1-dioxide)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;
(±) 3-(2-Benzo[b]thiophenyl-1,1-dioxide)-8-ethyl-8-azabicyclo[3.2.1]oct-2-ene;
(±) 3-(2-Benzo[b]thiophenyl-1,1-dioxide)-8-allyl-8-azabicyclo[3.2.1]oct-2-ene;
(±) 3-(2-Benzo[b]thiophenyl-1,1-dioxide)-8-benzyl-8-azabicyclo[3.2.1]oct-2-ene;
(±) 3-(2-Benzo[b]thiophenyl-1,1-dioxide)-9-H-9-azabicyclo[3.3.1]non-2-ene;
(±) 3-(2-Benzo[b]thiophenyl-1,1-dioxide)-9-methyl-9-azabicyclo[3.3.1]non-2-ene;
(±) 3-(2-Benzo[b]thiophenyl-1,1-dioxide)-9-ethyl-9-azabicyclo[3.3.1]non-2-ene;
(±) 3-(2-Benzo[b]thiophenyl-1,1-dioxide)-9-benzyl-9-azabicyclo[3.3.1]non-2-ene;
or a pharmaceutically-acceptable addition salt thereof.
5. The chemical substance of claim 1 , which is a benzo[b]thiazole of Formula IB, wherein
X represents a group of Formula III, wherein
═ represents a double bond;
n is 0 or 1; and
R represents hydrogen, alkyl or aralkyl.
6. The chemical substance of claim 1 , which is
(±) 3-(2-Benzo[b]thiazolyl-1,1-dioxide)-8-H-8-azabicyclo[3.2.1]oct-2-ene;
(±) 3-(2-Benzo[b]thiazolyl-1,1-dioxide)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;
(±) 3-(2-Benzo[b]thiazolyl-1,1-dioxide)-8-ethyl-8-azabicyclo[3.2.1]oct-2-ene;
(±) 3-(2-Benzo[b]thiazolyl-1,1-dioxide)-8-benzyl-8-azabicyclo[3.2.1]oct-2-ene;
(±) 3-(2-Benzo[b]thiazolyl-1,1-dioxide)-9-H-9-azabicyclo[3.3.1]non-2-ene;
(±) 3-(2-Benzo[b]thiazolyl-1,1-dioxide)-9-methyl-9-azabicyclo[3.3.1]non-2-ene;
(±) 3-(2-Benzo[b]thiazolyl-1,1-dioxide)-9-ethyl-9-azabicyclo[3.3.1]non-2-ene; or
(±) 3-(2-Benzo[b]thiazolyl-1,1-dioxide)-9-benzyl-9-azabicyclo[3.3.1]non-2-ene;
or a pharmaceutically-acceptable addition salt thereof.
7. The chemical substance of claim 1 , which is
(±)3-(2-benzo[b]thiophenyl-1,1-dioxide)-8-H-8-azabicyclo[3.2.1]oct-2-ene.
8. A pharmaceutical composition comprising a therapeutically effective amount of a chemical substance of any of claims 1 , 2 , 3 - 6 , or 7 , any of its enantiomers or any mixture of its enantiomers, or a pharmaceutically-acceptable addition salt thereof, together with at least one pharmaceutically-acceptable carrier or diluent.
9. A method of the treatment or alleviation of pain of a living animal body, including a human, which method comprises the step of administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of a chemical substance of any of claims 1, 2, 3-6 or 7, any of its enantiomers or any mixture of its enantiomers, or a pharmaceutically-acceptable addition salt thereof.
10. The method of claim 9 , wherein the disease, disorder or condition is mild, moderate or even severe pain of acute, chronic or recurrent character, as well as pain caused by migraine, postoperative pain, and phantom limb pain.