HK1068628B - Nicotinic acetyl-choline receptors inhibitor compounds, their preparation and use - Google Patents

Description

Nicotinic acetylcholine receptor inhibitor compounds, their preparation and use

Technical Field

The present invention relates to novel compounds which 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.

Background

The endogenous cholinergic neurotransmitter acetylcholine exerts its biological effects through two types of cholinergic receptors, muscarinic acetylcholine receptors (machrs) and nicotinic acetylcholine receptors (nachrs).

Since muscarinic acetylcholine receptors are generally recognized as quantitatively superior to nicotinic acetylcholine receptors in brain regions important for memory and cognition, much research aimed at developing drugs for the treatment of memory-related disorders has focused on the synthesis of muscarinic acetylcholine receptor modulators.

However, in recent years there has been interest in the development of nAchR modulators. Some diseases are associated with degeneration of the cholinergic system, i.e., senile dementia of the alzheimer type, cognitive impairment due to vascular dementia and organic brain injury diseases directly related to alcoholism. In fact, there are several CNS disorders attributable to cholinergic, dopaminergic, adrenergic, or 5-hydroxytryptamine deficiency.

Summary of The Invention

The present invention seeks to provide novel modulators of nicotinic receptors and/or monoamine receptors, which modulators are useful in the treatment of diseases or disorders associated with cholinergic receptors, particularly the nicotinic acetylcholine receptor (nAChR), the monoamine receptors 5-HTR, DAR and NER, and the biogenic amine transporters of 5-HT, DA and NE.

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.

The compounds of the invention may also be used as diagnostic tools or monitoring agents in a variety of diagnostic methods, particularly in vivo receptor imaging (neuroimaging), and they may be used in labeled or unlabeled form.

In a first aspect the present invention provides novel chemical substances represented by the general formula I

Any enantiomer or any mixture of enantiomers thereof, or a pharmaceutically-acceptable addition salt thereof, wherein A, B, D, E and G independently of each other represent a carbon (C) or nitrogen (N) atom, forming an aromatic ring system; x represents

A radical of the formula II

A radical of the formula III

A radical of the formula IV

A radical of the formula V

A radical of the formula VI

A radical of the formula VII

Or a radical of the formula VIII

In the above-mentioned formula, the compound of formula,represents a single bond or a double bond (optional double bond); n is 0, 1, 2 or 3; m is 1, 2 or 3; r represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl.

In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a chemical substance of the invention, any of its enantiomers or any mixture of its enantiomers, or a pharmaceutically-acceptable addition salt thereof, and at least one pharmaceutically-acceptable carrier or diluent.

Another aspect of the invention relates to the use of a chemical substance of the invention for the treatment, prevention or alleviation of a disease or a disorder or a condition responsive to modulation of cholinergic receptors and/or monoamine receptors.

In another aspect, the invention provides a method of treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body which disorder or disease is responsive to modulation of cholinergic receptors and/or monoamine receptors, which method comprises the step of administering to a living animal body, including a human, in need thereof a therapeutically effective amount of a chemical substance according to the invention.

Other objects of the present invention will be apparent to those skilled in the art from the following detailed description and examples.

Detailed Description

In a first aspect the present invention provides novel chemical substances represented by the general formula I

Any enantiomer or any mixture of enantiomers thereof, or a pharmaceutically-acceptable addition salt thereof, wherein A, B, D, E and G represent, independently of each other, a carbon (C) or nitrogen (N) atom, and wherein no more than two of B, D, E and G represent a nitrogen atom, and the remainder of B, D, E and G represent carbon atoms, thereby forming an aromatic ring system; x represents

A radical of the formula II

A radical of the formula III

A radical of the formula IV

A radical of the formula V

A radical of the formula VI

A radical of the formula VII

Or a radical of the formula VIII

In the above-mentioned formula, the compound of formula,represents a single bond or a double bond (optional double bond);

n is 0, 1, 2 or 3;

m is 1, 2 or 3; while

R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl.

In a preferred embodiment, the chemical of the invention is

Benzo [ b ] thiophene derivatives of formula IA

Benzo [ b ] thiazole derivatives of formula IB

Thienopyridine derivatives of formula IC

Thienopyridine derivatives of formula ID

Thienopyridine derivatives of formula IE

Or thienopyridine derivatives of formula IF

In the above formula

A and X are as defined above.

In a more preferred embodiment, the chemical substance of the invention is a benzo [ b ] thiophene derivative of formula IA, wherein X represents a group of formula II, wherein n is 0, 1 or 2; m is 1, 2 or 3; r represents hydrogen, alkyl or aralkyl.

In a most preferred embodiment, the benzo [ b ] thiophene derivative of the present invention is

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -imidazolidine;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -3-methyl-imidazolidine;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -1, 3-diazacyclohexane;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -3-methyl-1, 3-diazacyclohexane;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -piperazine;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -4-methyl-piperazine;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -4-ethyl-piperazine;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -4-benzyl-piperazine;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -homopiperazine;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -4-methyl-homopiperazine;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -4-ethyl-homopiperazine;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -4-benzyl-homopiperazine;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -1, 4-diazacyclooctane;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -4-methyl-1, 4-diazacyclooctane;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -4-ethyl-1, 4-diazacyclooctane;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -4-benzyl-1, 4-diazacyclooctane;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -1, 5-diazacyclooctane;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -5-methyl-1, 5-diazacyclooctane;

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -5-ethyl-1, 5 diazacyclooctane; or

(±)1- (2-benzo [ b ] thienyl-1, 1-dioxide) -5-benzyl-1, 5-diazacyclooctane;

or a pharmaceutically acceptable addition salt thereof.

In another preferred embodiment, the chemical substance of the invention is a benzo [ b ] thiazole derivative of formula IB, wherein X represents a group of formula II, wherein n is 0, 1 or 2; m is 1, 2 or 3; r represents hydrogen, alkyl or aralkyl.

In a most preferred embodiment, the benzo [ b ] thiazole derivative of the invention is

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -imidazolidine;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -3-methyl-imidazolidine;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -1, 3-diazacyclohexane;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -3-methyl-1, 3-diazacyclohexane;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -piperazine;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -4-methyl-piperazine;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -4-ethyl-piperazine;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -4-benzyl-piperazine;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -homopiperazine;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -4-methyl-homopiperazine;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) 4-ethyl-homopiperazine;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -4-benzyl-homopiperazine;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -1, 4-diazacyclooctane;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -4-methyl-1, 4-diazacyclooctane;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -4-ethyl-1, 4-diazacyclooctane;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -4-benzyl-1, 4-diazacyclooctane;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -1, 5-diazacyclooctane;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -5-methyl-1, 5-diazacyclooctane;

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -5-ethyl-1, 5 diazacyclooctane; or

(±)1- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -5-benzyl-1, 5-diazacyclooctane;

or a pharmaceutically acceptable addition salt thereof.

In a third preferred embodiment, the chemical substance of the invention is benzo [ b ] of formula IA]Thiophene derivatives, in which X represents a radical of the formula III, in whichRepresents a double bond; n is 0 or 1; r represents hydrogen, alkyl or aralkyl.

In a most preferred embodiment, the benzo [ b ] thiophene derivative of formula IA is

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -8-H-8-azabicyclo [3.2.1] oct-2-ene;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -8-ethyl-8-azabicyclo [3.2.1] oct-2-ene;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -8-allyl-8-azabicyclo [3.2.1] oct-2-ene;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -8-benzyl-8-azabicyclo [3.2.1] oct-2-ene;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -9-H-9-azabicyclo [3.3.1] non-2-ene;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -9-methyl-9-azabicyclo [3.3.1] non-2-ene;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -9-ethyl-9-azabicyclo [3.3.1] non-2-ene;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -9-benzyl-9-azabicyclo [3.3.1] non-2-ene;

or a pharmaceutically acceptable addition salt thereof.

In a fourth preferred embodiment, the chemical substance of the invention is a benzo [ b ] of formula IB]Thiazole derivatives, wherein X represents a group of the formula III, whereinRepresents a double bond; n is 0 or 1; r represents hydrogen, alkyl or aralkyl.

In a most preferred embodiment, the benzo [ b ] thiazole derivative of formula IB 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.

In a fifth preferred embodiment, the chemical substance of the invention is benzo [ b ] of formula IA]Thiophene derivatives, in which X represents a group of the formula IV, in whichRepresents a double bond; n is 0 or 1; r represents hydrogen or alkyl.

In a most preferred embodiment, the benzo [ b ] thiophene derivative of formula IA is

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -7-H-7-azabicyclo [3.3.0] oct-2-ene;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -7-methyl-7-azabicyclo [3.3.0] oct-2-ene;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -7-ethyl-7-azabicyclo [3.3.0] oct-2-ene; or

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -7-benzyl-7-azabicyclo [3.3.0] oct-2-ene;

or a pharmaceutically acceptable addition salt thereof.

In a sixth preferred embodiment, the chemical substance of the invention is a benzo [ b ] of formula IB]Thiazole derivatives, wherein X represents a group of the formula IV, whereinRepresents a double bond; n is 0 or 1; r represents hydrogen or alkyl.

In a most preferred embodiment, the benzo [ b ] thiazole derivative of formula IB is

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -7-H-7-azabicyclo [3.3.0] oct-2-ene;

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -7-methyl-7-azabicyclo [3.3.0] oct-2-ene;

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -7-ethyl-7-azabicyclo [3.3.0] oct-2-ene; or

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -7-benzyl-7-azabicyclo [3.3.0] oct-2-ene;

or a pharmaceutically acceptable addition salt thereof.

In a seventh preferred embodiment, the chemical substance of the invention is a benzo [ b ] thiophene derivative of formula IA, wherein X represents a group of formula V, wherein n is 0, 1 or 2; m is 1 or 2; r represents hydrogen or alkyl.

In a most preferred embodiment, the benzo [ b ] thiophene derivative of formula IA is

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -9-H-3, 9-diazabicyclo [4.2.1] nonane;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -9-methyl-3, 9-diazabicyclo [4.2.1] nonane;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -9-ethyl-3, 9-diazabicyclo [4.2.1] nonane;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -10-H-3, 10-diazabicyclo [4.3.1] decane;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -10-methyl-3, 10-diazabicyclo [4.3.1] decane;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -10-ethyl-3, 10-diazabicyclo [4.3.1] decane;

or a pharmaceutically acceptable addition salt thereof.

In an eighth preferred embodiment, the chemical substance of the invention is a benzo [ b ] thiazole derivative of formula IB, wherein X represents a group of formula V, wherein n is 0, 1 or 2; m is 1 or 2; r represents hydrogen or alkyl.

In a most preferred embodiment, the benzo [ b ] thiazole derivative of formula IB is

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -9-H-3, 9-diazabicyclo [4.2.1] nonane;

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -9-methyl-3, 9-diazabicyclo [4.2.1] nonane;

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -9-ethyl-3, 9-diazabicyclo [4.2.1] nonane;

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -10-H-3, 10-diazabicyclo [4.3.1] decane;

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -10-methyl-3, 10-diazabicyclo [4.3.1] decane; or

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -10-ethyl-3, 10-diazabicyclo [4.3.1] decane;

or a pharmaceutically acceptable addition salt thereof.

In a ninth preferred embodiment, the chemical substance of the invention is a benzo [ b ] thiophene derivative of formula IA, wherein X represents a group of formula VI, wherein n is 0 or 1; r represents hydrogen, alkyl, phenyl or benzyl.

In a most preferred embodiment, the benzo [ b ] thiophene derivative of formula IA is

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -7-H-3, 7-diazabicyclo [3.3.0] octane;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -7-methyl-3, 7-diazabicyclo [3.3.0] octane;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -7-phenyl-3, 7-diazabicyclo [3.3.0] octane;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -7-benzyl-3, 7-diazabicyclo [3.3.0] octane;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -7-H-3, 7-diazabicyclo [3.3.1] nonane;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -7-methyl-3, 7-diazabicyclo [3.3.1] nonane;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -7-phenyl-3, 7-diazabicyclo [3.3.1] nonane;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -7-benzyl-3, 7-diazabicyclo [3.3.1] nonane;

or a pharmaceutically acceptable addition salt thereof.

In a tenth preferred embodiment, the chemical substance of the invention is a benzo [ b ] thiazole derivative of formula IB, wherein X represents a group of formula VI, wherein n is 0 or 1; r represents hydrogen, alkyl, phenyl or benzyl.

In a most preferred embodiment, the benzo [ b ] thiazole derivative of formula IB is

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -7-H-3, 7-diazabicyclo [3.3.0] octane;

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -7-methyl-3, 7-diazabicyclo [3.3.0] octane;

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -7-phenyl-3, 7-diazabicyclo [3.3.0] octane;

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -7-benzyl-3, 7-diazabicyclo [3.3.0] octane;

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -7-H-3, 7-diazabicyclo [3.3.1] nonane;

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -7-methyl-3, 7-diazabicyclo [3.3.1] nonane;

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -7-phenyl-3, 7-diazabicyclo [3.3.1] nonane; or

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -7-benzyl-3, 7-diazabicyclo [3.3.1] nonane;

or a pharmaceutically acceptable addition salt thereof.

In an eleventh preferred embodiment, the chemical substance of the invention is a benzo [ b ] thiophene derivative of formula IA, wherein X represents a group of formula VII, wherein R represents hydrogen or an alkyl group.

In a most preferred embodiment, the benzo [ b ] thiophene derivative of formula IA is

(±)2- (2-benzo [ b ] thienyl-1, 1-dioxide) - (1S, 4S) - (+) -5-H-2, 5-diazabicyclo- [2.2.1] -heptane;

(±)2- (2-benzo [ b ] thienyl-1, 1-dioxide) - (1S, 4S) - (+) -5-methyl-2, 5-diazabicyclo- [2.2.1] -heptane;

or a pharmaceutically acceptable addition salt thereof.

In a twelfth preferred embodiment, the chemical substance according to the invention is a benzo [ b ] thiazole derivative of formula IB, wherein X represents a group of formula VII, wherein R represents hydrogen or alkyl.

In a most preferred embodiment, the benzo [ b ] thiazole derivative of formula IB is

(±)2- (2-benzo [ b ] thiazolyl-1, 1-dioxide) - (1S, 4S) - (+) -5-H-2, 5-diazabicyclo- [2.2.1] -heptane; or

(±)2- (2-benzo [ b ] thiazolyl-1, 1-dioxide) - (1S, 4S) - (+) -5-methyl-2, 5-diazabicyclo- [2.2.1] -heptane;

or a pharmaceutically acceptable addition salt thereof.

In a thirteenth preferred embodiment, the chemical of the invention is benzo [ b ] of formula IA]Thiophene derivatives, in which X represents a group of the formula VIII, in whichRepresents a single bond or a double bond.

In a most preferred embodiment, the benzo [ b ] thiophene derivative of formula IA is

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -quinuclidine;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -quinuclidin-2-ene; or

(±) -3- (2-benzothienyl-1, 1-dioxide) -quinuclidin-2-ene-N-methyl;

or a pharmaceutically acceptable addition salt thereof.

In a fourteenth preferred embodiment, the chemical substance of the present invention is benzo [ b ] of formula IB]Thiazole derivatives, wherein X represents a group of the formula VIII, whereinRepresents a single bond or a double bond.

In a most preferred embodiment, the benzo [ b ] thiazole derivative of formula IB is

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -quinuclidine; or

(±)3- (2-benzo [ b ] thiazolyl-1, 1-dioxide) -quinuclidin-2-ene;

or a pharmaceutically acceptable addition salt thereof.

Definition of substituents

In the context of the present invention, alkyl denotes a monovalent saturated straight or branched hydrocarbon chain. The hydrocarbon chain preferably contains from one to eighteen carbon atoms (C)_1-18-alkyl), more preferably containing one to six carbon atoms (C)_1-6-an alkyl group; lower alkyl) including pentyl, isopentyl, neopentyl, tert-pentyl, hexyl and isohexyl. In a preferred embodiment, alkyl represents C_1-4Alkyl groups including butyl, isobutyl, sec-butyl and tert-butyl. In another preferred embodiment of the invention, alkyl represents C_1-3Alkyl groups, which may be in particular methyl, ethyl, propyl or isopropyl.

In the context of the present invention, alkenyl denotes carbon chains containing one or more double bonds, including dienes, trienes and polyenes. In a preferred embodiment, the alkenyl groups of the present invention contain 2 to 8 carbon atoms (C)_2-8Alkenyl), more preferably 2 to 6 carbon atoms (C)_2-6Alkenyl) comprising at least one double bond. In a most preferred embodiment, the alkenyl groups of the present invention are vinyl groups; 1-or 2-propenyl; 1-, 2-or 3-butenyl, or 1, 3-butadienyl; 1-, 2-, 3-, 4-or 5-hexenyl, or 1, 3-hexadienyl, or 1, 3, 5-hexanetrienyl; 1-, 2-, 3-, 4-, 5-, 6-or 7-octenyl, or 1, 3-octadienyl, or 1, 3, 5-octatrienyl, or 1, 3, 5, 7-octatetraenyl.

In the context of the present invention, alkynyl denotes carbon chains containing one or more triple bonds, including diynes, triynes and polyacetylenes. In a preferred embodiment, alkynyl groups of the present invention contain 2 to 8 carbon atoms (C)_2-8Alkynyl), more preferably containing 2 to 6 carbon atoms (C)_2-6-alkynyl) comprising at least one triple bond. In its most preferred embodiment, the alkynyl group of the present invention is ethynyl; 1-or 2-propynyl; 1-, 2-or 3-butynyl, or 1, 3-butynyl; 1-, 2-, 3-or 4-pentynyl, or 1, 3-pentadiynyl; 1-, 2-, 3-, 4-or 5-hexynyl, or 1, 3-hexadiynyl, or 1, 3, 5-hexadiynyl; 1-, 2-, 3-, 4-, 5-or 6-heptynyl, or 1, 3-heptyldiynyl, or 1, 3, 5-heptyltribuynyl; 1-, 2-, 3-, 4-, 5-, 6-or 7-octynyl, or 1, 3-octadiynyl, or 1, 3, 5-octtriynyl, or 1, 3, 5, 7-octatetraynyl.

In the context of the present invention, cycloalkanesThe radical is a cyclic alkyl radical, preferably having 3 to 7 carbon atoms (C)_3-7Cycloalkyl) including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In the context of the present invention, cycloalkyl-alkyl denotes cycloalkyl as defined above, the cycloalkyl group being substituted on alkyl as also defined above. Examples of preferred cycloalkyl-alkyl groups of the present invention include cyclopropylmethyl and cyclopropylethyl.

In the context of the present invention, aryl represents a monocyclic or polycyclic aromatic hydrocarbon radical. Examples of preferred aryl groups in the present invention include phenyl, indenyl, naphthyl, azulenyl, fluorenyl and anthracenyl.

In the context of the present invention, aralkyl denotes an aryl group as defined above, which is linked to an alkyl group also as defined above. Examples of preferred aralkyl groups in the present invention include benzyl.

Pharmaceutically acceptable salts

The compounds of the present invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salt and prodrug forms of the compounds of the invention.

Examples of pharmaceutically acceptable addition salts include, but are not limited to, non-toxic inorganic and organic acid addition salts, such as hydrochloride derived from hydrochloric acid, hydrobromide derived from hydrobromic acid, nitrate derived from nitric acid, perchlorate derived from perchloric acid, phosphate derived from phosphoric acid, sulfate derived from sulfuric acid, formate derived from formic acid, acetate derived from acetic acid, aconitate derived from aconitic acid, ascorbate derived from ascorbic acid, benzenesulfonate derived from benzenesulfonic acid, benzoate derived from benzoic acid, cinnamate derived from cinnamic acid, citrate derived from citric acid, dihydronaphthoate derived from dihydronaphthoic acid, heptanoate derived from heptanoic acid, fumarate derived from fumaric acid, glutamate derived from glutamic acid, glycolate derived from glycolic acid, lactate derived from lactic acid, maleic acid salts derived from maleic acid, malonic acid salts derived from malonic acid, mandelic acid salts derived from mandelic acid, methanesulfonic acid salts derived from methanesulfonic acid, naphthalene-2-sulfonic acid salts derived from naphthalene-2-sulfonic acid, phthalic acid salts derived from phthalic acid, salicylic acid salts derived from salicylic acid, sorbic acid salts derived from sorbic acid, stearic acid salts derived from stearic acid, succinic acid salts derived from succinic acid, tartaric acid salts derived from tartaric acid, p-toluenesulfonic acid salts derived from p-toluenesulfonic acid and the like. Such salts may be formed by methods known and described in the art.

Other acids, such as oxalic acid, may not be considered pharmaceutically acceptable, but may also be used to prepare salts which are useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

The metal salts of the compounds of the present invention include alkali metal salts, such as sodium salts of the compounds of the present invention containing carboxyl groups.

In the context of the present invention, an "onium salt" of a nitrogen-containing compound is also contemplated as a pharmaceutically acceptable salt. Preferred "onium salts" include alkyl-onium salts, cycloalkyl-onium salts, and cycloalkylalkyl-onium salts.

Stereoisomers

The compounds of the invention may exist in (+) and (-) forms as well as in racemic form (±). The racemates of these isomers and the individual isomers themselves are within the scope of the present invention.

The racemic forms can be resolved into the optical antipodes by known methods and techniques. One way to separate diastereomeric salts is by liberation of an optically active amine compound by treatment with an optically active acid and with a base. Another method for resolving racemates into the optical antipodes is based on chromatography on an optically active matrix. The racemic compounds of the invention can thus be resolved into their optical antipodes, for example by fractional crystallization of the d-or l- (tartaric acid, mandelic acid or camphorsulfonic acid) salt.

The compounds of the present invention may also be resolved by reacting them with optically active activated carboxylic acids, such as those derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphoric acid, to form diastereomeric amides, or reacting them with optically active chloroformates, or the like, to form diastereomeric carbamates.

Other methods of resolving optical isomers are well known in the art. These methods include those described by Jaques J, Collet A, and Wilen S "Enantiomers，Racemates，and Resolutions", John Wiley and Sons, New York (1981).

Optically active compounds can also be prepared from optically active starting materials.

Preparation method

The chemical substances of the invention can be prepared by conventional methods of chemical synthesis, for example as described in the examples. The starting materials for the processes described in this application are known or can be readily prepared from commercially available chemicals by conventional methods.

Furthermore, one compound of the present invention can be converted to another compound of the present invention using conventional methods.

The final product of the reaction described herein may be isolated by conventional techniques such as extraction, crystallization, distillation, chromatography and the like.

Biological activity

The present invention relates to novel chemical entities which are found to be cholinergic ligands at the nicotinic acetylcholine receptors (nAChR) and modulators of the monoamine receptors, particularly modulators of the 5-HT, DA and NE biogenic amine transporters. Preferred compounds of the invention also exhibit selective α 7 activity.

In the context of the present invention, the term "modulator" encompasses agonists, partial agonists, antagonists and allosteric modulators of receptors.

Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as CNS related diseases, PNS related diseases, diseases related to smooth muscle contraction, endocrine disorders, diseases related to neurodegeneration, diseases related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

In a preferred embodiment, the compounds of the present invention are useful for the treatment of diseases, disorders, or conditions associated with the central nervous system. Such diseases or disorders include anxiety, cognitive disorders, learning deficit, memory deficit and dysfunction, Alzheimer's disease, attention deficit hyperactivity disorder, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, tourette's syndrome, depression, mania, bipolar disorder, schizophrenia, Obsessive Compulsive Disorder (OCD), panic disorders, eating disorders such as anorexia nervosa, bulimia and obesity, narcolepsy, nociception, AIDS-dementia, senile dementia, peripheral neuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post-traumatic syndrome, social phobia, sleep disorders, pseudodementia, ganser's syndrome, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, mutism, trichotillomania and jet lag.

In another preferred embodiment, the compounds of the present invention are useful for the treatment of diseases, disorders, or conditions associated with smooth muscle contraction, including spastic disorders, angina, premature labor, convulsions, diarrhea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, premature ejaculation, and erectile difficulty.

In another preferred embodiment, the compounds of the present invention are useful for the treatment of endocrine disorders such as thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.

In another preferred embodiment, the compounds of the invention are useful for the treatment of neurodegenerative diseases, including transient hypoxia and induced neurodegeneration.

In another preferred embodiment, the compounds of the present invention are useful in the treatment of inflammatory diseases, disorders or conditions, including inflammatory skin diseases such as acne and rosacea, Chron's disease, inflammatory bowel disease, ulcerative colitis and diarrhea.

In another preferred embodiment, the compounds of the invention are useful for the treatment of mild, moderate or even severe pain, acute, chronic or recurrent, as well as pain caused by migraine, postoperative pain and pain in the prosthetic limb.

Finally, the compounds of the invention are useful in the treatment of withdrawal symptoms caused by the termination of use of addictive substances. These addictive substances include nicotine-containing products such as tobacco, opioids such as heroin, cocaine and morphine, benzodiazepines * and benzodiazepine * -like drugs, and alcohol. In general, withdrawal from addictive substances is often a traumatic experience characterized by anxiety and frustration, anger, anxiety, impaired concentration, restlessness, reduced heart rate, and increased appetite and weight gain.

As used herein, "treatment" encompasses treatment, prevention and alleviation of withdrawal symptoms and withdrawal, as well as treatments capable of resulting in an active reduction in the intake of addictive substances.

In another aspect, the compounds of the invention are useful as diagnostic agents, e.g., for identifying and localizing nicotinic receptors in a variety of tissues.

Neural imaging

The chemical substances of the invention are useful as diagnostic tools or monitoring agents in a variety of diagnostic methods, in particular for in vivo receptor imaging (neuroimaging).

In another aspect, the invention provides a method for non-invasively determining the distribution of a tracer compound in an intact living animal or human by physical detection. According to the method, the tracer compound is a compound of the invention, or any enantiomer thereof or any mixture thereof, an N-oxide thereof, a pharmaceutically acceptable salt thereof, in labelled or unlabelled form.

In a preferred embodiment, the physical detection method is selected from the group consisting of PET, SPECT; MRS, MRI, CAT, or a combination thereof.

The labelled compounds of the invention preferably contain at least one radionuclide as label. Positron emitting radionuclides may be used. In the context of the present invention, the radionuclide is preferably selected from²H (deuterium),³H (tritium),¹¹C、¹³C、¹⁴C、¹⁵O、¹³N、¹²³I、¹²⁵I、¹³¹I、¹⁸F and^99mTc。

an example of a commercially available labeling agent useful for preparing a labeled compound of the present invention is [2 ], [¹¹C]O₂，¹⁸F and NaI with different iodine isotopes.

Specifically, the term¹¹C]O₂Can be converted into [2 ]¹¹C]A methylating agent, e.g. [ solution ]¹¹C]H₃I and 2¹¹C]-methyl trifluoromethanesulfonate.

The tracer compound may be selected according to the detection method chosen.

In a preferred embodiment, the labeled or unlabeled compounds of the invention can be detected by suitable spectroscopy, in particular UV spectroscopy and/or fluorescence spectroscopy.

In another preferred embodiment, the compounds of the invention are labeled by incorporating isotopes, which may be specific for isotopes of naturally occurring atoms, including²H (deuterium),³H (tritium),¹¹C、¹³C、¹⁴C、¹⁵O、¹³N、¹²³I、¹²⁵I、¹³¹I、¹⁸F and^99mtc, the labeled compound and isotope incorporation can be determined by conventional scintillation counting techniques.

In a third preferred embodiment, the physical method of detecting the tracer compound of the invention is selected from Positron Emission Tomography (PET), single photon emission imaging computed tomography (SPECT), Magnetic Resonance Spectroscopy (MRS), Magnetic Resonance Imaging (MRI) and computer axial X-ray tomography (CAT) or a combination thereof.

A diagnostically effective amount of a labeled or unlabeled compound of the invention is administered to a living subject, including a human, prior to practicing the methods of the invention.

The compounds of the invention are believed to be particularly suitable for in vivo receptor imaging (neuroimaging).

In a particularly preferred embodiment, the physical method of detecting the compounds of the present invention is Positron Emission Tomography (PET).

It is presently believed that a diagnostically effective amount of a labeled or unlabeled compound of the invention administered prior to performing an in vivo assay of the invention is in the range of 0.1ng to 100mg per kilogram body weight, preferably in the range of 1ng to 10mg per kilogram body weight.

Pharmaceutical composition

In another aspect, the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of a chemical substance of the invention.

Although the compounds of the invention may be administered therapeutically as raw compounds, it is preferred that the pharmaceutical compositions be formulated with one or more adjuvants, excipients, carriers, buffers, diluents and/or other conventional pharmaceutical adjuvants, optionally in the form of physiologically acceptable salts, for the introduction of the active ingredient.

In a preferred embodiment, the invention provides a pharmaceutical composition comprising a chemical substance of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers, and optionally other therapeutic and/or prophylactic ingredients well known and used in the art. The carriers must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical compositions of the present invention may be administered by any convenient route, which is appropriate for the desired treatment. Preferred routes of administration include oral, in particular in the form of tablets, capsules, dragees, powders or liquids, and parenteral, in particular cutaneous, subcutaneous, intramuscular or intravenous injection. The pharmaceutical compositions of the present invention may be prepared by any person skilled in the art using standard methods and conventional techniques appropriate to the intended formulation. If desired, compositions suitable for sustained release of the active ingredient may be employed.

More details on formulation and administration techniques can be found in the latest editionRemington’s Pharmaceutical Sciences(Maack publishing company, Easton, Pa.).

The actual dosage will depend on the nature and severity of the condition being treated and is within the discretion of the physician and may be varied by titration of the dosage to achieve the desired therapeutic effect in accordance with the particular circumstances of the invention. However, it is presently contemplated that pharmaceutical compositions containing from about 0.1 to about 500mg, preferably from about 1 to about 100mg, most preferably from about 1 to about 10mg of active ingredient per single dose are suitable for treatment.

The active ingredient may be administered in one or more doses per day. In some cases satisfactory results are obtained at doses as low as 0.1. mu.g/kg i.v. and 1. mu.g/kg p.o.. The upper limit of the dosage range is currently believed to be about 10mg/kg i.v. and 100mg/kg p.o.. Preferred ranges are from about 0.1 μ g/kg to about 10 mg/kg/day i.v. and from about 1 μ g/kg to about 100 mg/kg/day p.o..

Method of treatment

The chemicals of the invention are valuable nicotinic receptors and monoamine receptor modulators and are therefore useful in the treatment of a range of conditions involving cholinergic dysfunction and a range of conditions responsive to the action of nAChR modulators.

In another aspect the present invention provides a method of treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to modulation of cholinergic receptors and/or monoamine receptors, which method comprises administering to such a living animal body, including a human, in need thereof an effective amount of a compound of the present invention.

In a preferred embodiment, the disease, disorder or condition involves the central nervous system.

In a preferred embodiment, the disease, disorder or condition is anxiety, cognitive disorders, learning deficit, memory deficits and dysfunction, Alzheimer's disease, attention deficit hyperactivity disorder, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, Tourette's syndrome, depression, mania, bipolar disorder, schizophrenia, Obsessive Compulsive Disorders (OCD), panic disorders, eating disorders such as anorexia nervosa, bulimia and obesity, narcolepsy, nociception, AIDS dementia, senile dementia, peripheral neuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post traumatic syndrome, social phobia, sleep disorders, pseudodementia, ganser's syndrome, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, mutism, trichotillomania and jet lag.

In another preferred embodiment, the disease, disorder or condition is associated with smooth muscle contraction, including spasmodic disorders, angina, premature labor, convulsions, diarrhea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, premature ejaculation, and erectile difficulty.

In a third preferred embodiment, the disease, disorder or condition is related to the endocrine system, such as thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.

In a fourth preferred embodiment, the disease, disorder or condition is a neurodegenerative disease, including transient hypoxia and induced neurodegeneration.

In a fifth preferred embodiment, the disease, disorder or condition is an inflammatory disease, including inflammatory skin diseases such as acne and rosacea, Chron's disease, inflammatory bowel disease, ulcerative colitis and diarrhea.

In a sixth preferred embodiment, the disease, disorder or condition is mild, moderate or even severe pain, acute, chronic or recurrent, as well as pain caused by migraine, postoperative pain and pain in the prosthetic limb.

In a seventh preferred embodiment, the disease, disorder or condition is associated with withdrawal symptoms resulting from the termination of the use of addictive substances, including nicotine-containing products such as tobacco, opioids such as heroin, cocaine and morphine, benzodiazepines * and benzodiazepine * -like drugs and alcohol.

It is now contemplated that suitable dosage ranges are from 0.1 to 1000mg per day, from 10 to 500mg per day, in particular from 30 to 100mg per day, depending generally on the exact mode of administration, the form of administration, the indication for which the administration is intended, the subject concerned and its body weight, and also on the preference and experience of the physician or veterinarian in charge.

In some cases satisfactory results are obtained at doses as low as 0.005mg/kg i.v. and 0.01mg/kg p.o.. The upper limit of the dosage range is about 10mg/kg i.v. and 100 mg/kgp.o.. Preferred dosage ranges are from about 0.001 to about 1mg/kg i.v. and from about 0.1 to about 10 mg/kgp.o..

Examples

The invention is further illustrated with reference to the following examples, which are not intended to limit the scope of the invention as claimed in any way.

Example 1

Preparation examples

All reactions involving air-sensitive reagents or intermediates were carried out under nitrogen atmosphere and in anhydrous solvents. Magnesium sulfate was used as a drying agent in the work-up step and the solvent was evaporated under reduced pressure.

(±) -3- (2-benzo [ b ]]Thienyl) -8-methyl-8-azabicyclo [3.2.1]Oct-2-ene hydrochloride

To a mixture of benzo [ b ] thiophene (20.2g, 151mmol) and diethyl ether (200ml) was added a solution of butyllithium in hexane (2.5M, 66ml, 166mmol) at room temperature. The mixture was stirred at reflux temperature for 1 hour and then cooled to-70 ℃. Tropinone (21.4g, 154mmol) dissolved in diethyl ether (150ml) was added at-70 ℃ and stirred for 1 hour. The reaction mixture was allowed to warm to room temperature overnight. Aqueous sodium hydroxide (200ml, 1M) was added and endo-and exo-3- (2-benzo [ b ] thienyl) -3-hydroxy-8-methyl-8-azabicyclo [3.2.1] octane was separated by filtration. Yield 46.8g, 96%.

A mixture of endo-and exo-3- (2-benzo [ b ] thienyl) -3-hydroxy-8-methyl-8-azabicyclo [3.2.1] octane (46.8g, 116.6mmol), hydrochloric acid (500ml, 25%) was stirred at reflux for 5 hours. The solvent was distilled off. The yield was 100%. Melting point 298 ℃.

(±) -3- (2-benzo [ b ]]Thienyl) -8-H-8-azabicyclo [3.2.1]Oct-2-ene hydrochloride

A mixture of (. + -.) -3- (2-benzothienyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene hydrochloride (24.4g, 0.0955mol), 1-chloroethyl-chloroformate (15.5ml, 0.143mol) and xylene (200ml) was heated and stirred at reflux temperature for 24 hours. Methanol (300ml) was added, followed by stirring and heating at reflux temperature for 22 hours. The mixture was cooled to room temperature and the product was filtered off. The crude product was recrystallized from diethyl ether. Yield 16g (69%). Melting point 252-.

(±) -3- (2-benzo [ b ]]Thienyl) -8-tert-Butoxycarbonyl-8-azabicyclo [3.2.1]Oct-2-ene

A mixture of (. + -.) -3- (2-benzo [ b ] thienyl) -8-H-butoxycarbonyl-8-azabicyclo [3.2.1] oct-2-ene (7.72g, 32mmol), triethylamine (4.5ml, 32mmol), di-tert-butyldicarbonatequinone (7.0g, 32mmol) and dichloromethane (50ml) was stirred for 2 hours. The mixture was washed with aqueous sodium hydroxide (50ml, 1M). Yield 9.38g, 86%.

(±) -3- (2-benzo [ b ]]Thienyl-1, 1-dioxide) -8-tert-butoxycarbonyl-8-azabicyclo [3.2.1]Oct-2-ene

A mixture of (. + -.) -3- (2-benzo [ b ] thienyl) -8-tert-butoxycarbonyl-8-azabicyclo [3.2.1] oct-2-ene (4.5g, 13.2mmol), m-chloroperbenzoic acid (10.0g, 58mmol) and chloroform (50ml) was stirred at room temperature for 4 hours. The mixture was filtered and the filtrate was evaporated. Aqueous sodium hydroxide (100ml, 1M) was added and the mixture was extracted with diethyl ether (3X 50 ml). The crude product was purified by chromatography using a mixture of ethyl acetate and heptane (1: 3). The title compound was isolated. Yield 3.31g, 67%.

(±) -3- (2-benzo [ b ]]Thienyl-1, 1-dioxide) -8-H-8-azabicyclo [3.2.1]Octa-2- Alkene fumarate (Compound 1)

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -8-tert-Butoxycarbonyl-8-azabicyclo [3.2.1] oct-2-ene (2.95g, 7.9mmol), trifluoroacetic acid (5.9ml, 79mmol) and dichloromethane (50 ml). The mixture was evaporated. Aqueous sodium hydroxide (30ml, 1M) was added, followed by extraction with ethyl acetate (3X 30 ml). Chromatography on silica gel eluting with dichloromethane, methanol and concentrated aqueous ammonia (89: 10: 1) afforded the title compound. Yield 1.52g, 70%. The corresponding salt was obtained by adding a mixture of diethyl ether and methanol saturated with fumaric acid (9: 1). Melting point 261-.

(±) -3- (2-benzo [ b ]]Thienyl-1, 1-dioxide) -8-methyl-8-azabicyclo [3.2.1]Pungent food -2-Enefumarate (Compound 2)

A mixture of (. + -.) 3- (2-benzo [ b ] thienyl-1, 1-dioxide) -8-H-8-azabicyclo [3.2.1] oct-2-ene (0.56g, 2.05mmol), formic acid (2.3ml, 61.5mmol) and formaldehyde (1.7ml, 61.5mmol) was stirred at 100 ℃ overnight. The mixture was evaporated. Aqueous sodium hydroxide (30ml, 1M) was added, followed by extraction with ethyl acetate (3X 30 ml). Chromatography on silica gel eluting with dichloromethane, methanol and concentrated aqueous ammonia (89: 10: 1) afforded the title compound. The corresponding salt was obtained by adding a mixture of diethyl ether and methanol saturated with fumaric acid (9: 1). Yield 0.42g, 51%. Melting Point 198.6-203.4 ℃.

(±) -3- (2-benzo [ b ]]Thienyl-1, 1-dioxide) -8-allyl-8-azabicyclo [3.2.1] Oct-2-ene (Compound 3)

A mixture of (. + -.) 3- (2-benzo [ b ] thienyl-1, 1-dioxide) -8-H-8-azabicyclo [3.2.1] oct-2-ene (0.16g, 0.58mmol), 3-bromo-1-propene (54. mu.l, 0.64mmol), diisopropylethylamine (102. mu.l, 0.58mmol), DMF (10ml) was stirred at 80 ℃ for 2 days. Aqueous sodium hydroxide (20ml, 1M) was added. The mixture was extracted with diethyl ether (3X 30 ml). Chromatography on silica gel eluting with dichloromethane, methanol and concentrated aqueous ammonia (89: 10: 1) afforded the title compound as an oil. Yield 50mg (28%).

(±) -3- (2-benzo [ b ]]Thienyl-1, 1-dioxide) -8-ethyl-8-azabicyclo [3.2.1]Pungent food -2-ene (Compound 4)

A mixture of (. + -.) 3- (2-benzo [ b ] thienyl-1, 1-dioxide) -8-H-8-azabicyclo [3.2.1] oct-2-ene (0.18g, 0.66mmol), 3-bromoethane (54. mu.l, 0.72mmol), diisopropylethylamine (115. mu.l, 0.66mmol), and DMF (10ml) was stirred at 80 ℃ for 2 days. Aqueous sodium hydroxide (20ml, 1M) was added. The mixture was extracted with diethyl ether (3X 30 ml). Chromatography on silica gel eluting with dichloromethane, methanol and concentrated aqueous ammonia (89: 10: 1) afforded the title compound as an oil. Yield 30mg (15%).

(±) -3- (2-benzothienyl) -quinuclidin-2-ene (intermediate compound)

To a mixture of benzothiophene (20.5g, 154mmol) in diethyl ether at 20 ℃ was added: butyllithium (67ml, 2.5M). The mixture was stirred at room temperature for 30 minutes. 3-quinuclidinone (19.2g, 153mmol) dissolved in diethyl ether (200ml) was added to the mixture at-70 ℃ followed by stirring at the same temperature for 1 hour. The temperature was raised to room temperature. Water (10ml) was added followed by aqueous sodium hydroxide (200ml, 1M). The mixture was stirred, filtered and washed with diethyl ether (50 ml). Yield (of alcohol): 33.55g (84%). A mixture of the alcohol (10.0g, 38.6mmol) and hydrochloric acid (100ml, 25%) was stirred at 70 ℃ for 3 days. The mixture was evaporated. Aqueous sodium hydroxide (125ml, 1M) was added and the mixture was extracted with diethyl ether.

Chromatography on silica gel eluting with dichloromethane, methanol and concentrated aqueous ammonia (89: 10: 1) afforded the title compound. Yield: 8.33g (88%).

(±) -3- (2-benzothienyl-1, 1-dioxide) -quinuclidin-2-ene-N-oxide (intermediate) Compound (I)

A mixture of (. + -.) -3- (2-benzothienyl) -quinuclidin-2-ene (3.0g, 12.3mmol), m-chloroperbenzoic acid (12.76g, 74mmol) and 50ml dichloromethane was stirred for 15 hours. The mixture was filtered, the solid washed with dichloromethane, and the filtrate was purified by silica gel chromatography eluting with dichloromethane, methanol and concentrated aqueous ammonia (89: 10: 1) to afford the title compound as a solid. Melting point 125-.

(±) -3- (2-benzothienyl-1, 1-dioxide) -quinuclidin-2-ene fumarate (Compound) 5)

A mixture of (±) -3- (2-benzothienyl-1, 1-dioxide) -quinuclidin-2-ene-N-oxide (1.35g, 4.7mmol), triphenylphosphine (3.67g, 14.0mmol) and dioxane (30ml) was stirred at reflux for 2 hours. The solvent was evaporated, aqueous sodium hydroxide (100ml, 1M) was added and the mixture extracted with dichloromethane (2X 50 ml). Chromatography on silica gel eluting with dichloromethane, methanol and concentrated aqueous ammonia (89: 10: 1) afforded the title compound as the free base. The corresponding salt was obtained by adding a mixture of diethyl ether and methanol saturated with fumaric acid (9: 1). Melting point 233 ℃.

(±) -3- (2-benzothienyl-1, 1-dioxide) -quinuclidin-2-ene-N-methyl iodide salt Compound 6)

A mixture of (. + -.) -3- (2-benzothienyl-1, 1-dioxide) -quinuclidin-2-ene (100mg, 0.4mmol), methyl iodide (75mg, 0.5mmol), and 5ml of dichloromethane was stirred at room temperature for 15 hours. The mixture was evaporated. The solid was triturated with diethyl ether (10 ml). Yield 100mg (95%). Melting Point 226.3 ℃.

Example 2

In vitro inhibition³Binding of H-alpha-bungarotoxin in rat brain

In this example, the affinity of the compounds of the invention for binding to the α 7-subtype of nicotinic receptor was determined.

Alpha-bungarotoxin is a peptide isolated from the venom of the elapidae bungarus multicinctus (bungarus multicinctus). The toxin has high affinity for neuronal and neuromuscular nicotinic receptors and acts as a potent antagonist.

³H- α -bungarotoxin labels nicotinic acetylcholine receptors formed from the α 7 subunit isoform found in the brain (isoform) and the α 1 isoform in the neuromuscular junction.

Tissue preparation

The preparation is carried out at 0-4 ℃. Using an Ultra-Turrax homogenizer at a temperature of 118mM NaCl, 4.8mM KCl, 1.2mM MgSO₄And 2.5mM CaCl₂15ml of 20mM Hepes buffer (pH7.5) brain cortex from male Wistar rats (150-250g) was homogenized for 10 seconds. The tissue suspension was centrifuged at 27000 Xg for 10 minutes. The supernatant was discarded and the pellet was washed 2 times by centrifugation at 27000 Xg for 10 min in 20ml of fresh buffer, after which the final pellet was resuspended in fresh buffer containing 0.01% BSA (35 ml per gram of original tissue) and used for binding assays.

Measurement of

To 25. mu.l of test solution and 25. mu.l³To H- α -bungarotoxin (2nM, final concentration) was added an aliquot of 500 μ l homogenate, mixed and incubated at 37 ℃ for 2 hours. Nonspecific binding was determined using (-) -nicotine (1mM, final concentration). After incubation, 5ml of ice-cold Hepes buffer containing 0.05% PEI was added to the samples and poured directly onto Whatman GF/C glass fiber filters (pre-soaked in 0.1% PEI for at least 6 hours) under suction and immediately washed with 2 × 5ml ice-cold buffer.

The amount of radioactivity on the filter was determined by conventional liquid scintillation counting. Specific binding is equal to total binding minus non-specific binding.

Testing the value with IC₅₀(suppression of³Concentration of test substance that binds specifically to H- α -bungarotoxin by 50%).

The results of these experiments are shown in table 1 below.

TABLE 1

To pair³Inhibition of H-alpha-bungarotoxin binding

Compound numbering	IC50(μM)
		Compound 2	0.018
Compound 3	0.85

Example 3

In vitro inhibition³Uptake of H-5-hydroxytryptamine in cortical synaptosomes

The 5-hydroxytryptamine transporter/uptake site on the nerve terminal may act to terminate neuronal signaling by removing 5-hydroxytryptamine from the synaptic cleft. By synaptosomal uptake³H-5-hydroxytryptamine (5-HT, 5-hydroxytryptamine) can be used for in vitro assay of 5-hydroxytryptamine transporter integrin activity.

The preparation is carried out at 0-4 ℃. Brain cortex from male Wistar rats (150-. Monoamine oxidase activity is inhibited in the presence of methylpropylbenzylamine.

The homogenate was centrifuged at 1000 Xg for 10 min. The resulting supernatant was then centrifuged at 27000 Xg for 50 minutes, and the supernatant was discarded. Precipitating (P)₂) Resuspended in oxygenated (96% O)₂∶4％CO₂Is equilibrated for at least 30 minutes) Krebs-Ringer incubation buffer (1000 ml per gram of original tissue) containing 122mM NaCl, 0.16mM EDTA, 4.8mM KCl, 12.7mM Na₂HPO₄、3.0mM NaH₂PO₄、1.2mM MgSO₄、1mMCaCl₂10mM glucose and 1mM ascorbic acid, pH 7.2.

Aliquots of 4.0ml of tissue suspension were added to 100. mu.l of the test solution and 100. mu.l³In H-5-HT (1nM, final concentration), mixed and incubated at 37 ℃ for 30 min. Non-specific uptake was determined using citalopram (1 μ M, final concentration, from Lundbeck, denmark).

After incubation, samples were poured directly onto Whatman GF/C glass fiber filters under suction. The filter was washed three times with 5ml of ice-cold 0.9% (w/v) NaCl solution.

The amount of radioactivity on the filter was measured by conventional liquid scintillation counting. Specific uptake was calculated as the difference between total uptake and non-specific uptake.

In computing IC₅₀Previously, 25-75% inhibition of specific binding had to be obtained.

Testing the value with IC₅₀(suppression of³The concentration of test substance (. mu.M)) at which specific binding of H-5-HT reaches 50% is given.

The results are shown in Table 2 below.

TABLE 2

To pair³Inhibition of H-5-hydroxytryptamine uptake

Compound numbering	IC50(μM)
		Compound 1	0.19
Compound 2	0.66

Claims (21)

1. A chemical substance represented by the general formula I

Any enantiomer or any mixture of enantiomers thereof or a pharmaceutically acceptable addition salt thereof, wherein

A. B, D, E and G independently of one another represent a carbon or nitrogen atom constituting an aromatic ring system; and is

X represents

A radical of the formula II

A radical of the formula III

A radical of the formula IV

A radical of the formula V

A radical of the formula VI

A radical of the formula VII

Or a radical of the formula VIII

In the above-mentioned formula, the compound of formula,

represents a single or double bond;

n is 0, 1, 2 or 3;

m is 1, 2 or 3; while

R represents hydrogen, C_1-6Alkyl radical, C_2-8-alkenyl, C_2-8-alkynyl, C_3-7-cycloalkyl, C_3-7-cycloalkyl group C_1-6-alkyl, phenyl or benzyl.

2. The chemical substance of claim 1, which is

Benzo [ b ] thiophene derivatives of formula IA

Benzo [ b ] thiazole derivatives of formula IB

Thienopyridine derivatives of formula IC

Thienopyridine derivatives of formula ID

Thienopyridine derivatives of formula IE

Or thienopyridine derivatives of formula IF

In the above formula

A and X are as defined in claim 1.

3. A chemical substance according to claim 1, which is a benzo [ b ] thiophene derivative of formula IA according to claim 2, wherein

X represents a group of formula II wherein

n is 0, 1 or 2;

m is 1, 2 or 3; and

r represents hydrogen, C_1-6-alkyl or benzyl.

4. The chemical substance of claim 1, which is a benzo [ b ] thiazole derivative of formula IB of claim 2, wherein

X represents a group of formula II wherein

n is 0, 1 or 2;

m is 1, 2 or 3; and

r represents hydrogen, C_1-6-alkyl or benzyl.

5. The chemical substance of claim 1, which is a benzo [ b ] thiophene derivative of formula IA of claim 2, wherein

X represents a group of formula III, wherein

Represents a double bond;

n is 0 or 1; and is

R represents hydrogen, C_1-6-alkyl or benzyl.

6. The chemical substance of claim 5 which is

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -8-H-8-azabicyclo [3.2.1] oct-2-ene;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -8-ethyl-8-azabicyclo [3.2.1] oct-2-ene;

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -8-allyl-8-azabicyclo [3.2.1] oct-2-ene;

or a pharmaceutically acceptable addition salt thereof.

7. The chemical substance of claim 1, which is a benzo [ b ] thiazole derivative of formula IB of claim 2, wherein

X represents a group of formula III, wherein

Represents a double bond;

n is 0 or 1; and is

R represents hydrogen, C_1-6-alkyl or benzyl.

8. The chemical substance of claim 1, which is a benzo [ b ] thiophene derivative of formula IA of claim 2, wherein

X represents a group of formula IV, wherein

Represents a double bond;

n is 0 or 1; and is

R represents hydrogen or C_1-6-an alkyl group.

9. The chemical substance of claim 1, which is a benzo [ b ] thiazole derivative of formula IB of claim 2, wherein

X represents a group of formula IV, wherein

Represents a double bond;

n is 0 or 1; and is

R represents hydrogen or C_1-6-an alkyl group.

10. The chemical substance of claim 1, which is a benzo [ b ] thiophene derivative of formula IA of claim 2, wherein

X represents a group of formula V, wherein

n is 0, 1 or 2;

m is 1 or 2; and is

R represents hydrogen or C_1-6-an alkyl group.

11. The chemical substance of claim 1, which is a benzo [ b ] thiazole derivative of formula IB of claim 2, wherein

X represents a group of formula V, wherein

n is 0, 1 or 2;

m is 1 or 2; and is

R represents hydrogen or C_1-6-an alkyl group.

12. The chemical substance of claim 1, which is a benzo [ b ] thiophene derivative of formula IA of claim 2, wherein

X represents a group of formula VI wherein

n is 0 or 1; and is

R represents hydrogen, C_1-6-alkyl, phenyl or benzyl.

13. The chemical substance of claim 1, which is a benzo [ b ] thiazole derivative of formula IB of claim 2, wherein

X represents a group of formula VI wherein

n is 0 or 1; and is

R represents hydrogen, C_1-6-alkyl, phenyl or benzyl.

14. The chemical substance of claim 1, which is a benzo [ b ] thiophene derivative of formula IA of claim 2, wherein

X represents a group of formula VII in which

R represents hydrogen or C_1-6-an alkyl group.

15. The chemical substance of claim 1, which is a benzo [ b ] thiazole derivative of formula IB of claim 2, wherein

X represents a group of formula VII in which

R represents hydrogen or C_1-6-an alkyl group.

16. The chemical substance of claim 1, which is a benzo [ b ] thiophene derivative of formula IA of claim 2, wherein

X represents a group of the formula VIII, wherein

Represents a single bond or a double bond.

17. The chemical substance of claim 16 which is

(±)3- (2-benzo [ b ] thienyl-1, 1-dioxide) -quinuclidin-2-ene; or

(±) -3- (2-benzothienyl-1, 1-dioxide) -quinuclidin-2-ene-N-methyl;

or a pharmaceutically acceptable addition salt thereof.

18. The chemical substance of claim 1, which is a benzo [ b ] thiazole derivative of formula IB of claim 2, wherein

X represents a group of the formula VIII, wherein

Represents a single bond or a double bond.

19. A pharmaceutical composition comprising a therapeutically effective amount of a chemical substance, any of its enantiomers or any mixture of its enantiomers, or a pharmaceutically-acceptable addition salt thereof, according to any one of claims 1 to 18, together with at least one pharmaceutically-acceptable carrier or diluent.

20. Use of a chemical substance according to any one of claims 1-18, any of its enantiomers or any mixture of its enantiomers, or a pharmaceutically-acceptable addition salt thereof, for the manufacture of a medicament for the treatment, prevention or alleviation of a disease or a disorder or a condition responsive to modulation of cholinergic receptors and/or monoamine receptors.

21. The use according to claim 20, wherein the disease, disorder or condition involves the central nervous system.