HK1143587A - Compounds with a combination of cannabinoid-cb1 antagonism and acetylcholinesterase inhibition - Google Patents

Description

Having cannabinoid-CB1Compounds with a combination of antagonism and acetylcholinesterase inhibition

Technical Field

The present invention relates to the fields of pharmaceutical and organic chemistry, and provides cannabis having propertieselement-CB₁Compounds, intermediates, formulations and methods of combination of antagonism and cholinesterase inhibition.

Background

The theory of "a target-a disease" has led the pharmaceutical industry for decades. With this strategy, many successful drugs have been discovered. Nevertheless, there are still many diseases that cannot be treated properly. These findings necessitate the theoretical elucidation of an alternative approach in which multiple targets are simultaneously modulated in the development of chemical entities. These drugs may exhibit beneficial properties, such as enhanced clinical efficacy, or drug-drug interactions without undesirable pharmacokinetics or adverse pharmacokinetic and pharmacodynamic properties. The latter can lead to unpredictable variability between individuals. In order to combine different therapeutic mechanisms, combinations of two or more drugs are still used in clinical practice. Alternatively, a multi-component drug may be used, wherein two or more pharmaceutically active compounds are formulated together into a single tablet or capsule to improve patient compliance. Another approach is drug treatment with chemical entities that can simultaneously modulate more than one biological target. It can clearly be seen that this "single individual-multiple target pathway" has the advantage of a lower risk of unwanted drug-drug interactions than a drug mixture or a multi-component drug. Several multi-target ligands are known. Most are found retrospectively or by chance: only some are reasonably designed.

Cannabinoid receptors are part of the endo-cannabinoid system and are involved in many diseases. Cannabinoid receptor, CB₁Detailed information on receptor modulators and their pharmacological activity is the subject of a recent review (Landsman, 1997; Lichtman, 2002; De Petrocellis, 2004; Di Marzo, 2004; Hertzog, 2004; Lange, 2004, 2005; Smith, 2005; Thakur, 2005; Patgett, 2005; Muccioli, 2005; Lambert, 2005; Vandervorde, 2005). CB disclosed in the cited review₁Potential therapeutic uses of receptor modulators include as a medicament for the treatment of psychosis, anxiety, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, predisposition, drug dependence, neurodegenerative disorders, dementia, dystonia, myospasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, parkinson's disease, alzheimer's disease, epilepsy, huntington's disease, Tourette's (Tourette's) syndrome, cerebral ischemia, cerebral stroke, craniocerebral trauma, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelination-related disorders, and for the treatment of painful conditions including neuropathic pain, septic shock, glaucoma, diabetes, cancer, emesis, nausea, gastrointestinal disorders, gastric ulcers, diarrhea, sexual dysfunction, impulse control disorders, and cardiovascular disorders.

Cholinesterase, including acetylcholinesterase and butyrylcholinesterase, is a serine hydrolase. Alzheimer's Disease (AD) is a neurodegenerative disease whose prevalence increases worldwide with increasing life expectancy. Cholinergic enhancers are currently the major therapeutic agents (Terry, 2003). Tacrine (trade name:) Is the first FDA-approved drug for the treatment of AD. The substance is an inhibitor of acetylcholinesterase and butyrylcholinesterase, and the medicine shows a clinically significant improvement effect on the cognition of AD patients. Currently, 3 other AchE inhibitors can also be used to treat AD: donepezilRivastigmineAnd galanthamineLike donepezil and rivastigmine, tacrine isA reversible inhibitor is presumed to play a central role by increasing the acetylcholine level in the cerebral cortex and by slowing down the degradation of acetylcholine from intact cholinergic neurons (Brufani, 1997; Weinstock, 1999). AchE inhibitors have been shown to have the ability to modulate amyloid preproprotein processing (Racchi, 2004). The structures of tacrine, amiloride, 7-methoxoline and SM-10888 are closely related, in contrast, for example, donepezil has a somewhat more elongated structure. The structure and cholinesterase inhibitory activity of compounds structurally related to tacrine have recently been reviewed (Marco, 2003), but more AchE inhibitors have been described in the (patent) literature.

Drug dependence has serious social, medical and economic problems. Effective treatments remain limited. Recently, it was found that AchE inhibitors acting on the brain inhibited cocaine-and morphine-induced conditioned place preference and blocked the induction and duration of cocaine-induced hyperkinesia. Centrally active AchE inhibitors are therefore potential therapeutic agents for new drug addiction (Hikida, 2003). At the same time, the suggestion is that cannabinoid CB₁Antagonists are useful in the treatment of drug addiction (Cohen, 2002; Hungund, 2002; Solinas, 2003). AchE inhibitors show efficacy not only in alzheimer's disease (Spencer, 1998), but also in other cognitive disorders such as dementia with Lewy bodies (McKeith, 2000), parkinson's disease (Werber, 2001), vascular dementia (Kumar, 2000) and traumatic brain injury (Masanic 2001). Butyrylcholinesterase is considered a potential target for alzheimer's disease, as it also modulates acetylcholine levels (Darvesh, 2003).

The cognitive disorder is also cannabinoid CB₁The therapeutic range underlying receptor antagonists (Castellano, 2003; Wolff, 2003). CB (CB)₁Receptor antagonists have been shown to increase acetylcholine (Ach) release in certain brain regions, including cortical and hippocampus (De Groot, 2006). Selective CB₁The receptor antagonist rimonabant showed neuroprotective activity in animal stroke trials (Berger, 2004). In summary, scientific literature, patents and patent applications indicate acetylcholinesterase inhibitionThe following therapeutic uses of the agent: alcoholism, alzheimer's disease, amnesia, arthritis, cancer, central nervous system disorders, cognitive disorders, constipation, dementia, dyspepsia, gastric motility disorders, gastrointestinal disorders, gastroparesis, glaucoma, irritable bowel syndrome, major depressive disorders, migraine, multiple sclerosis, myopathy, muscular atrophy, myasthenia gravis, neurodegenerative disorders, neuropathic pain, nicotine dependence, pedioculus capitis infection, poisoning, post viral infection fatigue syndrome, psychiatric disorders, senile dementia, schistosomiasis, urinary dysfunction and xerostomia.

Having cannabinoid-CB as frequently observed symptomatology in different diseases₁Compounds with antagonistic and cholinesterase inhibitory effects can be used for the treatment of cannabinoid CB₁Either antagonists or cholinesterase inhibitors may be effective. Thus, the compounds of the invention may be useful in the treatment of addiction, predisposition, alcoholism, alzheimer's disease, amnesia, anxiety, appetite disorders, arthritis, attention deficit, cancer, cardiovascular disorders, central nervous system disorders, cerebral stroke, cerebral ischemia, cognitive disorders, constipation, dementia, demyelination-related disorders, depression, diabetes, diarrhea, drug dependence, dyspepsia, dystonia, emesis, epilepsy, gastric motility disorders, gastric ulcers, gastrointestinal disorders, gastroparesis, glaucoma, huntington's disease, impulse control disorders, irritable bowel syndrome, memory disorders, migraine, multiple sclerosis, myopathy, muscle atrophy, muscle spasm, myasthenia gravis, nausea, neurodegenerative disorders, neuroinflammatory disorders, neuropathic pain, nicotine dependence, obesity, pain disorders, parkinson's disease, head lice (pedilus capitis) infection, Plaque sclerosis (plaque sclerosis), poisoning, post viral infection fatigue syndrome, psychiatric disorders, psychosis, senile dementia, septic shock (septic shock), sexual dysfunction, schistosomiasis, spinal cord injury, stroke, Tourette's syndrome, traumatic brain injury, tremor, urinary dysfunction, viral encephalitis, and xerostomia.

Of particular importance are the therapeutic cannabinoids CB of the present invention₁Antagonists and the use of cholinesterase inhibitors for the treatment of diseases. Simultaneous attack of these diseases by two different mechanisms of action may have a synergistic effect. The compounds of the invention are particularly useful for the treatment of alzheimer's disease, cognitive disorders, memory disorders, dementia, attention deficit, traumatic brain injury, drug dependence, addiction and substance abuse.

Cannabinoid CB₁The main pharmacophores of receptor antagonists are the subject of several reviews (Lange, 2005; Reggio, 2003). Scheme 1 embodies this.

Scheme 1: CB (CB)₁Receptor antagonist pharmacophores and CB₁A putative key role for the receptor

In scheme 1, Ar₁And Ar₂Represents phenyl, optionally substituted by one or two halogen atoms, trifluoromethyl, or methoxy. The "spacer" comprises a five-membered heterocyclic group such as 4, 5-dihydropyrazole, imidazole, pyrazole, thiazole, thiophene or pyrrole or the spacer comprises a phenyl or six-membered heterocyclic group such as pyridine, pyrimidine or pyrazine. For example, in MK-0364 (see below), the spacer may also contain an azetidine moiety, a 1, 3-benzodioxole moiety, or an alkyl moiety. Furthermore, one of the aryl groups may be fused to the spacer, or may be connected to the spacer through another ring: so-called conformational constraints. Several conformational constraints have been successfully applied in this pharmacophore model. Hydrogen bond acceptors (H-bond acceptors) represent carbonyl, sulfonyl or nitrogen atoms which may be incorporated into a heterocyclic ring structure such as an imidazole ring. In scheme 1, "Lip" represents a lipophilic moiety such as piperidin-1-ylamino, pyrrolidinyl-1-amino, cycloalkylamino, phenylamino, arylamino, benzyl-amino, or alkylamino.

Molecular modeling studies have shown that the presence of hydrogen bond receptors is critical: it is considered to be in contact with CB₁The Lys-192 amino acid residue side chain in the receptor interacts, stabilizing its inactive state. For the explanation of CB₁The receptor antagonistic pharmacophore (pharmacophore) model, a number of CBs are listed below₁Specific examples of receptor antagonists. In bold is CB₁The hydrogen bond acceptor atom (oxygen in carbonyl, oxygen in sulfonyl, or N in heteroaryl ring) assumed in the receptor antagonist:

selective CB has been known for more than a decade₁The receptor antagonist SR141716A (rimonabant). A number of other selective CBs were subsequently invented₁A receptor antagonist. Several acetylcholinesterase inhibitors have also been known for many years. For example, tacrine was approved in 1993 in the united states. But has not disclosed any display CB so far₁A compound which is a combination of receptor antagonist and acetylcholinesterase inhibitor activity.

The object of the present invention is to develop a composition having CB₁A compound having a combination of antagonism and acetylcholinesterase inhibition.

Content providing method and apparatus

We have found that known cannabinoid-CB is encompassed₁Molecules that are essential for the antagonist and for the known acetylcholinesterase inhibitor tacrine share two molecular resulting activities: cannabinoid-CB₁Antagonism and acetylcholinesterase inhibition.

The invention concerns with CB₁A compound having a combination of antagonism and acetyl and/or butyrylcholinesterase inhibition. In particular, the present invention concernsIs provided with CB₁A compound having a combination of an antagonistic effect and an acetylcholinesterase inhibitory effect.

In some embodiments, the invention also relates to compounds of formula (1):

and tautomers, stereoisomers, N-oxides, isotopically-labeled analogs thereof, or pharmacologically acceptable salts, hydrates or solvates of any of the foregoing.

-A represents any known cannabinoid-CB₁A basic building block for an antagonist comprising at least two phenyl rings independently optionally substituted with 1 or 2 substituents selected from halogen, methoxy and trifluoromethyl, said basic building block and said cannabinoid-CB₁An antagonist, wherein the hydrogen bond acceptor moiety is a carbonyl group, a sulfonyl group, or a nitrogen or oxygen atom incorporated in a heteroaromatic ring structure,

-T represents a linker consisting of a saturated or unsaturated linear carbon chain of 2 to 8 atoms, wherein the carbon chain may be substituted with 1 to 5 substituents selected from methyl, ethyl, hydroxy, fluoro or amino, which may contain a further nitrogen atom, optionally with C_1-3Alkyl, or the carbon chain may contain further oxygen or sulfur atoms, or carbonyl, sulfonyl, amide, sulfonamide, ureido, or aryl, the aryl being optionally substituted with 1 to 4 substituents selected from halogen, cyano, methyl, methoxy, trifluoromethyl, OCHF₂、OCF₃、SCF₃Or a substituent of a nitro group,

b represents the basic building block of any known acetylcholinesterase inhibitor,

-n is 0 or 1.

Other embodiments provide one or more compounds of formula (1), wherein A represents any one of the following patent applicationsDisclosed CB₁Basic building blocks of antagonists: EP 1602658, EP576357, EP 656354, FR 2789078, FR 2789079, FR 2799124, FR 2804604, FR 2849032, FR 2856683, FR 2856684, FR 2860792, FR 2864958, FR 2869905, FR 2873372, FR 2874012, FR 2876691, FR 2880023, FR 2880890, FR 2881744, US 20040122089, US 20040157838, US20040157839, US 20040176418, US 20040214837, US 20040214855, US 20040214856, US 20040242593, US 20040248881, US 20040259887, US 20040266845, US 20050009870, US 20050065189, US 20050096379, US 20050101592, US 20050165012, US 20050171179, US 20050187208, US 20050187259, WO 20050187259, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO, WO2005103052, WO 2005115977, WO 2005118553, WO 2006025069, WO 2006030285, WO 2006041797, WO 2006047516, WO 2006060461, WO 2006074445, WO 2006080040, WO 2006106054 and WO 2006087732, wherein B represents the basic building block of an AchE inhibitor disclosed in any one of the following patent applications: DE 3805744, EP 1020469, EP1020470, EP 141393, EP 154864, EP 1600447, EP 298202, EP 306825, EP 306826, EP 326106, EP 354594, EP 401715, EP 409676, EP 413667, EP 415634, EP 441517, EP 457318, EP 468401, EP 471296, EP 471298, EP 477903, EP 481429, EP 487071, EP 495709, EP 516520, EP 535496, EP 567090, EP 579263, EP 611769, EP 614888, EP 627400, EP 695 637586, EP 648771, EP 987262, JP 02270875, JP 03112989, JP 04159225, JP 05306286, JP 07048370, JP 07048370, JP 07048370, RU2041878, RU 2398, US 07048370, US 07048370, US 07048370, US 07048370, US 36495472, US 364972, WO 36525472, US 07048370, US 364972, WO 07048370, US 364972, US 07048370, US 07048370, WO 3636363672, US 364972, US 07048370, WO 07048370, US 36363672, US 363636363672, WO 363636363672, US 36363672, WO 3636525472, US 07048370, US 07048370, US, WO 2001098271, WO 2003033489, WO 2003082794, WO 2004032929, WO 2004106275, WO 2005005413, WO 2006039767, WO 2006052496, WO 2006080043, WO 2006103120, WO 9214710, WO 9217475, WO 9303034, WO 9304063, WO 9305779, WO 9307140, WO 9313083, WO 9429272, WO 9620176, WO 9703987, WO 9708146, WO 9713754, WO 9721681, WO 9738993, WO 9800412, WO 9919329 and WO 9964421.

Further embodiments provide one or more compounds of formula (1): wherein A represents CB₁Basic building blocks of antagonists, wherein CB₁Antagonists: 11C-JHU-75528, A-796260, AM 251, AM 630, AVE-1625, MK-0364, CP-272871, CP-945598, GRC-10389, LY-2077855, LY-320135, NIDA-41020, 0-2093, rimonabant, SLV319, SLV326, SR-140098, SR-144385, SR-147778, surfabant, V-24343, WIN-54461 and WIN-56098, wherein B represents the basic structural unit of AchE inhibitor, wherein the AchE inhibitor is selected from aceclidine, anbeilonium, amiloride, AS-1397, BGC-20-1259, bisorcymsine, bromochlororobenium, bromophenol phosphorus, BW-284-C-51, caroxamine, carbafuran, CHF-2060, CHF-2822, CHF-2957, CI-1002, cisatracurium besylate, CM-2433, CM-2501, vascellarine (desoxypeganine), diazine, donepezil, E-2030, etalonium chloride, EN-101, etastine, ER-127528, (-) -dolichol, F-7896, thidiazanabasine, FK-3732, FK-539-32, FK-G-960, FR-32, FK-R-2932, FK-C-R-2957, and pharmaceutically acceptable salts thereof, More's amines, Giantrodia alkaloids, Hoe-065, HP-290, huperzine A, icopiprazole, INM-176, ipidaxolin, isatin, isoflurophos (isoflurophosphate), etopride, JES-9501, KA-672, KW-5092, ladostigil, malathion, MCI-225, mebendazole, memantin, memoquin, methanesulfonyl fluoride, N-methylcrotosol, metrazine, MF-268, MF-8615, MFS-3, MHP-133, mifepristone, melameilin, neostigmine, nitroflurbiprofen, NP-0362, NP-7557, NXX-066, ONO-1603, P-10358, P-11012, P-11149, P-11467, P-26, palirophosphotini, paradoxin, parathion, phoxim-151832, (-) -151832, phenylalanine, phydroxyline, and phydroxyfop-9526, Plinacasan, pradimin, pyridostimine, rivaline, rivastigmine, Ro-46-5934, RS-1439, S-9977, SDZ-ENX-792, SGS-742, SM-10888, SP-004, T-82, tacrine, 7-methoxytacrine, di- (7) -tacrine, TAK-802, tolserine, UR-1827, viccridine, Z-338, zanapezil, ziprasidone, and ZT-1.

In another embodiment, the invention relates to compounds of formula (1), wherein A represents a fragment (A)^1a)、(A^1b)、(A²)、(A³)、(A⁴)、(A⁵)、(A⁶)、(A⁷) Or (A)⁸) One of (1):

wherein X represents a sulfonyl group or a carbonyl group, the "+" symbol represents the point at which the fragment is linked to the linker T of formula (1), R¹、R²And R³Independently represents one or more hydrogen atoms, trifluoromethyl or halogen, R⁴Represents a hydrogen or halogen atom, or a methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, propyl, methylthioalkyl, methylsulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl, ethylsulfonyl, C_1-3-dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl, the other symbols having the meanings given above.

In another embodiment, the invention relates to compounds of formula (1), wherein A represents a fragment (A)^1a)、(A^1b)、(A²)、(A³)、(A⁴)、(A⁵)、(A⁶)、(A⁷) Or (A)⁸) And B represents a fragment (B)¹)、(B²) Or (B)³) One of (1):

wherein the "+" symbol represents the point at which the fragment is linked to linker T of formula (1), R⁵Represents a hydrogen or halogen atom, or a methoxy or trifluoromethoxy group, and m is an integer having a value of 0, 1 or 2, the other symbols having the meanings given above.

In another embodiment, the invention relates to compounds of formula (1), wherein A represents a fragment (A)^1a)、(A^1b)、(A²)、(A³)、(A⁴)、(A⁵)、(A⁶)、(A⁷) Or (A)⁸) Wherein the acetylcholinesterase inhibitor of fragment B is tacrine, amiloride, or 7-methoxyleneR represents a hydrogen atom or C, or SM-10888_1-3Alkyl, the other symbols have the meanings given above.

In another embodiment, the invention relates to compounds of formula (1), wherein A represents a fragment (A)^1a)、(A^1b) Or (A)²) Wherein the acetylcholinesterase inhibitor of fragment B is tacrine and the other symbols have the meanings given above.

In another embodiment, the invention relates to compounds of formula (1) wherein A represents a fragment (A)⁹) Or (A)¹⁰) One of (1):

and the other symbols have the meanings given above.

In another embodiment, the invention relates to a compound of formula (1):

a compound of formula (1) and tautomers, stereoisomers, N-oxides, isotopically-labelled analogues thereof, any or pharmacologically acceptable salts, hydrates or solvates thereof having cannabinoid-CB₁Combination of antagonism and cholinesterase inhibition, in particular acetylcholinesterase inhibition, useful in the treatment of diseases in which cannabinoid-CB is involved₁Diseases of the receptors and the acetylcholinesterase site, or diseases which can be treated by modulation of these receptors, such as addiction, predisposition, alcoholism, alzheimer's disease, amnesia, anxiety, appetite disorders, arthritis, attention deficit, cancer, cardiovascular diseases, central nervous system diseases, cerebral stroke, cerebral ischemia, cognitive disorders, constipationDementia, demyelination-related diseases, depression, diabetes, diarrhea, drug dependence, dyspepsia, dystonia, emesis, epilepsy, gastric motility disorders, gastric ulcers, gastrointestinal disorders, gastroparesis, glaucoma, huntington's disease, impulse control disorders, irritable bowel syndrome, memory disorders, migraine, multiple sclerosis, myopathies, muscle atrophy, muscle spasms, myasthenia gravis, nausea, neurodegenerative disorders, neuroinflammatory disorders, neuropathic pain, nicotine dependence, obesity, pain disorders, parkinson's disease, head lice infection, plaque sclerosis, poisoning, post viral infection fatigue syndrome, psychiatric disorders, psychosis, senile dementia, septic shock, sexual dysfunction, schistosomiasis, spinal cord injury, stroke, tourette's syndrome, traumatic brain injury, viral tremor, urinary dysfunction, encephalitis, and xerostomia.

Other embodiments of the invention include, but are not limited to:

treatment e.g. by cannabinoid-CB₁A pharmaceutical composition for the treatment of a disease or condition treatable by a combination of antagonism and acetylcholinesterase inhibition, the composition comprising a compound of formula (1) and a pharmaceutically acceptable carrier;

treatment by cannabinoid-CB₁A method of treating a disease or condition treatable by a combination of antagonism and acetylcholinesterase inhibition comprising administering to a mammal in need of such treatment a compound of formula (1);

a pharmaceutical composition for treating a disease or condition, e.g., selected from the diseases listed herein;

a method of treating a disease or condition selected from the diseases listed herein, the method comprising administering to a patient in need of such treatment a compound of formula (1);

a pharmaceutical composition for treating a disease or condition selected from the diseases listed herein, the composition comprising a compound of formula (1) and a pharmaceutically acceptable carrier;

a method of treating a disease or condition selected from the diseases listed herein, which method comprises administering to a patient in need of such treatment a compound of formula (1).

An anti-cannabinoid-CB₁A method of antagonizing an interacting receptor and inhibiting acetylcholinesterase comprising administering to a subject in need thereof an effective amount of a compound of formula (1);

the invention also provides the use of a compound according to formula (1) for the manufacture of a medicament.

The invention further relates to combination therapies in which a compound of the invention, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered with another therapeutic agent or agents, simultaneously or sequentially or as a combined formulation, for the treatment of one or more of the listed diseases. These additional therapeutic agents may be administered prior to, concurrently with, or subsequent to the administration of the compounds of the present invention.

The invention also provides compounds, pharmaceutical compositions, kits and methods of treating a disease or condition selected from the diseases listed herein comprising administering to a patient in need of such treatment a compound of formula (1).

The compounds of the present invention have cannabinoid-CB₁A combination of antagonism and cholinesterase inhibition, in particular acetylcholinesterase inhibition. Agonistic or antagonistic/inhibitory activity of the compounds of the invention is readily demonstrated, for example, using one or more assays described herein or known in the art.

The invention also provides methods of making the compounds of the invention and intermediates used in those methods.

Isolation and purification of the compounds and intermediates described herein can be carried out, if desired, by any suitable isolation or purification method, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative low or high-pressure liquid chromatography, or a combination of these methods. Specific illustrations of suitable separation and isolation methods can be obtained from the formulations and examples. However, other equivalent separation or isolation methods may of course also be used.

The compounds of the invention may contain one or more asymmetric centers, thus giving rise to racemates and racemic mixtures, individual enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all such possible optical isomers and diastereomers, as mixtures or as pure or partially pure compounds, are encompassed by the present invention. The present invention includes all isomeric forms of these compounds. Formula (1) shows the structure of such compounds without indicating the preferred stereochemistry. The independent synthesis of these diastereomers or their chromatographic separation can be achieved by appropriate modification of the methods described herein, according to methods known in the art. Their absolute stereochemistry is determined by X-ray diffraction crystallography of the crystalline products or crystalline intermediates from which they are derived, if necessary using reagents containing asymmetric centers of known absolute configuration. If desired, racemic mixtures of the compounds can be separated to isolate individual enantiomers. The separation can be carried out by methods well known in the art, such as combining a racemic mixture of compounds with an enantiomerically pure compound to form a diastereomeric mixture, and then separating the diastereomeric entities by standard methods, such as fractional crystallization or chromatography. The binding reaction typically involves the formation of a salt with an enantiomerically pure acid or base such as (-) -di-p-toluoyl-D-tartaric acid and/or (+) -di-p-toluoyl-L-tartaric acid. The diastereomeric derivatives are then converted into the pure enantiomers by cleavage of additional chiral residues. Racemic mixtures of the compounds can also be separated directly by chromatography using a chiral stationary phase (methods well known in the art). Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

Cis and trans isomers of the compounds of formula (1) or pharmacologically acceptable salts thereof are also within the scope of the present invention, and the same applies to tautomers of the compounds of formula (1) or tautomers of pharmacologically acceptable salts thereof.

Some crystal forms of these compounds may exist as polymorphs: they are also intended to be included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates), or common organic solvents, and such solvates are also included within the scope of the present invention.

Isotopically labeled compounds of formula (1) or pharmacologically acceptable salts thereof, including isotopically labeled compounds of formula (1) detectable by PET or SPECT, are also included within the scope of the present invention. The same applies to the use of¹³C]-，[¹⁴C]-，[¹⁸F]-，[³H]-，[¹²⁵I]-or other highly isotopically labelled atom compounds of formula (1) which are suitable for use in receptor binding or metabolic studies.

The compounds of the invention may be used as reagents or standards in biochemical studies of nervous system functions, disorders and diseases.

Definition of

In the context of the present specification, the term "having cannabinoid-CB₁Antagonistic compounds "and" cannabinoid-CB₁Antagonists "refer to compounds having this activity-measured by well-defined and accepted pharmacological assays, including those described herein-that do not exhibit substantial cross-reactivity to another receptor. In one embodiment, the compounds of the invention are as cannabinoid-CB₁The antagonist is at least 10 times more potent than an agonist or antagonist of any other receptor. Preferred are compounds with 100-fold selectivity, most preferred are compounds with a selection factor of 1000 or higher. The term "compound having cholinesterase inhibitory activity" or "cholinesterase inhibitor" refers to a compound having cholinesterase inhibitory activity-determined by well-established and accepted pharmacological assays, including those described herein-that does not exhibit substantial cross-reactivity to another receptor. In one embodiment, the compounds of the invention act as cholinesterase inhibitorsThe formulation is at least 10 times more effective than inhibitors of any other enzyme. Preferred are compounds with 100-fold selectivity, most preferred are compounds with a selection factor of 1000 or higher. "having cannabinoid-CB₁Antagonistic and cholinesterase inhibitory activity "are compounds that have both activities-as determined by well-defined and accepted pharmacological assays, including those described herein-that do not exhibit substantial cross-reactivity to another receptor or enzyme. In one embodiment, the compounds of the invention are as cannabinoid-CB₁Antagonists and as cholinesterase inhibitors are at least 10 times more effective than either agonists or antagonists as any other receptor and as inhibitors of any other enzyme. Preferred are compounds with 100-fold selectivity, most preferred are compounds with a selection factor of 1000 or higher.

General terms used in the description of the compounds described herein have their usual meanings. The term alkyl as used herein refers to a monovalent saturated branched or straight hydrocarbon chain. Unless otherwise specified, these chains may contain from 1 to 18 carbon atoms. Representative of these alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, and the like. When limited to "lower", alkyl groups will contain 1 to 6 carbon atoms. The same carbon content also applies to the original term "alkane", and derivative terms such as "alkoxy". The amount of carbon comprising various hydrocarbon moieties can be represented by a header representing the minimum and maximum number of carbon atoms in that moiety, i.e., header C_x-C_yThe number of carbon atoms present is defined to include the integer "x" to the integer "y". For example "alkyl (C)_1-3) "means methyl, ethyl, n-propyl or isopropyl," alkyl (C)_1-4) "means" methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, or 2-methyl-n-propyl ".

The term "acyl group"Refers to alkyl (C)_1-3) Carbonyl, arylcarbonyl or aryl-alkyl (C)_1-3) A carbonyl group. "aryl" includes monocyclic or fused bicyclic aromatic or heteroaromatic groups including, but not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, imidazo [2, 1-b ]][1，3]Thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1, 3, 5-triazinyl, phenyl, indazolyl, indolyl, indolizinyl, isoindolyl, benzo [ b ]]Furyl, 1, 2, 3, 4-tetrahydro-naphthyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, indanyl, indenyl, benzo [ b]Thienyl, 2, 3-dihydro-1, 4-benzodioxin-5-yl, benzimidazolyl, benzothiazolyl, benzo [1, 2, 5 ]]Thiadiazolyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, naphthyl, pteridinyl, or azulenyl. "halo" or "halogen" refers to chlorine, fluorine, bromine or iodine; "hetero", as in "heteroalkyl, heteroaryl", etc., means containing one or more N, O or S atoms. "Heteroalkyl" includes alkyl groups having heteroatoms in any position, and thus includes N-bonded, O-bonded, or S-bonded alkyl groups.

The term "substituted" means that the specified group or moiety has one or more substituents. When any group may have a plurality of substituents, and may have various possible substituents, the substituents are independently selected, and need not be the same. The term "unsubstituted" means that the specified group has no substituent. With respect to substituents, the term "independently" means that when more than one substituent is possible, they may be the same or different from each other.

The terms "oxygen", "sulfur" and "carbonyl (carbo)" as part of another group as used herein refer to an oxygen atom, a sulfur atom and a carbonyl (C ═ 0), respectively, as a linker between the two groups, e.g., hydroxyl, oxyalkyl, sulfanyl, carboxyalkyl, and the like. The term "amino" as used herein alone or as part of another group refers to a nitrogen atom that serves as a linker either at the terminus or between two additional groupsAnd may be a primary, secondary or tertiary amine (2 hydrogen atoms bonded to a nitrogen atom, 1 hydrogen atom bonded to a nitrogen atom and no hydrogen atom bonded to a nitrogen atom, respectively). As used herein, the terms "sulfinyl" and sulfonyl as part of another group are-SO-or-SO, respectively₂-。

To provide a more concise description, the term "compound" when not explicitly mentioned includes tautomers, stereoisomers, N-oxides, isotopically labeled analogs, or pharmacologically acceptable salts, hydrates or solvates.

The term "leaving group" (L) as used herein refers to a charged or uncharged atom or group that is removed in a substitution or displacement reaction. The term refers to a group that is easily removed by nucleophiles such as amine, thiol or alcohol nucleophiles. Such leaving groups are well known in the art. Examples include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halogens (Br, Cl, I), triflates (triflates), methanesulfonates, tosylates, and the like.

N-oxides of the above compounds are within the scope of the present invention. Tertiary amines may or may not produce N-oxide metabolites. The degree to which N-oxidation occurs can vary from trace to near quantitative transitions. N-oxides may be more effective, or less effective, than their corresponding tertiary amines. While N-oxides can be readily reduced to varying degrees in the human body by chemical means to their corresponding tertiary amines. Some N-oxides can be reduced to the corresponding tertiary amines in near quantitative amounts, in other cases the conversion is only a minor reaction, even not at all (Bickel, 1969).

Any compound that is metabolized in vivo to a biologically active agent (i.e., a compound of formula (1)) is a prodrug within the scope and spirit of the present application. Prodrugs are therapeutic agents that are not active by themselves, but may be converted to one or more active metabolites. Thus, in the methods of treatment of the present invention, the terms "administering" and "use in therapy" shall include the compounds specifically described or notDescribed in vivo but converted in vivo to specific compounds following administration to a patient for the treatment of various said conditions. Prodrugs are bioreversible derivatives of drug molecules that are used to overcome some of the obstacles to the use of the parent drug molecule. These include, but are not limited to, solubility, permeability, stability, pre-systemic metabolism and targeting limitations (Bundgaard, 1985; King, 1994; Stella, 2004; Ettmayer, 2004;2005). Prodrugs, i.e., compounds that are metabolized to compounds of formula (1) when administered to a human or mammal by any known route, are encompassed by the present invention. In particular, it relates to compounds having primary and secondary amino or hydroxyl groups. These compounds can be reacted with organic acids to give compounds of formula (1) in which additional groups are present which are easily removable after application, such as, but not limited to, amidines, enamines, mannich bases, hydroxy-methylene derivatives, O- (acyloxymethylene carbamate) derivatives, carbamates, esters, amides or enaminones.

By "crystalline forms" is meant different solid forms of the same compound, such as polymorphs, solvates, and amorphous forms. "polymorphs" are crystal structures in which compounds can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Polymorphism is a phenomenon that often occurs and is affected by crystallization conditions such as temperature, supersaturation level, presence of impurities, polarity of solvent, cooling rate. Different polymorphs typically have different X-ray diffraction patterns, solid state NMR spectra, infrared or raman spectra, melting points, densities, hardness, crystal morphology, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystal form to dominate. A "solvate" is generally a crystalline form comprising a stoichiometric or non-stoichiometric amount of a solvent. In general, during crystallization, some compounds have a tendency to incorporate a fixed molar ratio of solvent in the crystalline solid state, thus forming solvates. When the solvate is water, a "hydrate" is formed. The compound of formula (1) and pharmacologically acceptable salts thereof may exist in the form of hydrates or solvates, and such hydrates and solvates are also included in the present invention. Examples thereof include 1/4 hydrate, dihydrochloride dihydrate and the like. The "amorphous" form is an amorphous material that is not ordered and generally lacks the characteristic powder X-ray diffraction pattern. Crystal forms have been described generally by Byrn (1995) and Martin (1995).

For purposes of a more concise description, some of the quantitative expressions given herein are not limited by the term "about". It is to be understood that each numerical value given herein, whether or not the term "about" is used explicitly, is intended to refer to the actual numerical value given, as well as the approximate value of that given, which can reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for that given value.

Throughout the description and claims of this application, the word "comprise" and variations of the word, such as "comprises" and "comprising", are not intended to exclude other additives, components, integers or steps.

Although the compounds of formula (1) may be administered as starting chemicals, it is preferred that they are present as "pharmaceutical compositions". According to a further aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula (1), or at least one pharmacologically acceptable salt or solvate thereof, or a mixture of any of the above, and one or more pharmaceutically acceptable carriers thereof, and optionally one or more other therapeutic agents. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The term "composition" as used herein includes a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. With respect to pharmaceutical compositions, the term includes products comprising one or more active ingredients and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. In general, pharmaceutical compositions are prepared by uniformly and directly bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation. The pharmaceutical composition contains sufficient active target compound to produce the desired effect on the development or condition of a disease. Thus, the pharmaceutical compositions of the present invention include any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Compounds of the invention and CB are determined as follows₁Affinity of the receptor and inhibition of acetylcholinesterase. Based on the determination of the affinity of a given compound of formula (1), we can evaluate the theoretical lowest effective dose. When the concentration of the compound is equal to the measured K_iAt twice the value, the compound will occupy almost 100% of the CB₁A receptor. When the concentration of a compound is equal to twice the measured inhibition constant, the compound will occupy almost 100% of the acetylcholinesterase. By converting this concentration to mg of compound per kg of patient body weight, we can obtain the theoretical lowest effective dose, and infer the ideal bioavailability. The actual dosage administered may be varied to higher or lower values by pharmacokinetic, pharmacodynamic and other considerations. Typical daily dosages of the active ingredient may vary within wide limits and will be determined by a physician, depending on a number of factors such as the relevant indication, the route of administration, the age, weight and sex of the patient. In general, the total daily dose administered to a patient in a single or individual dose may be, for example, from 0.001 to 10mg/kg body weight per day, more usually from 0.01 to 1,000mg per day of total active ingredient. The dose may be administered to a patient in need of treatment 1 to 3 times daily, or each time with the desired efficacy, for a period of at least 2 months, more typically at least 6 months, or for an extended period.

The term "therapeutically effective amount" as used herein refers to the amount of a therapeutic agent that treats a disease treatable by administration of a composition of the invention. The amount is an amount sufficient to exhibit a detectable therapeutic or ameliorative response in a tissue system, animal or human. Such effects may include, for example, treatment of the diseases listed herein. The precise effective amount for a subject will depend upon the size and health of the subject, the nature and extent of the condition being treated, the recommended amount by the treating physician (researcher, veterinarian, medical doctor or other clinician), and the therapeutic agent or combination of therapeutic agents selected for administration. It is therefore not useful to specify an exact effective amount in advance. The term "pharmacologically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio. Pharmacologically acceptable salts are well known in the art. The compounds of the present invention may be prepared in situ when they are ultimately isolated and purified, or separately by reacting the compounds of the present invention with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases or acids (Berge, 1977). Regeneration of the "free base" form involves contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the different salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, the salts and parent forms of the compound are equivalent. "Complex" refers to a complex of a compound of the present invention, for example, a complex of formula (1) complexed with a metal ion, wherein at least one of the metal ions is chelated or separated. The complex may be prepared by methods well known in the art (Dwyer, 1964).

The term "treatment" as used herein refers to any treatment of a disease or condition in a mammal, such as a human, and includes: (1) inhibiting the disease or disorder, i.e., arresting its development, (2) relieving the disease or disorder, i.e., causing regression of the disease, or (3) stopping symptoms of the disease. The term "inhibit" includes its generally accepted meaning, including arresting, preventing, suppressing, alleviating, ameliorating or slowing, stopping or reversing progression, severity or symptoms produced. Thus, where appropriate, the method includes medical therapeutic and/or prophylactic administration. The term "medical treatment" as used herein is intended to include prophylactic, diagnostic and therapeutic regimens performed in vivo or in vitro in humans or other mammals. "mammal" includes economically important animals, such as bovine, ovine and porcine animals, particularly those that produce meat, as well as domestic animals, sport animals, zoo animals, and humans, the latter being preferred. The term "subject" as used herein refers to an animal, preferably a mammal, most preferably a human, who is the subject of treatment, observation or experiment.

Abbreviations

AchE acetylcholinesterase

AD Alzheimer's disease

APT bound proton assay

BOP benzotriazol-1-yl-oxytriphosphorium hexafluorophosphate

CB₁Cannabinoid receptor subtype-1

CB₂Cannabinoid receptor subtype-2

CHO Chinese hamster ovary (cell)

CIP 2-chloro-1, 3-dimethylimidazolinium hexafluorophosphate

DCC cyclohexyl carbodiimide

DIPEA N, N-diisopropylethylamine

DMAP 4-dimethylaminopyridine

DMSO dimethyl sulfoxide

HEK human embryo kidney (cell)

HBTU O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate

HOAt N-hydroxy-7-azabenzotriazole (azabenzotriazole)

m.p. melting point c.q. melting range

MS mass spectrometry

PET positron emission tomography

p-TsOH p-toluenesulfonic acid

PyAOP 7-azabenzotriazol-1-yl-oxytis- (pyrrolidine) -phosphonium hexafluorophosphate

PyBOP benzotriazol-1-yl-oxy tris- (pyrrolidine) -phosphonium hexafluorophosphate

SPECT single photon emission computed tomography

TBTU O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate

THF tetrahydrofuran

Example 1: analytical method

Unless otherwise stated, using Bruker ARX 400 (R) (K)¹H：400MHz，¹³C: 100MHz) at 300K, NMR spectra were determined in the indicated solvents (¹H NMR and¹³c NMR, APT). The spectra were determined in deuterated chloroform or dichloromethane from Cambridge Isotrope Laboratories Ltd. In tetramethylsilane (C)¹H，¹³C) Or CCl₃F(¹⁹F) The ppm low magnetic field gives the chemical shift (δ). The coupling constant J is in Hz. The designations 'q' (quartet), 'dq' (doublequartet),'t' (triplet), 'dt' (doublet),'d' (doublet), 'dd' (doublet),'s' (singlet), 'bs' (broad singlet), and'm' (multiplet) are used to designate the peak shapes in the NMR spectrum.

Flash chromatography refers to purification using the indicated eluents and silica gel (Acros: 0.030-0.075mm or Merck silica gel 60: 0.040-0.063 mm). Column chromatography: merck silica gel 60(0.063-0.200 mm). Melting points are recorded on a B ü chi B-545 melting point apparatus. All reactions involving moisture sensitive compounds or conditions were carried out under an anhydrous nitrogen atmosphere. The reaction was detected by using Thin Layer Chromatography (TLC) on silica coated plastic plate (Merck pre-coated silica gel 60F 254) and using the indicated eluent. By UV light (254nm) or I₂To develop the spots. Methylene chloride (phosphorus pentoxide and calcium hydride), tetrahydrofuran (sodium/benzophenone ketyl) and petroleum ether (60-80) were freshly distilled before use. All other commercially available chemicals were used without further purification.

Example 2: general aspects of the Synthesis

The known cannabinoid-CB is described in the patent application and/or in the scientific literature₁Synthesis of the basic building blocks of the antagonist. For example, basic cannabinoid building blocks (A) are disclosed^1a)(WO01070700，Lange，2004^b)，(A^1b)(WO 03026648)，(A²)(WO 03027076，WO 03040107，WO 03063781，Lange，2005^b；Dyck(2004)，(A³) (EP0576357, EP 1150961, Lan, 1999; seltzman, 1995; dutta, 1994 and Katoch-Rouse, 2003), (A)⁴)(WO 03007887，Plummer，2005)，(A⁵)(WO0307069)，(A⁶)(WO 03078413，Lange，2005^b)，(A⁷)(WO 2004026301，Lange，2005^b(ii) a Dyck, 2004) and (A)⁸)(WO 2004013120)。

Typically, the synthesis of compounds of formula (1) wherein n ═ 0 is accomplished by reacting a compound of formula a-L, wherein L represents a leaving group, with a compound of general formula B, wherein B is a nucleophile. The synthesis of a compound of formula (1) wherein n-1 is accomplished by reacting a compound of formula a-T-L, wherein L is a leaving group, with a compound of general formula B, wherein B is a nucleophile. Synthesis of compounds of formula (1) wherein n ═ 1 can also be accomplished by reacting a compound of formula a-L (L is a leaving group) with a compound of formula T-B, wherein T is a nucleophile. Another alternative is to react a compound of formula A-T, wherein T is a nucleophile, with a compound of formula L-B, wherein L is a leaving group.

The specific synthesis of compounds of formula (I) wherein B represents tacrine or tacrine analogues is shown in scheme 2:

scheme 2

Anthranilic acid analogs (II), wherein R₅Representing a hydrogen or halogen atom or a methoxy, methyl or trifluoromethyl group may be reacted in an inert organic solvent such as toluene, for example cyclohexanone (III), to give the spiro compound of formula (IV). The compound of formula (IV) may be reacted with a chlorinating agent such as phosphorus oxychloride (POCl)₃) Reaction to give 9-chloro-1, 2, 3, 4-tetrahydroacridine derivative (V) (Carlier, 1999)^a) The latter may be reacted with formula H₂N-T-NH₂Wherein the linker T consists of a saturated or unsaturated linear carbon chain of 2 to 8 atoms, wherein the carbon chain may be substituted with 1 to 5 substituents selected from methyl, ethyl, hydroxy, fluoro or amino, the carbon chain may incorporate a further nitrogen atom, optionally with C_1-3Alkyl substitution, or the carbon chain may incorporate a further oxygen or sulphur atom or a carbonyl or sulfonyl group or an amide (C (═ O) -NH) group or a sulphonamide (S (O) — NH)₂) -NH) or ureido or phenyl or aryl, wherein phenyl or aryl is optionally substituted by a substituent selected from the group consisting of halogen, cyano, methyl, methoxy, trifluoromethyl, OCHF₂、OCF₃、SCF₃Or 1-4 substituents of nitro to give compounds of the general formula (VI). The reaction is preferably carried out in an inert organic solvent such as 1-pentanol at elevated temperature (Carlier, 1999)^b). Compounds of formula (VI) may be reacted with compounds of formula A-L, wherein A represents any known cannabinoid-CB containing at least two phenyl rings₁Basic building blocks for antagonists, whichWherein the phenyl rings are optionally independently substituted with 1 or 2 substituents selected from halogen, methoxy and trifluoromethyl, said basic building blocks and said cannabinoid-CB₁Antagonist hydrogen bond receptor binding wherein the hydrogen bond receptor moiety represents a carbonyl, sulfonyl or nitrogen or oxygen atom incorporated into a heteroaromatic ring structure and L represents a leaving group. When L represents a hydroxyl group as part of a carboxylic acid group, an activating or coupling agent may be added to increase the rate of reaction. (Bodanszky, 1994; Akaji, 1994; Albericio, 1997). This reaction gives compounds of formula (1) wherein A has the meaning given above, T represents the linker mentioned above and B represents tacrine or a tacrine analogue.

A compound of formula (1) wherein A represents a structural unit (A)^1a) Or (A)^1b) Wherein R is¹、R²And R³The synthesis of independently representing one or more hydrogen, trifluoromethyl or halogen atoms is shown in scheme 3:

scheme 3

Formula (A)^1a1) In the presence of DMAP in an inert organic solvent such as CH₂Cl₂Neutralizing POCl₃Reacting to obtain the formula (A)^1a2) With a compound of formula HRN-T-B, wherein T represents a linker and B represents tacrine or an analogue thereof, which reaction gives a compound of formula (1), wherein A has the above (A)^1a) Given the meaning, T represents a linker, B represents tacrine or an analogue thereof, R represents a hydrogen atom or C_1-3An alkyl group. Similarly, formula (A)^1b1) In the presence of DMAP in an inert organic solvent such as CH₂Cl₂Neutralizing POCl₃Reacting to obtain the formula (A)^1b2) The latter may be reacted with a compound of formula HRN-T-B, wherein T represents a linker and B represents tacrine or an analogue thereof.This reaction can give compounds of formula (1) wherein A has the above (A)^1b) Given the meaning, T represents a linker, B represents tacrine or an analogue thereof, R represents a hydrogen atom or C_1-3An alkyl group.

A compound of formula (1) wherein A represents a structural unit (A)²) Wherein R represents a hydrogen atom or C_1-3Alkyl radical, R¹And R²Independently represents one or more hydrogen, trifluoromethyl or halogen atoms, R₄Represents a hydrogen or halogen atom or a methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, propyl, methylthioalkyl, methylsulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl, ethylsulfonyl, C_1-3-dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl, the other symbols having the meanings given above. Formula (A)²ⁱ¹) Can be reacted with a compound of the general formula HRN-T-B to give a compound of the formula (1) A-T-B, wherein the A moiety is derived from the substructure A². Can be prepared by trimethyl aluminum AlMe₃The reaction is catalyzed (Levin, 1982).

Alternatively, the formula (A) may be²ⁱ¹) Hydrolysis of the Compound to formula (A)²ⁱ²) The corresponding carboxylic acid of (a). Formula (A)²ⁱ²) Can be reacted with a compound of formula HRN-T-B to give a compound of formula (1) wherein the A moiety is derived from substructure A². Preference is given to carrying out the reaction by activation and coupling methods, for example to form active esters, or in the presence of so-called coupling agents, for example DCC, HBTU, TBTU, HOAt, PyBOP, BOP, CIP, 2-chloro-1, 3-dimethylimidazolinium chloride or PyAOP (Bodanszky, 1994; Akaji, 1994; Albericio, 1997; Montalbeti, 2005). Alternatively, formula (A)²ⁱ²) Can be converted to the compound of formula (A) in the presence of a chlorinating agent such as thionyl chloride or oxalyl chloride²ⁱ³) Corresponding acid chlorides of. Formula (A)²ⁱ³) Can be reacted with a compound of formula HRN-T-B to give a compound of formula (1) wherein the A moiety is derived from substructure A². A base such as DIPEA may be added to the reaction mixture to scavenge the hydrochloric acid produced, or an excess of HRN-T-B may be used for this purpose.

Similarly, as shown above, formula (A)³)、(A⁴)、(A⁵)、(A⁶)、(A⁷) Or (A)⁸) Can be converted into compounds of formula (1) A-T-B, wherein the A moieties are each derived from a substructure (A)³)、(A⁴)、(A⁵)、(A⁶)、(A⁷) Or (A)⁸)。

The choice of a particular synthetic method depends on various factors known to those skilled in the art, such as the compatibility of the functional groups with the reagents used, the possibility of using protecting groups, catalysts, activating and coupling agents, and the final structural characteristics present in the final compound to be prepared.

Pharmacologically acceptable salts may be obtained by standard procedures well known in the art, for example by mixing a compound of the invention with a suitable acid, for example an inorganic or organic acid.

Example 3: synthesis of specific Compounds

The synthesis of specific compounds is described below in order to illustrate the invention in further detail and is therefore not intended to limit the scope of the invention in any way. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. Accordingly, the specification and examples should be considered as exemplary only.

Compound 1

Part A: as described (Carlier, 1999)^a) Spiro [2H-3, 1-benzoxazine-2, 1' -cyclohex-4 (1H) -one was synthesized from anthranilic acid and cyclohexanone in toluene with a yield of 73%. This compound was converted to 9-chloro-1, 2, 3, 4-tetrahydroacridine (Carlier, 1999)^a) The latter was reacted with 1, 2-diaminoheptane in 1-propanol in a yield of 99% to give N- [9 ' - (1 ', 2 ', 3 ', 4 ' -tetrahydro-acridinyl)]-1, 7-diaminoheptane (Carlier, 1999)^b)。

Analogously, N- [9 ' - (1 ', 2 ', 3 ', 4 ' -tetrahydroacridinyl) was prepared from 1, 2-diaminobutane and 9-chloro-1, 2, 3, 4-tetrahydroacridine]1, 7-diaminobutane, yield 78%. N- [9 ' - (1 ', 2 ', 3 ', 4 ' -tetrahydroacridinyl)]-1, 7-diaminobutane:¹H-NMR(400MHz，CDCl₃): δ 1.53-1.61(m, 2H), 1.69-1.77(m, 2H), 1.91-2.20(m, 6H), 2.70-2.78(m, 4H), 3.08(br s, 2H), 3.45-3.55(m, 2H), 4.31(br s, 1H), 7.27-7.37(m, 1H), 7.53-7.58(m, 1H), 7.93-7.99(m, 2H). And part B: as described (Lange, 2004)^b) To obtain 3- (4-chlorophenyl) -N- [ (4-chlorophenyl) sulfonyl group]-4-phenyl-4, 5-dihydro-1H-pyrazole-1-carboxamide. This compound (1.5 g, 3.16mol) was dissolved in dichloromethane (30ml), and DMAP (1.707 g, 13.9mmol) and POCl were added successively₃(0.59g, 3.85mmol) and the resulting mixture was refluxed for 5 hours. The mixture was cooled to room temperature and concentrated in vacuo to give crude 3- (4-chlorophenyl) -N- [ (4-chlorophenyl) sulfonyl]-4-phenyl-4, 5-dihydro-1H-pyrazole-1-carboxypyrrole chloride (carboximidoyl chloride). The resulting 3- (4-chlorophenyl) -N- [ (4-chlorophenyl) sulfonyl group]-4-phenyl-4, 5-dihydro-1H-pyrazole-1-carboxypyrrole chloride (carboximidoyl chloride) was dissolved in dichloromethane (30ml) and reacted with N- [9 ' - (1 ', 2 ', 3 ', 4 ' -tetrahydro-acridinyl) at 0 ℃]1, 7-Diaminoheptane (1.48 g, 4.75mmol) and DIPEA (1.02 g, 7.9mmol) at reflux temperature for 72 h. The mixture was cooled to room temperature and washed successively with water and brine, over Na₂SO₄Dried, filtered and concentrated. By flash chromatography (gradient: dichloromethane ≧ bisMethyl chloride/methanol 95/5(v/v)) to give pure 4-chloro-N- { [3- (4-chlorophenyl) -4-phenyl-4, 5-dihydro-1H-pyrazolyl]- [7- (1, 2, 3, 4-Tetrahydroacridin-9-ylamino) -heptylamino]Methylene } benzenesulfonamide (compound 1) (0.85 g, 35% yield). Melting point: 87-89 ℃.

Similarly, from 3- (4-chlorophenyl) -N- [ (4-chloro-phenyl) sulfonyl ] -4-phenyl-4, 5-dihydro-1H-pyrazole-1-carboxamide and N- [9 ' - (1 ', 2 ', 3 ', 4 ' -tetrahydro-acridinyl) ] -1, 7-diamino-butane, 4-chloro-N- { [3- (4-chlorophenyl) -4-phenyl-4, 5-dihydro-1H-pyrazolyl ] - [7- (1, 2, 3, 4-tetrahydro-acridin-9-yl-amino) butylamino ] methylene } benzenesulfonamide (compound 2, m.p.: 87-89 ℃ C.).

Compound 3

Part A: ethyl 2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylate was obtained according to WO 03040107. A magnetically stirred solution of ethyl 2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylate (5.80g, 0.0149mol) in tetrahydrofuran (40ml) was added to a solution of LiOH (0.715g) in water (40 ml). The resulting mixture was heated at 70 ℃ for 16 hours. The resulting mixture was cooled to room temperature and then treated with concentrated hydrochloric acid (3.5 ml). Tetrahydrofuran was evaporated in vacuo and the resulting mixture was stirred overnight. The precipitate formed was collected by filtration and washed with petroleum ether (40-60) to give 2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylic acid (4.52 g, 84% yield).¹H-NMR(400MHz，CDCl₃): δ 1.09(t, J ═ 7, 3H), 2.90(q, J ═ 7, 2H), 3.70(br s, 1H), 7.12(d t, J ═ 8 and 2, 2H), 7.22-7.28(m, 1H), 7.29-7.38(m, 5H).

And part B: to magnetically stirred N- [9 ' - (1 ', 2 ', 3 ', 4 ' -tetrahydro-acridinyl)]1, 7-Diaminoheptane (3.25g, 10.4mmol) in dichloromethaneTo a solution (50ml) were added 2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylic acid (2.8 g, 7.8mmol), HOAt (1.3 g, 9.4mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.8 g, 9.4mmol) successively. The resulting mixture was stirred at room temperature for 60 hours and washed successively with water (2 × 100ml) and brine (100 ml). Followed by reaction with Na₂SO₄The organic layer was dried, filtered and concentrated. The crude product obtained was purified by flash chromatography (gradient: dichloromethane/ethanol ═ 99/1 ═ dichloromethane/methanol ═ 90/10(v/v)) to give pure N- [7- (1, 2, 3, 4-tetrahydroacridin-9-ylamino) heptyl ester]-2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxamide (compound 3) (2.25g, 53% yield). Melting point: 143 ℃ and 145 ℃.

Analogously, N- [4- (1, 2, 3, 4-tetrahydroacridin-9-ylamino) butyl ] -2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxamide was prepared from 2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylic acid and N- [9 ' - (1 ', 2 ', 3 ', 4 ' -tetrahydroacridinyl) ] -1, 7-diaminobutane (compound 4, m.p.: 103 ℃ 105 ℃).

Example 4: preparation for use in animal experiments

For oral administration (p.o.): to the desired amount (0.5-5mg) of compound 1 in a glass tube was added some glass beads and the solid was milled by vortex for 2 minutes. After addition of 1ml of 1% methylcellulose in water and 2% (v/v) of poloxamer 188(Lutrol F68), the compound was suspended by vortexing for 10 minutes. The pH was adjusted to 7 with a few drops of aqueous NaOH (0.1N). The remaining particles in suspension were further suspended with an ultrasonic bath.

For intraperitoneal (i.p.) administration: to a glass tube the desired amount (0.5-15mg) of solid compound 1 was added a quantity of glass beads and the solid was milled by vortex for 2 minutes. After addition of 1ml of an aqueous solution of 1% methylcellulose and 5% mannitol, the compound was suspended by vortexing for 10 minutes. Finally the pH was adjusted to 7.

Example 5: pharmacological methods

Human cannabinoid-CB₁The in vitro affinity of the receptor is determined by stably transfecting human cannabinoid CB therein₁Determined from a membrane preparation of CHO cells of a receptor, used³H]CP-55, 940 acts as a radioligand. In the presence or absence of a compound of the present invention³H]Ligand culture after the newly prepared cell membrane preparation, bound and free ligand separation is carried out by filtration through a glass fiber filter. Radioactivity on the filters was determined by liquid scintillation counting.

Inhibition of acetylcholinesterase in human HEK-293 cells. Compounds were dissolved in DMSO (10mM) and diluted to the test concentration in assay buffer. For each analysis, to determine the IC₅₀The surrounding 3log concentration range was tested: IC of e.g. 0.3. mu.M₅₀IC at 10, 1, 0.1 and 0.01. mu.M, 10nM₅₀300, 30, 3, and 0.3 nM. All assays were performed in duplicate. The optimal maximum concentration for the assay is 10. mu.M. After incubation of the test compounds with the acetylcholinesterase enzyme preparation (human recombinant expressed in HEK-293 cells) and the substrate thioacetylcholine (50. mu.M) for 30 min at 37 ℃, the sulfur-binding products were determined photometrically.

Results at each tested concentration (two times) are expressed as% of all products formed; determination of IC from concentration-generated inhibition curves by nonlinear regression analysis with Hill equation curve fitting₅₀The value is obtained. The pIC for results₅₀And (4) expressing. Compounds with no significant affinity at concentrations of 10. mu.M and higher are considered to be inactive pIC' s₅₀＜5.0(Ellman，1961)。

Example 6: results of pharmacological experiments

Shown in the following table are the CBs obtained according to the protocol given above₁Receptor affinity data and acetylcholinesterase inhibition data.

The results clearly show that the compounds of the invention are directed to cannabinoid-CB₁The receptor has affinity and inhibitory activity against cholinesterase. Their affinity is equivalent to rimonabant, while, for example, compound 4 is equivalent to tacrine as a cholinesterase inhibitor. This is in close relation to the effective CB as described in, for example, WO03/027076 (structures shown below)₁Antagonists are in full contrast, the latter being completely inactive as cholinesterase inhibitors.

Example 7: pharmaceutical preparation

For clinical use, the compounds of formula (1) may be formulated into pharmaceutical compositions, which are important and novel embodiments of the present invention, as they comprise the compound, more particularly the specific compounds described herein. Types of pharmaceutical compositions that can be used include, but are not limited to, tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, suspensions, and other types described herein or apparent to those of ordinary skill in the art in light of the specification and general knowledge in the art. The active ingredient may, for example, be in the form of an inclusion complex in a cyclodextrin, an ether thereof or an ester thereof. The composition can be administered orally, intravenously, subcutaneously, tracheally, bronchially, intranasally, pulmonarily, dermally, buccally, rectally, parenterally, or by other routes. The pharmaceutical formulation comprises at least one compound of formula (1) in admixture with at least one pharmaceutically acceptable adjuvant, diluent and/or carrier. A suitable range for the total amount of active ingredient is from about 0.1% (w/w) to about 95% (w/w), suitably from 0.5% to 50% (w/w), preferably from 1% to 25% (w/w) of the formulation. In some embodiments, the amount of active ingredient is greater than about 95% (w/w) or less than about 0.1% (w/w).

The compounds of the invention can be brought into a form suitable for administration by customary methods, including the administration of auxiliary substances such as liquid or solid, pulverulent ingredients, for example liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances customary in pharmacy. Commonly used auxiliary substances include magnesium carbonate, titanium dioxide, lactose, sucrose, sorbitol, mannitol and other sugars or sugar alcohols, talc, milk protein, gelatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower oil, groundnut or sesame oil, polyethylene glycols and solvents, such as sterile water and mono-or polyhydric alcohols such as glycerol, and disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then granulated or compressed into tablets. Tablets were prepared with the following ingredients:

the components were mixed and compressed into tablets, each weighing 230 mg.

The active ingredient may be separately premixed with the other inactive ingredients before mixing to make the formulation. The active ingredients may also be mixed with each other before being mixed with the inactive ingredients to form a formulation.

Soft gelatin capsules may be prepared from capsules containing a mixture of the active ingredient of the invention, vegetable oil, fat or other suitable carrier for soft gelatin capsules. Hard gelatin capsules may contain granules of the active ingredient. Hard gelatin capsules may also contain the active ingredient and solid powdered ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.

Dosage units for rectal administration may be prepared (i) in the form of suppositories containing a mixture of the active substance and a neutral fat base; (ii) in the form of gelatin rectal capsules comprising a mixture of the active substance and vegetable oil, liquid paraffin or other carriers suitable for gelatin rectal capsules; (iii) pre-made in the form of a micro-enema; or (iv) a dry micro-enema that is reconstituted in a suitable solvent just prior to administration.

Liquid preparations may be prepared as syrups, elixirs, drops or suspensions, for example solutions or suspensions, containing the active ingredient and the remaining components, for example sugars or sugar alcohols and mixtures of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, the liquid formulation may contain colouring agents, flavouring agents, preservatives, saccharin and carboxymethylcellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder which is reconstituted with a suitable solvent prior to use. Solutions for parenteral administration may be prepared as solutions of the formulations of the present invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may be prepared as dry preparations which are reconstituted with a suitable solvent prior to use.

The formulations and "kits of parts" provided according to the invention comprise one or more containers filled with one or more ingredients of the pharmaceutical compositions of the invention, for use in medical treatment. Materials associated with such containers may be written, such as instructions for use or precautions dictated by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which reflects approval by the agency for manufacture, use or sale in human or veterinary medicine. Use of the formulations of the invention in the preparation of a medicament for the treatment of a condition requiring or requiring antagonism of CB₁Receptor and/or inhibition of acetylcholine estersUse in the medicine of, and medical treatment of, enzymatic disorders, involving administration of a compound having or requiring antagonism to CB₁Patients susceptible to diseases in which the receptor and/or inhibition of acetylcholinesterase is administered a therapeutically effective total amount of at least one compound of formula (1) or a prodrug thereof.

By way of example and not limitation, several pharmaceutical compositions are given, including preferred active compounds for systemic use or topical application. The compounds may be replaced (or substituted) with other compounds of the present invention or combinations thereof. The concentration of the active ingredient may vary over a wide range as discussed herein. The amounts and types of ingredients that can be included are well known in the art.

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Claims (21)

1. Having cannabinoid-CB₁A compound which is a combination of an antagonistic effect and a cholinesterase inhibitory activity.

2. The compound of claim 1 having cannabinoid-CB₁A combination of antagonism and acetylcholinesterase inhibitory activity.

3. The compound of claim 1, having formula (1):

or a tautomer, stereoisomer, N-oxide, isotope-labeled analog thereof, or a pharmacologically acceptable salt, hydrate, or solvate of any of the foregoing, wherein:

-A represents any known cannabinoid-CB₁A basic building block for an antagonist comprising at least two phenyl rings independently optionally substituted with 1 or 2 substituents selected from halogen, methoxy and trifluoromethyl, said basic building block and said cannabinoid-CB₁An antagonist, wherein the hydrogen bond acceptor moiety is a carbonyl group, a sulfonyl group, or a nitrogen or oxygen atom incorporated in a heteroaromatic ring structure,

-T represents a linker consisting of a saturated or unsaturated linear carbon chain of 2 to 8 atoms, wherein the carbon chain may be substituted with 1 to 5 substituents selected from methyl, ethyl, hydroxy, fluoro or amino, which may contain a further nitrogen atom, optionally with C_1-3Alkyl, or the carbon chain may contain further oxygen or sulfur atoms, or carbonyl, sulfonyl, amide, sulfonamide, ureido, or aryl, the aryl being optionally substituted with 1 to 4 substituents selected from halogen, cyano, methyl, methoxy, trifluoromethyl, OCHF₂、OCF₃、SCF₃Or a substituent of a nitro group,

b represents the basic building block of any known acetylcholinesterase inhibitor,

-n is 0 or 1.

4. A compound of formula (1) according to claim 3, wherein a represents CB₁Basic building blocks of antagonists, wherein CB₁The antagonist is selected from 11C-JHU-75528, A-796260, AM 251, AM 630, AVE-1625, MK-0364, CP-272871, CP-945598, GRC-10389, LY-2077855, LY-320135, NIDA-41020, 0-2093, rimonabant, SLV319, SLV326, SR-140098, SR-144385, SR-147778, surinabant, V-24343, WIN-54461 and WIN-56098, wherein B represents the basic building block of an AchE inhibitor, wherein Ach represents the basic building block of an AchE inhibitor, and whereinThe E inhibitor is selected from aceclidine, amberlotin, amiloride, AS-1397, BGC-20-1259, bisnorcymserine, bromodechloroambenonitum, bromophenol phosphorus, BW-284-C-51, Carbamine, carbafuran, CHF-2060, CHF-2822, CHF-2957, CI-1002, cisatracurium besilate, CM-2433, CM-2501, vasicidin, diazinon, donepezil, E-2030, efenol chloride, EN-101, exemestane, ER-127528, (-) -dolichol alkali, F-3796, cartap, FK-960, FP-7832, FR-152558, galantamine, distigmine, bamboo alkali, Hoe-065, HP-290, huperzine A, impatien, INM-176, Iphirine, Iphipride, indolophos-51, isofluridide, indomethacin, indometha, JES-9501, KA-672, KW-5092, ladostigil, malathion, MCI-225, mebendazole, memantine, memoquin, methanesulfonyl fluoride, N-methyl physostigmine, metrazophorine, MF-268, MF-8615, MFS-3, MHP-133, mifepristone, melameilin, neostigmine, nitrofluoropyrafen, NP-0362, NP-7557, NXX-066, P-10358, P-11012, P-11149, P-ONO 11467, P-26, paliroden, paranitrophenylphosphate, parathion, PD-151832, (-) -phenylhydroxyalanine, physostigmine, pranocardine, sitan, pirstine, rivanidulaline, rivastigmine, Ro-46-5934, RS-1439, SDS-14377, SDZ-792-S-792, SGS-792-S-742, SGS-861S-861, SM-10888, SP-004, T-82, tacrine, 7-methoxytacrine, bis- (7) -tacrine, TAK-802, tolerine, UR-1827, dacridine, Z-338, zanapezil, azithicone and ZT-1,

and tautomers, stereoisomers, prodrugs and N-oxides of the compounds of formula (1), and isotope-labeled analogs of the compounds of formula (1), and pharmacologically acceptable salts, hydrates, solvates, complexes and conjugates of said compounds of formula (1) and tautomers, stereoisomers, prodrugs, N-oxides or isotope-labeled analogs thereof.

5. A compound of formula (1) according to claim 3, wherein: a represents a fragment (A)^1a)、(A^1b)、(A²)、(A³)、(A⁴)、(A⁵)、(A⁶)、(A⁷) Or (A)⁸) In the above-mentioned manner, the first and second substrates are,

wherein X represents a sulfonyl group or a carbonyl group, the "+" symbol represents the point at which the fragment is linked to the linker T of formula (1), R¹、R²And R³Independently represents one or more hydrogen, trifluoromethyl or halogen atoms, R⁴Represents a hydrogen or halogen atom, or a methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, propyl, methylthioalkyl, methylsulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl, ethylsulfonyl, C_1-3- -dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl, and T, B and n have the meanings given in claim 3, and wherein R represents a hydrogen atom or C_1-3An alkyl group.

6. A compound of formula (1) according to claim 5, wherein fragment B is selected from fragment (B)¹)，(B²) Or (B)³) One of (1):

wherein the "+" symbol represents the point at which the fragment is linked to linker T of formula (1), R⁵Represents a hydrogen or halogen atom, or a methoxy or trifluoromethoxy group, and m is an integer having a value of 0, 1 or 2, T has the meaning given in claim 5, and n ═ 1.

7. A compound of formula (1) according to claim 5, wherein the acetylcholinesterase inhibitor of fragment B is tacrine, amitriptyline, 7-methoxytacrine or SM-10888, T has the meaning given in claim 5, and n-1.

8. A compound of formula (1) according to claim 5, wherein A represents the fragment (A)^1a)，(A^1b) Or (A)²) Wherein the acetylcholinesterase inhibitor of fragment B is tacrine, and n is 1.

9. A compound of formula (1) according to claim 3, wherein: a represents a fragment (A)⁹) Or (A)¹⁰) One of (1):

and T, B and n have the meanings given in claim 3, and wherein R represents a hydrogen atom or C_1-3An alkyl group.

10. A compound of formula (1) according to claim 3, selected from:

4-chloro-N- { [3- (4-chlorophenyl) -4-phenyl-4, 5-dihydro-1H-pyrazolyl ] - [7- (1, 2, 3, 4-tetrahydroacridin-9-ylamino) heptylamino ] methylene } benzenesulfonamide

4-chloro-N- { [3- (4-chlorophenyl) -4-phenyl-4, 5-dihydro-1H-pyrazolyl ] - [7- (1, 2, 3, 4-tetrahydroacridin-9-yl-amino) butylamino ] methylene } benzenesulfonamide

N- [7- (1, 2, 3, 4-Tetrahydroacridin-9-ylamino) heptyl ] -2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxamide

N- [4- (1, 2, 3, 4-tetrahydroacridin-9-ylamino) butyl ] -2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxamide.

11. A compound of formula (1) according to claim 3, selected from:

12. a compound of formula (1) as claimed in any one of claims 3 to 11, which is an optically active enantiomer, or a tautomer, stereoisomer, N-oxide, isotope-labeled analog, or a pharmacologically acceptable salt, hydrate, or solvate of any of the foregoing.

13. A process for the preparation of a compound of formula (1) as claimed in claim 3, wherein a represents the structural unit (a)^1a) Or (A)^1b) Wherein R is¹、R²And R³Independently represents one or more hydrogen atoms, trifluoromethyl or halogen atoms,

the method is characterized in that: general formula (A)^1a1) Or (A)^1b1) With a chlorinating agent in the presence of a base in an inert organic solvent to obtain a compound of the general formula (A)^1a2) Or (A)^1b2) Corresponding derivatives which can be reacted with compounds of the general formula HRN-T-B, wherein B represents tacrine or a tacrine analogue, T has the meaning given in claim 3, and R represents a hydrogen atom or C_1-3Alkyl, as indicated below:

14. a compound prepared according to claim 13.

15. A medicament comprising a compound according to any one of claims 1 to 12, or a pharmacologically acceptable salt, hydrate, solvate, complex or conjugate thereof.

16. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, at least one pharmaceutically acceptable auxiliary substance, or a combination of two or more thereof; and a pharmacologically active amount of at least one compound of any one of claims 1 to 12, or a pharmacologically acceptable salt, hydrate, solvate thereof.

17. The pharmaceutical composition according to claim 16, further comprising: at least one other therapeutic agent.

18. Use of a compound as claimed in any one of claims 1 to 12 for the preparation of a medicament for the treatment of addiction, predisposition, alcoholism, alzheimer's disease, amnesia, anxiety, appetite disorders, arthritis, attention deficit, cancer, cardiovascular disorders, central nervous system disorders, cerebral stroke, cerebral ischemia, cognitive disorders, constipation, dementia, demyelination-related disorders, depression, diabetes, diarrhea, drug dependence, dyspepsia, dystonia, emesis, epilepsy, gastric motility disorders, gastric ulcers, gastrointestinal disorders, gastroparesis, glaucoma, huntington's disease, impulse control disorders, irritable bowel syndrome, memory disorders, migraine, multiple sclerosis, myopathy, muscle atrophy, muscle spasms, myasthenia gravis, nausea, neurodegenerative disorders, neuroinflammatory disorders, neuropathic pain, nicotine dependence, obesity, anxiety, depression, diarrhea, drug dependence, dyspepsia, dystonia, emesis, gastric motility disorders, gastric ulcer, gastric dystonia, glaucoma, Pain disorders, Parkinson's disease, head lice infection, plaque sclerosis, poisoning, post viral infection fatigue syndrome, psychiatric disorders, psychosis, senile dementia, septic shock, sexual dysfunction, schistosomiasis, spinal cord injury, stroke, Tourette's syndrome, traumatic brain injury, tremor, urinary dysfunction, viral encephalitis, and xerostomia.

19. Use according to claim 18 for the preparation of a pharmaceutical composition for the treatment of alzheimer's disease, cognitive disorders, memory disorders, dementia, attention deficit, traumatic brain injury, drug dependence, addiction and substance abuse.

20. A compound according to any one of claims 1-12 for use in the treatment of addiction, predisposition, alcoholism, alzheimer's disease, amnesia, anxiety, appetite disorders, arthritis, attention deficit, cancer, cardiovascular disorders, central nervous system disorders, cerebral stroke, cerebral ischemia, cognitive disorders, constipation, dementia, demyelination-related disorders, depression, diabetes, diarrhea, drug dependence, dyspepsia, dystonia, emesis, epilepsy, gastric motility disorders, gastric ulcers, gastrointestinal disorders, gastroparesis, glaucoma, huntington's disease, impulse control disorders, irritable bowel syndrome, memory disorders, migraine, multiple sclerosis, myopathy, muscle atrophy, muscle spasms, myasthenia gravis, nausea, neurodegenerative disorders, neuro nitine disorders, neuropathic pain, dependence, obesity, pain disorders, depression, diabetes, diarrhea, drug addiction, dyspepsia, dystonia, emesis, gastric motility disorders, gastric ulcer, gastrointestinal disorders, gastroparesis, glaucoma, huntington's disease, impulse control disorders, irritable bowel syndrome, memory disorders, Parkinson's disease, head lice infection, plaque sclerosis, poisoning, post viral infection fatigue syndrome, psychiatric disorders, psychosis, senile dementia, septic shock, sexual dysfunction, schistosomiasis, spinal cord injury, stroke, Tourette's syndrome, traumatic brain injury, tremor, urinary dysfunction, viral encephalitis, and xerostomia.

21. A compound according to any one of claims 1 to 12 for use in the treatment of alzheimer's disease, cognitive disorders, memory disorders, dementia, attention deficit, traumatic brain injury, drug dependence, addiction and substance abuse.