HK1128695A

HK1128695A - Novel chromene and thiochromene carboxamide derivatives, methods for preparing same and therapeutic applications of same

Info

Publication number: HK1128695A
Application number: HK09108443.7A
Authority: HK
Inventors: P‧索科洛夫; T‧安贝尔; L‧韦尔涅; F‧奎西亚特
Original assignee: 皮埃尔法布雷医药公司
Priority date: 2006-07-21
Filing date: 2007-07-20
Publication date: 2009-11-06

Abstract

The present invention relates to novel chromene or thiochromene carboxamide derivatives, the preparation of same, pharmaceutical compositions of same and the use of same as dopamine D3 ligands as a medicament for central nervous system disorders.

Description

Novel benzopyran and 1, 2-benzothiopyranamide derivatives, preparation thereof and therapeutic use thereof

The present invention relates to benzopyran and 1, 2-benzothiopyramide derivatives (chromene and chromane carboxamide derivatives), to processes for their preparation, to pharmaceutical compositions containing them and to their therapeutic use as dopamine D3 receptor (DRD3) agonists, partial agonists or antagonists for the treatment of various neurological and psychiatric disorders.

Schizophrenia is a term used to describe a group of pathologies of unknown origin, which affects approximately 1% of the general population. The pathology is characterized by a number of symptoms, classified as positive (hallucinations, confusion, split thinking) and negative (social and emotional rigidity avoidance), which develop during adolescence or adolescence and can persist for many years in a chronic form that exacerbates the attack.

Patients suffering from schizophrenia may be treated with drugs known as neuroleptics, also known as antipsychotics. The therapeutic effect of antipsychotics is generally understood to result from blocking receptors in the brain for the neurotransmitter dopamine. Five subtypes of dopamine receptors are known, called D1, D2, D3, D4 and D5(Sokoloff et al, Novel dopamine receptor subtypes for antipsychotic drugs, annals New-York Academy of sciences 1995, 757, 278); conventional antipsychotics are D2 and D3 receptor antagonists. However, antipsychotics often cause undesirable extrapyramidal side Effects (EPS) and abnormal movement known as tardive dyskinesia due to blockade of D2 receptors in the striatal region of the brain. Blockade of receptor D3(DRD3) was suggested to be responsible for the therapeutic effect of antipsychotics (Schwartz, j.c. eur. neuropsychopharmacol.2003, 13 (suppl.4): S166). Thus, drugs that selectively modulate the function of DRD3 are considered to be effective antipsychotics without neurological side effects (international patent WO 91/15513).

Molecules that selectively bind to DRD3 and act as agonists, antagonists, or partial agonists may selectively modulate DRD 3. Antipsychotic activity resulting from modulation of DRD3 function can be predicted in animals using a mouse schizophrenia model (Leriche, l. neuropharmacology 2003, 45, 174). Furthermore, studies have shown that selective blockade of DRD3, without concomitant blockade of DRD2 and DRD3, increases extracellular levels of dopamine and acetylcholine, and other neurotransmitters, in the prefrontal cortex (Lacroix, l.p. neurosychophacol.2003, 28, 839). Dopamine and acetylcholine in this region of the brain are essential for cognitive function. It is therefore believed that selective DRD3 antagonists may improve cognition, which is altered in schizophrenia and neurodegenerative conditions such as alzheimer's disease.

Depression is a common mood condition characterized by perception of intense sadness, pessimistic thought, and self-depreciation, often accompanied by diminished energy, enthusiasm, and libido. Inability to experience pleasure from normal happy life events, also known as anhedonia, is also considered a common depressive symptom. An important role of pleasure and motivation is the projection of dopaminergic neurons to the brain nucleus accumbens region (Koob g.f. sem. neurosci.1992, 4, 139; salarone j.d. behav. brain res.1994, 61, 117). Thus, such neurons have been implicated in the neurobiology of depression, particularly anhedonia, and the therapeutic action of certain antidepressant drugs (Kapur S. and Mann J.biol.Psychiatry 1992, 32, 1-17; Willner P.int.Clin.Psychopharmacol.1991, 12, S7-S14). Recent studies have shown that various antidepressant therapies selectively increase the expression of DRD3 in the nucleus accumbens (Lammers c.h.mol.psychiatry 2000, 5, 378), suggesting that increasing DRD3 function may be a new modality of antidepressant therapy. An increase in the function of the DRD 3D 3 receptor can be obtained with DRD3 agonists or partial agonists, resulting in an effective treatment of depression.

Dependence or addiction to drugs or other addictive substances is a chronic, recurrent condition that persists in dangerous foraging and compulsive medication despite patient perception of negative consequences (derache-Gamonet v.science2004, 305, 1014; Vanderschuren l.j. science2004, 305, 1017). The withdrawal phenomenon (Withdry phenomenon), which occurs when addicts abstain from addictive substances, can be triggered or exacerbated by environmental stimuli, acquires an excitatory motive force due to the fact that they repeat concomitant drug action in humans (Childress A.R.am.J.Psychiatry 1999, 156, 11; Robinson T.E.brain Research Reviews 1993, 18, 247) and animals (Goldberg S.R.NIDA Res.monogr.1981, 37, 241; Arroy M.Psychopharmacology 1999, 140, 331). In animals, highly selective DRD3 agonists or partial agonists specifically reduce responses accompanied by cocaine (Pilla M. Nature, 1999, 400, 371; Le Foll, B. Eur. J. Neurosci.2002, 15, 2016; VorelS. R. J. Neurosci.2002, 22, 9595), opiates (France H. Neuroreport 2004, 15, 2245) or nicotine ((Le Foll B. mol. Psychiatry 2003, 8, 225) stimulation, but do not affect the first effect of the drug.

Parkinson's disease is a condition characterized by resting tremor, a rigid limb and an inability to move (difficulty in initiating movement). The disease is caused by degeneration of dopaminergic neurons. The treatment of parkinson's disease is based on dopamine replacement by administration of L-DOPA (3, 4-dihydroxy-L-phenylalanine) or dopamine direct agonists. However, in many cases, the long-term use of L-DOPA is accompanied by the occurrence of abnormal exercise, which is called dyskinesia. Studies have shown that modulation of DRD3 with highly selective partial agonists attenuates dyskinesias in a non-human primate model of parkinson's disease (Bezard e.nat. med.2003, 6, 762). Thus, the compounds disclosed herein are considered to be a supplemental treatment for parkinson's disease. Furthermore, as studies have shown that DRD3 agonists enhance neurogenesis in rats, they can also be used as drugs to delay disease progression.

Mutation of the DRD3 gene is associated with and co-segregates essential tremor, a common neurological disorder characterized by intention tremor in all or part of the body in the absence of additional neurological conditions (Lucotte g. This mutation increased DRD3 function. Thus, normalization of DRD3 function by use of DRD3 antagonists or partial agonists may be effective in treating essential tremor.

The terms "dopamine D3 receptor", "D3 receptor" or "DRD 3" as used above denote the dopamine receptor subtype which is predominantly expressed in the limbic system (SokoloffP, Nature, 1990, 347, 146-151). DRD3 has been disclosed in International patent WO 91/15513.

The term "partial agonist of the D3 receptor" as used above denotes a compound which forms a complex with DRD3 and acts as a combined agonist-antagonist, i.e. it induces a physiological response of a lower intensity than the natural modulator, dopamine. In vitro, DRD3 partial agonists produced an active response in cells expressing DRD3 with a maximal intensity lower than that produced by dopamine or full agonists, such as quinpirole [ (4 aR-trans) -4, 4a, 5, 6, 7, 8, 8a, 9-octahydro-5-propyl-1H (or 2H) -pyrazole (3, 4-g) quinoline ]. Partial agonists of DRD3 may also partially prevent the response produced by dopamine or its full agonists. In vivo, partial agonists of DRD3 produce a dopaminergic response, particularly when dopamine levels are reduced, as is the case in rats with 6-hydroxydopamine-induced injury or in monkeys injected with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Moreover, partial agonists of DRD3 may act as in vivo antagonists, particularly when DRD3 is subject to sustained dopamine stimulation.

By "DRD 3 antagonist" is meant a molecule that forms a complex with DRD3, which prevents dopamine or agonist-triggered responses in cells expressing DRD 3.

The term "salt" as used above denotes the addition salts of the compounds of the present invention with inorganic acids and bases. Preferably, the salts are pharmaceutically acceptable, i.e., they are non-toxic to the patient to whom they are administered. Examples of acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalate salts, and the like. (see, e.g., S.M. Berge et al, "Pharmaceutical salts," J.pharm.Sci., 66: pages 1-19 (1977)). Base addition salts include the metal and amino pharmaceutically acceptable salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium and ammonium salts. Suitable amino base addition salts are prepared from amines which are sufficiently basic to form stable salts, preferably including amines which are frequently used in pharmaceutical chemistry due to low toxicity in pharmaceutical applications. The amines include ammonia, aminophylline, N-methyl-glucosamine, ornithine, choline, N '-dibenzylethylenediamine, chloroprocaine, diethanolamine (diethhalamine), procaine, N' -benzylphenethylamine, diethylamine, piperazine, dimethylamine, trimethylamine, ethylamine, bases prepared from amino acids such as lysine and arginine, or dicyclohexylamine and the like.

"pharmaceutically acceptable" refers to molecular substances and compositions that do not produce adverse, allergic, or other undesirable effects when administered to an animal or human.

The term "pharmaceutically acceptable excipient" as used herein includes any diluent, adjuvant or excipient, such as preservatives, fillers, disintegrants, wetting agents, emulsifiers, dispersants, antibacterial agents, antifungal agents, or agents that delay intestinal and digestive absorption and resorption. The use of such media or carriers is well known to those skilled in the art. Except where the agent is chemically incompatible with the benzopyran or 1, 2-benzothiopyran amide derivative, the use of the agent with the compounds of the present invention in pharmaceutical compositions is envisaged.

In the context of the present invention, the term "treatment" as used herein means preventing or inhibiting the occurrence or development of the condition to which the term applies, or one or more symptoms of said condition.

"therapeutically active amount" means an amount of benzopyran or 1, 2-benzothiopyranamide derivative effective to achieve the desired therapeutic effect of the present invention.

In the present invention, the term "patient" means a human or non-human mammal affected or susceptible to a pathology. Preferably, the patient is a human.

The present invention is directed to novel benzopyran or 1, 2-benzothiopyran amide derivatives, processes for their preparation, and their use as DRD3 receptor ligands for the treatment of neurological or psychiatric diseases, conditions or disorders. The novel compound is a compound of a general formula 1

General formula 1

Wherein:

x represents a heteroatom, O or S;

r1 represents a hydrogen atom or one or more identical or different substituents on the carbocyclic ring, e.g. halogen, Cl, F, Br or C_1-4Alkoxy, OH, C_1-4Alkyl or CF₃A group;

r2 represents a hydrogen atom or C_1-4An alkyl group;

r3 represents a hydrogen atom or one or more identical or different substituents, such as halogen, Cl, F, Br or C_1-4Alkyl radical, C_1-4Alkoxy or thioalkoxy, O (CH)₂)_nO wherein N is 1 or 2, NO₂、NH₂、NHCOCH₃、NHSO₂CH₃、OH、CF₃CN, COOEt or CH₂An OH group, an optionally substituted phenyl or benzyl substituent, or R3 is fused to the aromatic ring to which it is attached to form a ring, e.g. aryl, heteroaryl or C₅、C₆Or C₇Cycloalkyl or heterocyclyl.

The invention also relates to pharmaceutically acceptable water-soluble salts of said compounds, their possible isomers as well as pharmaceutical compositions containing them and their use as medicaments for the treatment of central nervous system disorders.

Benzopyran and 1, 2-benzothiopyran amide compounds of the general formula 1 are novel compounds. The literature, for example patents WO 9929687 and WO 2000075136, mention chromenes or benzopyrans for the treatment of gastric disorders. Compounds of the 2-oxo-2H-benzopyran-3-carboxylic acid structure are reported in j.med.chem.2003, 46, 3883. Patents WO 2004004729 and WO 2003028728 describe butylphenyl piperazine heteroaryl amides as D3 ligands and WO 2006008133 describes nicotine receptor modulators, but none of these documents mention benzopyrans or 1, 2-benzothiopyrans of the present invention.

The fact that oxygen or sulfur heteroatoms are introduced within the ring structure, thus forming benzopyrans or 1, 2-benzothiopyrans, shows the advantages of these compounds as D3 dopamine antagonists or partial agonists.

Preferred compounds are shown below:

2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (4-methoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (2-fluorophenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (4-fluorophenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [ 4-phenylpiperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (2-chlorophenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (4-chlorophenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3-chlorophenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3-trifluoromethylphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (2-trifluoromethylphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (4-trifluoromethylphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (4-nitrophenyl) piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3-nitrophenyl) piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3-aminophenyl) piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3-acetamidophenyl) piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3-methanesulfonylaminophenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (2-nitrophenyl) piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dimethylphenyl) piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3, 4-dimethylphenyl) piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (2, 4-dimethylphenyl) piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (2-methylphenyl) piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3-methoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (2-hydroxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (4-hydroxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3, 4-methylenedioxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3, 4-dimethoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3, 5-dimethoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (2-cyanophenyl) piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (4-cyanophenyl) piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3-ethoxycarbonylphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (4-ethoxycarbonylphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3-hydroxymethylphenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2-fluorophenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3-methoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (4-methoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (4-cyanophenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2-cyanophenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3-ethoxycarbonylphenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3-hydroxymethylphenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3, 4-dimethoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3, 4-methylenedioxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2, 2-dimethyl-2H-benzopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2, 2-dimethyl-2H-benzopyran-3-carboxylic acid {4- [4- (2-cyanophenyl) -piperazin-1-yl ] -butyl } -amide,

2, 2-dimethyl-2H-benzopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl ] -butyl } -amide,

2, 2-dimethyl-2H-benzopyran-3-carboxylic acid {4- [4- (3-hydroxymethylphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-fluorophenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-chlorophenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-chlorophenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-trifluoromethylphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-methoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (4-methoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3, 4-dimethoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-hydroxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (4-hydroxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-cyanophenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (4-cyanophenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-methoxycarbonylphenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxymethylphenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-fluorophenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-chlorophenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-trifluoromethylphenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-methoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3, 4-dimethoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-ethoxycarbonylphenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxymethylphenyl) -piperazin-1-yl ] -butyl } -amide,

2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-cyanophenyl) -piperazin-1-yl ] -butyl } -carboxylic acid amide,

2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxymethylphenyl) -piperazin-1-yl ] -butyl } -amide,

2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl ] -butyl } -carboxylic acid amide,

2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-fluorophenyl) -piperazin-1-yl ] -butyl } -amide,

2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -butyl } -amide,

2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-chlorophenyl) -piperazin-1-yl ] -butyl } -amide,

2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl ] -butyl } -amide,

2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl ] -butyl } -amide,

5-bromo-8-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

5-bromo-8-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dichloro-methoxyphenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (2-fluorophenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (2-cyanophenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (4-cyanophenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (3, 4-dimethoxy-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (3, 4-methylenedioxy-phenyl) -piperazin-1-yl ] -butyl } -amide,

7-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxy-phenyl) -piperazin-1-yl ] -butyl } -amide,

7-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3-cyano-phenyl) -piperazin-1-yl ] -butyl } -amide,

7-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dichloro-phenyl) -piperazin-1-yl ] -butyl } -amide,

7-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3-hydroxy-phenyl) -piperazin-1-yl ] -butyl } -amide,

7-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dihydro-benzo [1, 4] dioxin-6-yl) -piperazin-1-yl ] -butyl } -amide,

7-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3-methoxy-carbonyl-) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2, 4-dichloro-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3-amino-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3-nitro-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3-acetylamino-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-benzo-1, 4-dioxanyl-) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3, 4-benzo-1, 4-dioxan-yl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2-oxo-2, 3-dihydro-1H-benzimidazol-4-yl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3H-benzimidazol-4-yl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2-oxo-2, 3-dihydro-1H-benzoxazol-7-yl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3-methylamino-carbonyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3-methanesulfonylamino-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (2, 4-dichloro-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (3-nitro-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (3-amino-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (3-acetamido-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (3-hydroxymethyl-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (3-methanesulfonylamino-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-fluoro-2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dichloro-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-fluoro-2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxy-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-fluoro-2H-benzopyran-3-carboxylic acid {4- [4- (3-cyano-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-fluoro-2H-benzopyran-3-carboxylic acid {4- [4- (3-acetylamino-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-fluoro-2H-benzopyran-3-carboxylic acid {4- [4- (3-hydroxy-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-fluoro-2H-benzopyran-3-carboxylic acid {4- [4- (3-nitro-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-fluoro-2H-benzopyran-3-carboxylic acid {4- [4- (3-methanesulfonylamino-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-fluoro-2H-benzopyran-3-carboxylic acid {4- [4- (3-amino-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-fluoro-2H-benzopyran-3-carboxylic acid {4- [4- (3-methylcarbamoyl-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-fluoro-2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-benzo-1, 4-dioxanyl) -piperazin-1-yl ] -butyl } -amide,

6-fluoro-2H-benzopyran-3-carboxylic acid {4- [4- (2-oxo-2, 3-dihydro-1H-benzimidazol-4-yl) -piperazin-1-yl ] -butyl } -amide,

6-fluoro-2H-benzopyran-3-carboxylic acid {4- [4- (3H-benzimidazol-4-yl) -piperazin-1-yl ] -butyl } -amide,

6-fluoro-2H-benzopyran-3-carboxylic acid {4- [4- (2-oxo-2, 3-dihydro-1H-benzoxazol-7-yl) -piperazin-1-yl ] -butyl } -amide,

6-fluoro-2H-benzopyran-3-carboxylic acid {4- [4- (3-methoxy-carbonyl) -piperazin-1-yl ] -butyl } -amide,

6-fluoro-5- (4- {4- [ 2H-benzopyran-3-carbonyl) -amino ] -butyl } -piperazin-1-yl) -benzofuran-2-carboxylic acid methyl ester,

2H-benzopyran-3-carboxylic acid {4- [4- (3, 4, 5-trimethoxy-phenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (1H-indol-4-yl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dihydro-benzo [1, 4] dioxin-6-yl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dihydro-benzo [1, 4] dioxin-5-yl) -piperazin-1-yl ] -butyl } -amide,

5- (4- {4- [ 2H-benzopyran-3-carbonyl) -amino ] -butyl } -piperazin-1-yl) -benzofuran-2-carboxylic acid methyl ester,

2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dihydro-1H-indol-4-yl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3-methanesulfonylamino-phenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (1-acetyl-2, 3-dihydro-1H-indol-4-yl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (2-oxo-2, 3-dihydro-benzoxazol-7-yl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (2-oxo-2, 3-dihydro-1H-benzimidazol-4-yl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3H-benzimidazol-4-yl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3-carbamoyl-phenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (3-methylcarbamoyl-phenyl) -piperazin-1-yl ] -butyl } -amide,

2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dihydro-benzofuran-7-yl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2, 3-dimethyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-methyl-phenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (4-chloro-phenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2, 4-dimethoxy-phenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-formyl-phenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-methanesulfonylamino-phenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-nitro-phenyl) -piperazin-1-yl ] -butyl } -amide,

5- (4- {4- [2H-1, 2-benzothiopyran-3-carbonyl) -amino ] -butyl } -piperazin-1-yl) -benzofuran-2-carboxylic acid methyl ester,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-oxo-2, 3-dihydro-1H-benzimidazol-4-yl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3H-benzimidazol-4-yl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-oxo-2, 3-dihydro-benzooxazol-7-yl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-methylcarbamoyl-phenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-carbamoyl-phenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2, 3-dihydro-benzo [1, 4] dioxin-6-yl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-acetylamino-phenyl) -piperazin-1-yl ] -butyl } -amide,

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2, 3-dihydro-benzo [1, 4] dioxin-5-yl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2, 3-dihydro-benzo [1, 4] dioxin-6-yl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-cyano-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-chloro-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxy-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-methoxy-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-fluoro-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2, 4-dimethoxy-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-methoxy-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-methanesulfonylamino-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-fluoro-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-methanesulfonylamino-phenyl) -piperazin-1-yl ] -butyl } -amide,

6-chloro-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-methanesulfonylamino-phenyl) -piperazin-1-yl ] -butyl } -amide.

The invention also relates to a method for preparing said compounds.

General formula (VII)1The compound is represented by the general formula2Is prepared by coupling a conventional peptide with substituted 4- (4-phenylpiperazin-1-yl) -butylamine. The peptide coupling methods described in the literature (Tet.2005, 61, 10827) are very diverse, leading the person skilled in the art to choose the most efficient method to apply and to obtain the purest compounds (SOCl)₂Oxalyl chloride/DMF, DCC, mixed anhydrides, CDI, BOP and its derivatives, TBTU, etc.).

General formula 2

R1 substituted salicylaldehyde is reacted with acrylonitrile in the presence of DABCO or DBU by Bayliss-Hillman reaction in the presence of t-BuOK according to the method of Wise, J.Med.chem.1988, 31, 688, or Bioorg.Med.chem.Lett.1996, 6, 1077, or Shiraishi, J.Med.chem.2000, 43, 2049 to give compounds of the general formula2And (ii) benzopyran carboxylic acid (X ═ O, R2 ═ H) (scheme 1). Alkali hydrolysis to obtain corresponding acid2(X＝O，R2＝H)。

Scheme 1

The general formula is obtained by 3 steps (scheme 2)2Corresponding 1, 2-benzothiopyranic acid (X. S, R2. H), 2-mercaptobenzoic acid in 2-mercaptobenzyl alcohol3Reduction with LAH followed by MnO in thiosalicylaldehyde (thiosalicylic aldehyde) in toluene according to Synthesis 1989, 763₂Oxidized to form dimers4. According to a similar method to benzopyranoic acids (Synthesis, 2001, 2389), the intermediate aldehyde is concentrated with acrylonitrile4To obtain 1, 2-benzothiopyranic acid2(X＝S，R2＝H)。

Similarly, substitution of acrylonitrile with 3, 3-dimethyl-acrylonitrile gives benzopyran or 1, 2-benzothiopyran carboxylic acid substituted in position 2 of general formula 2 (X ═ O or S, R2 ═ Me).

Flow chart 2

(hydrazinolytic phthalimidobutylpiperazine derivatives) according to various well-known methods described in the literature, for example, j.med.chem.2001, 44, 31756Methods of (e), or bioorg, med, chem, lett, 2004, 14, 195, (reduction of nitriles via LAH)7Methods of (e), or j.med.chem.2003, 46, 3883 (reduction of nitriles via Ni-Raney)7Method of (d), or finally j.med.chem.2002, 45, 5727 (with B)₂H₆Dimethyl sulfide reduction of nitriles7Method (d) to give a compound of the formula5Substituted 4- (4-phenylpiperazin-1-yl) -butylamine of (scheme 3). Various methods are selected according to the substituent on the benzene ring attached to piperazine.

Flow chart 3

Preparation:

polysubstituted 4-phenyl-piperazine or 4- (4-phenylpiperazin-1-yl) -butylamine were prepared according to various methods described in the literature. The 4-acetyl, methylsulfonyl or amino-phenylpiperazine derivatives were prepared in several steps. Lopez-Rodriguez (J.Med. chem.2001, 44, 186-197) describes the catalytic hydrogenation of nitro-phenylpiperazine in the presence of palladium to give the aniline intermediate, Orus (Pharmazie, 2002, 57, 515-518) describes the acetylation or mesylation of the aniline intermediate by acetyl or methanesulfonyl chloride in basic medium. Heterocyclic phenyl-piperazines, such as benzimidazolone, benzimidazole-piperazine, benzoxazolone piperazine, and derivatives thereof, such as benzo-1, 4-dioxanyl or dihydro-indole-piperazine, are prepared according to the methods described in patent WO9736893 or EPO 189612. Similarly, Devlin (Synth. Commun.1995, 25, 711-.

General formula (VII)2And benzopyran or 1, 2-benzothiopyranic acid of the general formula5The coupling of primary amines of (a) is performed under standard peptide coupling conditions, preferably the methods described in j.org.chem.1996, 61, 2322, bioorg.med.chem.2005, 13, 519, org.lett.2005, 7(16)3481 and j.org.chem.2006, 71, 3364.

The general formula can also be synthesized according to scheme 41A compound wherein R3 represents a hydroxymethyl group or a phenol group:

flow chart 4

According to J.chem.Soc.Perkin Trans I, 2000, 219, general formula2Is initially amidated with aminobutanol to give the general formula8Then with PPh₃/I₂Iodination to give compounds of the formula9The compound of (1). Conventional condensation with substituted phenylpiperazines (K) according to the same method described in j.med.chem.2003, 46, 3822₂CO₃/CH₃CN) to give the general formula1The compound of (1).

Evaluation of the general formula of the invention by cell expression of human recombinant DRD31As a ligand of DRD3, a modulator of DRD3 activity. The inventors have demonstrated that1The compounds are powerful ligands, inhibition constants (K)_i) From 0.1 to 10nM/1^-1. These same compounds show a clear affinity for the dopamine D2 receptor, which is 100 to 500 times weaker. These same compounds p α₁-adrenergic receptors have an affinity which is 20 to 500 times weaker than that of the D3 receptor. General formula (VII)1The compounds are antagonists (intrinsic activity)<0.10), partial agonist (0.2)<Intrinsic activity<0.6) or full agonists (intrinsic activity)>0.8). Certain of the general formulae1The biological results of the compounds are shown in table 2 at the end of the description.

Given the selective modulation of dopamine signaling, DRD3 produces this signal in the limbic region involved in emotional and cognitive processes, the compounds of the invention are suitable for a variety of therapeutic applications, and do not interfere with the dopaminergic signaling (e.g., the posterior region) of the extrapyramidal, anterior pituitary, or vegetative system. Thus, the compounds of the present invention are free of the side effects of existing compounds that result in blocking the D2 receptor expressed outside the pyramidal tract, in the anterior pituitary, and in plant systems. Thus, the derivatives of the invention may be used for the preparation of a pharmaceutical composition or medicament for the treatment of a neurological or psychiatric disease, condition or disorder, e.g. psychosis, in which DRD3 is involved.

In addition, since one consequence of antidepressant is increased expression of DRD3 in brain regions involved in stimulation, the compounds may mimic antidepressant effects. Therefore, the derivative can be used for preparing a medicinal composition and a medicament for treating depression.

In view of the role of DRD3 in drug dependence, pharmaceutical compositions or medicaments based on the derivatives of the invention can be used for administration to cocaine, heroin, alcohol, tobacco and other addictive substance dependent or addicted patients to cause their withdrawal and/or to promote detoxification.

In a similar manner, the derivatives of the invention, which are typically partial agonists of DRD3, may also be used as a supplemental treatment for the treatment of Parkinson's disease by L-DOPA.

In a similar manner, the derivatives of the invention, as DRD3 antagonists and partial agonists, may also be useful in the treatment of essential tremor.

Thus, the general formula1The compounds, or acid or base salts thereof, may be used to treat neurological or psychiatric disorders, particularly those which may be treated by DRD3 antagonists, agonists or partial agonists.

The invention therefore also relates to a pharmaceutical composition comprising at least one compound according to the invention in combination with customary pharmaceutically acceptable excipients. The invention also relates to a method of treating a neurological or psychiatric condition, disease or disorder by administering to a patient in need thereof a therapeutically effective amount of a compound of formula1A compound is provided. The invention also relates to the general formula1The use of the compounds as medicaments, and the general formula1Use of a compound in the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder.

Examples of conditions, diseases, or neurological or psychiatric disorders of the invention include psychosis (particularly schizophrenia), depression, essential tremor, dependence on or addiction to various drugs or addictive substances such as tobacco or alcohol, cognitive disorders resulting from aging or neurodegenerative diseases such as alzheimer's disease, parkinson's disease, movement disorders, tardive dyskinesia or other movement disorders involving the use of drugs in the treatment of parkinson's disease or schizophrenia.

The derivatives of formula 1 of the present invention may be administered by oral, systemic, parenteral, nasal or rectal routes. In particular, the derivatives may be administered orally in suitable formulations. Formulations suitable for oral administration to a patient include therapeutic systems (e.g., capsules, cartridges, or tablets), each containing a predetermined amount of a compound of formula1A compound; the formulation may also comprise a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

General formula (VII)1The amount of compound in the compositions of the present invention can be adjusted so that it has an amount of active agent that is effective to achieve the desired therapeutic response using the composition for the particular method of administration. Thus, the amount selected will depend on the desired therapeutic effect, the route of administration, the duration of treatment, and other factors.

The total daily dosage range of the useful compounds of the invention, administered in single or divided doses, may be, for example, from 0.001 to 100 mg/kg body weight/day, with a preferred range being from 0.01 to 10 mg/kg/day.

The specific dosage for a given patient depends on a variety of factors including body weight, general health, sex, diet, duration and route of administration, absorption, rate of intestinal absorption and excretion, combination with other drugs, and the severity of the particular condition being treated.

The following non-limiting examples illustrate the preparation of the compounds of the present invention:

example 1: 2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl]-butyl } -amide.

Step 1: preparation of 2-H-benzopyran-3-carbonitrile.

2-H-benzopyran was obtained according to the method described in j.med.chem.1988, 31, 688 in the following manner: heated to 80 ℃ 15 g salicylaldehyde (0.123 mol) was diluted in 50.8 g acrylonitrile (0.958 mol) and then 6.9 g DABCO (0.061 mol) was added to the mixture. After heating for 8 hours, the reaction mixture was returned to room temperature. 100 ml of 1N NaOH were added and then extracted three times with 50 ml of dichloromethane. Washed with water and MgSO₄After drying, filtration and concentration, the oil obtained is chromatographed on silica gel, eluting with dichloromethane, to give 10.5 g of 2H-benzopyran-3-carbonitrile as a white powder in 55% yield.¹H NMR(DMSO)：4.88(s，2H，O-CH₂-), 6.90(d, 1H, aryl H), 7.03(t, 1H, aryl H), 7.31(m, 2H, aryl H), 7.58(s, 1H, H)₄)。

Step 2: and (4) hydrolyzing the nitrile.

Heated to 100 ℃ and 5 g of the 2H-benzopyran-3-carbonitrile obtained in the above step were dissolved in 50 ml of 10% NaOH. After refluxing for 2 hours, the reaction mixture was brought to room temperature and then a large amount of water (100 ml) was added. Acidification was carefully carried out using concentrated HCl (to pH1) at about 0-5 ℃. The acid precipitate in the aqueous phase was recovered by filtration, washed with water and then dried under vacuum. 5.4 g of 2H-benzopyran-3-carboxylic acid were obtained in the form of a cream-colored powder with a yield of 96%.¹H NMR(DMSO)：4.90(s，2H，O-CH₂-), 6.85(d, 1H, aryl H), 6.95(t, 1H, aryl H), 7.25(m, 2H, aryl H), 7.44(s, 1H, H)₄)，12.55(s，1H，CO₂H)。

And step 3: preparation of 2- {4- [4- (2-methoxy-phenyl) -piperazin-1-yl ] -butyl } -isoindole-1, 3-dione.

10 g of 1- (2-methoxyphenyl) -piperazine (0.052 mol), 14.7 g of N- (4-bromobutyl) -phthalimide (0.052 mol) are dissolved continuously in 200 ml of acetonitrile. 7.2 g of K are added₂CO₃(0.052 mol) and KI crystals. The mixture was placed in acetonitrile at reflux for 12 hours. After returning to room temperature, the reaction medium is evaporated off and the product is taken up in 250 ml of water. Three times of extraction with dichloromethane, followed by MgSO₄Dried and concentrated, and the resulting yellow oil is taken up in 150 ml of isopropyl ether and separated; the oil was triturated to give a precipitate, which was isolated by filtration. After 2 washes with isopropyl ether, 17.7 g of 2- {4- [4- (2-methoxy-phenyl) -piperazin-1-yl are isolated]-butyl } -isoindole-1, 3-dione, white powder, yield 87%. This intermediate was used directly in step 4.

¹H NMR(CD₃OD)：1.52(m，2H，CH2)，1.75(m，2H，CH₂) 2.47(t, 2H, CH2-N piperazine), 2.64(m, 4H, piperazine), 3.03(m, 4H, piperazine), 3.71(t, 2H, CH)₂Phthalimide), 3.76(s, 3H, -OCH₃) 6.94(m, 4H, aryl piperazine), 7.82(m, 4H, aryl phthalimide (arylpth)).

And 4, step 4: preparation of 4- [4- (2-methoxy-phenyl) -piperazin-1-yl ] -butylamine.

17.7 g of 2- {4- [4- (2-methoxy-phenyl) -piperazin-1-yl prepared previously in step 3]-butyl } -isoindole-1, 3-dione (0.045 mol) was dissolved in 200 ml of absolute ethanol. 8.8 ml of hydrazine hydrate solution (0.18 ml) was added0 mole), the mixture was refluxed in ethanol for 6 hours. A white precipitate formed. After returning to room temperature, the precipitate is filtered, washed with ethanol and the organic filtrate is evaporated off. The resulting residue was taken up in 150 ml of dichloromethane and then washed twice with equal volumes of water. After drying, the organic phase is then concentrated to give 4- [4- (2-methoxy-phenyl) -piperazin-1-yl]Butylamine, yellow oil, yield 65%. The amine is used directly in step 5 of amide formation.¹H NMR(CD₃OD)：1.52(m，4H，-CH₂-CH₂)，2.42(m，2H，CH₂-NH₂) 2.64(m, 6H, 4H piperazine + CH)₂Piperazine (pip.)), 3.05(m, 4H, piperazine), 3.71(t, 2H, CH)₂Phthalimide), 3.83(s, 3H, -OCH₃) 6.94(m, 4H, aryl piperazine).

And 5: preparation of 2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl ] -butyl } -amide.

0.33 g of 2H-benzopyran-3-carboxylic acid (1.9 mmol) obtained in the preceding step 2 and 0.5 g of 4- [4- (2-methoxy-phenyl) -piperazin-1-yl]Butylamine (1.9 mmol) was dissolved continuously in 10 ml of dichloromethane. 0.5 ml triethylamine (3.8 mmol) and 0.61 g TBTU (1.9 mmol) were added. The mixture was stirred for 4 hours. The organic volume was adjusted to 25 ml and the organic phase was then washed twice with 25 ml of water. After drying and concentration, the organic residue is chromatographed on silica gel, eluting with a suitable dichloromethane-ethyl acetate gradient. After purification, 2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl]-butyl } -amide, thick brown oil, yield 70%.¹H NMR(CDCl₃Base): 1.65-1.68(m, 4H, -CH)₂-CH₂-)，2.46(t，2H，-CH₂-N), 2.66(m, 4H, H-piperazine), 3.09(m, 4H, H-piperazine), 3.37-3.41(m, 2H, -CH)₂-N-CO-)，5.00(s，2H，O-CH₂)，6.50(s，1H，-NH)，6.83-7.26(m9H, aryl H + H₄)。

Preparation of salt: 0.554 g of the base (1.31 mmol) was dissolved in 10 ml of ethyl acetate. 0.83 ml of a 3.3N isopropanol-HCl (2.7 mmol) solution was added. After concentration, the salt was taken up in ether, then filtered and dried. Isolation of 2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl]-butyl } -amide dihydrochloride, cream colored powder, yield 74%. Analysis (salt): c₂₅H₃₁O₃N₃-2HCl mass spectrum 421.54. MS (APCI)⁺，600℃)：MH⁺＝422.2(100％)。MP＝224℃。

Example 2: 2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dichlorophenyl) -piperazin-1-yl]-butyl } -amide.

The compound was prepared according to the procedure of example 1, but using the corresponding reagent. The acid used was 2H-benzopyran-3-carboxylic acid obtained in step 2 of example 1; 4- [4- (2-methoxy-phenyl) -piperazin-1-yl obtained according to steps 3 and 4 as in example 1]-butylamine, the amine used was prepared from 1- (2, 3-dichlorophenyl) -piperazine. Thus, 2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dichlorophenyl) -piperazin-1-yl group is obtained]-butyl } -amide, yellow solid, yield 57%.¹H NMR(CDCl₃)：1.63-1.68(m，4H，-CH₂-CH₂-)，2.48(t，2H，-CH₂-N), 2.65(m, 4H, H-piperazine), 3.06(m, 4H, H-piperazine), 3.37-3.42(m, 2H, -CH)₂-N-CO-)，5.00(s，2H，O-CH₂) 6.46(s, 1H, -NH), 6.84-7.21(m, 7H, aryl H).

Preparation of salt: 0.434 g of the base (0.87 mmol) was dissolved in 10 ml of ethyl acetate. 0.3 ml of a 3.3N isopropanol-HCl (1 mmol) solution was added. After concentration, the salt was taken up in ether, filtered and then dried. Separation into 2H-benzopyran-3-carboxylAcid {4- [4- (2, 3-dichlorophenyl) -piperazin-1-yl]-butyl } -amide hydrochloride, cream colored powder, yield 83%. Analysis (salt): c₂₄H₂₇O₂N₃Cl₂-HCl mass spectrum 496.87. MS (ESI)⁺，250℃)：MH⁺＝460.1(100％)。MP＝201℃。

Example 3: 2H-benzopyran-3-carboxylic acid {4- [4- (2-fluorophenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.63-1.68(m, 4H, -CH)₂-CH₂-)，2.48(t，2H，-CH₂-N), 2.67(m, 4H, H-piperazine), 3.12(m, 4H, H-piperazine), 3.37-3.42(m, 2H, -CH)₂-N-CO-)，5.00(s，2H，O-CH₂) 6.45(s, 1H, -NH), 6.83-7.07(m, 9H, aryl H + H4). Analysis (sel): c₂₄H₂₈O₂FN₃-HCl mass spectrum 445.97. MS (ESI)⁺，250℃)：MH⁺＝410.3(100％)。MP＝231℃。

Example 4: 2H-benzopyran-3-carboxylic acid [4- (4-phenylpiperazin-1-yl) -butyl]-an amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.62-1.66(m, 4H, -CH)₂-CH₂-)，2.45(t，2H，-CH₂-N), 2.60-2.63(m, 4H, H-piperazine), 3.19-3.21(m, 4H, H-piperazine), 3.40(t, 2H, -CH)₂-N-CO-)，5.00(s，2H，O-CH₂) 6.36(s, 1H, -NH), 6.71-7.27(m, 10H, ar)H + H4). Analysis (salt): c₂₄H₂₉O₂N₃-HCl mass spectrum 427.98. MS (ESI)⁺，400℃)：MH⁺＝392.3(100％)。MP＝239℃。

Example 5: 2H-benzopyran-3-carboxylic acid {4- [4- (4-chlorophenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.63-1.67(m, 4H, -CH)₂-CH₂-)，2.44(t，2H，-CH₂-N), 2.59-2.61(m, 4H, H-piperazine), 3.14-3.17(m, 4H, H-piperazine), 3.40(t, 2H, -CH)₂-N-CO-)，4.99(s，2H，O-CH₂) 6.24(s, 1H, -NH), 6.71-7.22(m, 9H, aryl H + H)₄). Analysis (salt): c₂₄H₂₈O₂ClN₃-HCl mass spectrum 462.42. MS (ESI)⁺，400℃)：MH⁺＝426.2(100％)。MP＝236℃。

Example 6: 2H-benzopyran-3-carboxylic acid {4- [4- (3-chlorophenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.66(m, 4H, -CH)₂-CH₂-)，2.44(t，2H，-CH₂-N), 2.56-2.60(m, 4H, H-piperazine), 3.18-3.21(m, 4H, H-piperazine), 3.40(t, 2H, -CH2-N-CO-), 5.00(s, 2H, O-CH)₂) 6.20(s, 1H, -NH), 6.73-7.20(m, 9H, aryl H + H4). Analysis (salt): c₂₄H₂₈O₂ClN₃-HCl mass spectrum 462.42.MS(ESI⁺，400℃)：MH⁺＝426.2(100％)。MP＝216℃。

Example 7: 2H-benzopyran-3-carboxylic acid {4- [4- (2-chlorophenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.65-1.67(m, 4H, -CH)₂-CH₂-)，2.47(t，2H，-CH₂-N), 2.65(m, 4H, H-piperazine), 3.07(m, 4H, H-piperazine), 3.37-3.41(m, 2H, -CH)₂-N-CO-)，5.01(s，2H，O-CH₂) 6.49(s, 1H, -NH), 6.84-7.35(m, 9H, aryl H + H4). Analysis (salt): c₂₄H₂₈O₂ClN₃-HCl mass spectrum 462.42. MS (ESI)⁺，400℃)：MH⁺＝426.2(100％)。MP＝201℃。

Example 8: 2H-benzopyran-3-carboxylic acid {4- [4- (4-fluorophenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.62-1.66(m, 4H, -CH)₂-CH₂-)，2.45(t，2H，-CH₂-N), 2.60-2.62(m, 4H, H-piperazine), 3.10-3.13(m, 4H, H-piperazine), 3.37-3.40(m, 2H, -CH)₂-N-CO-)，5.00(s，2H，O-CH₂) 6.37(s, 1H, -NH), 6.82-7.22(m, 9H, aryl H + H4). Analysis (salt): c₂₄H₂₈O₂FN₃-HCl mass spectrum 445.97. MS (ESI)⁺，400℃)：MH⁺＝410.2(100％)。MP＝243℃。

Example 9: 2H-benzopyran-3-carboxylic acid {4- [4- (2-methylphenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.63-1.67(m, 4H, -CH)₂-CH₂-)，2.29(s，3H，CH₃)，2.46(t，2H，-CH₂-N), 2.61(m, 4H, H-piperazine), 2.92-2.94(m, 4H, H-piperazine), 3.39(t, 2H, -CH)₂-N-CO-)，5.01(s，2H，O-CH₂) 6.49(s, 1H, -NH), 6.84-7.26(m, 9H, aryl H + H4). Analysis (salt): c₂₆H₃₃O₂N₃-HCl. Mass spectrum 442. MS (ESI)⁺，400℃)：MH⁺＝406.3(100％)MP＝187℃。

Example 10: 2H-benzopyran-3-carboxylic acid {4- [4- (2, 4-dimethylphenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.64-1.68(m, 4H, -CH)₂-CH₂-)，2.26(s，6H，CH₃)，2.44(t，2H，-CH₂-N), 2.48(m, 4H, H-piperazine), 2.89(m, 4H, H-piperazine), 3.40(t, 2H, -CH₂-N-CO-)，5.01(s，2H，O-CH₂) 6.48(s, 1H, -NH), 6.84-7.20(m, 8H, aryl H + H4). Analysis (salt): c₂₆H₃₃O₂N₃-HCl mass spectrum 456.03. MS (ESI)⁺，400℃)：MH⁺＝420.3(100％)MP＝207℃。

Example 11: 2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dimethylphenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.63-1.67(m, 4H, -CH)₂-CH₂-)，2.21(s，3H，CH₃)，2.26(s，3H，CH₃)，2.44(t，2H，-CH₂-N), 2.48(m, 4H, H-piperazine), 2.89(m, 4H, H-piperazine), 3.39(t, 2H, -CH)₂-N-CO-)，5.01(s，2H，O-CH₂) 6.48(s, 1H, -NH), 6.84-7.20(m, 8H, aryl H + H4). Analysis (salt): c₂₆H₃₃O₂N₃-HCl, mass spectrum 456.03. MS (ESI)⁺，400℃)：MH⁺＝420.3(100％)。MP＝202℃。

Example 12: 2H-benzopyran-3-carboxylic acid {4- [4- (2-cyanophenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.65-1.66(m, 4H, -CH)₂-CH₂-)，2.50(t，2H，-CH₂-N), 2.68-2.70(m, 4H, H-piperazine), 3.22-3.25(m, 4H, H-piperazine), 3.39(m, 2H, -CH)₂-N-CO-)，5.00(s，2H，O-CH₂) 6.41(s, 1H, -NH), 6.83-7.56(m, 9H, aryl H + H4). Analysis (salt): c₂₅H₂₈O₂N₄-HCl, mass spectrum 452.99. MS (ESI)⁺，400℃)：MH⁺＝417.3(100％)，MP＝194℃。

Practice ofExample 13: 2H-benzopyran-3-carboxylic acid {4- [4- (4-cyanophenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.64-1.67(m, 4H, -CH)₂-CH₂-)，2.44(t，2H，-CH₂-N), 2.57-2.59(m, 4H, H-piperazine), 3.31-3.33(m, 4H, H-piperazine), 3.4(m, 2H, -CH)₂-N-CO-)，4.99(s，2H，O-CH₂) 6.15(s, 1H, -NH), 6.82-7.52(m, 9H, aryl H + H4). Analysis (salt): c₂₅H₂₈O₂N₄-HCl, mass spectrum 452.99. MS (ESI)⁺，400℃)：MH⁺＝417.3(100％)。MP＝212℃。

Example 14: 2H-benzopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl]-butyl } -amide.

This compound was obtained according to the procedure of example 1, but using the corresponding reagent. The acid used was 2H-benzopyran-3-carboxylic acid obtained in step 2 of example 1; 4- [4- (2-methoxy-phenyl) -piperazin-1-yl obtained according to steps 3 and 4 as in example 1]-butylamine, the amine used was prepared from 1- (3 cyanophenyl) -piperazine. To obtain 2H-benzopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl]-butyl } -amide, light brown solid, yield 72%.¹H NMR(CDCl₃Base): 1.64-1.68(m, 2H, -CH)₂-)，2.03(m，2H，-CH2-)，2.47(t，2H，-CH₂-N), 2.61-2.64(m, 4H, H-piperazine), 3.21-3.38(m, 4H, H-piperazine), 3.38-3.42(m, 2H, -CH)₂-N-CO-)，4.99(s，2H，O-CH₂-)，6.32(s，1H，-NH)，6.84-7.32(m, 9H, aryl H + H)₄)。

Preparation of salt: 0.580 g of the base (1.4 mmol) was dissolved in 10 ml of ethyl acetate. 0.44 ml of a 3.3N isopropanol-HCl (1 mmol) solution was added. After concentration, the salt was taken up in ether, then filtered and dried. Isolation of H-benzopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl]-butyl } -amide hydrochloride, cream colored powder, yield 83%. Analysis (salt): c₂₅H₂₈O₂N₄-HCl mass spectrum 452.99. MS (ESI)⁺，250℃)：MH⁺＝417.2(100％)。MP＝229℃。

Example 15: 2H-benzopyran-3-carboxylic acid {4- [4- (4-trifluoromethylphenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.65-1.67(m, 4H, -CH)₂-CH₂-)，2.50(t，2H，-CH₂-N), 2.59-2.61(m, 4H, H-piperazine), 3.29-3.26(m, 4H, H-piperazine), 3.42(t, 2H, -CH)₂-N-CO-)，4.99(s，2H，O-CH₂) 6.28(s, 1H, -NH), 6.82-7.52(m, 9H, aryl H + H4). Analysis (salt): c₂₅H₂₈O₂N₃F₃-HCl mass spectrum 495.98. MS (ESI)⁺，400℃)：MH⁺＝460.3(100％)。MP＝261.9℃。

Example 16: 2H-benzopyran-3-carboxylic acid {4- [4- (3-trifluoromethylphenyl) -piperazin-1-yl]-butyl } -amide.

Obtained according to the method of example 1To the derivatives, but the corresponding reagents are used.¹H NMR(CDCl₃Base): 1.66(m, 4H, -CH)₂-CH₂-)，2.44(t，2H，-CH₂-N), 2.56-2.60(m, 4H, H-piperazine), 3.18-3.21(m, 4H, H-piperazine), 3.41(t, 2H, -CH)₂-N-CO-)，5.00(s，2H，O-CH₂) 6.29(s, 1H, -NH), 6.83-7.33(m, 9H, aryl H + H4). Analysis (salt): c₂₅H₂₈O₂F₃N₃HCI, mass spectrum 495.98. MS (ESI)⁺，400℃)：MH⁺＝460.3(100％)。MP＝234℃。

Example 17: 2H-benzopyran-3-carboxylic acid {4- [4- (2-trifluoromethylphenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.65-1.67(m, 4H, -CH)₂-CH₂-)，2.50(t，2H，-CH₂-N), 2.66(m, 4H, H-piperazine), 2.97(m, 4H, H-piperazine), 3.40(t, 2H, -CH₂-N-CO-)，5.02(s，2H，O-CH₂) 6.61(s, 1H, -NH), 6.83-7.62(m, 9H, aryl H + H4). Analysis (salt): c₂₅H₂₈O₂N₃F₃-HCl mass spectrum 495.98. MS (ESI)⁺，400℃)：MH⁺＝460.3(100％)。MP＝161℃。

Example 18: 2H-benzopyran-3-carboxylic acid {4- [4- (4-nitrophenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.64-1.65(m, 4H, -CH)₂-CH₂-)，2.43-2.45(t，2H，-CH₂-N), 2.58-2.66(m, 4H, H-piperazine), 3.38-3.43(m, 4H, H-piperazine), 3.55(m, 2H, CH)₂-N-CO-)，5.00(s，2H，O-CH₂) 6.17(s, 1H, -NH), 6.71-8.12(m, 9H, aryl H + H)₄). Analysis (salt): c₂₄H₂₈O₄N₄-HCl. Mass spectrum 472.98. MS (ESI)⁺，400℃)：MH⁺＝437.2(100％)。MP＝243℃。

Using the corresponding reagents, the following compounds were obtained in a similar manner:

example 19: 2H-benzopyran-3-carboxylic acid {4- [4- (3-nitrophenyl) -piperazin-1-yl]-butyl } -amide.

And (3) analysis: c₂₄H₂₈N₄O₄，MW＝436.52

Example 20: 2H-benzopyran-3-carboxylic acid {4- [4- (3-nitrophenyl) -piperazin-1-yl]-butyl } -amide.

And (3) analysis: c₂₄H₂₈N₄O₄，MW＝436.52

Example 21: 3- (4- {4- [ (2H-benzopyran-3-carbonyl) -amino group]-butyl } -piperazin-1-yl) -benzoic acid ethyl ester hydrochloride.

¹H NMR(CDCl₃Base): 1.39(t, 3H, -O-CH)₂-CH ₃)，1.65-1.66(m，4H，-CH₂-CH₂-)，2.46(t，2H，-CH₂-N), 2.62-2.64(m, 4H, H-piperazine), 3.24-3.27(m, 4H, H-piperazine), 3.38-3.41(t, 2H, -CH)₂-N-CO-)，4.36(q，2H，-O-CH ₂-CH₃)，5.00(s，2H，O-CH₂) 6.33(s, 1H, -NH), 6.78-7.58(m, 9H, aryl H + H4). Analysis (salt): c₂₇H₃₃O₄N₃-HCl, mass spectrum 500.04, MS (ESI)⁺，400℃)：MH⁺＝464.3(100％)。MP＝229℃。

Example 22: 4- (4- {4- [ (2H-benzopyran-3-carbonyl) -amino group]-butyl } -piperazin-1-yl) -benzoic acid ethyl ester hydrochloride.

¹H NMR(CDCl₃Base): 1.37(t, 3H, -O-CH)₂-CH ₃)，1.67(m，4H，-CH₂-CH₂-)，2.44(t，2H，-CH₂-N), 2.58-2.60(m, 4H, H-piperazine), 3.31-3.34(m, 4H, H-piperazine), 3.37-3.42(t, 2H, -CH)₂-N-CO-)，4.34(q，2H，-O-CH ₂-CH₃)，5.00(s，2H，O-CH₂) 6.27(s, 1H, -NH), 6.64-7.92(m, 9H, aryl H + H4). Analysis (salt): c₂₇H₃₃O₄N₃-HCl, mass spectrum 500.04. MS (ESI)⁺，400℃)：MH+＝464.3(100％)。MP＝237℃。

Example 23: 2H-benzopyran-3-carboxylic acid {4- [4- (3, 5-dimethoxyphenyl) -piperazin-1-yl]-butyl } -amide hydrochloride.

¹H NMR(CDCl₃Base): 1.66(m, 4H, -CH)₂-CH₂-)，2.46-2.48(t，2H，-CH₂-N), 2.62-2.65(m, 4H, H-piperazine), 3.19-3.22(m, 4H, H-piperazine), 3.39(t, 2H, -CH)₂-N-CO-)，3.77(s，6H，-OCH₃)，5.00(s，2H，O-CH₂) 6.37(s, 1H, -NH), 6.88-7.26(m, 9H, aryl H + H4). Analysis (salt): c₂₅H₂₈O₂N₃F₃-HCl, mass spectrum 495.98. MS (ESI)⁺，400℃)：MH⁺＝452.3(100％)。MP＝213℃。

The following compounds were obtained in a similar manner from the corresponding reagents:

example 24: 2H-benzopyran-3-carboxylic acid {4- [4- (3-methoxyphenyl) -piperazin-1-yl]-butyl } -amide hydrochloride.

And (3) analysis: c₂₅H₃₁N₃O₃，MW＝421.54

Example 25: 2H-benzopyran-3-carboxylic acid {4- [4- (4-methoxyphenyl) -piperazin-1-yl]-butyl } -amide hydrochloride.

And (3) analysis: c₂₅H₃₁N₃O₃，MW＝421.54

Example 26: 2H-benzopyran-3-carboxylic acid {4- [4- (3, 4-dimethoxyphenyl) -piperazin-1-yl]-butyl } -amide hydrochloride.

And (3) analysis: c₂₆H₃₃N₃O₄，MW＝451.57

Example 27: 2H-benzopyran-3-carboxylic acid {4- [4- (3, 4-methylenedioxyphenyl) -piperazin-1-yl]-butyl } -amide hydrochloride.

And (3) analysis: c₂₅H₂₉N₃O₄，MW＝435.53

Example 28: 6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dichlorophenyl) -piperazin-1-yl]-butyl } -amide.

Step 1: preparation of 6-chloro-2H-benzopyran-3-carbonitrile.

6-chloro-2H-benzopyran-3-carbonitrile was prepared according to the same procedure as in step 1 of example 1. Heated to 80 ℃ and 10 g of 5-chlorosalicylaldehyde (0.064 mol) diluted in 17 g of acrylonitrile (0.32 mol) were added to the mixture 1.6 g of DABCO (0.015 mol). After heating for 8 hours, the reaction mixture was returned to room temperature. 100 ml of 1N NaOH are added, extracted three times with dichloromethane and MgSO₄The organic phase was dried, filtered and concentrated under vacuum. The resulting solid was chromatographed on silica gel (eluent: dichloromethane) to give 6.1 g of 6-chloro-2H-benzopyran-3-carbonitrile as a yellow powder in 50% yield.¹H NMR(DMSO)：4.92(s，2H，O-CH₂-), 6.94(d, 1H, aryl H), 7.31-7.39(m, 2H, aryl H), 7.55(s, 1H, H4).

Step 2: and (4) hydrolyzing the nitrile.

6-chloro-2H-benzopyran-3-carbonitrile obtained from the previous step was hydrolyzed by the same method as described in example 1, to give 6-chloro-2H-benzopyran-3-carboxylic acid as yellow powder in yield of 94% in step 2, which was directly used in the following step.¹HNMR(DMSO)：4.93(s，2H，O-CH₂-), 6.87(d, 1H, aryl H), 7.28(dd, 1H, aryl H), 7.43(s, 1H, H)₄) 7.45(d, 1H, aryl H), 13.01(m, 1H, COOH).

And step 3: preparation of 6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent. The acid used was 6-chloro-2H-benzopyran-3-carboxylic acid obtained in the previous step 2; 4- [4- (2-methoxy-phenyl) -piperazin-1-yl obtained according to steps 3 and 4 as in example 1]-butylamine, the amine used was prepared from 1- (2, 3-dichlorophenyl) -piperazine. To obtain 6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dichlorophenyl) -piperazine-1-yl]-butyl } -amide, yellow solid, yield 54%.¹H NMR(CDCl₃Base): 1.65-1.69(m, 4H, -CH)₂-CH₂-)，2.47(t，2H，-CH₂-N), 2.65(m, 4H, H-piperazine), 3.06(m, 4H, H-piperazine), 3.33-3.42(m, 2H, -CH)₂-N-CO-)，5.00(s，2H，O-CH₂-), 6.52(s, 1H, -NH), 6.77-7.17(m, 7H, aryl H + H4).

Preparation of salt: 0.464 g of the base (0.94 mmol) was dissolved in 10 ml of ethyl acetate. 0.33 ml of a 3.3N isopropanol-HCl (1 mmol) solution was added. After concentration, the salt was taken up in ether, then filtered and dried. Isolation to 6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dichlorophenyl) -piperazin-1-yl]-butyl } -amide hydrochloride, cream colored powder, yield 83%. Analysis (salt): c₂₄H₂₆O₂N₃Cl₃-HCl mass spectrum 531.31. MS (ESI)⁺，250℃)：MH⁺＝496.1(100％)。MP＝214℃。

Example 29: 6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl]-butyl } -amide

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.63-1.66(m, 4H, -CH)₂-CH₂-)，2.46(t，2H，-CH₂-N), 2.66(m, 4H, H-piperazine), 3.09(m, 4H, H-piperazine), 3.38(m, 2H, CH)₂-N-CO-)，3.75(s，3H，OCH₃)，4.90(s，2H，O-CH₂) 6.62(s, 1H, -NH), 6.77-7.15(m, 8H, aryl H + H)₄). Analysis (salt): c₂₅H₃₀O₃N₃Cl-HCl. Mass spectrum 492.45. MS (ESI)⁺，400℃)：MH⁺＝456.2(100％)。MP＝155℃。

Example 30: 6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (2-fluorophenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.61-1.66(m, 4H, -CH)₂-CH₂-)，2.45(t，2H，-CH₂-N), 2.63-2.65(m, 4H, H-piperazine), 3.09-3.12(m, 4H, H-piperazine), 3.37-3.41(m, 2H, -CH)₂-N-CO-)，5.00(s，2H，O-CH₂) 6.49(s, 1H, -NH), 6.77-7.15(m, 8H, aryl H + H)₄). Analysis (salt): c₂₄H₂₇O₂N₃ClF-HCl. Mass spectrum 480.41. MS (ESI)⁺，250℃)：MH⁺＝444.2(100％)。MP＝214℃。

Example 31: 6-chloro-2H-benzopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.63-1.67(m, 4H, -CH)₂-CH₂-)，2.43(t，2H，-CH₂-N), 2.59-2.61(m, 4H, H-piperazine), 3.20-3.23(m, 4H, H-piperazine), 3.37-3.42(m, 2H, -CH)₂-N-CO-)，4.99(s，2H，O-CH₂) 6.56(s, 1H, -NH), 6.76-7.40(m, 8H, aryl H + H)₄). Analysis (salt): c₂₅H₂₇O₂N₄Cl-HCl. Mass spectrum 487.43. MS (APCI)⁺，500℃)：MH⁺451.2 (100%). MP-120 ℃ thermal decomposition (decom).

Example 32: 2H-1, 2-Benzothiopyran-3-carboxylic acid {4- [4- (2, 3-dichlorophenyl) -piperazin-1-yl]-butyl } -amide.

Step 1: 2, 2' -dithio-diphenylaldehyde.

The method used is described in Synthesis 1989, 763. A1L round-bottom flask under nitrogen was charged with 5 g of 2-mercaptobenzyl alcohol (0.035 mol, 1 eq.) and 350 ml of dry toluene. Then 46 g of MnO were added₂(0.53 mol, 15 eq.) the mixture was reacted at 40 ℃ for 5 hours. After returning to room temperature, the toluene compound is filtered through silica gel and then eluted with 50/50 n-heptane/dichloromethane mixture. 3.5 g of 2, 2' -dithiodiphenylaldehyde are recovered as a white solid (yield 70%).¹H NMR(CDCl₃)：7.37-7.41(m，2H)，7.47-7.51(m，2H)，7.77-7.79(m，2H)，7.86-7.88(m，2H)，10.23(s，2H，CHO)。

Step 2: 2H-1, 2-benzothiopyran-3-carbonitrile.

The method used is described in Synthesis 2001, 2389. In a 250 ml round bottom flask, 3.5 g of 2, 2' -dithiodiphenylaldehyde (0.013 mol, 1 eq) obtained in the previous step 1 were introduced, and 13 ml of acrylonitrile (0.197 mol, 15 eq) and 3 ml of DBU (0.02 mol, 1.5 eq) were added dropwise. The mixture became homogeneous and orange. After standing overnight at room temperature, the mixture was chromatographed directly, eluting with 40/60 n-heptane/dichloromethane. 4.24 g of 2H-1, 2-benzothiopyran-3-carbonitrile were recovered as a yellow solid (yield 90%), which was used directly in the next step.¹H NMR(DMSO-d₆)：3.76(d，2H，J_HH＝0.8Hz，SCH₂) 7.20-7.38(m, 4H, ar), 7.54(s, 1H, CH ═ c).

And step 3: preparation of 1' -acid 2H-1, 2-benzothiopyran-3-carboxylic acid

In a 250 ml round bottom flask, 1.23 g of 2H-1, 2-benzothiopyran-3-carbonitrile (0.007 mol) obtained in the preceding step 2 and 22 ml of 10% NaOH were introduced. The mixture was heated at 100 ℃ and 110 ℃ for 3 hours. Return to room temperature and then extract with dichloromethane. The aqueous phase was then acidified and extracted again with dichloromethane. Na for organic phase₂SO₄Dried, filtered and evaporated. 1 g of 2H-1, 2-benzothiopyran-3-carboxylic acid was recovered as a yellow solid (73% yield), which was used directly in the next step.¹H NMR(CDCl₃)：3.75(s，2H，SCH₂) 7.12-7.33(m, 4H, ar), 7.67(s, 1H, CH ═ s).

And 4, step 4: preparation of 2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -butyl } -amide

2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl ] was obtained according to example 1]-butyl } -amide, but using 2H-1, 2-benzothiopyran-3-carboxylic acid in the previous step 3. 0.7 g of 2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] are recovered]-butyl } -amide (73% yield).¹H NMR(DMSO)：1.45-1.55(m，4H，CH₂)，2.35-2.38(m，2H，CH₂N)，2.51-2.54(m，4H，CH₂Piperazine), 2.97-3.02(m, 4H, CH)₂Piperazine), 3.18-3.23(m, 2H C)H ₂NHCO)，3.67(s，2H，CH₂S), 7.10-7.30(m, 8H, aryl H and CH ═), 8.26(t, 1H, NHCO).

Preparation of salt: 0.68 g of the base (1.47 mmol, 1 eq) was dissolved in 5 ml of dichloromethane. 0.94 ml of a 3.3N HCl in isopropanol (2.1 equiv.) solution was introduced. Evaporated and taken up in ether. The salt formed is filtered and dried. Yield: 90%, MP 21%5℃，¹H NMR(DMSO)：1.50-1.58(m，2H，CH₂)，1.76-1.81(m，2H，CH₂)，3.15-3.27(m，8H，CH₂)，3.42-3.45(m，2H，CH₂)，3.56-3.59(m，2H，CH₂)，3.69(s，2H，CH₂S), 7.17-7.39(m, 8H, aryl H and CH ═), 8.40(t, 1H, NHCO). MS (ESI, 400 ℃): MH⁺＝476.1(100％)；M+2H⁺＝478.1(62％)。

Example 33: 2H-1, 2-Benzothiopyran-3-carboxylic acid {4- [4- (2-fluorophenyl) -piperazin-1-yl]-butyl } -amide

2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl ] was obtained according to example 1]-butyl } -amide, but using the corresponding reagents. 0.62 g of 2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-fluorophenyl) -piperazin-1-yl ] are recovered]-butyl } -amide (73% yield).¹H NMR(DMSO)：1.48-1.51(m，4H，CH₂)，2.33-2.36(m，2H，CH₂N), around 2.5, coated with DMSO (4H, CH)₂Piperazine), 2.99-3.01(m, 4H, CH)₂Piperazine), 3.18-3.23(m, 2H, CH)₂NHCO)，3.67(s，2H，CH₂S), 6.95-7.30(m, 9H, aryl H and CH ═), 8.25(t, 1H, NHCO).

Preparation of salt: 0.62 g of the base (1.4 mmol, 1 eq) was dissolved in 5 ml of dichloromethane. 0.9 ml of a 3.3N HCl in isopropanol (2.2 equiv.) solution was introduced. Evaporated and taken up in ether. The salt formed is filtered and dried. Yield: 90 percent. MP 212 ℃.¹H NMR(DMSO)：1.51-1.58(m，2H，CH₂)，1.76-1.83(m，2H，CH₂)，3.13-3.26(m，8H，CH₂)；，3.47-3.59(m，4H，CH₂)，3.70(s，2H，CH₂S), 7.04-7.34(m, 9H, aryl H and CH ═), 8.44(t, 1H, NHCO), 11.06(S, 1H, HCl). MS (ESI, 400 ℃): MH⁺＝426(100％)。

Example 34: 2H-1, 2-Benzothiopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl]-butyl } -amide

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.67-1.75(m, 4H, -CH)₂-CH₂-)，2.45(t，2H，-CH₂-N), 2.65(m, 4H, H-piperazine), 3.06(m, 4H, H-piperazine), 3.40(m, 2H, -CH₂-N-CO-)，3.70(s，2H，S-CH₂)，3.85(s，3H，O-CH₃) 6.68(s, 1H, -NH), 6.79-7.28(m, 9H, aryl H + H)₄). Analysis (salt): c₂₅H₃₁O₂N₃The S-HCl mass spectrum is 474.07. MS (APCI)⁺，600℃)：MH⁺＝438.2(100％)。MP＝208℃。

Example 35: 2H-1, 2-Benzothiopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl]-butyl } -amide

2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl ] was obtained according to example 1]-butyl } -amide, but using the corresponding reagents. 0.61 g of 2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl ] are recovered]-butyl } -amide (yield 70%).¹HNMR(DMSO)：1.48-1.55(m，4H，CH₂)，2.32-2.35(m，2H，CH₂N)，2.47-2.50(m，4H，CH₂Piperazine), 3.16-3.22(m, 6H, 2 CH)₂And CH₂NHCO)，3.67(s，2H，CH₂S), 7.13-7.39(m, 9H, aryl H), 8.26(t, 1H, NHCO).

Preparation of salt: 0.61 g of the base (1.4 mmol, 1 eq) was dissolved in 5 ml of dichloromethane. 0.9 ml of a 3.3N HCl in isopropanol (2.1 equiv.) solution was introduced. Evaporated and taken up in ether. The salt formed is filtered and dried. Yield: 70 percent. MP 209 ℃.¹H NMR(DMSO)：1.50-1.60(m，2H，CH₂)，1.73-1.77(m，2H，CH₂)，3.10-3.19(m，6H，CH₂)，3.21-3.26(m，2H，CH₂)，3.54-3.58(m，2H，CH₂)，3.69(s，2H，CH₂S)，3.95-3.98(m，2H，CH₂) 7.17-7.45(m, 9H, aryl H and CH ═), 8.36(t, 1H, NHCO), 10.22(s, 1H, HCl). MS (ESI, 400 ℃): MH + ═ 433.2 (100%).

In a similar manner, the following compounds were obtained from the corresponding reagents:

example 36: 2H-1, 2-Benzothiopyran-3-carboxylic acid {4- [4- (4-cyanophenyl) -piperazin-1-yl]-butyl } -amide.

And (3) analysis: c₂₅H₂₈N₄OS。MW＝432.59

Example 37: 2H-1, 2-Benzothiopyran-3-carboxylic acid {4- [4- (2-cyanophenyl) -piperazin-1-yl]-butyl } -amide.

And (3) analysis: c₂₅H₂₈N₄OS。MW＝432.59

Example 38: 2H-1, 2-Benzothiopyran-3-carboxylic acid {4- [4- (3-methoxyphenyl) -piperazin-1-yl]-butyl } amide.

And (3) analysis: c₂₅H₃₁N₃O₂S。MW＝437.61

Example 39: 2H-1, 2-Benzothiopyran-3-carboxylic acid {4- [4- (4-methoxyphenyl) -piperazin-1-yl]-butyl } -amide.

And (3) analysis: c₂₅H₃₁N₃O₂S。MW＝437.61

Example 40: 2H-1, 2-Benzothiopyran-3-carboxylic acid {4- [4- (3, 4-dimethoxyphenyl) -piperazin-1-yl]-butyl } -amide.

And (3) analysis: c₂₆H₃₃N₃O₃S。MW＝467.64。

EXAMPLE 41: 2H-1, 2-Benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl]-butyl } -amide.

Step 1: preparation of 2H-1, 2-benzothiopyran-3-carboxylic acid (4-hydroxybutyl) -amide.

In a 250 ml round bottom flask under nitrogen, 2 g of 2H-1, 2-benzothiopyran-3-carboxylic acid (0.010 mol, 1 eq.), 150 ml of dry dichloromethane and 15 drops of dry dimethylamide are introduced. The mixture was cooled to 0 ℃ and 1.07 ml of oxalyl chloride (12 mmol, 1.2 eq) was added dropwise. The mixture was then left at room temperature for 2 hours, evaporated, 150 ml of dry dichloromethane was added back to the solution and 30 ml of a dry dichloromethane solution containing 1.02 ml of 4-amino-1-butanol (11 mmol, 1.1 eq) and 4.2 ml of triethylamine (30 mmol, 3 eq) was added. After stirring overnight at room temperature, the mixture was concentrated, purified on silica gel and eluted with 90/10 dichloromethane/acetone mixture. 2.1 g of 2H-1, 2-benzothiopyran-3-carboxylic acid (4-hydroxy-butyl) -amide are recovered as a yellow solid (yield: 80%) which is used directly in the next step.¹H NMR(DMSO-d₆)：1.41-1.55(m，4H，CH₂)，3.16-3.19(m，2H，CH₂N)，3.39-3.44(m，2H，CH₂O)，3.67(s，2H，CH₂S), 4.41(t, 1H, OH), 7.16-7.30(m, 5H, aryl and CH ═ S), 8.24(t, 1H, NHCO).

Step 2: preparation of 2H-1, 2-benzothiopyran-3-carboxylic acid (4-iodo-butyl) -amide.

In a 100 ml round bottom flask under nitrogen, 1.65 g of triphenylphosphine (6.3 mmol, 1 eq), 0.43 g of imidazole (6.3 mmol, 1 eq) and 25 ml of dry dichloromethane were introduced. 1.76 g iodine (6.9 mmol, 1.1 eq) was added. A precipitate formed and the mixture turned orange. After 5 minutes, a solution of 1.66 g of 2H-1, 2-benzothiopyran-3-carboxylic acid (4-hydroxy-butyl) -amide from previous step 1 (6.3 mmol, 1 eq) in 25 ml of dichloromethane was added. After 4 hours at room temperature, the reaction mixture was evaporated and purified by chromatography on silica eluting with 70/30 n-heptane/ethyl acetate. 1.7 g of 2H-1, 2-benzothiopyran-3-carboxylic acid (4-iodo-butyl) -amide are obtained as an orange solid (yield: 72%).¹H NMR(DMSO-d₆)：1.50-1.61(m，2H，CH₂)，1.74-1.84(m，2H，CH₂)，3.18-3.23(m，2H，CH₂)，3.26-3.33(m，2H，CH₂)，3.67(s，2H，CH₂S), 7.15-7.30(m, 5H, aryl H and CH ═), 8.29(t, 1H, NHCO).

And step 3: preparation of 2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl ] -butyl } -amide

In a 250 ml round bottom flask, 0.35 g of 3-hydroxyphenylpiperazine (2 mmol, 1.1 eq), 0.33 g of K are introduced₂CO₃(24 mmol, 1.3 eq.) and 20 ml acetonitrile. A solution of 0.7 g of 2H-1, 2-benzothiopyran-3-carboxylic acid (4-iodo-butyl) -amide from the previous step 2 (1.9 mmol, 1 eq) in 10 ml of acetonitrile was added. The mixture was refluxed for 6 hours. After returning to room temperature, the mixture is evaporated, taken up in dichloromethane and washed with water. Then the organic phase is treated with Na₂SO₄Dried, filtered, evaporated and purified by chromatography on silica gel eluting with 95/5 dichloromethane/methanol. 0.4 g of 2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl ] are recovered]Butyl } -amide, white solid (yield: 50%).¹H NMR(DMSO)：1.50(m，4H，CH₂)，2.30-2.34(m，2H，CH₂N)，2.46-2.50(m，4H，CH₂Piperazine), 3.04-3.06(m, 4H, CH)₂Piperazine), 3.18-3.23(m, 2H, CH)₂NHCO)，3.67(s，2H，CH₂S), 6.19(d, 1H, arene), 6.28(S, 1H, arene), 6.35(d, 1H, arene), 6.96(t, 1H, arene), 7.15-7.30(m, 5H, arene, and CH ═ 8.25(t, 1H, NHCO), 9.08(S, 1H, OH).

Preparation of salt: 0.4 g of the base (0.94 mmol, 1 eq) was dissolved in 5 ml of methanol. 0.4 ml of a 5N HCl in isopropanol (2 equiv.) solution was introduced. Evaporated and taken up in ether. The salt formed is filtered and dried. Yield: 57 percent. MP 182-184℃。¹H NMR(DMSO)：1.51-1.58(m，2H，CH₂)，1.72-1.80(m，2H，CH₂)，2.99-3.17(m，6H，CH₂)，3.21-3.26(m，2H，CH₂)，3.52-3.54(m，2H，CH₂)，3.69(s，2H，CH₂S)，3.71-3.74(m，2H，CH₂) 6.30(dd, 1H, ar H), 6.36(s, 1H, ar H), 6.42(d, 1H, ar H), 7.03(t, 1H, ar H), 7.16-7.32(m, 5H, ar H and CH ═), 8.39(t, 1H, NHCO), 9.27 (s, 1H, OH), 10.47(s, 1H, HCl). MS (APCI +, 150 ℃): MH⁺＝424.2(100％)。

In a similar trans form, the following compounds were obtained from the corresponding reagents:

example 42: 2H-1, 2-Benzothiopyran-3-carboxylic acid {4- [4- (2-hydroxyphenyl) -piperazin-1-yl]-butyl } -amide.

And (3) analysis: c₂₄H₂₉N₃O₂S，MW＝423.58。

Example 43: 2H-1, 2-Benzothiopyran-3-carboxylic acid {4- [4- (4-hydroxyphenyl) -piperazin-1-yl]-butyl } -amide.

And (3) analysis: c₂₄H₂₉N₃O₂S，MW＝423.58。

Example 44: 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl]-butyl } -amide

Step 1: preparation of 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carbonitrile.

The method used was the method described in Synthesis 2001, 2389. In a 500 ml round bottom flask, 7 g of 2, 2' -dithiobenzaldehyde (25 mmol, 1 eq) obtained previously in step 1 of example 28 were introduced, 40 ml of dimethylacrylonitrile (0.38 mol, 15 eq) were added and 6 ml of DBU (38 mmol, 1.5 eq) were added dropwise. The mixture was heated at 100 ℃ for 5 hours and then returned to room temperature for direct chromatography, eluting with 50/50 n-heptane/dichloromethane. 5 g of 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carbonitrile were recovered (yield: 50%).¹H NMR(DMSO)：1.50(s，6H，2CH₃) 7.23-7.27(m, 1H, aryl), 7.33-7.36(m, 2H, aryl), 7.47(d, 1H, aryl), 7.57(s, 1H, CH ═ a).

Step 2: preparation of 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid

In a 100 ml round-bottom flask, 0.5 g of 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carbonitrile obtained in the preceding step 1 (2.5 mmol, 1 eq.) was introduced, and 10 ml of a saturated aqueous solution of KOH and methanol were added to completely dissolve the mixture. Heating at 100 deg.C for 8 hr. After returning to room temperature, ice was added and acidified with concentrated HCl. Extraction was performed with ethyl acetate. Na for organic phase₂SO₄Dried, filtered, evaporated and purified by silica gel eluting with 95/5 dichloromethane/methanol. 0.2 g of 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid was recovered (yield: 59%).¹H NMR(DMSO)：1.56(s，6H，2CH₃) 7.16-7.20(m, 1H, aryl H), 7.25-7.28(m, 2H, aryl H), 7.33(s,1H, CH), 7.43(d, 1H, ar), 12.75(s, 1H, COOH).

And step 3: preparation of 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl ] -butyl } -amide.

2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl ] was obtained according to example 1]Process for the preparation of (E) -butyl } -amide, but using the acid prepared in the previous step 2 and 4- [4- (3-cyano-phenyl) -piperazin-1-yl prepared according to the same procedure as step 4 in example 1]Butylamine, but the corresponding reagents are used. 0.7 g of 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl ] are recovered]Butyl } -amide (yield: 58%).¹H NMR (DMSO): 1.50 (Width s, 10H, 2 CH)₂And 2CH₃)，2.32-2.35(m，2H，CH₂) 2.69 (width s, 4H, CH)₂)，3.15-3.21(m，6H，CH₂) 6.71(s, 1H, aryl), 7.13-7.39(m, 8H, aryl and CH ═), 8.35(t, 1H, NHCO).

Preparation of salt: 0.7 g of the base (1.52 mmol, 1 eq) was dissolved in 5 ml of ethyl acetate. 0.7 ml of a 5N HCl in isopropanol (2.2 equiv.) solution was introduced. Evaporated and taken up in diethyl ether and ethyl acetate. The salt formed is filtered and dried. Yield: 62 percent. MP 155 ℃.¹H NMR (DMSO): 1.51 (Width s, 8H, CH)₂And 2CH₃)，1.75-1.79(m，2H，CH₂)，3.05-3.28(m，8H，CH₂)，3.54(d，2H，CH₂)，3.96(d，2H，CH₂) 6.79(s, 1H, aryl H), 7.15-7.26(m, 4H, aryl H), 7.34-7.46(m, 4H, aryl H), 8.39(t, 1H, NHCO), 10.96(s, 1H, HCl). MS (ESI, 250 ℃): MH⁺＝461.2(100％)。

Example 45: 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl]-butyl } -amide.

Step 1: preparation of 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid (4-hydroxybutyl) -amide.

This compound was prepared according to the procedure for 2H-1, 2-benzothiopyran-3-carboxylic acid (4-hydroxybutyl) -amide obtained in step 1 of example 41. 0.4 g of 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid (4-hydroxy-butyl) -amide was recovered (yield: 23%).¹H NMR(DMSO)：1.43-1.48(m，4H，CH₂)，1.49(s，6H，CH₃)，3.10-3.15(m，2H，CH₂)，3.39-3.43(m，2H，CH₂) 4.40(t, 1H, OH), 6.69(s, 1H, CH ═ 7.15-7.26(m, 3H, ar H), 7.35(d, 1H, ar H), 8.30(t, 1 NHCO).

Step 2: preparation of 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid (4-iodobutyl) -amide.

This compound was prepared according to the procedure for 2H-1, 2-benzothiopyran-3-carboxylic acid (4-iodobutyl) -amide, obtained in step 2 of example 41. 0.44 g of 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid (4-iodobutyl) -amide was recovered (yield: 80%).¹H NMR(DMSO)：1.50(s，6H，CH₃)，1.52-1.59(m，2H，CH₂)，1.77-1.84(m，2H，CH₂)，3.13-3.18(m，2H，CH₂)，3.30-3.33(m，2H，CH₂) 6.71(s, 1H, CH ═), 7.15-7.26(m, 3H, aryl), 7.35(d, 1H, aryl), 8.36(t, 1H, NHCO).

And step 3: preparation of 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl ] -butyl } -amide hydrochloride.

2H-1, 2-Benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl ] obtained according to step 3 of example 41]-butyl } -amide, but using the iodine derivative of the previous step 2 and N-3-hydroxyphenylpiperazine. 0.4 g of 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl ] are recovered]-butyl } -amide (yield: 77%).¹H NMR (DMSO): 1.50 (width s, 10H, CH)₂And CH₃)，2.32-2.34(m，2H，CH₂N)，2.44-2.51(m，4H，CH₂Piperazine), 3.04-3.06(m, 4H, CH)₂Piperazine), 3.14-3.17(m, 2H, CH)₂NHCO), 6.19(dd, 1H, arene), 6.28(s, 1H, arene), 6.35(dd, 1H, arene), 6.71(s, 1H, CH ═ o), 6.96(t, 1H, arene), 7.16-7.26(m, 3H, arene), 7.35(dd, 1H, arene), 8.34(t, 1H, NHCO), 9.09(s, 1H, OH).

Preparation of salt: 0.4 g of the base (0.88 mmol, 1 eq) was dissolved in 5 ml of methanol. 0.35 ml of a 5N HCl in isopropanol (2 equiv.) solution was introduced. Evaporated and taken up in acetone. The salt formed is filtered and dried. Yield: 67%. MP ═ 90 ℃ or higher is viscous and actually melts at about 145 ℃. MS (ESI, 400 ℃): MH⁺＝452.2(100％)。

Example 46: 2H-benzopyran-3-carboxylic acid {4- [4- (3-hydroxymethylphenyl) -piperazin-1-yl]-preparation of butyl } -amide.

Step 1: 2H-benzopyran-3-carboxylic acid (4-hydroxy-butyl) amide.

This compound was prepared according to the procedure for 2H-1, 2-benzothiopyran-3-carboxylic acid (4-hydroxy-butyl) -amide obtained in step 1 of example 41, but using the 2H-benzopyran-3-carboxylic acid prepared in step 2 of example 1. 1.5 g of 2H-benzopyran-3-carboxylic acid (4-hydroxy-butyl) -amide were recovered (yield: 56%).¹H NMR(DMSO-d₆)：1.40-1.54(m，4H，CH₂)，3.14-3.19(m，2H，CH₂N)，3.38-3.43(m，2H，CH ₂OH)，4.40(t，1H，OH)，4.89(d，2H，J_HH＝1.2Hz，CH₂O), 6.83(d, 1H, aryl), 6.93-6.97(m, 1H, aryl), 7.19-7.24(m, 3H, 2 aryl and CH ═), 8.20(t, 1H, NHCO).

Step 2: 2H-benzopyran-3-carboxylic acid (4-iodo-butyl) -amide.

This compound was prepared according to the procedure for 2H-1, 2-benzothiopyran-3-carboxylic acid (4-iodo-butyl) -amide, obtained in step 2 of example 41. 0.7 g of 2H-benzopyran-3-carboxylic acid (4-iodo-butyl) -amide are obtained as an orange solid (yield: 50%).¹H NMR(DMSO-d₆)：1.52-1.59(m，2H，CH2)，1.75-1.82(m，2H，CH2)，3.16-3.21(m，2H，CH₂)，3.29-3.32(m，2H，CH₂)，4.89(s，2H，CH₂O), 6.84(d, 1H, aryl), 6.95(t, 1H, aryl), 7.20-7.24(m, 3H, 2 aryl and CH ═ s), 8.24(t, 1H, NHCO).

And step 3: preparation of (3-piperazin-1-yl-phenyl) -methanol.

From 4- (3-hydroxymethyl-)Preparation of phenyl) -piperazine-1-carboxylic acid tert-butyl ester from piperazine by reacting it with NaBH₄Reduction to the corresponding aldehyde was similar to bioorg.med.chem.lett.2003, 13, 3793. In a 250 ml round bottom flask, 1 g of 4- (3-hydroxymethyl-phenyl) -piperazine-1-carboxylic acid tert-butyl ester (4 mmol, 1 eq) was introduced, followed by the addition of 25 ml of ethanol and 25 ml of 30% HCl. Stirred at room temperature for 8 hours. The ethanol was then concentrated and the mixture was made alkaline. Extraction was carried out with dichloromethane. Na for organic phase₂SO₄Dry, filter, evaporate and purify on silica gel using a dichloromethane/ethyl acetate gradient. 0.6 g (3-piperazin-1-yl-phenyl) -methanol was recovered (yield: 79%).¹H NMR(DMSO)：2.80-2.83(m，4H，CH₂Piperazine), 3.00-3.02(m, 4H, CH2 piperazine), 4.42(d, 2H, C)H ₂OH), 5.06(t, 1H, OH), 6.71(d, 1H, ar H), 6.76(dd, 1H, ar H), 6.86(s, 1H, ar H), 7.13(t, 1H, ar H).

And 4, step 4: 2H-benzopyran-3-carboxylic acid {4- [4- (3-hydroxymethylphenyl) -piperazin-1-yl ] -butyl } -amide.

2H-1, 2-Benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl ] obtained according to step 3 of example 41]-butyl } -amide, but using the reagents prepared in the previous step 2 (iodine derivative) and the previous step 3. 0.2 g of 2H-benzopyran-3-carboxylic acid {4- [4- (3-hydroxymethylphenyl) -piperazin-1-yl ] -are recovered]Butyl } -amide (yield: 24%).¹H NMR(DMSO)：1.48-1.51(m，4H，CH₂)，2.32-2.34(m，2H，CH₂N), around 2.5, coated with DMSO (4H, CH)₂Piperazine), 3.09-3.12(m, 4H, CH)₂Piperazine), 3.17-3.20(m, 2H, C)H ₂NHCO)，4.42(d，2H，CH ₂OH)，4.89(d，2H，J_HH＝1.2Hz，CH₂O), 5.06(t, 1H, OH), 6.72(d, 1H, aryl H), 6.78(dd, 1H, aryl H), 6.84(d, 1H, aryl H), 6.87(s, 1H, aryl H),6.94(td, 1H, ar H), 7.14(t, 1H, ar H), 7.19-7.23(m, 3H, ar H and CH ═ s), 8.21(t, 1H, NHCO).

Preparation of salt: 0.2 g of the base (0.5 mmol, 1 eq) was dissolved in 5 ml of dichloromethane. 0.2 ml of a 5N HCl in isopropanol (2.2 equiv.) solution was introduced. Evaporated and taken up in ether. The salt formed is filtered and dried. Yield: and 55 percent. MP 194 ℃.¹H NMR(DMSO)：1.51-1.57(m，2H，CH₂)，1.68-1.74(m，2H，CH₂)，2.98-3.25(m，8H，CH₂)，3.50-3.52(m，2H，CH₂)，3.79-3.82(m，2H，CH₂)，4.45(s，2H，CH2OH)，4.91(d，2H，J_HH＝1.2Hz，CH₂O), 6.82-6.88(m, 3H, aryl H), 6.95-6.97(m, 2H, aryl H), 7.19-7.26(m, 4H, aryl H and CH ═ O), 8.31(t, 1H, NHCO), 9.85(s, 1H, HCl). MS (APCI +, 400 ℃): MH⁺＝422.2(100％)。

Similarly, but using 2H-1, 2-benzothiopyran-3-carboxylic acid (4-iodo-butyl) -amide obtained in step 2 of example 41, the following compound of the example was obtained:

example 47: 2H-1, 2-Benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxymethylphenyl) -piperazin-1-yl]-preparation of butyl } -amide.

And (3) analysis: c₂₅H₃₁N₃O₂S，MW＝437.61

Example 48: 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-cyanophenyl) -piperazin-1-yl]-butyl } -amide.

According toExample 1 2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl]Process for the preparation of (E) -butyl } -amide, using the acid prepared in step 2 of example 44 and 4- [4- (3-cyano-phenyl) -piperazin-1-yl prepared according to the same procedure as step 4 of example 1]Butylamine, but using the corresponding reagent. To obtain 2, 2-dimethyl-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2-cyanophenyl) -piperazin-1-yl]-butyl } -amide. And (3) analysis: c₂₇H₃₂N₄OS，MW：460.65。

Example 49: 5-bromo-8-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2-fluorophenyl) -piperazin-1-yl]-butyl } -amide hydrochloride.

Step 1: preparation of 5-bromo-8-methoxy-2H-benzopyran-3-carbonitrile.

5-bromo-8-methoxy-2H-benzopyran-3-carbonitrile was prepared from 6-bromo-3-methoxysalicylaldehyde according to the same method as in step 1 of example 1. The yield was 40%.¹H NMR(DMSO)：3.78(s，3H，-OCH₃)，4.87(s，2H，O-CH₂-), 7.05(d, 1H, aryl H), 7.25(d, 1H, aryl H), 7.54(s, 1H, H)₄)。C₁₁H₉BrO₄。MW：285.10。

Step 2: preparation of 5-bromo-8-methoxy-2H-benzopyran-3-carboxylic acid

5-bromo-8-methoxy-2H was prepared according to the same method as in step 2 of example 1-benzopyran-3-carboxylic acid. The yield was 96%.¹H NMR(DMSO)：3.77(s，3H，-OCH₃)，4.89(s，2H，O-CH₂-), 6.99(d, 1H, aryl H), 7.19(d, 1H, aryl H), 7.42(s, 1H, H)₄) 13.5(s, ech. -COOH). F: 121 deg.C (thermolysis).

And step 3: preparation of 5-bromo-8-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2-fluorophenyl) -piperazin-1-yl ] -butyl } -amide.

The compound was prepared according to the procedure of example 1, but using the corresponding reagent. The acid used was 5-bromo-8-methoxy-2H-benzopyran-3-carboxylic acid obtained in the previous step 2, and the amine used was 4- [4- (2-methoxy-phenyl) -piperazin-1-yl from 1- (2-fluorophenyl) -piperazine according to steps 3 and 4 in example 1]-butylamine by the same method. To obtain 5-bromo-8-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2-fluorophenyl) -piperazin-1-yl]-butyl } -amide.¹H NMR(CDCl₃Base): 1.65-1.71(m, 4H, -CH)₂-CH₂-)，2.45-2.48(t，2H，-CH₂-N), 2.63-2.65(m, 4H, H-piperazine), 3.08-3.10(m, 4H, H-piperazine), 3.38-3.51(m, 2H, -CH)₂-N-CO-)，3.86(s，3H-OCH₃)，5.02(s，2H，O-CH₂) 6.54(s, 1H, -NH), 6.69-7.26(m, 7H, aryl H + H)₄). Analysis (salt): c₂₅H₂₉O₃N₃BrF-2 HCl. Mass spectrum 605.79. MS (ESI)⁺，400℃)：MH⁺＝520(100％)。MP＝157℃。

Example 50: 5-bromo-8-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl]-butyl } -amide.

This derivative was obtained according to the procedure of example 49, and similar to example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.64-1.71(m, 4H, -CH)₂-CH₂-)，2.47(t，2H，-CH₂-N), 2.61-2.66(m, 4H, H-piperazine), 3.07(m, 4H, H-piperazine), 3.38-3.43(m, 2H, -CH)₂-N-CO-)，3.85-3.86(2s，6H，-OCH₃and-OCH₃)，5.02(s，2H，O-CH₂) 6.73(s, 1H, -NH), 6.80-7.26(m, 7H, aryl H + H)₄). Analysis (salt): c₂₆H₃₂O₄N₃Mass spectrum of Br-HCl 566.93. MS (APCI)⁺，600℃)：MH⁺＝532.2(100％)。MP＝176℃。

Example 51: 5-bromo-8-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dichlorophenyl) -piperazin-1-yl]-butyl } -amide.

This compound was prepared in a similar manner to example 49 above and similar to example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.63-1.73(m, 4H, -CH)₂-CH₂-)，2.48(t，2H，-CH₂-N), 2.61-2.65(m, 4H, H-piperazine), 3.04(m, 4H, H-piperazine), 3.38-3.43(m, 2H, -CH)₂-N-CO-)，3.86(s，3H-OCH₃)，5.02(s，2H，O-CH₂) 6.67(s, 1H, -NH), 6.82-7.15(m, 6H, aryl H + H)₄). Analysis (salt): c₂₅H₂₈O₃N₃BrCl₂-HCl. Mass spectrum 605.79. MS (ESI)⁺，400℃)：MH⁺＝570(100％)。MP＝205℃。

Example 52: 5-bromo-8-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl]-butyl } -amide.

This compound was prepared in a similar manner to example 49 above and similar to example 1, but using the corresponding reagent.¹H NMR (DMSO base): 1.64-1.66(m, 4H, -CH)₂-CH₂-)，2.33-2.34(t，2H，-CH₂-N), 2.50-2.51(m, 4H, H-piperazine), 3.20-3.21(m, 4H, H-piperazine), 3.32(m, 2H, -CH)₂-N-CO-)，3.77(s，3H-OCH₃) 4.87(s, 2H, O-CH2), 6.31(s, 1H, -NH), 6.94-7.35(m, 7H, aryl H + H)₄) 8.43(s, 1H, -NH). Analysis (salt): c₂₆H₂₉O₃N₄Mass spectrum of Br-HCl 561.91. MS (ESI)⁺，400℃)：MH⁺＝525.1(100％)。MP＝155℃。

Example 53: 2H-benzopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl]-butyl } -amide.

2H-1, 2-Benzothiopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl ] obtained according to step 4 of example 46]The process of-butyl } -amide prepares this compound but uses the corresponding reagents, i.e., the iodo derivative and N- (3-hydroxyphenyl) piperazine, prepared in step 2 of example 46. 0.25 g of 2H-benzopyran-3-carboxylic acid {4- [4- (3-hydroxyphenyl) -piperazin-1-yl ] are recovered]-butyl } -amide (yield 25%).¹H NMR(DMSO)：1.48-1.50(m，4H，CH₂)，2.30-2.33(m，2H，CH₂N)，2.45-2.48(m 4H，CH₂Piperazine), 3.04-3.06(m, 4H, CH)₂Piperazine), 3.16-3.19(m, 2H, CH)₂NHCO)，4.89(d，2H，J_HH＝0.8Hz，CH₂O), 6.19(d, 1H, arene), 6.28(s, 1H, arene), 6.35(d, 1H, arene), 6.83(d, 1H arene), 6.93-6.98(m, 2H, arene), 7.20-7.23(m, 3H, arene and CH ═ s), 8.21(t, 1H, N)HCO)，9.08(s，1H，OH)。

Preparation of salt: 0.25 g of the base (0.61 mol, 1 eq) was dissolved in 5 ml of ethyl acetate. 0.3 ml of a 5N HCl in isopropanol (2.2 equiv.) solution was introduced. Evaporated and taken up in pentane. The salt formed is filtered and dried. Yield: 68 percent. MP 199 ℃.¹H NMR(DMSO)：1.49-1.56(m，2H，CH₂)，1.70-1.76(m，2H，CH₂)，3.00-3.16(m，6H，CH₂)，3.19-3.24(m，2H，CH₂)，3.51-3.54(m，2H，CH₂)，3.71-3.74(m，2H，CH₂)，4.91(d，2H，JHH＝0.8Hz，CH₂O), 6.30(dd, 1H, arene), 6.36 (width s, 1H, arene), 6.43(dd, 1H, arene), 6.84(d, 1H, arene), 6.95(td, 1H, arene), 7.03(t, 1H, arene), 7.21-7.25(m, 2H, arene), 7.27(s, 1H, CH ═ s), 8.33(t, 1H, NHCO), 9.30 (width s, 1H, OH), 10.25(s, 1H, HCl). MS (ESI, 250 ℃): MH⁺＝408.2(100％)。

Similarly, but using the corresponding reagents, the following compounds were prepared:

example 54: 6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2-methoxyphenyl) -piperazin-1-yl]-butyl } -amide.

This derivative was obtained according to the procedure of example 1, using 6-methoxy-2H-benzopyran-3-carboxylic acid obtained according to j.med.chem.1988, 31, 688.¹H NMR(CDCl₃Base): 1.64-1.66(m, 4H, -CH)₂-CH₂-)，2.46(t，2H，-CH₂-N), 2.66(m, 4H, H-piperazine), 3.09(m, 4H, H-piperazine), 3.37-3.40(t, 2H, -CH)₂-N-CO-)，3.72(s，3H，OCH₃)，3.86(s，3H，-OCH₃)，4.94(s，2H，O-CH₂) 6.54(s, 1H, -NH), 6.62-7.01(m, 7H, aryl H + H)₄). Analysis (salt): c₂₆H₃₃O₄N₃-HCl. Mass spectrum 488.03. MS (ESI)⁺，400℃)：MH⁺＝452.3(100％)。MP＝165℃。

Example 55: 6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2, 3-dichlorophenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.67-1.73(m, 4H, -CH)₂-CH₂-)，2.48(t，2H，-CH₂-N), 2.65(m, 4H, H-piperazine), 3.04(m, 4H, H-piperazine), 3.38-3.43(m, 2H, -CH)₂-N-CO-)，3.86(s，3H，OCH₃)，5.03(s，2H，O-CH₂) 6.67(s, 1H, -NH), 6.82-7.14(m, 5H, aryl H + H)₄). Analysis (salt): c₂₅H₂₈O₃Cl₂N₃Br-HCl. Mass spectrum 605.79. MS (ESI)⁺，400℃)：MH⁺＝570.0(100％)。MP＝205℃。

Example 56: 6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (2-fluorophenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.64-1.66(m, 4H, -CH)₂-CH₂-)，2.46(t，2H，-CH₂-N), 2.66(m, 4H, H-piperazine), 3.09(m, 4H, H-piperazine), 3.37-3.40(t, 2H, -CH)₂-N-CO-)，3.72(s，3H，OCH₃)，3.86(s，3H，-OCH₃)，4.94(s，2H，O-CH₂) 6.54(s, 1H, -NH), 6.62-7.01(m, 7H, ar)H+H₄). Analysis (salt): c₂₆H₃₃O₄N₃-HCl. Mass spectrum 488.03. MS (ESI)⁺，400℃)：MH⁺＝452.3(100％)。MP＝154℃。

Example 57: 6-methoxy-2H-benzopyran-3-carboxylic acid {4- [4- (3-cyanophenyl) -piperazin-1-yl]-butyl } -amide.

The derivative was obtained according to the procedure of example 1, but using the corresponding reagent.¹H NMR(CDCl₃Base): 1.64-1.66(m, 4H, -CH)₂-CH₂-)，2.44(t，2H，-CH₂-N), 2.60(m, 4H, H-piperazine), 3.21(m, 4H, H-piperazine), 3.37-3.42(m, 2H, -CH)₂-N-CO-)，3.75(s，3H，OCH₃)，4.93(s，2H，O-CH₂) 6.31(s, 1H, -NH), 6.75-7.40(m, 7H, aryl H + H)₄). Analysis (salt) C₂₆H₃₀O₃N₄-HCl mass spectrum 483.01. MS (ESI)⁺，400℃)：MH＝447.3(100％)。MP＝159℃。

In a similar manner, the following compounds were obtained with the corresponding reagents:

example 58: 2H-benzopyran-3-carboxylic acid {4- [4- (2-hydroxyphenyl) -piperazin-1-yl]-butyl } -amide.

¹H NMR(CDCl₃Base): 1.59-1.65(m, 4H, -CH)₂-CH₂-)，2.45(t，2H，-CH₂-N), 2.62(m, 4H, H-piperazine), 2.89(m, 4H, H-piperazine), 3.40(m, 2H, -CH₂-N-CO-)，5.01(s，2H，O-CH₂)，6.31(s，1H，-NH)，6.81-7.26(m，9HAryl H + H₄). Analysis (salt): c₂₄H₂₉O₃N₃-HCl. Mass spectrum 443.98. MS (ESI)⁺，250℃)：MH⁺＝408.1(100％)。MP＝189℃。

Example 59: 2H-benzopyran-3-carboxylic acid {4- [4- (4-hydroxyphenyl) -piperazin-1-yl]-butyl } -amide.

¹H NMR(CDCl₃Base): 1.65-1.67(m, 4H, -CH)₂-CH₂-)，2.51(t，2H，-CH₂-N), 2.71(m, 4H, H-piperazine), 3.11(m, 4H, H-piperazine), 3.41(m, 2H, -CH₂-N-CO-)，5.00(s，2H，O-CH₂) 6.51(s, 1H, -NH), 6.74-7.21(m, 9H, aryl H + H)₄). Analysis (salt): c₂₄H₂₉O₃N₃-HCl. Mass spectrum 443.98. MS (ESI)⁺，250℃)：MH⁺＝408.3(100％)。MP＝236℃。

Example 60: 2H-benzopyran-3-carboxylic acid {4- [4- (4-cyanophenyl) -piperazin-1-yl]-butyl } -amide.

And (3) analysis: c₂₆H₃₀N₄O₃。MW＝446.55

Example 61: 2H-benzopyran-3-carboxylic acid {4- [4- (2-cyanophenyl) -piperazin-1-yl]-butyl } -amide.

And (3) analysis: c₂₆H₃₀N₄O₃。MW＝446.55

Example 62: 2H-benzopyran-3-carboxylic acid {4- [4- (3-methoxyphenyl) -piperazin-1-yl]-butyl } -amide.

And (3) analysis: c₂₆H₃₃N₃O₄。MW＝451.57

Example 63: 2H-benzopyran-3-carboxylic acid {4- [4- (3, 4-dimethoxyphenyl) -piperazin-1-yl]-butyl } -amide.

And (3) analysis: c₂₇H₃₅N₃O₅。MW＝481.60

Example 64: 2H-benzopyran-3-carboxylic acid {4- [4- (3, 4-methylenedioxyphenyl) -piperazin-1-yl]-butyl } -amide.

And (3) analysis: c₂₆H₃₁N₃O₅。MW＝465.55

Other examples consistent with the compounds of the present invention are set forth in table I below.

Certain compounds of the invention are identified as pKi, and are directed to dopamine D2 and D3 receptors and alpha₁Binding inhibition constants for adrenergic receptors are shown in table 2 below.

TABLE 2

Example No. 2	pKi D3⁽¹⁾	pKi D2⁽¹⁾	pKi α₁ ⁽²⁾	Intrinsic activity
Example No. 2	pKi D3⁽¹⁾	pKi D2⁽¹⁾	pKi α₁ ⁽²⁾	Intrinsic activity	2	9.09	6.91	7.29	nt⁽³⁾
55	9.10	6.6	7.13	0	2	9.09	6.91	7.29	nt⁽³⁾
55	9.10	6.6	7.13	0	54	9.27	6.38	8.05	nt
102	9.66	7.03	8.05	0.59	54	9.27	6.38	8.05	nt
102	9.66	7.03	8.05	0.59	35	8.62	5.5	7.32	0.18
89	9.66	7.46	6.78	0	35	8.62	5.5	7.32	0.18
89	9.66	7.46	6.78	0	111	9.17	6.85	7.84	0.26
110	10.17	8.12	8.44	0.81	111	9.17	6.85	7.84	0.26
110	10.17	8.12	8.44	0.81	105	9.22	6.88	7.81	nt
41	9.18	5.42	7.08	0.64	105	9.22	6.88	7.81	nt
41	9.18	5.42	7.08	0.64	16	8.57	6.35	7.55	nt

(1) Determination of spiperone [2 ] as described by Cussac et al in Nauyn-Schmiedeberg's Arch. Pharmacol.2000, 361, 569³H]Binding inhibition by CHO cells.

(2) For example, the assay of prazosin [2 ] in Nauyn-Schmledeberg's Arch Pharmacol 1979, 308, 223 by Hornung et al³H]Combined with the inhibitory effect of rat brain tissue.

(3) Not detected

Claims

1. Compounds of formula 1

General formula 1

Wherein:

x represents a heteroatom, O or S;

r2 represents a hydrogen atom or C_1-4An alkyl group;

r3 represents a hydrogen atom or one or more identical or different substituents, such as halogen, Cl, F, Br or C_1-4Alkyl radical, C_1-4Alkoxy or thioalkoxy, O (CH)₂)_nO wherein n is 1 or 2, NO₂、NH₂、NHCOCH₃、NHSO₂CH₃、OH、CF₃CN, COOEt or CH₂OH, an optionally substituted phenyl or benzyl substituent, or R3 fused to the aromatic ring to which it is attached, to form a ring, e.g. aryl, heteroaryl or C₅、C₆Or C₇Cycloalkyl or heterocyclyl.

2. The compound of claim 1, wherein said compound is selected from the group consisting of:

2H-benzopyran-3-carboxylic acid {4- [ 4-phenylpiperazin-1-yl ] -butyl } -amide,

5- (4- {4- [2H-1, 2-Benzothiopyran-3-carbonyl) -amino ] -butyl } -piperazin-1-yl) -benzofuran-2-carboxylic acid methyl ester

2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (2, 3-dihydro-benzo [1, 4] dioxin-5-yl) -piperazin-1-yl ] -butyl { -amide,

6-methoxy-2H-1, 2-benzothiopyran-3-carboxylic acid {4- [4- (3-methanesulfonylamino-phenyl) -piperazin-1-yl ] -butyl { -amide,

3. A process for the preparation of compounds of the general formula 1 according to claims 1 and 2, wherein one process prepares an optionally substituted benzopyran or 1, 2-benzothiopyranic acid of the general formula 2 or the corresponding acid chlorides,

general formula 2

Which is then coupled with a primary amine of formula 5 in dichloromethane in the presence of TBTU and triethylamine,

wherein the various substituents R1, R2, R3 and X are as defined in claim 1,

or one of the processes for preparing optionally substituted benzopyrans or 1, 2-benzothiopyranic acids of the general formula 2 or the corresponding acid chlorides,

general formula 2

Which is then coupled with 4-aminobutanol, activated and then alkylated with substituted phenylpiperazines of the general formula 10,

wherein the various substituents R1, R2, R3 and X are as defined in claim 1.

4. A pharmaceutical composition comprising at least one compound of claims 1 and 2 in combination with a pharmaceutically acceptable excipient.

5. A compound according to claims 1 and 2 for use as a medicament.

6. Use of a compound according to claims 1 and 2 in the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder.

7. The use according to claim 5, wherein the disease is Parkinson's disease.

8. The use of claim 6, wherein the disease is accompanied by treatment of Parkinson's disease.

9. The use according to claim 6, wherein the disease is a psychotic disorder.

10. The use according to claim 9, wherein the psychosis is schizophrenia.

11. Use of a compound according to claims 1 and 2 for the manufacture of a medicament for the treatment of drug or other addictive substance dependence or addiction.

12. Use according to claim 11, wherein the dependence and addiction is to nicotine or alcohol.

13. The use according to claim 6, wherein the condition is a cognitive disorder.

14. The use according to claim 13, wherein the cognitive disorder is associated with alzheimer's disease or with aging.

15. The use according to claim 6, wherein the disease is depression.

16. The use according to claim 6, wherein the disease is essential tremor.