TECHNICAL FIELD
The disclosure relates to chromone derivatives  to processes for their preparation  to pharmaceutical compositions containing them and to their therapeutic applications as agonists  partial agonists or antagonists of the dopamine receptor D3 (DRD3) for the treatment of various neurological and psychiatric conditions.

BACKGROUND AND PRIOR ART OF THE DISCLOSURE
Schizophrenia is a term used to describe a group of pathologies of unknown origin that affects approximately 1 % of the general population. This pathology is characterised by a variety of symptoms  classified as positive symptoms (hallucinations  deliria  disorganised thought) and negative symptoms (social withdrawal and affective flattening)  at an age commencing in adolescence or the beginning of adulthood  and can persist in chronic form with episodes of exacerbation for many years.

Patients affected by schizophrenia can be treated with medicaments called neuroleptics  also known by the name antipsychotics. The therapeutic effect of antipsychotics is generally acknowledged as resulting from the blockade of receptors of the neuromediator dopamine in the brain. There are five known sub-types of dopamine receptors  called D1  D2  D3  D4 and D5 (Sokoloff  P. et al.  Novel dopamine receptor subtypes as targets for antipsychotic drugs. Annals New-York Academy of Sciences 1995  757  278) and the conventional antipsychotics are D2 and D3 receptor antagonists. However  antipsychotics are frequently responsible for undesirable extrapyramidal side-effects (EPS) and abnormal movements called tardive dyskinesias  which are attributed to the blockade of D2 receptors in the striatal region of the brain. Blockade of the D3 receptor (DRD3) has been suggested as being responsible for the therapeutic effects of antipsychotics (Schwartz J.C. et al.  Eur. Neuropsychopharmacol. 2003  13(suppl. 4): S 166). Hence  pharmacological agents that selectively modulate DRD3 function are considered to be effective antipsychotics free from neurological side-effects (International patent application WO 91/15513).

The selective modulation of DRD3 receptors can be achieved with molecules that bind selectively to DRD3 and that act as agonists  as antagonists or as partial agonists. The antipsychotic activity resulting from the modulation of DRD3 function can be predicted in animals by employing schizophrenic mouse models (Leriche L. et al.  Neuropharmacology 2003  45  174). It has moreover been demonstrated that selective blockade of DRD3  but not the concomitant blockade of DRD2 and DRD3  increases the extracellular levels of dopamine and acetylcholine  another neuromediator  in the prefrontal cortex (Lacroix L.P. et al.  Neuropsychophamacol. 2003  28  839). Dopamine and acetylcholine in that region of the brain are essential for cognitive function. It is consequently thought that selective antagonists of DRD3 can improve cognition  which is altered in schizophrenia and also in neurodegenerative pathologies such as Alzheimer""s disease.

Antipsychotics in general  and aripiprazole  quetiapine and olanzapine in particular  are used in the treatment of the acute manic phase of bipolar disorder. Antagonists or partial agonists of DRD3 are thus also considered as medicaments for the treatment of bipolar disorder.

Genetically modified mice carrying a mutation that disables DRD3 (DRD3 "knockout") are less anxious in behavioural tests predictive of an anxiogenic or anxiolytic activity (Steiner H. et al.  1: Physiol Behav. 1997  63 137-41). Consequently  a pharmacological disablement of DRD3  such as is obtained by using a DRD3 antagonist described in the present disclosure  is also a treatment for anxiety.

Depression is a common mood pathology that is characterised by feelings of intense sadness  pessimistic thoughts and self-depreciation  often accompanied by loss of energy  enthusiasm and libido. The incapacity to feel pleasure from normally pleasant experiences  also known by the name of anhedonia  is also regarded as a common symptom in depression. A significant role in pleasure and motivation has been attributed to the dopaminergic neurons in a region of the brain called the nucleus accumbens (Koob G.F. et al.  Sem. Neurosci. 1992  4  139 ; Salamone J.D. et al.  Behav. Brain Res. 1994  61  117). These neurons have consequently been suggested as being implicated in the neurobiology of depression  especially anhedonia  and in the therapeutic effects of some antidepressant medicaments (Kapur S. and Mann J. Biol. Psychiatry 1992  32  1-17 ; Willner P.  Int. Clin. Psychopharmacol. 1997  12  S7-S14). It has been demonstrated that various antidepressant treatments selectively increase the expression of DRD3 in the nucleus accumbens (Lammers C.H. et al.  Mol. Psychiatry 2000  5  378)  suggesting that increasing DRD3 function could be a new mode of antidepressant treatment. An increase in the function of the D3 receptor DRD3 can be achieved using agonists or partial agonists of DRD3  which might therefore be an effective treatment for depression.

Dependence on drugs or addictive substances  also known as drug addiction  is a chronic and recurrent pathology in which behaviour involving risk-taking and the search for addictive substances  and the compulsive behaviour of drug-taking  persist despite the negative consequences perceived by the patient (Deroche-Gamonet V. et al.  Science 2004  305  1014 ; Vanderschuren L.J. et al.  Science 2004  305  1017). The withdrawal phenomenon that occurs during abstinence from addictive substances can be triggered or exacerbated by environmental stimuli that have acquired a motivational force as a result of having repeatedly been associated with the effects of a drug  both in man (Childress A.R. et al.  Am. J. Psychiatry 1999  156  11 ; Robinson T.E. et al.  Brain Research Reviews 1993  18  247) and in animals (Goldberg S.R. et al.  NIDA Res. Monogr. 1981  37  241 ; Arroyo M. Psychopharmacology 1999  140  331). In animals  highly selective DRD3 agonists or partial antagonists specifically reduce the responses to stimuli associated with cocaine (Pilla M. Nature  1999  400  371; Le Foll  B. Eur. J. Neurosci. 2002  15  2016; Vorel S.R. J. Neurosci. 2002  22  9595)  with an opiate (Frances H. et al.  Neuroreport 2004   15  2245) or with nicotine (Le Foll B. et al.  Mol. Psychiatry 2003  8  225)  while having no influence on the primary effects of the drugs. The density of DRD3 is abnormally high in the brain of cocaine addicts (Staley J.K. et al.  J. Neurosci. 1996  16  6106). Partial agonists or antagonists of DRD3 are therefore thought to be effective medicaments for facilitating abstinence and reducing the risk of relapse.

Parkinson""s disease is a pathology characterised by tremor at rest  limb rigidity and akinesia (difficulty in initiating movements). The disease is caused by a degeneration of dopaminergic neurons. The treatment of Parkinson""s disease is based on the substitution of dopamine through the administration of L-dihydroxyphenylamine (L-DOPA) or direct dopamine agonists. Long-term use of L-DOPA  however  is associated in a very significant number of cases with the occurrence of abnormal movements called dyskinesias. It has been demonstrated in a non-human primate model of Parkinson""s disease that the modulation of DRD3 with a highly selective partial agonist attenuates dyskinesias (Bezard E. et al.  Nat. Med. 2003  6  762). The compounds described in the present document are consequently considered as additive treatments in Parkinson""s disease. It has  moreover  been demonstrated that a DRD3 agonist increases neurogenesis in the rat  so that DRD3 agonists might also be medicaments that delay progression of the disease.

A mutation in the DRD3 gene is associated and co-segregated with essential tremor  a common and hereditary neurological disorder that is characterised by action tremor of all or part of the body in the absence of any other neurological pathology (Jeanneteau et al.  Proc. Natl. Acad. Sci. USA 2006  103  10753). The mutation increases DRD3 function. The normalisation of DRD3 function by using partial agonists or antagonists of DRD3 might therefore be an effective treatment for essential tremor.

Dopamine controls erectile function and dopaminergic agents have been proposed as a treatment for erectile dysfunction (Guiliano F.  Ramplin O. Physiol Behav. 2004  83  189-201). More specifically  the pro-erectile effects of dopaminergic agonists are mediated by the D3 receptor in rodents (Collins G.T. et al.  J. Pharmacol. Exp. Ther.  2009  329  210-217) and a selective D3 receptor antagonist delays ejaculation during coitus in the rat (Clément P. et al.  J. Sex. Med.  2009  6  980-988). Agonists  partial agonists and antagonists of DRD3 such as those described in the present disclosure may thus be a treatment for various dysfunctions of erectile function.

The literature mentions phenylpiperazine chromones for use in combating malaria in Biochemical and Biophysical Research Communications 2007  358(3)  686. Indian J. Chem.  section B  2002  41B(4)  817  describes phenylpiperazinomethylchromone compounds. Mannich bases using methoxychromones are known from Farmaco Edizione Scientifica 1977  32 (9)  635. A patent specification  US 3410851  describes flavones having anticonvulsive  analgesic or bronchodilatory properties. The compounds of the present disclosure are distinguished by the fact that they have a carbon chain of 4 methylenes between the chromone moiety and phenylpiperazine  which confers upon them the property of being dopaminergic D3 receptor ligands.

The patent applications WO2003028728  WO2004004729 and WO2006077487 and the patent specification EP1841752 describe heteroaryl phenylpiperazine butyl carboxamides as DRD3 ligands. Patent application WO2008009741 mentions chromene and thiochromene carboxamides demonstrating an affinity for the D3 dopaminergic receptor for use as antipsychotics. Patent application WO2006072608 mentions arylpiperazines having dopaminergic and serotonergic receptor modulating properties for use in neuropsychiatric disorders such as schizophrenia. The publication J. Med. Chem. 2009  52  151 also mentions those same derivatives. All of the products described in the above-cited patent specifications have a carboxamide chain in their structure.

STATEMENT OF THE DISCLOSURE
Accordingly  the present disclosure relates to a compound of general formula 1


wherein-
R1 represents one or more identical or different substituent(s) on the benzene ring  each representing  independently  a hydrogen atom or a halogen atom  or a C14alkoxy group or an OH group  or a C1-4alkyl group or an O(CH2)nO- group in which n = 1 or 2 
-R2 represents a hydrogen atom or a C1-4alkyl group 
-A and B represent  independently  either a nitrogen atom or a carbon atom 
-R3 represents a hydrogen atom or one or more identical or different substituent(s) selected from the group composed of- a halogen atom  a C1 4alkyl group  a C1-4alkoxy or C1-4thioalkoxy group  an -O(CH2)nO- group in which n = 1 or 2  an NO2 group  an NHSO2R4 group  an NHR5 group  an OH group  a C1-4haloalkyl group  a CN group  a C1-4alkoxycarbonyl group  a C1 4alkylcarbonyl group  a C1-4hydroxyalkyl group and a benzyl or phenyl substituent optionally substituted by a C1-4alkoxy or a C1-4alkyl group or a halogen atom 
-or R3 constitutes a ring fused with the benzene ring carrying it  selected from the group composed of a naphthalene  an indole  a benzimidazole  a carbostyril  a benzoxazolone and a benzimidazolone 
-R4 represents a C1-4alkyl group or a C1-4dialkylamino group or a C1-4alkoxyalkyl group or a C1-4dialkylaminoalkyl group or a phenyl or phenyl-C1-4alkyl group 
-R5 represents a hydrogen atom or a C1-4alkylcarbonyl group or a C1-4alkoxy-carbonyl group  and also their pharmaceutically acceptable salts; a process for preparation of compounds of general formula 1  characterised in that an optionally substituted chromone of formula 4 (X = Cl  Br  I) is prepared  which is reacted with a piperazine of formula 5 


radicals R1  R2  R3  A and B have the meanings given above; a process for preparation of compounds of general formula 1  characterised in that an optionally substituted phenol derivative of formula 6 is prepared starting from a compound of formula 3 (X = Cl  Br)  and is reacted with DMF or the dimethylacetal of DMF or of DMA 

The radicals R1  R3  A and B have meanings given above  under alkylation conditions in presence of a base such as K2CO3  Cs2CO3 or NEt3  in a solvent such as acetonitrile or methyl ethyl ketone; a pharmaceutical composition comprising compound of general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; a process for obtaining a pharmaceutical composition  said process comprising acts of a) preparing compound of general formula I by above processes and b) adding pharmaceutically acceptable excipient to the compound or pharmaceutically acceptable salt thereof to obtain the pharmaceutical composition; and a method of modulating DRD3 Receptor  said method comprising act of contacting compound of general formula I with cell expressing DRD3 receptors to modulate the DRD3 receptor.

DETAILED DESCRIPTION OF THE DISCLOSURE
The present disclosure relates to a compound of general formula 1


wherein:
R1 represents one or more identical or different substituent(s) on the benzene ring  each representing  independently  a hydrogen atom or a halogen atom  or a C14alkoxy group or an OH group  or a C1-4alkyl group or an O(CH2)nO- group in which n = 1 or 2.
-R2 represents a hydrogen atom or a C1-4alkyl group.
-A and B represent  independently  either a nitrogen atom or a carbon atom.
-R3 represents a hydrogen atom or one or more identical or different substituent(s) selected from the group composed of: a halogen atom  a C1 4alkyl group  a C1-4alkoxy or C1-4thioalkoxy group  an -O(CH2)nO- group in which n = 1 or 2  an NO2 group  an NHSO2R4 group  an NHR5 group  an OH group  a C1-4haloalkyl group  a CN group  a C1-4alkoxycarbonyl group  a C1 4alkylcarbonyl group  a C1-4hydroxyalkyl group and a benzyl or phenyl substituent optionally substituted by a C1-4alkoxy or a C1-4alkyl group or a halogen atom 
-or R3 constitutes a ring fused with the benzene ring carrying it  selected from the group composed of a naphthalene  an indole  a benzimidazole  a carbostyril  a benzoxazolone and a benzimidazolone.
-R4 represents a C1-4alkyl group or a C1-4dialkylamino group or a C1-4alkoxyalkyl group or a C1-4dialkylaminoalkyl group or a phenyl or phenyl-C1-4alkyl group 
-R5 represents a hydrogen atom or a C1-4alkylcarbonyl group or a C1-4alkoxy-carbonyl group  and also their pharmaceutically acceptable salts.

In an embodiment of the present disclosure  the compound is characterised in that R1 represents one or more identical or different substituent(s) selected from the group composed of a C1 4alkoxy group  an OH group and an -O(CH2)nO- group in which n = 1 or 2.

In another embodiment of the present disclosure  the compound is characterised in that R2 represents a hydrogen atom.

In yet another embodiment of the present disclosure  the compound is characterised in that R3 represents a hydrogen atom when A and/or B represents a nitrogen atom.

In still another embodiment of the present disclosure  the compound is characterised in that A and B simultaneously represent a carbon atom.

In still another embodiment of the present disclosure  the compound is characterised in that R3 represents one or more identical or different substituent(s) selected from the group composed of : a halogen atom  a C1-4alkoxy group  an -O(CH2)nO- group in which n = 1 or 2  an NHSO2R4 group  an OH group and a CN group.

In still another embodiment of the present disclosure  the compound is characterised in that R3  together with the benzene ring carrying it  represents an indole group or a benzimidazole group or a carbostyril group.

In still another embodiment of the present disclosure  the compound is characterised in that it is selected from the following group of compounds:
- 6 7-dimethoxy-3-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-chromen-4-one
- 3-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-benzonitrile
- 3-{4-[4-(2 3-dichlorophenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 3-{4-[4-(3-hydroxyphenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 6 7-dimethoxy-3-[4-(4-pyrimidin-2-yl-piperazin-1-yl)-butyl]-chromen-4-one
- 6 7-dimethoxy-3-[4-(4-pyridin-2-yl-piperazin-1-yl)-butyl]-chromen-4-one
- 3-{4-[4-(2 3-difluorophenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 3-{4-[4-(1H-benzimidazol-4-yl-)piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 3-{4-[4-(1H-indol-4-yl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 5-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-1H-quinolin-2-one
- 6 7-dimethoxy-3-{4-[4-(3-nitrophenyl)-piperazin-1-yl]-butyl}-chromen-4-one
- 3-{4-[4-(3-aminophenyl)-piperazin-1-yl-]-butyl}-6 7-dimethoxychromen-4-one
- N-(3-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide
- N-(3-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-acetamide
- methyl (3-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-carbamate
- 7-{4-[4-(2 3-dichlorophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one
- 7-{4-[4-(2 3-difluorophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one
- 7-{4-[4-(3-nitrophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one
- 7-{4-[4-(3-aminophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one
-N-(3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl-acetamide
-N-(3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide
-N-(3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-ethanesulfonamide
-2-dimethylaminoethanesulfonic acid (3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-amide
-2-methoxyethanesulfonic acid (3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-amide
- 7-{4-[4-(1H-indol-4-yl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one
- 3-{4-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 6-methoxy-3-[4-(4-phenyl-piperazin-1-yl)-butyl]-chromen-4-one
- 6-methoxy-3-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-chromen-4-one
- 6-methoxy-3-{4-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-butyl}-chromen-4-one
-7-{4-[4-(2 3-dichlorophenyl)piperazin-1-yl-]-butyl}-6-methyl-[1 3]dioxolo[4 5-g]chromen-8-one
-6 7-methoxy-7 6-hydroxy-3-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-chromen-4-one
-7-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-3H-benzoxazol-2-one
-4-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-1 3-dihydrobenzimidazol-2-one.

The present disclosure further relates to a process for preparation of compounds of general formula 1  characterised in that an optionally substituted chromone of formula 4 (X = Cl  Br  I) is prepared  which is reacted with a piperazine of formula 5.


radicals R1  R2  R3  A and B have the meanings given above.

The present disclosure also relates to a process for preparation of compounds of general formula 1  characterised in that an optionally substituted phenol derivative of formula 6 is prepared starting from a compound of formula 3 (X = Cl  Br)  and is reacted with DMF or the dimethylacetal of DMF or of DMA.

The radicals R1  R3  A and B have the meanings given above  under alkylation conditions in presence of a base such as K2CO3  Cs2CO3 or NEt3  in a solvent such as acetonitrile or methyl ethyl ketone.
The present disclosure further relates to a pharmaceutical composition comprising at least one compound of general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

The present disclosure further relates to a process for obtaining a pharmaceutical composition  said process comprising acts of: a) preparing compound of general formula I by above processes; and b) adding pharmaceutically acceptable excipient to the compound or pharmaceutically acceptable salt thereof to obtain the pharmaceutical composition.

In an embodiment of the present disclosure  the pharmaceutically acceptable excipient is chosen from group comprising diluent  adjuvant  preservative  filler disintegrator  wetting agent  emulsifier  dispersant  antibacterial or antifungal agent  or also agents that would allow intestinal and digestive absorption and resorption to be delayed.

The present disclosure further relates to a method of modulating DRD3 Receptor  said method comprising act of contacting compound of general formula I with cell expressing DRD3 receptors to modulate the DRD3 receptor.

In an embodiment of the present disclosure  the compound is a dopaminergic D3 receptor ligand.

In another embodiment of the present disclosure  the compound is an agonist or partial agonist or antagonist of DRD3 receptor.

The products of the present disclosure are distinguished from the described compounds by the fact that they do not have a carboxamide chain but  unexpectedly  are potent D3 dopaminergic receptor ligands.

As used above  the term "D3 dopamine receptor"  "D3 receptor" or "DRD3" denotes a dopamine receptor sub-type chiefly expressed in the limbic system (Sokoloff P et al.  Nature  1990  347  146-151). DRD3 is described in international patent application WO 91/15513.

As used above  the term "D3 receptor partial agonist" denotes a compound that forms a complex with DRD3 and acts as a combined agonist-antagonist  that is to say it induces a physiological response of an intensity lower than that of the natural mediator  dopamine. In vitro  in a cell expressing DRD3  a DRD3 partial agonist produces an active response the maximum intensity of which is lower than that produced by dopamine or by a full agonist  for example quinpirole (trans(-)-4aR-4 4a 5 6 7 8 8a 9-octahydro-5-propyl-1H(or 2H)pyrazolo[3 4g]quinoline). A DRD3 partial agonist may also partially prevent the response produced by dopamine or its full agonists. In vivo  a DRD3 partial agonist produces dopaminergic responses  especially when the levels of dopamine are reduced  as is the case in rats having lesions caused by 6-hydroxydopamine or in monkeys intoxicated with 1 methyl-4-phenyl-1 2 3 6-tetrahydropyridine (MPTP). In addition  in vivo a DRD3 partial agonist may act as an antagonist  especially when the DRD3 is subject to sustained stimulation by dopamine.

"A DRD3 antagonist" denotes a molecule that forms a complex with DRD3 and is capable of preventing a response triggered by dopamine or an agonist thereof in a cell expressing DRD3.

As used here  the term "salts" denotes inorganic acid and base addition salts of the compounds of the present disclosure. Preferably  the salts are pharmaceutically acceptable  that is to say  they are non-toxic for the patient to whom they are administered.

The expression "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce any adverse allergic effect or other undesirable reaction when administered to an animal or human.

When used herein  the expression "pharmaceutically acceptable excipient" includes any diluent  adjuvant or excipient  such as preservative  filler disintegrator  wetting agent  emulsifier  dispersant  antibacterial or antifungal agent  or also agents that would allow intestinal and digestive absorption and resorption to be delayed. The use of those media or vectors is well known in the art. Except where the agent is chemically incompatible with a chromone derivative  its use in pharmaceutical compositions containing the compounds according to the disclosure is envisaged.

In the context of the disclosure  the term "treatment" as used herein means preventing or inhibiting the appearance or progression of the condition to which the term is applied  or of one or more symptoms of that condition.

"Therapeutically active amount" means an amount of a chromone derivative that is effective in obtaining the desired therapeutic effect according to the disclosure.

According to the disclosure  the term "patient" refers to a human or non-human mammal affected or very susceptible to being affected by a pathology. Preferably  the patient is a human.

In the context of the present disclosure  a C1-4alkyl group is understood as a linear or branched hydrocarbon chain containing from 1 to 4 carbon atoms  for example a methyl group  an ethyl group  a propyl group or a butyl group.

In the context of the present disclosure  a C1-4alkoxy group is understood as a linear or branched hydrocarbon chain containing from 1 to 4 carbon atoms and an oxygen atom  for example a methoxy group  an ethoxy group  a propoxy group or a butoxy group.

In the context of the present disclosure  a C1-4thioalkoxy group is understood as a linear or branched hydrocarbon chain containing from 1 to 4 carbon atoms  an oxygen atom and a sulfur atom  for example a thiomethoxy group  a thioethoxy group  a thiopropoxy group or a thiobutoxy group.

In the context of the present disclosure  a C1-4dialkylamino group is understood as an amine disubstituted by linear or branched C1-4alkyl groups  for example a dimethylamino group  a diethylamino group  a dipropylamino group or a dibutylamino group.

In the context of the present disclosure  halogen is understood as fluorine  chlorine or bromine.

In the context of the present disclosure  a C1-4haloalkyl group is understood as a C1-4alkyl group monosubstituted  disubstituted or trisubstituted by a halogen  for example a CF3 group  a CHF2 group  a CH2F group  a CCl3 group  a CHCl2 group  a CH2Cl group  a CBr3 group  a CHBr2 group or a CH2Br group.

In the context of the present disclosure  a C1-4dialkylaminoalkyl group is understood as a C1-4dialkylamino group as defined hereinbefore bonded to a C1 4alkyl group by a carbon atom  for example a dimethylaminomethyl group  a dimethylaminoethyl group  a diethylaminomethyl group or a diethylaminoethyl group.

In the context of the present disclosure  a C1-4alkoxyalkyl group is understood as a C1-4alkyl group as defined hereinbefore bonded to a C1-4alkoxy group by a carbon atom  for example a methoxymethyl group  an ethoxymethyl group  a methoxyethyl group or an ethoxyethyl group.

In the context of the present disclosure  a C1-4hydroxyalkyl group is understood as an alkyl group as defined hereinbefore in which a hydrogen atom is substituted by a hydroxyl group  for example a CH2OH group  a C2H4OH group  a C3H6OH group or a C4H8OH group.

In the context of the present disclosure  a C1-4alkylcarbonyl group is understood as an alkyl group as defined hereinbefore bonded to a carbonyl group by the carbon atom  for example a COCH3 group  a COC2H5 group  a COC3H7 group or a COC4H9 group.

In the context of the present disclosure  a C1-4alkoxycarbonyl group is understood as an alkoxy group as defined hereinbefore bonded to a carbonyl group by the carbon atom  for example a COOCH3 group  a COOC2H5 group  a COOC3H7 group or a COOC4H9 group.

In the context of the present disclosure  a C1-4phenylalkyl group is understood as a phenyl group bonded by a carbon atom to an alkyl group as defined hereinbefore.

The disclosure relates to chromone derivatives  to processes for their preparation  and to their use as a medicament  as DRD3 receptor ligands  for the treatment of neurological or psychiatric diseases  conditions or disorders. Those compounds correspond to the general formula 1.

wherein:
R1 represents one or more identical or different substituent(s) on the benzene ring  each representing  independently  a hydrogen atom or a halogen atom  or a C14alkoxy group or an OH group or a C1-4alkyl group or an O(CH2)nO- group in which n = 1 or 2.
-R2 represents a hydrogen atom or a C1-4alkyl group.
-A and B represent  independently  either a nitrogen atom or a carbon atom.
-R3 represents a hydrogen atom or one or more identical or different substituent(s) selected from the group composed of : a halogen atom  a C1 4alkyl group  a C1-4alkoxy or C1-4thioalkoxy group  an -O(CH2)nO- group in which n = 1 or 2  an NO2 group  an NHSO2R4 group  an NHR5 group  an OH group  a C1-4halo¬alkyl group  a CN group  a C1-4alkoxycarbonyl group  a C1 4alkylcarbonyl group  a C1-4hydroxyalkyl group and a benzyl or phenyl substituent optionally substituted by a C1-4alkoxy or a C1-4alkyl group or a halogen atom 
-or R3 constitutes a ring fused with the benzene ring carrying it  selected from the group composed of a naphthalene  an indole  a benzimidazole  a carbostyril  a benzoxazolone and a benzimidazolone.
-R4 represents a C1-4alkyl group or a C1-4dialkylamino group or a C1-4¬alkoxyalkyl group or a C1-4dialkylaminoalkyl group or a phenyl or phenyl-C1-4¬alkyl group 
-R5 represents a hydrogen atom or a C1-4alkylcarbonyl group or a C1-4¬alkoxy¬carbonyl group 
and also their pharmaceutically acceptable salts.

According to the disclosure  compounds of the general formula (I) are those wherein:
- R1 represents one or more identical or different substituent(s) selected from the group composed of a C1-4alkoxy group  an OH group and an -O(CH2)nO- group in which n = 1 or 2.

According to the disclosure  compounds of the general formula (I) are those wherein:
- R2 represents a hydrogen atom.

According to another embodiment of the disclosure  compounds of the general formula (I) are those wherein R3 represents a hydrogen atom when A and/or B represent a nitrogen atom.

According to the disclosure  compounds of the general formula (I) are those wherein:
- A and B simultaneously represent a carbon atom.

According to the disclosure  compounds of the general formula (I) are those wherein:
- R3 represents one or more identical or different substituent(s) selected from the group composed of: a halogen atom  a C1-4alkoxy group  an -O(CH2)nO- group in which n = 1 or 2  an NHSO2R4 group  an OH group and a CN group.

According to another embodiment of the disclosure  compounds of the general formula (I) are those wherein:
- R3  together with the benzene ring carrying it  represents an indole group or a benzimidazole group or a carbostyril group.

According to another embodiment of the disclosure  compounds of the general formula (I) are those wherein :
-R1 represents one or two identical or different substituents which each represent  independently  a methoxy group  or an -O(CH2)nO- group in which n = 1 or an OH group.
-R2 represents a hydrogen atom
-A represents a carbon atom and B represents a nitrogen atom or a carbon atom
When A and B represent a carbon atom:
-R3 represents one or two identical or different substituent(s) selected from the group composed of: a hydrogen atom  a CN group  a chlorine atom  a fluorine atom  an OH group  an NO2 group  an NHSO2R4 group  an NHR5 group  a CF3 group  a methoxy group 
-or R3 constitutes a ring fused with the benzene ring carrying it selected from the group composed of: benzimidazole  benzoxazolone  indole  benzimidazolone and carbostyril.
-When A represents a carbon atom and B represents a nitrogen atom :
-R3 represents a hydrogen atom
-R4 represents a methyl group  or an ethyl group  or a dimethylaminoethyl group or an ethoxymethyl group.
-R5 represents a hydrogen atom  a COCH3 group or a COOCH3 group

The following are examples of compounds according to the disclosure:
- 6 7-dimethoxy-3-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-chromen-4-one
- 3-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-benzonitrile
- 3-{4-[4-(2 3-dichlorophenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 3-{4-[4-(3-hydroxyphenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 6 7-dimethoxy-3-[4-(4-pyrimidin-2-yl-piperazin-1-yl)-butyl]-chromen-4-one
- 6 7-dimethoxy-3-[4-(4-pyridin-2-yl-piperazin-1-yl)-butyl]-chromen-4-one
- 3-{4-[4-(2 3-difluorophenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 3-{4-[4-(1H-benzimidazol-4-yl-)piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 3-{4-[4-(1H-indol-4-yl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 5-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-1H-quinolin-2-one
- 6 7-dimethoxy-3-{4-[4-(3-nitrophenyl)-piperazin-1-yl]-butyl}-chromen-4-one
- 3-{4-[4-(3-aminophenyl)-piperazin-1-yl-]-butyl}-6 7-dimethoxychromen-4-one
-N-(3-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide
-N-(3-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-acetamide
-methyl (3-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-carbamate
-7-{4-[4-(2 3-dichlorophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one
- 7-{4-[4-(2 3-difluorophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one
- 7-{4-[4-(3-nitrophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one
- 7-{4-[4-(3-aminophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one
- N-(3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl-acetamide
- N-(3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide
- N-(3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-ethanesulfonamide
- 2-dimethylaminoethanesulfonic acid (3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-amide
- 2-methoxyethanesulfonic acid (3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-amide
- 7-{4-[4-(1H-indol-4-yl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one
- 3-{4-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 6-methoxy-3-[4-(4-phenyl-piperazin-1-yl)-butyl]-chromen-4-one
- 6-methoxy-3-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-chromen-4-one
- 6-methoxy-3-{4-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-butyl}-chromen-4-one
- 7-{4-[4-(2 3-dichlorophenyl)piperazin-1-yl-]-butyl}-6-methyl-[1 3]dioxolo[4 5-g]chromen-8-one
- 6 7-methoxy-7 6-hydroxy-3-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-chromen-4-one
- 7-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-3H-benzoxazol-2-one
- 4-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-1 3-dihydrobenzimidazol-2-one

The disclosure relates also to pharmaceutically acceptable salts thereof  as well as to pharmaceutical compositions containing them  and to their use as medicaments intended for the treatment of disorders of the central nervous system.

The present disclosure relates also to a process for the preparation of those compounds.

The compounds of the general formula 1 are prepared according to scheme 1.

Scheme 1

A Friedel-Crafts reaction  or Fries reaction with a substituted aromatic methoxy compound 2 (Y = Me)  or substituted phenol compound 3 (Y = H) yields an aromatic ketone 3 (Y = Me  H). That reaction uses an omega halogenated hexanoic acid halide  such as 6-bromohexanoyl chloride. Condensation takes place with or without solvent in the presence of a Lewis acid  such as AlCl3  according to a method analogous to that described in Chem. Ber. 1939  72  1414  or J. Org. Chem. 1955  20  38 with chloro or bromoacetyl chloride or bromide. Here  the reaction uses bromohexanoyl chloride  which is condensed in the ortho position of the phenol function to form derivative 3. Where a solvent is employed  a chlorinated solvent  such as methylene chloride  can be used for a reaction at ambient temperature or low temperature or  for a reaction at higher temperature  dichloroethane or 1 1-2 2-tetrachloroethane  for example  may be used. The phenols used with the corresponding substituents are either commercially available  or known from the literature and prepared by demethylation in the presence of agents conventionally employed to demethylate aromatic methoxy compounds  such as HBr and Lewis acids (AlCl3  BBr3). The Friedel Crafts reaction can also be carried out on a methoxylated aromatic ring rich in electrons. The demethylation step yielding the intermediate 3 can take place after the acylation step. The phenol 3 (Y = H)  thus acylated  can be cyclised with the acetal of dimethylformamide (= DMF) or of dimethylamine (= DMA)  with heating  to yield a halogenated chromone 4. That cyclisation to form a chromone can also be carried out in DMF in the presence of PCl5 and etherate of BF3  as well as with ethyl formate in the presence of sodium according to Bull. Soc. Chim. Fr. 1944  5  302. The halobutyl chromone derivative 4 is then brought together with substituted arylpiperazines or heteroarylpiperazines of formula 5 in standard manner in the presence of a base such as K2CO3 or caesium carbonate in acetonitrile or methyl ethyl ketone to yield derivatives of formula 1. That procedure is used with piperazines of formula 5 wherein A  B and R3 are as defined hereinabove. A variant of the process can be used and comprises introducing the piperazine moiety prior to the formation of the chromone ring: thus  the condensation of the piperazine of formula 5 with the halogenated phenol of formula 3 under the same conventional alkylation conditions in basic medium (K2CO3 / CH3CN or methyl ethyl ketone) to yield compounds of formula 6. The formation of the chromone ring can then be carried out by cyclisation with DMF or the acetal of DMF or of DMA. Using that method  introducing piperazine prior to cyclisation to the chromone  allows a purer cyclised compound to be obtained than by the method of forming the chromone starting from derivative 3 (Y = H). In fact  the heating conditions for cyclisation with DMF at elevated temperature generate dimethylamine which may react with the halogenated derivative 3  yielding a secondary product (formula 4  X = NMe2)  and requires an additional purification. The person skilled in the art will be able to select a suitable method according to the substituents carried by the phenylpiperazine 5. Modifications of the piperazine substituents can also be made in the last steps  such as  for example  using piperazine of formula 5 (A = B = C  R3 = 3-NO2). Reduction of the nitro group in the product of formula 1 (A = B = C  R3 = 3-NO2) is conventionally effected by catalytic reduction with hydrogen using palladium-on-carbon or Raney nickel  or by treatment with a metal such as iron in acid medium  to yield the corresponding aniline (formula 1  A = B = C  R3 = 3-NH2). The aniline group can thus be acylated in the presence of pyridine or another base with acetyl chloride  yielding the acetamide derivative  with methyl chloroformate  yielding the methyl carbamate  or with methanesulfonyl chloride  yielding the methylsulfonamide. The reaction of the chloroethylsulfonyl chloride can be carried out in the same manner  and then the vinyl intermediate obtained can be brought together with dimethylamine or with sodium methoxide to yield  respectively  a dimethylaminoethylsulfonamide or methoxyethylsulfonamide substituent. The literature mentions heterocyclic arylpiperazines  such as 4-piperazin-1-yl-1H-indole  4-piperazin-1-yl-1H-benzimidazole  7-piperazin-1-yl-3-H-benzoxazol-2-one  4-piperazin-1-yl-1 3-dihydrobenzimidazol-2-one 5-piperazin-1-yl-1H-quinolin-2-one. Heterocyclic piperazines can be prepared by reaction of the corresponding anilines with nitrogen mustards (bischloroethylamines). Those nitrogen mustards can be N-substituted by a benzyl protecting group  which is removable by simple hydrogenolysis with Pd/C under hydrogen when the condensation with piperazine has been effected (Fr2504532 ; Fr2524884 ; Bioorg. Med. Chem. Lett. 1998  8  2675 ; Bioorg. Med. Chem. Let. 2001  11  2345  J. Med. Chem. 2002  45  4128 ; J. Med. Chem. 2004  47  871 ; Synth. Commun. 2006  36  1983 ; Synthesis 1977  33 ; Tet. Let. 1970  5265 ; Chem. Pharm. Bull. 1981  29  651 or 1979  27  2627 ; Tet. 2000  56  3245).

The disclosure thus relates also to the following preparation processes:

Process for the preparation of compounds of the general formula 1  characterised in that an optionally substituted chromone of formula 4 (X = Cl  Br  I) is prepared  which is reacted with a piperazine of formula 5.

The radicals R1  R2  R3  A and B have the meanings given hereinbefore.

Process for the preparation of compounds of the general formula 1  characterised in that an optionally substituted phenol derivative of formula 6 is prepared starting from a compound of formula 3 (X = Cl  Br)  and is reacted with DMF (= dimethylformamide) or the dimethylacetal of DMF or of DMA (= dimethylamine).

The radicals R1  R3  A and B have the meanings given hereinbefore  under alkylation conditions in the presence of a base such as K2CO3  Cs2CO3 or NEt3  in a solvent such as acetonitrile or methyl ethyl ketone.

The disclosure relates also to a pharmaceutical composition comprising at least one compound of the general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

Given the selective modulation of the transmissions of dopamine exerted by the receptor DRD3 in the limbic regions  which are implicated in emotive and cognitive processes  the compounds of the disclosure are suitable in various therapeutic applications and do not interfere with dopaminergic transmissions of the extra-pyramidal  antehypophysial or vegetative systems (for example the area postrema). The compounds of the disclosure can thus be used for the preparation of pharmaceutical compositions and medicaments for the treatment of neurological or psychiatric disease  conditions or disorders involving the DRD3 receptor  such as psychotic states.

Furthermore  since an effect of antidepressant medicaments is to increase the expression of the DRD3 receptor in regions of the brain involved in motivation  the compounds of the disclosure are able to imitate the action of antidepressant medicaments. The compounds can thus be employed for the preparation of pharmaceutical compositions and medicaments for the treatment of depression.

Given the role of the DRD3 receptor in drug-dependence states  pharmaceutical compositions or medicaments based on the compounds described in the present disclosure may usefully be administered in states associated with abstinence and/or to facilitate the detoxification of individuals dependent on cocaine  heroin  alcohol  tobacco  and other addictive substances.

The compounds according to the disclosure  like partial agonists of the DRD3 receptor generally  may also be employed as a supplementary treatment to the treatment of Parkinson""s disease with L-DOPA.

The compounds according to the disclosure  like partial agonists and antagonists of the DRD3 receptor generally  may also be employed for the treatment of essential tremor.

Accordingly  compounds of formula 1  bases or salts  can be used for the treatment of neurological or psychiatric conditions  especially conditions that can be treated by DRD3 receptor agonists  partial agonists or antagonists.

The disclosure relates also to a method of treating neurological or psychiatric conditions  diseases or disorders that comprises administering a compound of formula 1 in a therapeutically effective amount to a patient requiring treatment. The disclosure relates in addition to compounds of formula 1 for their use as medicaments.

The disclosure relates also to compounds of formula 1 for the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder or erectile dysfunction or dependence on drugs or on addictive substances.

The disclosure relates to compounds of the general formula (I) for the manufacture of a medicament for the treatment of Parkinson""s disease  psychosis  schizophrenia  dyskinesias associated with Parkinson""s disease  cognitive deficiency optionally associated with age or with Alzheimer""s disease  mood disorder  essential tremor  anxiety  depression  bipolar disorder  sexual impotence  premature ejaculation  alcoholism and nicotine addiction.

Compounds of formula 1 according to the disclosure can be administered by the oral  systemic  parenteral  nasal or rectal route. The compound can especially be administered by the oral route in an appropriate formulation. The dosages of the compounds of formula 1 in the compositions of the disclosure can be adjusted to obtain an amount of active substance that is effective in obtaining the desired therapeutic response for a composition peculiar to the method of administration. The dosage level chosen depends therefore on the desired therapeutic effect  the administration route  the desired duration of treatment and other factors.

Compounds of formula 1 were evaluated in vitro as DRD3 ligands and modulators of the activity of that receptor in accordance with the disclosure in cells expressing human recombinant DRD3 receptor. The inhibition constants (Ki) were measured by inhibition of the binding of [3H]spiperone as described by Cussac et al.  in Naunyn-Schmiedeberg’s Arch. Pharmacol . 2000  361  569. The inventors demonstrated that the compounds of formula 1 behave as potent ligands  with Ki values from 0.1 to 30 nanomole.litre-1. Those same compounds exhibit a noticeable affinity for the D2 receptor of dopamine that is from 10 to 200 times weaker. Compounds of formula 1 were evaluated for their agonist  partial agonist  or antagonist activity by using the MAP-kinase activity test on human recombinant receptors described in Cussac D. et al.  Mol. Pharmacol. 1999  56  1025-1030. The intrinsic activities of the compounds of formula 1 are between 0 (antagonist) and 0.80 (agonist).

Compounds of formula 1 were evaluated in vivo in the test of hyperactivity induced by MK-801 in the mouse (Leriche L. et al.  Neuropharmacology 2003  45  174). The ED50 values of compounds of formula 1 are between 0.01 and 6 mg/kg.
The total daily dose of the compounds for use in accordance with this disclosure  administered in single or divided doses  may be in amounts of  for example  from 0.001 to approximately 100 mg/kg body weight daily.

The specific dose level for any particular patient will depend on a variety of factors  including body weight  general health  sex  diet  duration and route of administration  levels of intestinal absorption and resorption and of excretion  combination with other medicaments and the severity of the particular condition being treated.

By way of example  but in a non-limiting manner  the preparations of the compounds of the disclosure are illustrated in the following Examples.

EXAMPLES
Example 1: 6 7-Dimethoxy-3-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-chromen-4-one

Step 1: 6-bromo-1-(2 4 5-trimethoxyphenyl)-hexan-1-one

6 ml (40 mmol) of 1 2 4-trimethoxybenzene are introduced into 80 ml of dry CH2Cl2 and the mixture is cooled to -10°C with stirring. 6-Bromohexanoyl chloride (6.2 ml  40 mmol) dissolved in 20 ml of CH2Cl2 is then added dropwise. AlCl3 (5.6 g  42 mmol) is progressively introduced in small portions into the reaction mixture. The reaction is maintained with stirring for 8h with a return to ambient temperature. The reaction mixture is then poured onto ice (200 ml) and acidified to pH 1 using HCl. The mixture is stirred until it returns to ambient temperature  1h. After evaporation of the CH2Cl2  the mixture is extracted with AcOEt  and the organic phases are separated  dried over MgSO4  filtered and evaporated. The residue is subjected to flash chromatography over SiO2 with a gradient of pure heptane to heptane-AcOEt 50-50. The pure fractions are evaporated to obtain 13.6 g (yield = 99%) of crystals. TLC SiO2 (heptane-ACOEt 70-30) Rf = 0.5; 1H NMR (CDCl3) : 7.41(s  1H)  6.50(s  1H)  3.95(s  3H)  3.91(s  3H)  3.87(s  3H)  3.43(t  2H  J = 6.76 Hz)  2.98(t  2H  J = 6.32 Hz)  1.91(m  2H)  1.71(m  2H)  1.51(m  2H).

Step 2: 6-Bromo-1-(2-hydroxy-4 5-dimethoxyphenyl)-hexan-1-one.

13.6 g of the product obtained in the above Step are dissolved in 80 ml of 48% HBr. The mixture is heated at 90°C for 5h. The reaction mixture is then poured onto ice (300 ml) and extracted with AcOEt. The organic phases are separated  dried over MgSO4  filtered and evaporated to obtain a green oil  which is subjected to flash chromatography over SiO2 with a gradient of pure heptane to heptane-AcOEt 85-15. 7.33 (yield = 56%) of 6-bromo-1-(2-hydroxy-4 5-dimethoxyphenyl)-hexan-1-one are obtained  1H NMR (CDCl3) : 12.7(s  1H)  7.08(s  1H)  6.46(s  1H)  3.91(s  3H)  3.87(s  3H)  3.44(t  2H  J = 8 Hz)  2.92(t  2H  J = 7.2 Hz)  1.93(m  2H)  1.78(m  2H)  1.55(m  2H); and also 1.4 g of the di-demethylated compound  6-bromo-1-(2 4/5-dihydro-5/4-methoxyphenyl)¬hexan-1-one  1H NMR (CDCl3) : 12.5(s  1H)  7.22(s  1H)  6.45(s  1H)  5.20(s  1H)  3.93(s  3H)  3.42(t  2H  J = 6.68 Hz)  2.89(t  2H  J = 7.32 Hz)  1.91(m  2H)  1.76(m  2H)  1.53(m  2H).

Step 3: 3-(4-Bromobutyl)-6 7-dimethoxychromen-4-one

1st method: A solution A is prepared from 500 mg of the compound of the above Step  6-bromo-1-(2-hydroxy-4 5-dimethoxyphenyl)-hexan-1-one (1.5 mmol)  dissolved in 0.60 ml (4.5 mmol) of Et2O-BF3  and the solution is cooled to 10°C. 2.3 ml of DMF are then added. There is prepared  in addition  a solution B of 4 ml of DMF and there is added thereto in small portions at 10°C 470 mg (2.25 mmol) of PCl5. Solution B is heated at 55°C for 20 min  and is then introduced dropwise into solution A  referred to at the beginning  with a return to ambient temperature. The mixture turns orangey yellow and precipitates. 50 ml of 0.1N HCl are introduced and the mixture is extracted with AcOEt  the organic phases are washed with saturated NaCl solution  separated  dried over MgSO4  filtered and evaporated. The residue is subjected to flash chromatography over SiO2 with a gradient of pure heptane to heptane-AcOEt 70-30. The purified fractions crystallise after evaporation. 300 mg of 3-(4-bromobutyl)-6 7-dimethoxychromen-4-one are obtained in the form of crystals (yield = 59%) ; TLC SiO2 hept-AcOEt 50-50 Rf = 0.4.

2nd method: A solution of 500 mg (1.5 mmol) of the compound of the above Step  6-bromo-1-(2-hydroxy-4 5-dimethoxyphenyl)-hexan-1-one  in 30 ml of dry toluene is refluxed  with stirring  with 0.6 ml (4.5 mmol) of DMF dimethylacetal. Reflux is continued for 5 h. After concentration  and purification by flash chromatography with a gradient of pure heptane to heptane-ACOEt 80-20  270 mg (yield = 53%) of 3-(4-bromobutyl)-6 7-dimethoxychromen-4-one are obtained  after evaporation  in the form of white crystals identical to those obtained by the 1st method. TLC SiO2 hept-AcOEt 70-30 Rf = 0.3. 1H NMR (DMSO) : 8.19(s  1H)  7.36(s  1H)  7.16(s  1H)  3.89(s  3H)  3.84(s  3H)  3.65(t  2H  J = 6.3 Hz)  2.38(t  2H  J = 7.3 Hz)  1.72(m  2H)  1.64(m  2H)  1.55(m  2H).

Step 4: 6 7-Dimethoxy-3-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-chromen-4-one.

The brominated derivative obtained in the above Step 3 (150 mg  0.44 mmol) is suspended in 10 ml of methyl ethyl ketone  and 120 mg (0.62 mmol) of 2-methoxyphenylpiperazine and 121 mg (0.87 mmol) of K2CO3  as well as 10 mg of tetrabutylammonium bromide  are added. The mixture is refluxed for 20 h and then concentrated. The residue is taken up in water and extracted with ethyl acetate. The organic phases are separated  dried over MgSO4  filtered and evaporated to yield a colourless oil. Flash chromatography over SiO2 eluted with a gradient of CH2Cl2 to CH2Cl2-MeOH 90-10 allows an oil to be obtained which crystallises in iPr2O. 128 mg (yield = 60%) of white crystals are obtained. M.p.°C = 124-130 ; MS (ESI) m/z = 453 (MH+) ; 1H NMR (CDCl3) : 7.72(s  1H)  7.55(s  1H)  6.92(m  5H)  3.97(s  3H)  3.86(s  3H)  3.12(m  4H)  2.69(m  4H)  2.49(m  4H)  1.64(m  4H).

The products of the following Examples are obtained by the same sequence of reactions:

Example 2: 3-{4-[4-(6 7-Dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-benzonitrile

By condensation of the brominated derivative  3-(4-bromobutyl)-6 7-dimethoxychromen-4-one  obtained in Step 3 of Example 1 with 3-cyano¬phenyl-piperazine  3-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-benzonitrile is obtained in a yield of 40%. M.p.°C = 154-155 ; analytical HPLC Sym C8  4.6x250mm  5µ  eluant : CH3CN-H2O  KH2PO4 30-70-6.8 g/l  pH4  r.t. = 9.72 min ; MS ESI  m/z = 448 (MH+) ; 1H NMR (DMSO) : 8.17(s  1H)  7.13-7.39(m  6H)  3.89(s  3H)  3.84(s  3H)  3.19(m  4H)  2.47(m  4H)  2.38(t  2H  J = 6.8 Hz)  2.32(t  2H  J = 6.8 Hz)  1.50(m  4H).

Example 3: 3-{4-[4-(2 3-Dichlorophenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one.

In a similar manner to Example 1  but using 2 3-dichlorophenylpiperazine  3-{4-[4-(2 3-dichlorophenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one is obtained in a yield of 62%. M.p.°C = 160-162 ; analytical HPLC Sym C8  4.6x250mm  5µ  eluant : CH3CN-H2O  KH2PO4 40-60-6.8 g/l  pH4  r.t. = 8.80 min ; MS ESI  m/z = 491; 1H NMR (CDCl3) : 7.72(s  1H)  7.55(s  1H)  7.14(m  2H)  6.95(m  1H)  6.83(s  1H)  3.97(s  6H  OCH3)  3.07(m  4H)  2.64(m  4H)  2.48(m  4H)  1.64(m  4H).

Preparation of the hydrochloride: 2.64 g of the base obtained above are dissolved in a mixture of 100 ml of acetone-MeOH (50-50). A solution of isopropanol  2N HCl  is added. The precipitated salt is filtered off to obtain  after drying in vacuo  2.02 g of the hydrochloride (yield = 72%). M.p.°C = 252 254.

Example 4: 3-{4-[4-(3-Hydroxyphenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one.

Using the same starting material  3-(4-bromobutyl)-6 7-dimethoxychromen-4-one obtained in Step 3 of Example 1  but with 3-hydroxyphenylpiperazine  and using a microwave reaction vessel (15 min  160°C  150 w)  3-{4-[4-(3-hydroxyphenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one is obtained in a similar manner to Example 1 in a yield of 17%. M.p.°C = 177-180 ; analytical HPLC Sym C8  4.6x250mm  5µ  eluant : CH3CN-H2O  KH2PO4 25-75-6.8 g/l  pH4  r.t. = 9.99 min ; MS ESI  m/z = 439 (MH+); 1H NMR (CDCl3) : 7.72(s  1H)  7.55(s  1H)  7.09(t  1H  J = 8 Hz)  6.83(s  1H)  6.49(d  1H  J = 8.28 Hz)  6.39(s  1H)  6.31(d  1H  J = 7.84 Hz)  3.97(s  6H  OCH3)  3.18(m  4H)  2.58(m  4H)  2.49(m  2H)  2.43(m  2H)  1.62(m  4H).

Example 5: 6 7-Dimethoxy-3-[4-(4-pyrimidin-2-yl-piperazin-1-yl)-butyl]-chromen-4-one.

In a similar manner to Example 1  but using 2-pyrimidinylpiperazine  6 7-dimethoxy-3-[4-(4-pyrimidin-2-yl-piperazin-1-yl)-butyl]-chromen-4-one is obtained in a yield of 77%. M.p.°C = 123-124 ; analytical HPLC Sym C8  4.6x250mm  5µ  eluant : CH3CN-H2O  KH2PO4 20-80-6.8 g/l  pH4  r.t. = 14.31 min ; MS ESI  m/z = 425 (MH+); 1H NMR (CDCl3) : 8.34(d  2H  J = 4.64 Hz)  8.17(s  1H)  7.36(s  1H)  7.15(s  1H)  6.60(t  1H  J = 4.6 Hz)  3.89(s  3H)  3.84(s  3H)  3.69(m  4H)  2.38(m  6H)  2.31(m  2H)  1.51(m  4H).

Example 6: 6 7-Dimethoxy-3-[4-(4-pyridin-2-yl-piperazin-1-yl)-butyl]-chromen-4-one.

In a similar manner to Example 1  but using 2-pyridinylpiperazine  6 7-dimethoxy-3-[4-(4-pyridin-2-yl-piperazin-1-yl)-butyl]-chromen-4-one is obtained in a yield of 50%. M.p.°C = 41-143 ; analytical HPLC XBridge  4.6x250mm  8.5µ  eluant : CH3CN-H2O  KH2PO4 20-80-6.8 g/l  pH4  r.t. = 14.21 min ; MS ESI  m/z = 424 (MH+); 1H NMR (DMSO) : 8.17(s  1H)  8.09(d  1H  J = 4.28 Hz)  7.5(t  1H  J = 7.6 Hz)  7.36(s  1H)  7.15(s  1H)  6.79(d  1H  J = 8.6 Hz)  6.61(t  1H  J = 5.8 Hz)  3.89(s  3H)  3.84(s  3H)  3.43(m  4H)  2.39(m  6H)  2.33(m  2H)  1.51(m  4H).

Example 7: 3-{4-[4-(2 3-Difluorophenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one 

In a similar manner to Example 1  but using 2 3-difluorophenylpiperazine described in J. Med. Chem. 2006  49  3628  3-{4-[4-(2 3-difluorophenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one is obtained in a yield of 33%. M.p.°C = 148-151; Anal: C25H28N2O4F2 = 458.51  calc C%65.49  H%6.16  N%6.11  found C%65.44  H% 6.29  N% 6.26; MS ESI  m/z = 459 (MH+); 1H NMR (DMSO) : 8.18(s  1H)  7.36(s  1H)  7.16(s  1H)  7.08(dd  1H  J = 14.4 Hz  J"" = 6.8 Hz)  6.96(dd  1H  J = 17.2 Hz  J"" = 8 Hz)  6.83(t  1H  J = 7.6 Hz)  3.89(s  3H)  3.84(s  3H)  3.32(m  4H)  3.02(m  4H)  2.36(m  4H)  1.50(m  4H).

Example 8: 3-{4-[4-(1H-Benzimidazol-4-yl-)piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one.

In a similar manner to Example 1  but using 4-benzimidazolyllpiperazine described in Tet.
2000  56  3245  3-{4-[4-(1H-benzimidazol-4-yl-)piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one is obtained in a yield of 66%. M.p.°C = 175-179; analytical HPLC XBridge  4.6x250mm  8.5µ  eluant : CH3CN-H2O  KH2PO4 20-80-6.8 g/l  pH4  r.t. = 9.41 min; MS ESI  m/z = 463 (MH+); 1H NMR (DMSO) : 12.3(m  1H)  8.19(s  1H)  8.04(s  1H)  7.37(s  1H)  7.16(s  1H)  7.03(m  2H)  6.48(m  1H)  3.89(s  3H)  3.85(s  3H)  3.45(m  4H)  3.32(m  4H)  2.57(m  4H)  2.40(m  4H)  1.54(m  4H).

Example 9: 3-{4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one.

In a similar manner to Example 1  but using 4-indolyl-piperazine described in J. Med. Chem. 2002  45  4128  3-{4-[4-(1H-indol-4-yl-)piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one is obtained in a yield of 69%. M.p.°C = 197-199; analytical HPLC XBridge  4.6x250mm  8.5µ  eluant : CH3CN-H2O  KH2PO4 30 70-6.8 g/l  pH4  r.t. = 8.15 min; MS ESI  m/z = 462 (MH+); 1H NMR (DMSO) : 11.0(m  1H)  8.19(s  1H)  7.37(s  1H)  7.22(m  1H)  6.96(m  2H)  6.43(m  1H)  6.35(m  1H)  3.89(s  3H)  3.85(s  3H)  3.09(m  4H)  2.57(m  4H)  2.40(m  4H)  1.54(m  4H).
Hydrochloride: M.p.°C = 244; Anal. C27H31N3O4  HCl = 510.43 (+ 5.88% H20) calc. C%63.26  H%6.37  N%8.20  found C%62.95  H%6.15  N%7.98.

Example 10: 5-{4-[4-(6 7-Dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-1H-quinolin-2-one.

Step 1: 5-Amino-1H-quinolin-2-one

A solution of 2.1 g (11 mmol) of 5-nitro-1H-quinolin-2-one (Chem. Pharm. Bull. 1981  29  651) in 40 ml of AcOH is hydrogenated with 210 mg of 10% Pd/C in the presence of hydrogen for 24h with vigorous stirring. The catalyst is filtered off and the mixture is evaporated. The residue is subjected to flash chromatography over SiO2 with a gradient of pure CH2Cl2 to CH2Cl2-MeOH 99 1. After evaporation  1.67 g (yield 97%) of yellow crystals are obtained. 1H NMR (DMSO) : 11.38(s  1H)  8.08(d  1H  J = 8 Hz)  7.10(t  1H  J = 7.6 Hz)  6.44(d  1H  J = 8 Hz)  6.33(d  1H  J = 8 Hz)  6.26(d  1H  J = 10 Hz)  5.85(s  2H).

Step 2: 5-Piperazin-1-yl-1H-quinolin-2-one.


800 mg of the derivative of the above Step (4.96 mmol) are introduced into a microwave reaction vessel with 890 mg (4.96 mmol) of bis-2-chloroethylamine with 1.25 ml of 2-(2-methoxyethoxy)-ethanol and heated at 150°C for 20 h. After the addition of 1N sodium hydroxide solution  the mixture is extracted with CH2Cl2. The organic phases are separated  dried over MgSO4  filtered and evaporated. Flash chromatography with a gradient of pure CH2Cl2 to CH2Cl2-MeOH-NH4OH 90-9-1 allows  after evaporation and trituration in ethyl ether  260 mg (yield = 23%) of yellow crystals to be isolated. MS  ESI m/z = 230 (MH+) ; 1H NMR (DMSO) : 11.67(s  1H)  7.99(d  1H  J = 10 Hz)  7.39(t  1H  J = 8 Hz)  6.98(d  1H  J = 8.4 Hz)  6.79(d  1H  J = 7.6 Hz)  6.45(d  1H  J = 10 Hz)  2.90(m  4H)  2.86(m  4H);

Step 3: 5-{4-[4-(6 7-Dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-1H-quinolin-2-one.

The piperazine obtained in the above Step is then condensed in the same manner as in Step 4 of Example 1 with the brominated derivative 3-(4-bromobutyl)-6 7-dimethoxychromen-4-one obtained in Step 3 of Example 1  but using acetonitrile as solvent. 300 mg (yield = 54%) of pale yellow crystals are obtained. M.p.°C = 243-246; analytical HPLC Xbridge C8  4.6x250mm  5µ  eluant : CH3CN-H2O  KH2PO4 20-80-6.8 g/l  pH4  r.t. = 12.69 min ; MS ESI  m/z = 490 (MH+).

Example 11: 6 7-Dimethoxy-3-{4-[4-(3-nitrophenyl)-piperazin-1-yl]-butyl}-chromen-4-one.

In a similar manner to Example 1  but using 3-nitrophenylpiperazine  6 7-dimethoxy-3-{4-[4-(3-nitrophenyl)-piperazin-1-yl]-butyl}-chromen-4-one is obtained in a yield of 16%. M.p.°C = 149-151 ; analytical HPLC Sym C8  4.6x250mm  5µ  eluant : CH3CN-H2O  KH2PO4 30-70-6.8 g/l  pH4  r.t. = 12.11 min ; MS APCI  m/z = 468; 1H NMR (CDCl3) : 7.72(s  1H)  7.71(d  1H  J = 7.8 Hz)  7.64(d  1H  J = 8.04 Hz)  7.55(s  1H)  7.36(t  1H  J = 8.2 Hz)  7.17(d  1H  J = 8.16 Hz)  6.83(s  1H)  3.97(s  6H)  3.29(m  4H)  2.61(m  4H)  2.47(m  4H)  1.63(m  4H).

Example 12: 3-{4-[4-(3-Aminophenyl)-piperazin-1-yl-]-butyl}-6 7-dimethoxychromen-4-one.

The nitro compound of the above Example 11 (910 mg  1.95 mmol) is hydrogenated in a mixture of 50 ml of CH2Cl2 and 50 ml of EtOH with 91 mg of 10% Pd/C under a hydrogen atmosphere for 24h with vigorous stirring. After removal of the catalyst by filtration and after evaporation  720 mg of pink crystals are isolated. Flash chromatography over SiO2  eluted with a gradient of pure CH2Cl2 to CH2Cl2-MeOH 95-5  allows 550 mg (yield = 64%) of beige crystals to be isolated by trituration with iPr2O. M.p.°C = 175-176 ; analytical HPLC Xbridge C8  4.6x250mm  5µ  eluant : CH3CN-H2O  KH2PO4 20-80-6.8 g/l  pH4  r.t. = 11.46 min ; MS ESI  m/z = 438 (MH+).

Example 13: N-(3-{4-[4-(6 7-Dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide.

427 mg (0.98 mmol) of the compound 3-{4-[4-(3-aminophenyl)-piperazin-1-yl-]-butyl}-6 7-dimethoxychromen-4-one obtained in the above Example 12 are suspended in 10 ml of CH2Cl2  0.16 ml (1.95 mmol) of pyridine is added and  at 0°C  75 µl (0.98 mmol) of mesyl chloride dissolved in 2 ml of CH2Cl2 are added dropwise. Stirring is maintained at ambient temperature for 8 h. The mixture is poured into water and extracted with CH2Cl2. The organic phases are separated  dried over MgSO4  filtered and evaporated. The residue is subjected to flash chromatography over SiO2 and eluted with a gradient of CH2Cl2 to CH2Cl2-MeOH 90-10. After evaporation  the oil obtained is crystallised in iPr2O to obtain 272 mg of beige crystals (yield = 54%). M.p.°C = 186-189 ; analytical HPLC Xbridge C8  4.6x250mm  5µ  eluant : CH3CN-H2O  KH2PO4 30-70-6.8 g/l  pH4  r.t. = 6.91 min ; MS ESI  m/z = 516 (MH+); 1H NMR (CDCl3) : 7.72(s  1H)  7.55(s  1H)  7.19(t  1H  J = 8.2 Hz)  6.83(s  1H)  6.78(s  1H)  6.73(d  1H  J = 8.52 Hz)  6.63(d  1H  J = 7.4 Hz)  6.29(m  1H)  3.97(s  6H)  3.19(m  4H)  2.99(s  3H)  2.59(m  4H)  2.49(m  2H)  2.44(m  2H)  1.59(m  4H).

Example 14: N-(3-{4-[4-(6 7-Dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-acetamide.

In a similar manner to Example 13  but using acetyl chloride and 3-{4-[4-(3-aminophenyl)-piperazin-1-yl-]-butyl}-6 7-dimethoxychromen-4-one obtained in Example 12  N-(3-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-acetamide is obtained.

Example 15: Methyl (3-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-carbamate.

In a similar manner to Example 13  but using methyl chloroformate and 3-{4-[4-(3-aminophenyl)-piperazin-1-yl-]-butyl}-6 7-dimethoxychromen-4-one obtained in Example 12  methyl (3-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-carbamate is obtained.

Example 16: 7-{4-[4-(2 3-Dichlorophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one.

Step 1: Preparation of 6-bromo-1-(6-hydroxybenzo[1 3]dioxo-5-yl)-hexane-1-one.

A solution of 1 g (7.2 mmol) of sesamol in 20 ml of CH2Cl2 is cooled to -10°C with stirring. 1.1 ml (7.2 mmol) of 6-bromohexanoyl chloride is added  and then 1 g (7.6 mmol) of AlCl3 in small portions. The temperature is allowed to rise to ambient temperature and stirring is maintained for 18 h. Hydrolysis is carried out by adding ice and acidification is carried out with concentrated HCl (2 ml). Extraction is carried out with CH2Cl2  and the organic phases  separated  dried over MgSO4  filtered and evaporated  are subjected to flash chromatography over SiO2 with a gradient of pure heptane to heptane-AcOEt 80-20 to obtain 500 mg of pale yellow crystals after evaporation (yield = 22%) MS  ESI  m/z = 314-316. 1H NMR (CDCl3) : 7.26(s  1H)  7.07(s  1H)  6.45(s  1H)  5.98(s  2H)  3.42(t  2H  J = 6.8 Hz)  2.87(t  2H  J = 7.6 Hz)  1.92(m  2H)  1.76(m  2H)  1.54(m  2H).
6-Bromo-1-(2-hydroxy-5-methoxyphenyl)-hexan-1-one is prepared in identical manner.

Step 2: Preparation of 6-[4-(2 3-dichlorophenyl)-piperazin-1-yl]-1-(6-hydroxybenzo[1 3]dioxol-5-yl)-hexan-1-one.

950 mg (3 mmol) of the brominated derivative obtained in the above Step  690 mg (3 mmol) of 2 3-dichlorophenylpiperazine  1.3 ml (9 mmol) of triethyl¬amine and 500 mg (3 mmol) of KI are added to 10 ml of CH3CN. The mixture is refluxed  with stirring  for 20 h. Saturated NaHCO3 solution (50 ml) is added  and extraction is carried out with AcOEt. The organic phases are separated  dried over MgSO4  filtered and evaporated. Flash chromatography over SiO2 eluted with a gradient of pure CH2Cl2 to CH2Cl2-MeOH 90-10 allows  after evaporation and crystallisation in iPr2O  960 mg (yield = 69%) of beige crystals to be obtained. 1H NMR (DMSO) : 7.45(s  1H)  7.30(m  2H)  7.13(m  1H)  6.57(s  1H)  6.08(s  2H)  2.96(m  6H)  2.50(m  4H)  2.33(m  2H)  1.63(m  2H)  1.48(m  2H)  1.36(m  2H)

Step 3: 7-{4-[4-(2 3-Dichlorophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one

A solution of 600 mg (1.30 mmol) of the compound obtained in the above Step in 5 ml of dimethylformamide dimethylacetal is heated at 90°C for 5 h with stirring. 50 ml of water are added and extraction with CH2Cl2 is carried out. The organic phases are separated  dried over MgSO4  filtered and evaporated. Flash chromatography over SiO2 eluted with a gradient of CH2Cl2 to CH2Cl2-MeOH 90-10 allows  after concentration and crystallisation in iPr2O  250 mg (yield = 40%) of beige crystals to be obtained. M.p.°C = 140-142 ; analytical HPLC Xbridge C8  4.6x250mm  5µ  eluant : CH3CN-H2O  KH2PO4 40-60-6.8 g/l  pH4  r.t. = 9.51 min ; MS ESI  m/z = 475-477; Anal C24H24N2O4Cl2 = 475.38 + 0.21 H2O  calc. C%60.64  H%5.09  N%5.89  found C%60.61  H%5.07  N%6.45; 1H NMR (DMSO) : 8.17(s  1H)  7.33(s  1H)  7.29(m  2H)  7.22(s  1H)  7.13(m  1H)  6.02(s  2H)  2.96(m  4H)  2.50(m  6H)  2.35(m  2H)  1.51(m  4H).

Example 17: 7-{4-[4-(2 3-Difluorophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-]chromen-8-one.

In an identical manner to the above Example 16  but using difluorophenylpiperazine  7-{4-[4-(2 3-difluorophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one is obtained . M.p.°C = 140-142 ; analytical HPLC Xbridge C8  4.6x250mm  5µ  eluant : CH3CN-H2O  KH2PO4 35-65-6.8 g/l  pH4  r.t. = 9.59 min ; MS ESI  m/z = 443 (MH+); Anal C24H24N2O4F2 = 442.46 + 0.78 H2O  calc. C%65.15  H%5.47  N%6.33  found C%65.41  H%5.71  N%6.77; 1H NMR (DMSO) : 8.16(s  1H)  7.33(s  1H)  7.22(s  1H)  7.08(m  1H)  6.96(m  1H)  6.83(t  1H  J = 8 Hz)  6.20(s  2H)  3.02(m  4H)  2.50(m  4H)  2.34(m  4H)  1.51(m  4H).

Example 18: 7-{4-[4-(3-Nitrophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one.

In an identical manner to the above Example 16  but using 3 nitrophenylpiperazine  7-{4-[4-(3-nitrophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one is obtained. MS ESI  m/z = 452 (MH+); 1H NMR (DMSO) : 8.17(s  1H)  7.62(s  1H)  7.57(d  1H  J = 7.6 Hz)  7.46(t  1H  J = 8.4 Hz)  7.39(d  1H  J = 8.4 Hz)  7.33(s  1H)  7.22(s  1H)  6.20(s  2H)  3.24(m  4H)  2.50(m  4H)  2.35(m  4H)  1.50(m  4H).

Example 19: 7-{4-[4-(3-Aminophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one.

In an identical manner to Example 12  but using the compound obtained in Example 18  the aniline 7-{4-[4-(3-aminophenyl)-piperazin-1-yl]-butyl}-[1 3]¬dioxolo¬[4 5-g]chromen-8-one is obtained. MS ESI  m/z = 422 (MH+); 1H NMR (CDCl3) : 7.68(s  1H)  7.52(s  1H)  7.03(t  1H  J = 8 Hz)  6.81(s  1H)  6.36(d  1H  J = 8 Hz)  6.25(d  1H  J = 2 Hz)  6.21(d  1H  J = 7.6 Hz)  6.08(s  2H)  3.16(m  4H)  2.57(m  2H)  2.47(t  2H  J = 6.4 Hz)  2.41(t  2H  J = 7.6 Hz)  1.59(m  4H).

Example 20: N-(3-{4-[4-(8-Oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl-acetamide.

In an identical manner to Example 14  but using 7-{4-[4-(3-aminophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one instead of 3-{4-[4-(3-aminophenyl)-piperazin-1-yl-]-butyl}-6 7-dimethoxychromen-4-one  N (3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-acetamide is obtained.

Example 21: N-(3-{4-[4-(8-Oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide.

In an analogous manner to Example 13  but using 7-{4-[4-(3-aminophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one obtained in Example 19 instead of 3-{4-[4-(3-aminophenyl)-piperazin-1-yl-]-butyl}-6 7-dimethoxy¬chromen-4-one  N-(3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide is obtained. M.p.°C=174; analytical HPLC Xbridge C8  4.6x250mm  5µ  eluant : CH3CN-H2O  KH2PO4 25-75-6.8 g/l  pH4  r.t. = 13.23 min; MS  ESI  m/z = 499 (MH+) ; 1H NMR (DMSO): 9.51(s 1H)  8.16(s  1H)  7.33(s  1H)  7.22(s  1H)  7.13(t  1H  J = 8.4 Hz)  6.73(s  1H)  6.67(d  1H  J = 8.4 Hz)  6.63(d  1H)  6.20(s  2H)  3.07(m  4H)  2.94(s  3H)  2.47(m  4H)  2.36(t  2H  J = 6.4 Hz and 6.8 Hz)  1.49(m  4H).

Hydrochloride: M.p.°C = 260  Anal. C25H30ClN3O6S = 499.59 + 0.34% H2O  calc. C%56.02  H%5.64  N%7.84  S%5.98  found C%56.37  H%5.69  N%7.65  S%6.89.

Example 22: N-(3-{4-[4-(8-Oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-ethanesulfonamide.

In an identical manner to Example 13  but using corresponding reactants  N-(3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-ethanesulfonamide is obtained. MS  ESI  m/z = 514 (MH+) ; 1H NMR of the hydrochloride (DMSO): 9.69(s 1H)  8.22(s  1H)  7.34(s  1H)  7.25(s  1H)  7.19(t  1H  J = 8.4 Hz)  6.80(s  1H)  6.73(m  1H)  6.21(s  2H)  3.71(m  2H)  3.54(m  2H)  3.08(m  6H)  2.40(m  2H)  1.72(m  2H)  1.55(m  2H).

Example 23: 2-dimethylaminoethanesulfonic acid (3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-amide.

Step 1: In a similar manner to Example 21  7-{4-[4-(3-aminophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one is condensed with 2-chloroethyl¬sulfonyl chloride. (3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-ethenesulfonamide is obtained. 1H NMR (DMSO): 9.79(s  1H)  8.16(s  1H)  7.33(s  1H)  7.22(s  1H)  7.09(t  1H  J = 8 Hz)  6.75(dd  1H  J = 16.4 Hz and 10 Hz)  6.67(d  1H)  6.63(dd  1H  J = 10 Hz and 2 Hz)  6.57(dd  1H  J = 8 Hz and 1.2 Hz)  6.20(s  2H)  6.09(d  1H  J = 16.4 Hz)  6.01(d  1H  J = 9.6 Hz)  3.05(m  4H)  2.47(m  4H)  2.34(m  4H)  1.51(m  4H).

Step 2: The compound of the above Step 1 (100 mg  0.2 mmol) is introduced into a sealed tube with 2 ml of 2M dimethylamine solution in MeOH at ambient temperature for 3 h. The batch is evaporated to dryness  and the residue is triturated with isopropanol HCl  the hydrochloride is introduced into iPr2O and filtered. MS  ESI  m/z = 557 (MH+) ; 1H NMR (DMSO) of the hydrochloride: 10.10(s  1H)  8.23(s  1H)  7.22(m  2H)  6.78(m  3H)  6.21(s  2H)  3.77(m  2H)  3.68(m  2H)  3.55(m  2H)  3.45(m  2H)  3.13(m  6H)  2.76(s  6H)  2.40(m  2H)  1.74(m  2H)  1.55(m  2H).

Example 24: 2-methoxyethanesulfonic acid (3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-amide

In a similar manner to Example 23  a solution of sodium methoxide can be used with the intermediate of Step 1 of Example 23 to yield 2-methoxy¬ethane¬sulfonic acid (3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-amide.

Example 25: 7-{4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one.

By means of the same reaction sequence as indicated in Example 16  but using 4-indolylpiperazine  7-{4-[4-(1H-indol-4-yl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one is obtained  M.p.°C=177-179 ; analytical HPLC Xbridge C8  4.6x250mm  5µ  eluant : CH3CN-H2O  KH2PO4 30-70-6.8 g/l  pH4  r.t. = 9.69 min; MS  ESI  m/z = 446 (MH+) ; 1H NMR (DMSO): 11.0(s  1H)  9.51(s 1H)  8.18(s  1H)  7.33(s  1H)  7.23(m  2H)  7.00(d  1H  J = 8 Hz)  6.94(t  1H  J = 7.2 Hz)  6.42(d  1H  J = 7.2 Hz)  6.34(s  1H)  6.20(s  2H)  3.09(m  4H)  2.57(m  4H)  2.37(m  4H)  1.51(m  4H).

Hydrochloride: Anal. C26H27N3O4  HCl = 481.98 + 0.54% H2O  calc. C%64.79  H%5.86  N%8.72  found C%63.78  H%5.70  N%8.46.

Example 26: 3-{4-[4-(3-Trifluoromethylphenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one.

By means of the same reaction sequence as in Steps 2 and 3 of Example 16  but using 6-bromo-1-(2-hydroxy-4 5-dimethoxyphenyl)-hexan-1-one prepared in Step 2 of Example 1  3-{4-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one is prepared in salt form with 1.5 equivalents of fumaric acid. M.p.°C = 220 ; TLC: SiO2 elution CHCl3-MeOH 90-10  Rf = 0.56; Anal. C26H29F3N2O4  C6H6O6 = 664.63  calc. C%57.82  H%5.30  N%4.21  F%8.57  found C%57.71  H%5.24  N%4.30  F%8.80%.

Example 27: 6-Methoxy-3-[4-(4-phenyl-piperazin-1-yl)-butyl]-chromen-4-one.

By means of the same reaction sequence as in Steps 2 and 3 of Example 16  but using 6-bromo-1-(2-hydroxy-4-methoxyphenyl)-hexan-1-one prepared according to Steps 1 and of Example 1  and using 1 4-dimethoxybenzene instead of 1 2 4-trimethoxybenzene  or using 4-methoxyphenol as starting material in accordance with the same procedure as that in Step 1 of Example 16  6-methoxy-3-[4-(4-phenyl-piperazin-1-yl)-butyl]-chromen-4-one is obtained  prepared in the form of white hydrochloride crystals. M.p.°C = 198 ; TLC: SiO2 elution CHCl3-MeOH-NH4OH 95-4.5-0.5  Rf = 0.45; Anal. C24H29ClN2O3 = 428.94  calc. C%67.20  H%6.81  N%6.53  Cl%8.26  found C%66.78  H%6.82  N%6.47  Cl%7.95%.

Example 28: 6-Methoxy-3-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-chromen-4-one.

In an identical manner to the above Example but using corresponding starting materials  6-methoxy-3-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-chromen-4-one is prepared in the form of white hydrochloride crystals. M.p.°C = 191 ; TLC: SiO2 elution CHCl3-MeOH-NH4OH 95-4.5-0.5  Rf = 0.67; Anal. C25H31ClN2O4 = 458.97  calc. C%65.42  H%6.81  N%6.10  Cl%7.72  found C%66.28  H%6.88  N%6.08  Cl%7.64%.

Example 29: 6-Methoxy-3-{4-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-butyl}-chromen-4-one.

In an identical manner to the above Example but using corresponding starting materials  6-methoxy-3-{4-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-butyl}-chromen-4-one is prepared in the form of white hydrochloride crystals. M.p.°C = 180 ; TLC: SiO2 elution CHCl3-MeOH-NH4OH 95-4.5-0.5  Rf = 0.56; Anal. C25H28ClF3N2O3 = 496.45  calc. C%60.42  H%5.68  N%5.64  Cl%7.13  F%11.48  found C%60.23  H%5.63  N%5.63  Cl%6.97%  F%11.28.

Example 30: 7-{4-[4-(2 3-Dichlorophenyl)piperazin-1-yl-]-butyl}-6-methyl-[1 3]dioxolo[4 5-g]chromen-8-one.

6-[4-(2 3-dichlorophenyl)-piperazin-1-yl]-1-(6-hydroxybenzo[1 3]dioxol-5-yl)-hexan-1-one (200 mg  0.43 mmol) obtained in Step 2 of Example 16 is introduced into a microwave reaction vessel with 1 ml of dimethylacetamide dimethylacetal and heated at 160°C for 5 min. The mixture is thrown into water and then extracted with AcOEt. The organic phases are separated  dried over MgSO4  filtered and evaporated. Flash chromatography over SiO2 with an elution gradient of CH2Cl2 to CH2Cl2-MeOH 90-10 allows  after evaporation and trituration in iPr2O  30 mg (yield 14%) of beige crystals to be obtained. M.p.°C=153-155 ; analytical HPLC Xbridge C8  4.6x250mm  5µ  eluant : CH3CN-H2O  KH2PO4 40-60-6.8 g/l  pH4  r.t. = 11.09 min; MS  ESI  m/z = 489-491 (MH+) ; 1H NMR (DMSO): 7.29(m  3H)  7.16(m  2H)  6.18(s  2H)  2.96(m  4H)  2.45(m  6H)  2.40(s  3H)  2.35(m  2H)  1.46(m  4H).

Example 31: 6/7-Methoxy-7/6-hydroxy-3-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-chromen-4-one

This compound is obtained by the same reaction sequence as for Example 1 in Steps 3 and 4  but using as starting material 6-bromo-1-(2 4-dihydro-5-methoxyphenyl)hexan-1-one obtained as secondary product in Step 2 of the demethylation of Example 1. Analytical HPLC Xbridge C8  4.6x250mm  5µ  eluant: CH3CN-H2O  KH2PO4 25-75-6.8 g/l  pH4  r.t. = 11.27 min; MS  ESI  m/z = 439 (MH+)

Example 32: 7-{4-[4-(6 7-Dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-3H-benzoxazol-2-one.

In a similar manner to Example 1  Step 4  but using 7-piperazin-1-yl-3H-benzoxazol-2-one described in Bioorg. Med. Chem. Let. 2001  11  2345  7-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-3H-benzoxazol-2-one is obtained.

Example 33: 4-{4-[4-(6 7-Dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-1 3-dihydrobenzimidazol-2-one.

In a similar manner to Example 1  Step 4  but using the hydrogenolysis derivative of 4-(4-benzylpiperazin-1-yl)-1 3-dihydrobenzimidazol-2-one described in Bioorg. Med. Chem. Let. 1998  8  2675  4-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-1 3-dihydrobenzimidazol-2-one is obtained.

WE CLAIM:
1. A compound of general formula 1

wherein:
R1 represents one or more identical or different substituent(s) on the benzene ring  each representing  independently  a hydrogen atom or a halogen atom  or a C14alkoxy group or an OH group  or a C1-4alkyl group or an O(CH2)nO- group in which n = 1 or 2.
-R2 represents a hydrogen atom or a C1-4alkyl group.
-A and B represent  independently  either a nitrogen atom or a carbon atom.
-R3 represents a hydrogen atom or one or more identical or different substituent(s) selected from the group composed of: a halogen atom  a C1 4alkyl group  a C1-4alkoxy or C1-4thioalkoxy group  an -O(CH2)nO- group in which n = 1 or 2  an NO2 group  an NHSO2R4 group  an NHR5 group  an OH group  a C1-4haloalkyl group  a CN group  a C1-4alkoxycarbonyl group  a C1 4alkylcarbonyl group  a C1-4hydroxyalkyl group and a benzyl or phenyl substituent optionally substituted by a C1-4alkoxy or a C1-4alkyl group or a halogen atom 
-or R3 constitutes a ring fused with the benzene ring carrying it  selected from the group composed of a naphthalene  an indole  a benzimidazole  a carbostyril  a benzoxazolone and a benzimidazolone.
-R4 represents a C1-4alkyl group or a C1-4dialkylamino group or a C1-4alkoxyalkyl group or a C1-4dialkylaminoalkyl group or a phenyl or phenyl-C1-4alkyl group 
-R5 represents a hydrogen atom or a C1-4alkylcarbonyl group or a C1-4alkoxy-carbonyl group 
and also their pharmaceutically acceptable salts.

2. The compound according to claim 1  characterised in that R1 represents one or more identical or different substituent(s) selected from the group composed of a C1 4alkoxy group  an OH group and an -O(CH2)nO- group in which n = 1 or 2.

3. The compound according to claim 1 or 2  characterised in that R2 represents a hydrogen atom.

4. The compound according to any one of claims 1 to 3  characterised in that R3 represents a hydrogen atom when A and/or B represents a nitrogen atom.

5. The compound according to any one of claims 1 to 3  characterised in that A and B simultaneously represent a carbon atom.

6. The compound according to any one of claims 1 to 3  characterised in that R3 represents one or more identical or different substituent(s) selected from the group composed of : a halogen atom  a C1-4alkoxy group  an -O(CH2)nO- group in which n = 1 or 2  an NHSO2R4 group  an OH group and a CN group.

7. The compound according to any one of claims 1 to 3  characterised in that R3  together with the benzene ring carrying it  represents an indole group or a benzimidazole group or a carbostyril group.

8. The compound according to any one of claims 1 to 7  characterised in that it is selected from the following group of compounds:
- 6 7-dimethoxy-3-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-chromen-4-one
- 3-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-benzonitrile
- 3-{4-[4-(2 3-dichlorophenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 3-{4-[4-(3-hydroxyphenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 6 7-dimethoxy-3-[4-(4-pyrimidin-2-yl-piperazin-1-yl)-butyl]-chromen-4-one
- 6 7-dimethoxy-3-[4-(4-pyridin-2-yl-piperazin-1-yl)-butyl]-chromen-4-one
- 3-{4-[4-(2 3-difluorophenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 3-{4-[4-(1H-benzimidazol-4-yl-)piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 3-{4-[4-(1H-indol-4-yl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 5-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-1H-quinolin-2-one
- 6 7-dimethoxy-3-{4-[4-(3-nitrophenyl)-piperazin-1-yl]-butyl}-chromen-4-one
- 3-{4-[4-(3-aminophenyl)-piperazin-1-yl-]-butyl}-6 7-dimethoxychromen-4-one
- N-(3-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide
- N-(3-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-acetamide
- methyl (3-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-carbamate
- 7-{4-[4-(2 3-dichlorophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one
- 7-{4-[4-(2 3-difluorophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one
- 7-{4-[4-(3-nitrophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one
- 7-{4-[4-(3-aminophenyl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one
- N-(3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl-acetamide
- N-(3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide
- N-(3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-ethanesulfonamide
- 2-dimethylaminoethanesulfonic acid (3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-amide
- 2-methoxyethanesulfonic acid (3-{4-[4-(8-oxo-8H-[1 3]dioxolo[4 5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-amide
- 7-{4-[4-(1H-indol-4-yl)-piperazin-1-yl]-butyl}-[1 3]dioxolo[4 5-g]chromen-8-one
- 3-{4-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-butyl}-6 7-dimethoxychromen-4-one
- 6-methoxy-3-[4-(4-phenyl-piperazin-1-yl)-butyl]-chromen-4-one
- 6-methoxy-3-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-chromen-4-one
- 6-methoxy-3-{4-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-butyl}-chromen-4-one
- 7-{4-[4-(2 3-dichlorophenyl)piperazin-1-yl-]-butyl}-6-methyl [1 3]dioxolo[4 5-g]chromen-8-one
- 6 7-methoxy-7 6-hydroxy-3-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-chromen-4-one
- 7-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-3H-benzoxazol-2-one
- 4-{4-[4-(6 7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-1 3-dihydrobenzimidazol-2-one

9. A process for preparation of compounds of general formula 1 according to any one of claims 1 to 8  characterised in that an optionally substituted chromone of formula 4 (X = Cl  Br  I) is prepared  which is reacted with a piperazine of formula 5.

radicals R1  R2  R3  A and B have the meanings given in claim 1.

10. A process for preparation of compounds of general formula 1 according to any one of claims 1 to 8  characterised in that an optionally substituted phenol derivative of formula 6 is prepared starting from a compound of formula 3 (X = Cl  Br)  and is reacted with DMF or the dimethylacetal of DMF or of DMA.

The radicals R1  R3  A and B have meanings given in claim 1  under alkylation conditions in presence of a base such as K2CO3  Cs2CO3 or NEt3  in a solvent such as acetonitrile or methyl ethyl ketone.

11. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

12. A process for obtaining a pharmaceutical composition as claimed in claim 11  said process comprising acts of:
a) preparing compound claimed in any of claims 1-8 by processes as claimed in claims 9-10; and
b) adding pharmaceutically acceptable excipient to the compound or pharmaceutically acceptable salt thereof to obtain the pharmaceutical composition.

13. The process as claimed in claim 12  wherein the pharmaceutically acceptable excipient is chosen from group comprising diluent  adjuvant  preservative  filler disintegrator  wetting agent  emulsifier  dispersant  antibacterial or antifungal agent  or also agents that would allow intestinal and digestive absorption and resorption to be delayed.

14. A method of modulating DRD3 Receptor  said method comprising act of contacting compound as claimed in claims 1 to 8 with cell expressing DRD3 receptors to modulate the DRD3 receptor.

15. The method as claimed in claim 14  wherein the compound is a dopaminergic D3 receptor ligand.

16. The method as claimed in claim 14  wherein the compound is an agonist or partial agonist or antagonist of DRD3 receptor.