N,N'-disubstituted benzimidazolone derivatives with affinity at the serotonin and dopamine receptors

Abstract

A compound of formula (I) 1 wherein: R.sup.1 is C.sub.1-C.sub.6-alkyl substituted by a group selected from OH, C.sub.1-C.sub.6-alkoxy, --OCONHC.sub.1-C.sub.6-alkyl, --OCONHC.sub.1-C.sub.6-alkyl, --NHSO.sub.2C.sub.1-C.sub.6-alkyl, and --NHCOC.sub.1-C.sub.6-alkyl, or R.sup.1 is C.sub.1-C.sub.6-alkyl substituted by a saturated or unsaturated 5- or 6-membered heterocycle containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen, the heterocycle optionally substituted by a group selected from C.sub.1-C.sub.4-alkyl, halogen, and benzyl; R.sup.2 and R.sup.3 together with the nitrogen form a saturated or unsaturated 5- or 6-membered heterocyclic ring optionally containing nitrogen or oxygen as an additional heteroatom, the heterocyclic ring thereof substituted by a group selected from phenyl, benzyl, and diphenylmethyl, each of these groups optionally mono- or di-substituted by one or two groups selected from CF.sub.3, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, phenyl, benzyl, halogen, and OH, or R.sup.2 and R.sup.3 together with the nitrogen form a saturated or unsaturated 5- or 6-membered heterocyclic ring optionally containing nitrogen or oxygen as an additional heteroatom, the heterocyclic ring thereof linked via a single bond, a methylene-bridge, or spiro-connected to a saturated or unsaturated heterocyclic group containing one or two heteroatoms selected from oxygen and nitrogen, the heterocyclic group optionally mono- or di-substituted by a group selected from CF.sub.3, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, phenyl, benzyl, halogen, .dbd.O, and OH, or R.sup.2 and R.sup.3 together with the nitrogen form a saturated or unsaturated bi- or tricyclic heterocyclic ring-system optionally containing nitrogen or oxygen as an additional heteroatom, the heterocyclic ring-system being optionally substituted by a group selected from CF.sub.3, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, phenyl, benzyl, halogen, .dbd.O, and OH; and A is C.sub.1-C.sub.6-alkylene, C.sub.2-C.sub.6-alkenylene, or C.sub.2-C.sub.6-alkynylene, their pharmaceutically acceptable salts, their preparation, and their use for therapeutic purposes.

Description

[0001] The present invention relates to novel pharmacologically active N,N-disubstituted benzimidazolone derivatives and their addition salts which bind the serotonin or dopamine receptors, to their preparation and their use for therapeutic purposes. These compounds are able to discriminate the different serotonin and dopamine receptor subtypes like 5-HT.sub.1A, 5-HT.sub.2A, and D.sub.4 at which they can act as agonists or antagonists. Owing to this pharmacological activity, the present compounds are useful in the treatment of anxiety disorders, affective disorders such as depression, psychosis and schizophrenia, eating disorders, sexual disorders, Parkinson, stroke and traumatic brain injury.

BACKGROUND OF THE INVENTION

[0002] Serotonin (5-HT) and dopamine (DA) recognize several well defined cell surface receptor subtypes. Among these, 5-HT.sub.1A and 5-HT2A having a high and a low affinity for 5-HT, respectively, and D.sub.4 at which DA has high affinity, have been implicated in many Central Nervous System (CNS) disorders.

[0003] In the previous art, several classes of compounds able to interfere with the neurotransmission at 5-HT or DA receptor subtypes are known. Particularly, derivatives based on the core structure of the aryl piperazine and benzimidazolone have been described (e.g., GB 2023594, U.S. Pat. No. 3,472,854, U.S. Pat. No. 4,954,503, WO-9616949, WO-9501965, and WO-9833784), and targeted both to generic 5-HT or DA receptors and to a specific receptor subtype. In another patent (U.S. Pat. No. 5,576,318) are described compounds based both on the benzimidazolone and phenylpiperazine structures: in this latter case the described affinities are limited to 5-HT.sub.1A and 5-HT.sub.2A receptor subtypes.

DETAILED DESCRIPTION OF THE INVENTION

[0004] Now we describe, and this is the object of the present invention, new derivatives of a benzimidazolone core structure. The N-substituents are alkyl chains bearing additional hydrophilic functional groups whereas the N'-substituents are alkyl or alkenyl spacers connecting the benzimidazolone scaffold to a large set of secondary amines bearing other diversity points. The compounds included in this invention possess an interesting affinity profile at the said serotonin and dopamine receptor subtypes: indeed some of them have a high and preferential affinity at a given site (e.g., 5-HT.sub.1A, 5-HT.sub.2A, or D.sub.4) whereas some others have a mixed affinity at the said receptors. Moreover, a selected pool of compounds possesses an agonistic activity at the 5-HT.sub.1A receptor coupled with an antagonistic activity at the 5-HT.sub.2A receptor. Owing to their peculiar profile, the present compounds may play a role in the regulation of neurotransmission at the serotonin and/or the dopamine sites and thus may be of value in the treatment of those diseases where an altered functioning of neurosignal transmission is present. Examples of these disorders include anxiety, depression, schizophrenia, Parkinson, sleep, sexual and eating disorders, stroke and brain injury. Particularly the compounds included in the present invention can be of value in the treatment of depression according to the mounting evidence that 5-HT.sub.1A full agonists or high efficiency partial agonists are required for a robust antidepressant effect. In fact, electrophysiology studies suggest that repeated administration of a variety of antidepressant treatments facilitate 5-HT.sub.1A neurotransmission in the hippocampus, possibly through either an increased sensitivity of post-synaptic 5-HT.sub.1A receptors or a decreased sensitivity of 5-HT.sub.1A autoreceptors. Furthermore, there is some evidence from controlled clinical trials to support this suggestion. In addition the compound's ability to block the 5-HT.sub.2A receptor is also of value: indeed, the stimulation of 5-HT.sub.1A and 5-HT.sub.2A receptors lead to opposite electrical events, inhibitory and excitatory, respectively. Thus only a concurrent activation of 5-HT.sub.1A coupled with antagonism at 5-HT.sub.2A receptors may completely and rapidly inhibit 5-HT post-synaptic cells, an important physiological event for antidepressant effects.

[0005] The present invention pertains to compounds of general formula (I) 2

[0006] wherein:

[0007] R.sup.1 denotes C.sub.1-C.sub.6-alkyl, preferably C.sub.1-C.sub.4-alkyl, being substituted by a group selected from OH, C.sub.1-C.sub.6-alkoxy, --OCONHC.sub.1-C.sub.6-alkyl, --OCONHC.sub.1-C.sub.6-alkyl, --NHSO.sub.2C.sub.1-C.sub.6-alkyl, and --NHCOC.sub.1-C.sub.6-alkyl, or

[0008] R.sup.1 denotes C.sub.1-C.sub.6-alkyl, preferably C.sub.1-C.sub.4-alkyl, being substituted by a saturated or unsaturated 5- or 6-membered heterocycle containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen, said heterocycle being optionally substituted by a group selected from C.sub.1-C.sub.4-alkyl, halogen, and benzyl;

[0009] R.sup.2 and R.sup.3 together with the nitrogen form a saturated or unsaturated 5- or 6-membered heterocyclic ring which may contain nitrogen or oxygen as an additional heteroatom, whilst the heterocyclic ring is substituted by a group selected from phenyl, benzyl, and diphenylmethyl, said group being optionally mono- or di-substituted by one or two groups selected from CF.sub.3, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, phenyl, benzyl, halogen, and OH, or

[0010] R.sup.2 and R.sup.3 together with the nitrogen form a saturated or unsaturated 5- or 6-membered heterocyclic ring which may contain nitrogen or oxygen as an additional heteroatom, said heterocyclic ring being linked via a single bond, a methylene-bridge or spiro-connected to another saturated or unsaturated heterocyclic group containing one or two heteroatoms selected from oxygen and nitrogen, said heterocyclic group being optionally mono- or di-substituted by a group selected from CF.sub.3, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, phenyl, benzyl, halogen, .dbd.O, and OH, or

[0011] R.sup.2 and R.sup.3 together with the nitrogen form a saturated or unsaturated bi- or tricyclic heterocyclic ring-system which may contain nitrogen or oxygen as an additional heteroatom, said heterocyclic ring-system being optionally substituted by a group selected from CF.sub.3, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, phenyl, benzyl, halogen, .dbd.O, and OH;

[0012] A denotes C.sub.1-C.sub.6-alkylene, preferably C.sub.1-C.sub.4-alkylene, C.sub.2-C.sub.6-alkenylene, preferably C.sub.2-C.sub.4-alkenylene, or C.sub.2-C.sub.6-alkynylene, preferably C.sub.2-C.sub.4-alkynylene,

[0013] or a pharmaceutically acceptable salt thereof.

[0014] Preferred compounds are those of formula (I), wherein:

[0015] R.sup.1 denotes C.sub.1-C.sub.4-alkyl, preferably C.sub.2-C.sub.3-alkyl, being substituted by a group selected from OH, C.sub.1-C.sub.4-alkoxy, --OCONHC.sub.1-C.sub.4-alkyl, --OCONHC.sub.1-C.sub.4-alkyl, --NHSO.sub.2C.sub.1-C.sub.4-alkyl, and --NHCOC.sub.1-C.sub.4-alkyl, or

[0016] R.sup.1 denotes C.sub.1-C.sub.4-alkyl, preferably C.sub.2-C.sub.3-alkyl, being substituted by a saturated or unsaturated 6-membered heterocycle containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen; p R.sup.2 and R.sup.3 together with the nitrogen form a saturated or unsaturated 5- or 6-membered heterocyclic ring which may contain nitrogen as an additional heteroatom, whilst the heterocyclic ring is substituted by a group selected from phenyl, benzyl, diphenylmethyl, pyridinyl, pyrimidinyl, benzimidazolonyl, and 3,4-methylenedioxibenzyl, said group being optionally mono- or di-substituted by a group selected from CF.sub.3, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, halogen, and OH;

[0017] A denotes C.sub.1-C.sub.4-alkylene or C.sub.2-C.sub.4-alkenylene,

[0018] or a pharmaceutically acceptable salt thereof.

[0019] Also preferred compounds are those of formula (I), wherein:

[0020] R.sup.1 denotes ethyl, being substituted by a group selected from OH, OCH.sub.3, OCH.sub.2CH.sub.3, --OCONHCH.sub.3, --OCONHCH.sub.2CH.sub.3, --NHSO.sub.2CH.sub.3, --NHSO.sub.2CH.sub.2CH.sub- .3, --NHCOCH.sub.3, --NHCOCH.sub.2CH.sub.3, morpholinyl, piperazinyl, and piperidinyl

[0021] R.sup.2 and R.sup.3 together with the nitrogen form a 6-membered saturated or unsaturated heterocyclic ring which may contain nitrogen as an additional heteroatom, whilst the heterocyclic ring is substituted by a group selected from phenyl, pyridinyl, pyrimidinyl, benzimidizalonyl, and substituted phenyl being mono- or di-substituted by a group selected from CF.sub.3, CH.sub.3, OCH.sub.3, F, and Cl;

[0022] A denotes C.sub.1-C.sub.4-alkylene or C.sub.2-C.sub.4-alkenylene,

[0023] or a pharmaceutically acceptable salt thereof.

[0024] Also of interest are compounds of formula (I), wherein:

[0025] R.sup.1 denotes ethyl, being substituted by a group selected from OH, OCH.sub.3, --OCONHCH.sub.2CH.sub.3, --NHSO.sub.2CH.sub.3, --NHCOCH.sub.3, morpholinyl, and piperidinyl;

[0026] R.sup.2 and R.sup.3 together with the nitrogen form a 6-membered saturated or unsaturated heterocyclic ring which may contain nitrogen as an additional heteroatom, whilst the heterocyclic ring is substituted by a group selected from pyridinyl, phenyl, and substituted phenyl being mono- or di-substituted by a group selected from CF.sub.3, CH.sub.3, OCH.sub.3, F, and Cl;

[0027] A denotes ethylene, propylene, butylene, or butenylene,

[0028] or a pharmaceutically acceptable salt thereof.

[0029] Of particular interest are compounds of formula (I), wherein:

[0030] R.sup.1 denotes ethyl, being substituted by a group selected from OH, OCH.sub.3, --OCONHCH.sub.2CH.sub.3, --NHSO.sub.2CH.sub.3, --NHCOCH.sub.3, morpholinyl, and piperidinyl;

[0031] R.sup.2 and R.sup.3 together with the nitrogen form a ring selected from the group consisting of piperazine, piperidine, and tetrahydropyridine, which is substituted by a group selected from pyridinyl, phenyl, and substituted phenyl being mono- or di-substituted by a group selected from CF.sub.3, CH.sub.3, and Cl;

[0032] A denotes ethylene, butylene, or butenylene,

[0033] or a pharmaceutically acceptable salt thereof.

[0034] Furthermore preferred are compounds of formula (I), wherein:

[0035] R.sup.1 denotes ethyl, being substituted by a group selected from OH, OCH.sub.3, --OCONHCH.sub.2CH.sub.3, and --NHSO.sub.2CH.sub.3;

[0036] R.sup.2 and R.sup.3 together with the nitrogen form a piperazine ring, being substituted by a group selected from trifluoromethylphenyl, methylphenyl, dimethylphenyl, and chlorophenyl; and

[0037] A denotes ethylene, butylene, or butenylene,

[0038] or a pharmaceutically acceptable salt thereof.

[0039] The most preferred compounds according to the invention are:

[0040] (a) 1-(2-methoxyethyl)-3-(4-{4-[3-(trifluoromethyl)phenyl]-1-pipera- zinyl}butyl)-1,3-dihydro-2H-benzimidazol-2-one;

[0041] (b) 1-{4-[4-(2,3-dimethylphenyl)-1-piperazinyl]butyl}-3-(2-hydroxye- thyl)-1,3-dihydro-2H-benzimidazol-2-one;

[0042] (c) 2-[2-oxo-3-(4-{4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}buty- l)-2,3-dihydro-1H-benzimidazol-1-yl]ethyl-ethylcarbamate;

[0043] (d) 1-(2-methoxyethyl)-3-(2-{4-[3-(trifluoromethyl)phenyl]-1-pipera- zinyl}ethyl)-1,3-dihydro-2H-benzimidazol-2-one;

[0044] (e) 1-{2-[4-(2,3-dimethylphenyl)-1-piperazinyl]ethyl}-3-(2-methoxye- thyl)-1,3-dihydro-2H-benzimidazol-2-one;

[0045] (f) 1-{2-[4-(3-chlorophenyl)-1-piperazinyl]ethyl}-3-(2-hydroxyethyl- )-1,3-dihydro-2H-benzimidazol-2-one;

[0046] (g) 2-[2-oxo-3-(2-{4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}ethy- l)-2,3-dihydro-1H-benzimidazol-1-yl]ethyl-ethylcarbamate;

[0047] (h) 2-(3-{2-[4-(2,3-dimethylphenyl)-1-piperazinyl]ethyl}-2-oxo-2,3-- dihydro-1H-benzimidazol-1-yl)ethyl-ethylcarbamate;

[0048] (i) N-[2-(3-{2-[4-(2,3-dimethylphenyl)-1-piperazinyl]ethyl}-2-oxo-2- ,3-dihydro-1H-benzimidazol-1-yl)ethyl]methanesulfonamide;

[0049] (j) N-[2-(3-{(2Z)-4-[4-(3-methylphenyl)-1-piperazinyl]-2-butenyl}-2- -oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]methanesulfonamide; and

[0050] (k) N-[2-(3-{(2E)-4-[4-(3-chlorophenyl)-1-piperazinyl]-2-butenyl}-2- -oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]methanesulfonamide.

[0051] If required, the compounds of general formula (I) may be converted into the salts thereof, particularly, for pharmaceutical use, into the pharmaceutically acceptable salts thereof with an inorganic or organic acid. Suitable acids for this purpose include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid. Moreover, mixtures of these acids may be used.

[0052] The alkyl groups meant here (including those which are components of other groups) are branched and unbranched alkyl groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as: methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and hexyl.

[0053] The alkylene groups meant here are branched and unbranched alkyl-bridges having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as: methylene, ethylene, n-propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, and hexylene.

[0054] Alkenyl groups (including those which are components of other groups) are the branched and unbranched alkenyl groups with 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, provided that they have at least one double bond, e.g., the alkyl groups mentioned above provided that they have at least one double bond, such as for example vinyl (provided that no unstable enamines or enolethers are formed), propenyl, isopropenyl, butenyl, pentenyl, and hexenyl.

[0055] Alkenylene groups are the branched and unbranched alkenyl-bridges with 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, provided that they have at least one double bond, e.g., the alkylene groups mentioned above provided that they have at least one double bond, such as for example vinylene (provided that no unstable enamines or enolethers are formed), propenylene, isopropenylene, butenylene, pentenylene, and hexenylene.

[0056] If not otherwise specified the alkenyl- and alkenylene-groups mentioned above are to be understood as embracing optionally existing stereoisomers. Accordingly, for instance the definition 2-butenyl is to be understood as embracing 2-(Z)-butenyl and 2-(E)-butenyl, etc.

[0057] The term alkynyl groups (including those which are components of other groups) refers to alkynyl groups having 2 to 6, preferably 2 to 4 carbon atoms, provided that they have at least one triple bond, e.g., ethynyl, propargyl, butynyl, pentynyl, and hexynyl.

[0058] Examples of N-linked 5- or 6-membered heterocyclic rings of general formula NR.sup.2R.sup.3 are as follows: pyrrole, pyrroline, pyrrolidine, piperidine, piperazine, morpholine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, and pyrazolidine, preferably morpholine, piperazine, and piperidine.

[0059] Examples of saturated or unsaturated bi- or tricyclic heterocyclic ring-system of formula NR.sup.2R.sup.3 which may contain nitrogen or oxygen as an additional heteroatom, are as follows: indole, tetrahydroindole, benzimidazole, benzoxazole, 1,2-dihydrochinoline, 1,2-dihydroisochinoline, .beta.-carboline, 9H-1,2,3,4-tetrahydropyridoind- ole, and 9,10-dihydroacridine.

[0060] Halogen means fluorine, chlorine, bromine, or iodine, preferably chlorine or bromine.

[0061] ".dbd.O" means an oxygen atom linked by a double bond.

[0062] The compounds of general formula (I) may be conveniently prepared by a variety of synthetic processes analogous to those known in the art using conventional methods. For example, these compounds may be prepared by alkylating the suitable secondary amine (III) with the proper benzimidazolone (II) bearing in the alkyl or alkenyl side chain suitable leaving group X such as halogen, methanesulfonate, or 4-methylbenzenesulfonate (Scheme 1). 3

[0063] Scheme 1

[0064] The reaction conditions for the conventional synthesis of compounds of formula (I) according to Scheme 1 are disclosed in EP 526 434 A1. Said reference additionally describes the possible synthetic pathways for the preparation of starting compounds (II).

[0065] According to a second option, the reaction sequence according to Scheme 1 can not only be conducted via the conventional synthetic methods outlined in EP 526 434 A1 but, in the alternative, via combinatorial chemistry. For this approach a set of N-alkyl-N'-halo alkyl/alkenyl benzimidazolones of formula (II) (hereinafter identified as Building Blocks or BB; see hereto Table 1) was prepared via the traditional methods described in EP 526 434 A1 and then combinatorially reacted with the suitable secondary amines of formula (III) (Table 2). The process was carried out in a special apparatus consisting of a lower vial (reacting chamber) and an upper vial (condenser). Each compound was reacted with each amine in DMF under stirring at a temperature between 40.degree. C. and 100.degree. C., preferably at 60.degree. C., for 6 to 8 hours in the presence of Na.sub.2CO.sub.3. The excess amine was then scavenged at room temperature by introducing a polystyrene isocyanatemethyl resin of formula (IV) able to catch the excess amine as an urea of formula (V) immobilized on the solid support (Scheme 2). 4

[0066] Scheme 2

[0067] The upper part of the reaction apparatus is substituted with another vial containing a frit inside and a connection to the vacuum. Filtration after turning over the apparatus and evaporation to dryness afforded the desired compounds of formula (I) in excellent yield and good purity. The parallel application of the aforementioned process to all of the compounds of formula (II) as shown in Table 1 and all of the selected amines (III) as shown in Table 2 allows the efficient synthesis of all of the compounds (I) according to the present invention.

1TABLE 1 Building Blocks (BB) of Formula (II) Subjected to the Process of Scheme 2 (II) 5 Building Building Block No. Structure Block No. Structure BB01 6 BB02 7 BB03 8 BB04 9 BB05 10 BB06 11 BB07 12 BB08 13 BB09 14 BB10 15 BB11 16 BB12 17 BB13 18 BB14 19 BB15 20 BB16 21 BB17 22 BB18 23 BB19 24 BB20 25 BB21 26 BB22 27 BB23 28 BB24 29 BB25 30 BB26 31 BB27 32 BB28 33

[0068]

2TABLE 2 Amines (AM) of Formula (III) Subjected to the Process of Scheme 2 (III) 34 Amine No. Structure Amine No. Structure AM01 35 AM02 36 AM03 37 AM04 38 AM05 39 AM06 40 AM07 41 AM08 42 AM09 43 AM10 44 AM11 45 AM12 46 AM13 47 AM14 48 AM15 49 AM16 50 AM17 51 AM18 52 AM19 53 AM20 54 AM21 55 AM22 56

[0069] For pharmaceutical use, the compounds of general formula (I) may be used as such or in the form of physiologically acceptable acid addition salts. The term "physiologically acceptable acid addition salts" includes the salts resulting from both organic and inorganic acids such as maleic, citric tartaric, methanesulfonic, acetic, benzoic, succinic, gluconic, isethionic, glycinic, lactic, malic, mucoic, glutammic, sulfamic, and ascorbic acids; inorganic acids include hydrochloric, hydrobromic, nitric, sulfuric, or phosphoric acid.

[0070] According to a further feature of the present invention, there are provided pharmaceutical compositions comprising as an active ingredient at least one compound of formula (I), as before defined, or a physiologically acceptable addition salt thereof in addition to one or more pharmaceutical carrier, diluents or excipients. For pharmaceutical administration, the compounds of general formula (I) and their physiologically acceptable acid addition salts may be incorporated into the conventional pharmaceutical preparation in solid, liquid, or spray form. The composition may, for example, be presented in a form suitable for oral, rectal, or parenteral administration or for nasal inhalation: preferred forms include, for example, capsules, tablets, coated tables, ampoules, suppositories, and nasal spray. The active ingredient may be incorporated in excipients or carriers conventionally used in pharmaceutical compositions such as, for example, talc, arabic gum, lactose, gelatine, magnesium stearate, corn starch, aqueous or nonaqueous vehicles, polyvinyl pyrrolidone, semisynthetic glycerides of fatty acids, benzalcon chloride, sodium phosphate, EDTA, or polysorbate 80.

[0071] In case it is desired to further increase the solubility of the compounds of general formula (I) or of their physiologically acceptable salts, surfactants or nonionic surfactants such as PEG 400, cyclodextrin, metastable polymorphs, or inert adsorbents such as bentonite, may be incorporated. Furthermore, some techniques may be employed by preparing, for example, eutectic mixtures and/or solid dispersion by using mannitol, sorbitol, saccharose, or succinic acid or physically-modified forms by using hydrosoluble polymers, PVP, or PEG 4000-20,000. The compositions are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of the active ingredient. Each dosage unit may conveniently contain from 0.01 mg to 100 mg, preferably from 0.1 to 50 mg.

[0072] However, it could be necessary to depart from the cited amounts, depending on the body weight or on the administration route, on the individual response to the medicament, on the type of formulation and on the time, or time range, in which the administration is carried out. Therefore, it can be sufficient, in some cases, to use a lower amount then the cited minimum amount, whereas in other cases the higher range could be exceeded. When administering higher amounts, it would be advisable to subdivide them in repeated administrations during the day. Moreover, the compounds of general formula (I) or the acid addition salts thereof can also be combined with other, different active substances.

[0073] The following examples illustrate the present invention, without limiting the scope thereof.

[0074] Examples of Pharmaceutical Formulations

3 A. Tablets Containing 100 mg of Active Substance Component Amount per tablet (mg) active substance 100 lactose 140 maize starch 240 polyvinylpyrrolidone 15 magnesium stearate 5 TOTAL 500

[0075] The finely ground active substance, lactose, and part of maize starch are mixed. The mixture is sieved, wetted with a solution of polyvinylpyrrolidone in water, kneaded, finely granulated, and dried. The granulate, the remaining maize starch, and magnesium stearate are sieved and mixed together. The mixture is compressed to tablets of suitable form and size.

4 B. Tablets Containing 80 mg of Active Substance Component Amount per tablet (mg) active substance 80 lactose 55 maize starch 190 polyvinylpyrrolidone 15 sodium carboxymethyl starch 23 magnesium stearate 2 TOTAL 400

[0076] The finely ground active substance, part of the maize starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed. The mixture is sieved and worked up with the remaining maize starch and water, to obtain a granulate, which is dried and sieved. This is added to sodium carboxymethyl starch and magnesium stearate and mixed, and the mixture is then compressed to tablets of suitable size.

5 C. Solutions for Vials Component Amount active substance 50 mg sodium chloride 50 mg water for injection 5 ml

[0077] The active substance is dissolved in water, optionally at pH of 5.5 to 6.5, and treated with sodium chloride as an osmolality agent. The resulting solution is filtered apyrogenically, and the filtrate is placed in vials under aseptic conditions, then the vials are sterilized and flame sealed. The vials contain 5 mg, 25 mg, and 50 mg of active substance.

[0078] Experimental

[0079] The following examples illustrate the preparation of all the new compounds included in the present invention. It should be understood that the invention is not limited to the given examples of chemical methods and processes for the preparation of the substances, as other conventional methods well known to those skilled in the art, are suitable too. In the following descriptions, each of the 28 Building Blocks prepared is identified by its relevant Tag.

[0080] A. Preparation of the Building Blocks (BB) of Formula (II)

[0081] Description 1

[0082] 1-[2-(1-piperidinyl)ethyl)-1,3-dihydro-2H-benzimidazol-2-one

[0083] A solution of 1-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one (35 g, 0.2 moles) in DMF (250 ml) was added dropwise to a suspension of 80% sodium hydride (6 g, 0.2 moles) in DMF (50 ml). The reaction mixture was first heated at 45.degree. C. for 30 minutes, allowed to cool at room temperature, and an additional amount of 80% sodium hydride (7.2 g, 0.24 moles) was added. Then 1-(2-chloroethyl)piperidine hydrochloride (44.16 g, 0.24 moles) was added portionwise and the reaction mixture was heated at 80.degree. C.-90.degree. C. for 3 hours. The mixture was then cooled at room temperature, adjusted to pH 3 with 37% aqueous HCl, and heated to 80.degree. C. for additional 2 hours. The reaction mixture was poured into water and washed with ethyl acetate. The aqueous phase was adjusted to pH 8-9 with a saturated sodium carbonate solution and extracted into ethyl acetate. The organic layer was taken to dryness to give an ivory solid which after crystallization from isopropyl ether afforded 22.9 g of the title compound. M.p. 123.degree. C.-125.degree. C.

[0084] According to the above described procedure, the following compound was prepared from the suitable intermediates:

[0085] 1-[2-(4-morpholinyl)ethyl]-1,3-dihydro-2H-benzimidazol-2-one

[0086] 11.7 g; m.p. 122.degree. C.-126.degree. C.

[0087] Description 2

[0088] 1-(2-methoxyethyl)-1,3-dihydro-2H-benzimidazol-2-one

[0089] Phenyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (80 g, 0.315 moles) was added to a suspension of 80% sodium hydride (11.3 g, 0.378 moles) in DMF (500 ml) and heated at 35.degree. C. for 1 hour. To the cooled solution, 2-chloroethylmethylether (43 ml, 0.472 moles) was added and the reaction mixture was heated at 100.degree. C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined extracts were taken to dryness to give 52 g of the protected intermediate. This was suspended in methanol (500 ml), a solution of K.sub.2CO.sub.3 (44 g) in water (230 ml) was added, and the mixture and stirred for 2 hours at room temperature. After evaporation, the reaction mixture was acidified and extracted into ethyl acetate. The organic layer was taken to dryness and from the crude oily residue, after crystallization with isopropyl ether, 21 g of the title compound was obtained as a white solid. M.p. 88.degree. C.

[0090] Description 3

[0091] 1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,3-dihydro-2H-benzimidazo- l-2-one

[0092] (a) Phenyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (50 g, 0.197 moles) was added to a suspension of 80% sodium hydride (7 g, 0.236 moles) in DMF (400 ml) and stirred for 1 hour at room temperature, then 2-(2-chloroethoxy)tetrahydro-2H-pyran (34.8 ml, 0.236 moles) was added and the reaction mixture was heated at 100.degree. C. for 7 hours. The reaction mixture was then poured into water and extracted into ethyl acetate. The organic layer was taken to dryness to give an oily residue.

[0093] (b) This residue (83 g) was dissolved in methanol, a solution of KOH (26 g in 260 ml water) was added and stirred for 2 hours at room temperature. The methanol was evaporated and the residue was extracted into ethyl acetate. The organic layer was washed with an aqueous 5% HCl solution, dried, and taken to dryness. The oily residue was crystallized from diisopropyl ether to give 26 g of the title compound. M.p. 115.degree. C.

[0094] Description 4

[0095] 1-(2-aminoethyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride

[0096] (a) A suspension of phenyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-car- boxylate (10 g, 39 mmoles) and 80% sodium hydride (1.3 g, 43 mmoles) in DMF (100 ml) was stirred at room temperature for 30 minutes. N-(2-bromoethyl)phthalimide (10 g, 39 mmoles) was added and the mixture heated at 100.degree. C. for 12 hours. The reaction mixture was then poured into 600 ml of water and stirred for 4 hours at room temperature. The precipitated phthaloyl derivative was filtered off (white solid; 6.5 g).

[0097] (b) This intermediate was suspended in methanol (70 ml), a 10% aqueous K.sub.2CO.sub.3 solution was added and the reaction mixture stirred overnight at room temperature. The methanol was evaporated, the residue was extracted with dichloromethane, and the aqueous solution was acidified with 10% aqueous HCl to give the corresponding 2-carboxybenzamido derivative which was filtered off (5 g).

[0098] (c) To the crude intermediate was added 32 ml of a 15% aqueous HCl solution and the resulting suspension was heated at 90.degree. C. for 3 hours. After cooling, the solid was filtered off and the acidic solution was taken to dryness to give 1.5 g of the hydrochloride of the title compound as a pinkish solid. M.p. >280.degree. C.

[0099] Description 5

[0100] N-[2-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]-acetamide

[0101] To a cooled solution of NaOH (0.41 g, 10 mmoles) in water (5 ml) were simultaneously added 1-(2-aminoethyl)-1,3-dihydro-2H-benzimidazol-2-- one hydrochloride (0.7 g, 3.3 mmoles) and a solution of acetic anhydride (0.37 ml, 3.9 mmoles) in dioxane (10 ml). The reaction mixture was stirred for 2 hours at room temperature and then taken to dryness. The residue was dissolved in water, adjusted to pH 4 with 10% aqueous HCl, and extracted with CHCl.sub.3. The organic layer was taken to dryness and from the crude residue 0.35 g of the title compound was obtained after crystallization from diethyl ether. M.p. 153.degree. C.

[0102] Description 6

[0103] N-[2-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]methanesulfonami- de

[0104] To a solution of 1-(2-aminoethyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (2.8 g, 13 mmoles) in THF (30 ml) and triethyl amine (5.5 ml, 39 mmoles) was added methanesulfonyl chloride (1.12 ml, 14 mmoles) and the reaction mixture was stirred for 2 hours at room temperature. The organic solvent was evaporated and the residue was partitioned into water and ethyl acetate. The organic layer was washed with saturated aqueous Na.sub.2CO.sub.3 solution and taken to dryness. The crude residue was purified by flash chromatography (CH.sub.2Cl.sub.2-methanol 96-4) to give 0.5 g of the title compound as a white solid. M.p. 162-170.degree. C.

[0105] Description 7

[0106] 1-(2-chloroethyl)-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,3-dihy- dro-2H-benzimidazol-2-one

[0107] Into a stirred solution of 1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]- -1,3-dihydro-2H-benzimidazol-2-one (6.5 g, 25 mmoles) in DMF (40 ml) 80% sodium hydride (0.9 g, 30 mmoles) was added. After 30 minutes of stirring and heating to 35.degree. C., 1-bromo-2-chloroethane (6.2 g, 48 mmoles) was added, the reaction temperature was increased to 90.degree. C. and kept for 6 hours then cooled at room temperature. The reaction mixture was poured into water, extracted with diethyl ether, and the organic layer was taken to dryness. The residue was purified by flash chromatography (cyclohexane-ethyl acetate 50-50) to give 2.8 g of the title compound as a thick oil which was used without any further purification.

[0108] According to the above described procedure, the following compounds were prepared from the suitable intermediates:

[0109] 1-(4-chlorobutyl)-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,3-dihy- dro-2H-benzimidazol-2-one

[0110] The compound was purified by flash chromatography (cyclohexane-ethyl acetate 50-50). Thick oil.

[0111] [BB01]: 1-(2-chloroethyl)-3-(2-methoxyethyl)-1,3-dihydro-2H-benzimi- dazol-2-one

[0112] White solid. M.p. 55.degree. C., from diisopropyl ether.

[0113] [BB01]: 1-(4-chlorobutyl)-3-(2-methoxyethyl)-1,3-dihydro-2H-benzimi- dazol-2-one

[0114] The compound was purified by flash chromatography (cyclohexane-ethyl acetate 50-50). Thick oil.

[0115] [BB15]: 1-[(2Z)-4-chloro-2butenyl)]-3-(2-methoxyethyl)-1,3-dihydro-- 2H-benzimidazol-2-one

[0116] The compound was purified by flash chromatography (cyclohexane-ethyl acetate 70-30). Thick oil.

[0117] [BB24]: N-{2-[3-(2-chloroethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1- -yl]ethyl}-acetamide

[0118] White solid. M.p. 140.degree. C.-142.degree. C., from acetone.

[0119] [BB06]: N-{2-[3-(4-chlorobutyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1- -yl]ethyl}-acetamide

[0120] Ivory solid. M.p. 100.degree. C., from diethyl ether.

[0121] Description 8

[0122] 1-[(2Z)-4-chloro-2-butenyl]-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl- ]-1,3-dihydro-2H-benzimidazol-2-one

[0123] To a solution of 1-[2-(tetrahydro-2H-pyran-2yloxy)ethyl]-1,3-dihydr- o-2H-benzimidazol-2-one (12 g, 46 mmoles) in DMF (120 ml) was added 80% sodium hydride (1.7 g, 55 mmoles) and the mixture was stirred at room temperature for 1 hour. Cis-1,4-dichloro-2-butene (5.8 ml, 55 mmoles) was added dropwise and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was taken to dryness and the residue was purified by flash chromatography (cyclohexane-ethyl acetate 70-30) to give 2.8 g of the title compound as a thick oil which was used without any further purification.

[0124] According to the above described procedure, the following compounds were prepared from the suitable intermediates:

[0125] 1-[(2E)-4-chloro-2-butenyl)]-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethy- l]-1,3-dihydro-2H-benzimidazol-2-one

[0126] The compound was purified by flash chromatography (cyclohexane-ethyl acetate 70-30). Waxy solid.

[0127] [BB16]: 1-[(2E)-4-chloro-2-butenyl)]-3-(2-methoxyethyl)-1,3-dihydro- -2H-benzimidazol-2-one

[0128] The compound was purified by flash chromatography (cyclohexane-ethyl acetate 70-30). Thick oil.

[0129] [BB25]: N-(2-{3-[(2Z)-4-chloro-2-butenyl]-2-oxo-2,3-dihydro-1H-benz- imidazol-1-yl]}ethyl)-acetamide

[0130] The compound was purified by flash chromatography (CH.sub.2Cl.sub.2-methanol 97-3). Waxy solid from diisopropyl ether, m.p. 118.degree. C.

[0131] [BB26]: N-(2-{3-[(2E)-4-chloro-2-butenyl]-2-oxo-2,3-dihydro-1H-benz- imidazol-1-yl]}ethyl)-acetamide

[0132] White solid from diethyl ether, m.p. 108.degree. C.

[0133] [BB13]: N-{2-[3-(2-chloroethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1- -yl]ethyl}methanesulfonamide

[0134] The compound was purified by flash chromatography (CH.sub.2Cl.sub.2-methanol 98-2). White low melting solid.

[0135] [BB07]: N-{2-[3-(4-chlorobutyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1- -yl]ethyl}methanesulfonamide

[0136] White solid, m.p. 104.degree. C. from diethyl ether.

[0137] [BB27]: N-(2-{3-[(2Z)-4-chloro-2-butenyl)]-2-oxo-2,3-dihydro-1H-ben- zimidazol-1-yl]ethyl}methanesulfonamide

[0138] The compound was purified by flash chromatography (CH.sub.2Cl.sub.2-methanol 97-3). White solid, m.p. 83.degree. C. from diethyl ether.

[0139] [BB28]: N-2-{3-[(2E)-4-chloro-2butenyl)]-2-oxo-2,3-dihydro-1H-benzi- midazol-1-yl]ethyl}methanesulfonamide

[0140] The compound was purified by flash chromatography (CH.sub.2Cl.sub.2-methanol 98-2). White solid, m.p. 98.degree. C. from diethyl ether.

[0141] Description 9

[0142] [BB08]: 1-(2-chloroethyl)-3-[(2-piperidinyl)ethyl]-1,3-dihydro-2H-b- enzimidazol-2-one

[0143] A solution of 1-[2-(1-piperidinyl)ethyl)-1,3-dihydro-2H-benzimidazo- l-2-one (4 g, 16.3 mmoles) in DMF (50 ml) was added to a suspension of 80% sodium hydride (0.49 g, 16.3 mmoles) in DMF (25 ml) and the reaction mixture was heated under stirring for 30 minutes at 40.degree. C. The solution was slowly transferred (3 hours) into a solution of 1-bromo-2-chloroethane (2.7 ml, 32.6 mmoles) in DMF (30 ml), the temperature was increased to 60.degree. C. and stirred for 5 hours. The reaction mixture was then taken to dryness under vacuum, and the residue partitioned between 5% aqueous HCl and diethyl ether. The aqueous layer was adjusted to pH 9 to 10 with sodium carbonate and extracted with ethyl acetate. After evaporation and flash chromatography purification (CH.sub.2Cl.sub.2-methanol-NH.sub.4OH 95-5-0.5), 2.2 g of the pure title compound was obtained as a clear oil.

[0144] According to the above described procedure, the following compounds were prepared from the suitable intermediates:

[0145] [BB02]: 1-(4-chlorobutyl)-3-[(2-(1-piperidinyl)ethyl]-1,3-dihydro-2- H-benzimidazol-2-one

[0146] The compound was purified by flash chromatography (CH.sub.2Cl.sub.2-methanol-NH.sub.4OH 95-5-0.5). Ivory solid, m.p. 82.degree. C.-87.degree. C. from diethyl ether.

[0147] [BB12]: 1-(2-chloroethyl)-3-[2-(4-morpholinyl)ethyl]-1,3-dihydro-2H- -benzimidazol-2-one

[0148] The compound was purified by flash chromatography (CH.sub.2Cl.sub.2-methanol-NH.sub.4OH 95-5-0.5). Thick oil.

[0149] [BB03]: 1-(4-chlorobutyl)-3-[2-(4-morpholinyl)ethyl]-1,3-dihydro-2H- -benzimidazol-2-one

[0150] The compound was purified by flash chromatography (CH.sub.2Cl.sub.2-methanol-NH.sub.4OH 95-5-0.5). Clear oil.

[0151] Description 10

[0152] [BB14]: 1-[(2Z)-4-chloro-2-butenyl)]-3-[2-(4-morpholinyl)ethyl]-1,3- -dihydro-2H-benzimidazol-2-one

[0153] A solution of 1-[2-(4-morpholinyl)ethyl]-1,3-dihydro-2H-benzimidazo- l-2-one (4 g, 16.2 mmoles) in DMF (50 ml) was added dropwise to a suspension of 80% sodium hydride (0.49 g, 16.2 mmoles) in DMF (50 ml) and the mixture was heated under stirring at 45.degree. C. for 30 minutes. This solution was slowly transferred (4 hours) to a solution of cis-1,4-dichloro-2-butene (3.43 ml, 32.4 mmoles) in DMF (20 ml). The reaction mixture was stirred overnight at room temperature, taken to dryness under vacuum, and partitioned between ethyl acetate and water. From the organic solution after evaporation and flash chromatography purification (CH.sub.2Cl.sub.2-methanol-NH4OH 95-5-0.5), 2.4 g of the title compound were obtained as an oil.

[0154] According to the above described procedure, the following compounds were prepared from the suitable intermediates:

[0155] [BB19]: 1-[(2E)-4-chloro-2-butenyl]-3-[2-(4-morpholinyl)ethyl]-1,3-- dihydro-2H-benzimidazol-2-one

[0156] The compound was purified by flash chromatography (CH.sub.2Cl.sub.2-methanol-NH.sub.4OH 95-5-0.5). Thick oil.

[0157] [BB17]: 1-[(2Z)-4-chloro-2-butenyl]-3-[2-(1-piperidinyl)ethyl]-1,3-- dihydro-2H-benzimidazol-2-one

[0158] The compound was purified by flash chromatography (CH.sub.2Cl.sub.2-methanol-NH.sub.4OH 95-5-0.5). Thick oil.

[0159] [BB18]: 1-[(2E)-4-chloro-2-butenyl]-3-[2-(1-piperidinyl)ethyl]-1,3-- dihydro-2H-benzimidazol-2-one

[0160] The compound was purified by flash chromatography (CH.sub.2Cl.sub.2-methanol-NH.sub.4OH 95-5-0.5). Thick oil.

[0161] Description 11

[0162] [BB10]: 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1,3-dihydro-2H-benzimi- dazol-2-one

[0163] A solution of 1-(2-chloroethyl)-3-[2-(tetrahydro-2H-pyran-2-yloxy)e- thyl]-1,3-dihydro-2H-benzimidazol-2-one (2.2 g) and a catalytic amount of p-toluenesulfonic acid (0.1 g) in methanol (30 ml) was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness, the residue was dissolved in CH.sub.2Cl.sub.2 and washed with a saturated aqueous solution of K.sub.2CO.sub.3. The organic layer was taken to dryness to give 1.5 g of the title compound as white solid. M.p. 135.degree. C.

[0164] According to the above described procedure, the following compounds were prepared from the suitable intermediates:

[0165] [BB04]: 1-(4-chlorobutyl)-3-(2-hydroxyethyl)-1,3-dihydro-2H-benzimi- dazol-2-one

[0166] Thick oil.

[0167] [BB20]: 1-[(2Z)-4-chloro-2-butenyl]-3-(2-hydroxyethyl)-1,3-dihydro-- 2H-benzimidazol-2-one

[0168] White solid, m.p. 80.degree. C. from diethyl ether.

[0169] [BB21]: 1-[(2E)-4-chloro-2-butenyl]-3-(2-hydroxyethyl)-1,3-dihydro-- 2H-benzimidazol-2-one

[0170] Ivory solid, m.p. 73.degree. C. from diethyl ether.

[0171] Description 12

[0172] [BB11]: 2-[3-(2-chloroethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl- ]ethyl-ethylcarbamate

[0173] 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1,3-dihydro-2H-benzimidazol-2-- one (2.6 g, 11 mmoles) and ethyl isocyanate (20 ml) were refluxed under stirring for 6 hours then left overnight at room temperature. The reaction mixture was taken to dryness and the residue was crystallized from diisopropyl ether to give 3 g of the title compound. M.p. 125.degree. C.

[0174] According to the above described procedure, the following compound was prepared from the suitable intermediate:

[0175] [BB05]: 2-[3-(4-chlorobutyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl- ]ethyl-ethylcarbamate

[0176] White solid, m.p. 75.degree. C. from diethyl ether.

[0177] Description 13

[0178] [BB22]: 2-{3-[(2Z)-4-chloro-2-butenyl]-2-oxo-2,3-dihydro-1H-benzimi- dazol-1-yl]ethyl-ethylcarbamate

[0179] 1-(4-chlorobutyl)-3-(2-hydroxyethyl)-1,3-dihydro-2H-benzimidazol-2-- one (1.8 g, 6.8 mmoles) and ethyl isocyanate (6 ml) were stirred at room temperature for 48 hours. The reaction mixture was then taken to dryness and the residue was crystallized from diethyl ether to give 1.8 g the title compound. M.p. 107.degree. C.

[0180] According to the above described procedure, the following compound was prepared from the suitable intermediate:

[0181] [BB23]: 2-{3-[(2E)-4-chloro-2-butenyl]-2-oxo-2,3-dihydro-1H-benzimi- dazol-1-yl}ethyl-ethylcarbamate

[0182] The compound was purified by flash chromatography (cyclohexane-ethyl acetate 50-50). White solid, m.p. 70.degree. C. from diethyl ether.

[0183] B. General Method for the Preparation of the Compounds of Formula (I)

[0184] A solution of each building block of formula (II) (0.1 mM) was reacted under stirring with each amine (0.2 mM) in anhydrous DMF (100 .mu.l) in the presence of Na.sub.2CO.sub.3 (0.3 mM) at a temperature ranging from room temperature to 100.degree. C., preferably between 60.degree. C. and 80.degree. C., for about 6 to 8 hours. Isocyanatemethyl Polystyrene Resin (loading 0.23 meq/g) (0.2 mM) was introduced and the mixture was gently stirred at room temperature for 8 hours. The resin was then filtered off under vacuum, washed with DMF, and filtered again. The collected solutions were evaporated to dryness in a speed-vac centrifuge. The compounds which were prepared according to the above described procedure are listed in Table 3.

[0185] Table 3 collects the structural formula of the synthesized compounds along with the corresponding characterizing mass data (i.e., [M+H].sup.+) obtained for each of the compounds according to the invention. The identification of the compounds and their purity was carried out by using positive APCI-LC/MS technique.

6TABLE 3 Compounds of Formula (I) (I) 57 Compound No. --R.sup.1 --A-- 58 [M + H].sup.+ 1 59 60 61 409 2 62 63 64 533 3 65 66 67 423 4 68 69 70 410 5 71 72 73 443 6 74 75 76 411 7 77 78 79 419 8 80 81 82 478 9 83 84 85 477 10 86 87 88 406 11 89 90 91 477 12 92 93 94 464 13 95 96 97 526 14 98 99 100 439 15 101 102 103 457 16 104 105 106 478 17 107 108 109 467 18 110 111 112 437 19 113 114 115 439 20 116 117 118 462 21 119 120 121 586 22 122 123 124 476 23 125 126 127 463 24 128 129 130 496 25 131 132 133 464 26 134 135 136 472 27 137 138 139 531 28 140 141 142 530 29 143 144 145 459 30 146 147 148 530 31 149 150 151 517 32 152 153 154 579 33 155 156 157 492 34 158 159 160 510 35 161 162 163 531 36 164 165 166 520 37 167 168 169 490 38 170 171 172 492 39 173 174 175 464 40 176 177 178 588 41 179 180 181 478 42 182 183 184 465 43 185 186 187 498 44 188 189 190 466 45 191 192 193 474 46 194 195 196 533 47 197 198 199 532 48 200 201 202 461 49 203 204 205 532 50 206 207 208 519 51 209 210 211 581 52 212 213 214 494 53 215 216 217 512 54 218 219 220 533 55 221 222 223 522 56 224 225 226 395 57 227 228 229 419 58 230 231 232 409 59 233 234 235 396 60 236 237 238 429 61 239 240 241 397 62 242 243 244 405 63 245 246 247 464 64 248 249 250 463 65 251 252 253 392 66 254 255 256 463 67 257 258 259 450 68 260 261 262 512 69 263 264 265 425 70 266 267 268 443 71 269 270 271 464 72 272 273 274 453 73 275 276 277 423 74 278 279 280 425 75 281 282 283 466 76 284 285 286 590 77 287 288 289 480 78 290 291 292 467 79 293 294 295 500 80 296 297 298 468 81 299 300 301 476 82 302 303 304 535 83 305 306 307 534 84 308 309 310 463 85 311 312 313 534 86 314 315 316 521 87 317 318 319 583 88 320 321 322 496 89 323 324 325 514 90 326 327 328 535 91 329 330 331 524 92 332 333 334 494 93 335 336 337 496 94 338 339 340 480 95 341 342 343 480 96 344 345 346 500 97 347 348 349 436 98 350 351 352 560 99 353 354 355 450 100 356 357 358 437 101 359 360 361 470 102 362 363 364 438 103 365 366 367 446 104 368 369 370 505 105 371 372 373 504 106 374 375 376 433 107 377 378 379 504 108 380 381 382 491 109 383 384 385 553 110 386 387 388 466 111 389 390 391 484 112 392 393 394 505 113 395 396 397 494 114 398 399 400 464 115 401 402 403 466 116 404 405 406 450 117 407 408 409 450 118 410 411 412 470 119 413 414 415 472 120 416 417 418 596 121 419 420 421 486 122 422 423 424 473 123 425 426 427 506 124 428 429 430 474 125 431 432 433 482 126 434 435 436 541 127 437 438 439 540 128 440 441 442 469 129 443 444 445 540 130 446 447 448 527 131 449 450 451 589 132 452 453 454 502 133 455 456 457 520 134 458 459 460 541 135 461 462 463 530 136 464 465 466 500 137 467 468 469 502 138 470 471 472 486 139 473 474 475 486 140 476 477 478 506 141 479 480 481 434 142 482 483 484 558 143 485 486 487 448 144 488 489 490 435 145 491 492 493 468 146 494 495 496 436 147 497 498 499 444 148 500 501 502 503 149 503 504 505 502 150 506 507 508 431 151 509 510 511 502 152 512 513 514 489 153 515 516 517 551 154 518 519 520 464 155 521 522 523 482 156 524 525 526 503 157 527 528 529 492 158 530 531 532 462 159 533 534 535 464 160 536 537 538 381 161 539 540 541 505 162 542 543 544 395 163 545 546 547 382 164 548 549 550 415 165 551 552 553 383 166 554 555 556 391 167 557 558 559 450 168 560 561 562 449 169 563 564 565 378 170 566 567 568 449 171 569 570 571 436 172 572 573 574 526 173 575 576 577 411 174 578 579 580 429 175 581 582 583 450 176 584 585 586 450 177 587 588 589 409 178 590 591 592 411 179 593 594 595 367 180 596 597 598 491 181 599 600 601 381 182 602 603 604 368 183 605 606 607 401 184 608 609 610 369 185 611 612 613 377 186 614 615 616 436 187 617 618 619 435 188 620 621 622 364 189 623 624 625 435 190 626 627 628 422 191 629 630 631 484 192 632 633 634 397 193 635 636 637 415 194 638 639 640 436 195 641 642 643 436 196 644 645 646 395 197 647 648 649 397 198 650 651 652 438 199 653 654 655 562 200 656 657 658 452 201 659 660 661 439 202 662 663 664 472 203 665 666 667 440 204 668 669 670 448 205 671 672 673 507 206 674 675 676 506 207 677 678 679 435 208 680 681 682 506 209 683 684 685 493 210 686 687 688 555 211 689 690 691 468 212 692 693 694 486 213 695 696 697 507 214 698 699 700 496 215 701 702 703 466 216 704 705 706 468 217 707 708 709 452 218 710 711 712 452 219 713 714 715 472 220 716 717 718 436 221 719 720 721 560 222 722 723 724 450 223 725 726 727 437 224 728 729 730 470 225 731 732 733 438 226 734 735 736 446 227 737 738 739 533 228 740 741 742 504 229 743 744 745 433 230 746 747 748 504 231 749 750 751 491 232 752 753 754 553 233 755 756 757 466 234 758 759 760 484 235 761 762 763 505 236 764 765 766 494 237 767 768 769 444 238 770 771 772 568 239 773 774 775 458 240 776 777 778 445 241 779 780 781 478 242 782 783 784 446 243 785 786 787 454 244 788 789 790 513 245 791 792 793 512 246 794 795 796 441 247 797 798 799 512 248 800 801 802 499 249 803 804 805 561 250 806 807 808 474 251 809 810 811 492 252 812 813 814 513 253 815 816 817 502 254 818 819 820 472 255 821 822 823 474 256 824 825 826 458 257 827 828 829 458 258 830 831 832 478 259 833 834 835 462 260 836 837 838 586 261 839 840 841 476 262 842 843 844 463 263 845 846 847 496 264 848 849 850 464 265 851 852 853 472 266 854 855 856 531 267 857 858 859 530 268 860 861 862 459 269 863 864 865 530 270 866 867 868 517 271 869 870 871 579 272 872 873 874 492 273 875 876 877 510 274 878 879 880 531 275 881 882 883 520 276 884 885 886 407 277 887 888 889 531 278 890 891 892 421 279 893 894 895 408 280 896 897 898 441 281 899 900 901 409 282 902 903 904 417 283 905 906 907 476 284 908 909 910 475 285 911 912 913 404 286 914 915 916 475 287 917 918 919 462 288 920 921 922 524 289 923 924 925 437 290 926 927 928 455 291 929 930 931 476 292 932 933 934 465 293 935 936 937 407 294 938 939 940 531 295 941 942 943 421 296 944 945 946 408 297 947 948 949 441 298 950 951 952 409 299 953 954 955 417 300 956 957 958 432 301 959 960 961 475 302 962 963 964 404 303 965 966 967 475 304 968 969 970 462 305 971 972 973 524 306 974 975 976 437 307 977 978 979 455 308 980 981 982 476 309 983 984 985 465 310 986 987 988 460 311 989 990 991 584 312 992 993 994 474 313 995 996 997 461 314 998 999 1000 694 315 1001 1002 1003 462 316 1004 1005 1006 470 317 1007 1008 1009 465 318 1010 1011 1012 528 319 1013 1014 1015 457 320 1016 1017 1018 528 321 1019 1020 1021 515 322 1022 1023 1024 577 323 1025 1026 1027 490 324 1028 1029 1030 508 325 1031 1032 1033 529 326 1034 1035 1036 518 327 1037 1038 1039 460 328 1040 1041 1042 584 329 1043 1044 1045 474 330 1046 1047 1048 461 331 1049 1050 1051 494 332 1052 1053 1054 462 333 1055 1056 1057 470 334 1058 1059 1060 465 335 1061 1062 1063 528 336 1064 1065 1066 457 337 1067 1068 1069 528 338 1070 1071 1072 515 339 1073 1074 1075 577 340 1076 1077 1078 490 341 1079 1080 1081 508 342 1082 1083 1084 529 343 1085 1086 1087 518 344 1088 1089 1090 462 345 1091 1092 1093 586 346 1094 1095 1096 476 347 1097 1098 1099 463 348 1100 1101 1102 496 349 1103 1104 1105 464 350 1106 1107 1108 472 351 1109 1110 1111 467 352 1112 1113 1114 530 353 1115 1116 1117 459 354 1118 1119 1120 530 355 1121 1122 1123 517 356 1124 1125 1126 579 357 1127 1128 1129 492 358 1130 1131 1132 510 359 1133 1134 1135 531 360 1136 1137 1138 520 361 1139 1140 1141 393 362 1142 1143 1144 517 363 1145 1146 1147 407 364 1148 1149 1150 394 365 1151 1152 1153 427 366 1154 1155 1156 395 367 1157 1158 1159 403 368 1160 1161 1162 476 369 1163 1164 1165 461 370 1166 1167 1168 390 371 1169 1170 1171 461 372 1172 1173 1174 448 373 1175 1176 1177 510 374 1178 1179 1180 423 375 1181 1182 1183 441 376 1184 1185 1186 462 377 1187 1188 1189 451 378 1190 1191 1192 393 379 1193 1194 1195 517 380 1196 1197 1198 407 381 1199 1200 1201 394 382 1202 1203 1204 427 383 1205 1206 1207 395 384 1208 1209 1210 403 385 1211 1212 1213 476 386 1214 1215 1216 461 387 1217 1218 1219 390 388 1220 1221 1222 461 389 1223 1224 1225 448 390 1226 1227 1228 510 391 1229 1230 1231 423 392 1232 1233 1234 441 393 1235 1236 1237 462 394 1238 1239 1240 451 395 1241 1242 1243 464 396 1244 1245 1246 588 397 1247 1248 1249 478 398 1250 1251 1252 465 399 1253 1254 1255 699 400 1256 1257 1258 466 401 1259 1260 1261 474 402 1262 1263 1264 469 403 1265 1266 1267 532 404 1268 1269 1270 461 405 1271 1272 1273 532 406 1274 1275 1276 519 407 1277 1278 1279 581 408 1280 1281 1282 494 409 1283 1284 1285 512 410 1286 1287 1288 533 411 1289 1290 1291 522 412 1292 1293 1294 464 413 1295 1296 1297 588 414 1298 1299 1300 478 415 1301 1302 1303 465 416 1304 1305 1306 498 417 1307 1308 1309 466 418 1310 1311 1312 474 419 1313 1314 1315 469 420 1316 1317 1318 532 421 1319 1320 1321 461 422 1322 1323 1324 532 423 1325 1326 1327 519 424 1328 1329 1330 581 425 1331 1332 1333 494 426 1334 1335 1336 512 427 1337 1338 1339 533 428 1340 1341 1342 522 429 1343 1344 1345 408 430 1346 1347 1348 532 431 1349 1350 1351 422 432 1352 1353 1354 409 433 1355 1356 1357 442 434 1358 1359 1360 410 435 1361 1362 1363 418 436 1364 1365 1366 477 437 1367 1368 1369 476 438 1370 1371 1372 405 439 1373 1374 1375 476 440 1376 1377 1378 463 441 1379 1380 1381 525 442 1382 1383 1384 438 443 1385 1386 1387 456 444 1388 1389 1390 477 445 1391 1392 1393 466 446 1394 1395 1396 436 447 1397 1398 1399 438 448 1400 1401 1402 422 449 1403 1404 1405 422 450 1406 1407 1408 442 451 1409 1410 1411 434 452 1412 1413 1414 558 453 1415 1416 1417 448 454 1418 1419 1420 435 455 1421 1422 1423 468 456 1424 1425 1426 436 457 1427 1428 1429 444 458 1430 1431 1432 503 459 1433 1434 1435 502 460 1436 1437 1438 431 461 1439 1440 1441 502 462 1442 1443 1444 489 463 1445 1446 1447 551 464 1448 1449 1450 464 465 1451 1452 1453 482 466 1454 1455 1456 503 467 1457 1458 1459 492 468 1460 1461 1462 462 469 1463 1464 1465 464 470 1466 1467 1468 448 471 1469 1470 1471 448 472 1472 1473 1474 468 473 1475 1476 1477 434 474 1478 1479 1480 558 475 1481 1482 1483 448 476 1484 1485 1486 435 477 1487 1488 1489 468 478 1490 1491 1492 436 479 1493 1494 1495 444 480 1496 1497 1498 503 481 1499 1500 1501 502 482 1502 1503 1504 431 483 1505 1506 1507 502 484 1508 1509 1510 489 485 1511 1512 1513 551 486 1514 1515 1516 464 487 1517 1518 1519 482 488 1520 1521 1522 503 489 1523 1524 1525 492 490 1526 1527 1528 462 491 1529 1530 1531 464 492 1532 1533 1534 448 493 1535 1536 1537 448

494 1538 1539 1540 468 495 1541 1542 1543 470 496 1544 1545 1546 594 497 1547 1548 1549 484 498 1550 1551 1552 471 499 1553 1554 1555 504 500 1556 1557 1558 472 501 1559 1560 1561 480 502 1562 1563 1564 539 503 1565 1566 1567 538 504 1568 1569 1570 467 505 1571 1572 1573 538 506 1574 1575 1576 525 507 1577 1578 1579 587 508 1580 1581 1582 500 509 1583 1584 1585 518 510 1586 1587 1588 539 511 1589 1590 1591 528 512 1592 1593 1594 498 513 1595 1596 1597 500 514 1598 1599 1600 484 515 1601 1602 1603 484 516 1604 1605 1606 504 517 1607 1608 1609 470 518 1610 1611 1612 594 519 1613 1614 1615 484 520 1616 1617 1618 471 521 1619 1620 1621 504 522 1622 1623 1624 472 523 1625 1626 1627 480 524 1628 1629 1630 539 525 1631 1632 1633 538 526 1634 1635 1636 467 527 1637 1638 1639 538 528 1640 1641 1642 525 529 1643 1644 1645 587 530 1646 1647 1648 500 531 1649 1650 1651 518 532 1652 1653 1654 539 533 1655 1656 1657 528 534 1658 1659 1660 498 535 1661 1662 1663 500 536 1664 1665 1666 484 537 1667 1668 1669 484 538 1670 1671 1672 504

[0186] The biological profile of the compounds of the invention, was assessed by evaluating their activity at the 5-HT.sub.1A, 5-HT.sub.2A, and D.sub.4 receptors, according to the methods described below.

[0187] Receptor Binding Studies

[0188] Receptor binding studies were carried out to determine the affinity of the compounds for 5-HT.sub.1A, 5-HT.sub.2A, and D.sub.4 receptors

[0189] 5-HT.sub.1A Radioligand Receptor Binding Assay

[0190] Membranes from CHO cells, expressing 5-HT.sub.1A human receptors were suspended in incubation buffer.

[0191] Binding Assay:

[0192] Binding assays were performed in MultiProbe 204 pipetting system (Packard), according to a predetermined mapping, consistent with the software Screen. The compounds were tested in singlicate at one concentration (10.sup.-1 M) in a total volume of 1000 .mu.l. 980 .mu.l of diluted membranes, 10 .mu.l DMSO or unlabelled ligand and 10 .mu.l of [.sup.3H]-8-OH-DPAT (0.6-0.7 nM) were incubated for 60 minutes at 27.degree. C. The reaction was stopped by rapid filtration through Tomtec Cell Harvester (48 wells) using Filtermat B (presoaked in 0.1% PEI) filters. Filters were washed with ice-cold 50 mM Tris-HCl (pH 7.4) buffer (9.times.700 .mu.l), dried, covered with MeltiLex B/HS scintillator sheets (Wallac) and heated at 80.degree. C. to 90.degree. C. for about 10 minutes, transferred into plastic sample bags (Wallac), sealed, and put into 1024 Beta Plate scintillation counter (Wallac). Non-specific binding was determined in the presence of 5-HT (10.sup.-5 M).

[0193] Data Analysis:

[0194] The specific radioligand binding to the receptor was defined by the difference between total binding and non-specific binding, determined in the presence of an excess of unlabelled ligand. Results were expressed as percentage of control specific binding obtained in the presence of the compounds. The affinity values (IC.sub.50) for the compounds were obtained by a nonlinear least squares regression analysis on the basis of a one binding site model.

[0195] 5-HT.sub.1A Functional Assay (cAMP)

[0196] CHO/5-HT.sub.1A cells were random seeded at a density of about 200,000/well in 24 well plates the day prior to the experiment. On the day of the experiment, cells were pretreated for 15 minutes at 37.degree. C. with 500 .mu.M isobutylmethylxantine (IBMX) dissolved in culture medium without serum. Wells were then divided in different groups in duplicate as follows: control, 10 .mu.M FSK, 10 .mu.M FSK+1 .mu.M 5-HT as positive standard and 10 .mu.M FSK+10 .mu.M of the different compound under evaluation. Sample solutions were added and incubated for additional 15 minutes at 37.degree. C. After incubation, the medium was aspirated and the reaction stopped by adding 200 .mu.l of lysis buffer. Plates were shaken for 5 minutes, then the lysate was removed and samples were stored at 4.degree. C. until the day of the assay. For the cAMP evaluation, samples were properly diluted and the cAMP content was measured by an enzyme immunoassay system.

[0197] Data Analysis:

[0198] Results are expressed as % inhibition of the cAMP accumulation induced by 10 .mu.M FSK.

[0199] D.sub.4 Radioligand Receptor Binding Assay

[0200] Membranes from CHO cells expressing D.sub.4 human receptors, were suspended in incubation buffer.

[0201] Binding Assay:

[0202] Binding assays were performed in MultiProbe 204 pipetting system (Packard), according to a predetermined mapping, consistent with the software Screen. The compounds were tested in singlicate at one concentration (10.sup.-7 M) in a total volume of 1000 .mu.l (980 .mu.l of diluted membranes, 10 .mu.l DMSO or unlabelled ligand and 10 .mu.l of [.sup.3H] YM-09151-2 (0.15-0.25 nM). After incubation for 120 minutes at 27.degree. C., the reaction was stopped by rapid filtration through Tomtec Cell Harvester (48 wells) using Filtermat B (presoaked in 0.1% PEI) filters. Filters were washed with ice-cold 50 mM Tris-HCl (pH 7.4) buffer (9.times.700 .mu.l), dried, covered with MeltiLex B/HS (Wallac) scintillator sheets and heated in oven at 80.degree. C. to 90.degree. C. for about 10 minutes, transferred into plastic sample bags (Wallac), sealed, and put into 1024 Beta Plate scintillation counter (Wallac). Non-specific binding was determined in the presence of clozapine dissolved in DMSO to a final concentration of 10.sup.-5 M.

[0203] Data Analysis:

[0204] The specific radioligand binding to the receptor was defined by the difference between total binding and non-specific binding, determined in the presence of an excess of unlabelled ligand. Results were expressed as percentage of control specific binding obtained in the presence of the compounds.

[0205] 5-HT.sub.2A Radioligand Receptor Binding Assay

[0206] Tissue Preparation:

[0207] Rats (male Sprague-Dawley, 200-250 g) were used. Cerebral frontal cortex was homogenized in 10 volumes of ice cold 0.32 M sucrose in 5 mM Tris-HCl (pH 74) buffer. After centrifugation of the homogenate (1,000.times.g for 10 minutes) the supernatant was then recentrifuged at 48,000.times.g for 15 minutes. The resulting pellet was gently homogenized in an equal volume of 50 mM Tris-HCl buffer (pH 7.4) and incubated at 37.degree. C. for 10 minutes. Membranes were then collected by centrifugation as above described and finally resuspended in 10 volumes of 50 mM Tris-HCl buffer (pH 7.4).

[0208] Binding Assay:

[0209] For displacement experiments membranes (980 .mu.l) were diluted in 50 mM Tris-HCl buffer (pH 7.4) to a final concentration of 1:100 (w/v); the tissue suspension was then incubated at 37.degree. C. for 10 minutes in a final volume of 1 ml in the presence of 0.5 nM [.sup.3H]-Ketanserin. Non-specific binding was determined by incubating similar samples with unlabelled methysergide (100 .mu.M). After incubation, samples prepared in a 24 wells cell culture cluster (Costar) were rapidly filtered by Inotech Cell Harvester (IH 201 filters). The filters were washed three times with 2 ml ice-cold Tris-HCl buffer and placed in polyethylene vials, then 4 ml of Filter Count scintillation cocktail (Packard) were added. The radioactivity present was counted by liquid scintillation spectrometry.

[0210] Data Analysis:

[0211] The affinity values (IC.sub.50) for the compounds were obtained by a nonlinear least squares regression analysis on the basis of a one binding site model.

[0212] 5-HT.sub.2A Functional Assay (PI turnover)

[0213] Tissue Preparation:

[0214] Cross-chopped miniprisms (350.times.350 .mu.m) were prepared from mouse whole cerebral cortices and incubated for 60 minutes at 37.degree. C. in Krebs-Henseleit buffer containing 2 g/l glucose.

[0215] Functional Assay:

[0216] Cerebral cortex miniprisms were distributed in vials and incubated for 30 minutes with approximately 170 nM [.sup.3H]-myoinositol (10-20 Ci/mmol) and 10 mM lithium chloride. Samples were divided in different groups in triplicate: control, 100 .mu.M 5-HT, 10 and 30 .mu.M flibanserin+100 .mu.M 5-HT, as standards, and 10 .mu.M of the different compound under investigation+100 .mu.M 5-HT. When 5-HT was added the incubation continued for 45 minutes. Compounds under investigation and flibanserin were added 10 minutes before dispensing 5-HT. Incubation was terminated by the addition of 940 .mu.l chloroform-methanol (1:2 v/v). Further aliquots of chloroform (310 .mu.l) and water (310 .mu.l) were added and labeled inositol phosphates (1 Ps) were extracted from the aqueous phase by ion exchange chromatography using Dowex resin in the formate form. After addition of 10 ml of PicoFluor 40 scintillation cocktail (Packard), the radioactivity present in an aliquot (400 .mu.l) of the aqueous extract was counted by liquid scintillation spectrometry.

[0217] Data Analysis:

[0218] Results are expressed as % inhibition of the PI turnover accumulation induced by 100 .mu.M 5-HT.

[0219] The following Tables 4 to 6 collect the biological data at the receptors of the new compounds.

7TABLE 4 % Inhibition at 5-HT.sub.1A and D.sub.4 Receptors 5-HT.sub.1A Receptor D.sub.4 Receptor 5-HT.sub.1A Receptor D.sub.4 Receptor Binding Assay Binding Assay Binding Assay Binding Assay Comp. % inhibition % inhibition Comp. % inhibition % inhibition No. (10.sup.-7 M) (10.sup.-7 M) No. (10.sup.-7 M) (10.sup.-7 M) 1 56 38 78 69 44 5 92 54 79 86 58 7 77 91 81 55 78 9 93 32 83 89 39 10 60 47 84 52 42 11 48 90 85 77 79 19 69 32 92 94 55 20 50 60 93 94 62 23 73 48 94 88 72 24 90 67 95 85 64 25 48 44 96 92 72 26 70 94 107 55 58 28 89 35 118 80 36 29 57 83 145 85 42 30 44 90 149 88 35 37 90 54 150 57 52 38 92 78 158 95 72 39 36 42 159 85 50 43 104 55 164 96 41 45 100 82 169 85 58 56 63 71 177 98 39 59 75 51 182 62 45 60 93 82 183 96 62 62 73 96 187 94 36 64 92 43 188 78 78 65 52 74 189 54 99 66 65 99 197 77 43 73 91 58 215 98 48 74 92 62 216 92 44 75 67 54 219 89 37 224 98 51 332 78 85 226 71 32 333 99 80 228 95 33 335 95 55 229 67 34 336 90 81 241 69 32 348 99 51 254 85 34 349 73 31 255 58 33 361 86 46 256 59 51 364 77 36 263 92 42 365 89 63 265 55 78 367 61 90 280 93 38 369 96 59

[0220]

8TABLE 5 5-HT.sub.1A Agonist Activity 5-HT.sub.1A Receptor Binding cAMP Compound No. IC.sub.50 (nM) % inhibition 5 13 63 9 9.9 48 37 16 44 60 6.2 65 64 12 52 73 13 45 83 15 64 158 13 48 164 4.2 73 168 5.0 71 177 3.3 76 183 7.2 66 187 8.2 44 202 1.7 72 206 2.1 80 215 0.85 83 217 5.2 68 219 15 61 228 6.0 82 254 7.4 66 263 8.8 63 284 4.9 82 285 5.2 47 296 8.2 82 297 7.9 74 301 2.6 83 310 15 63 314 7.1 44 318 3.1 61 330 7.9 62 333 16 67 335 3.5 69 347 13 65 348 3.5 57 352 4.1 79 365 15 82 369 3.5 84 370 4.4 52 381 44 79 382 11 64 386 6.7 82 403 5.5 84 404 2.1 60 415 14 82 416 7.9 77 420 1.8 87 421 0.66 56 446 7.3 81 459 8.8 86 468 3.1 66 472 3.1 67 481 11 82 499 5.0 74 503 2.8 87 504 3.6 50 512 0.59 68 514 7.9 67 520 8.1 70 521 0.61 67 525 1.5 87 536 9.5 55

[0221]

9TABLE 6 5-HT.sub.2A Antagonist Activity 5-HT.sub.2A Receptor Binding PI Turnover Compound No. IC.sub.50 (nM) % inhibition 9 16 45 73 0.90 42 83 43 86 168 46 22.00 177 7.7 39 183 27 12.00 206 17 90 215 3.2 83 254 65 64 514 74 41 521 30 48

Claims

We claim:

1. A compound of formula (I) 1673wherein: R.sup.1 is C.sub.1-C.sub.6-alkyl substituted by a group selected from OH, C.sub.1-C.sub.6-alkoxy, --OCONHC.sub.1-C.sub.6-alkyl, --OCONHC.sub.1-C.sub.6-alkyl, --NHSO.sub.2C.sub.1-C.sub.6-alkyl, and --NHCOC.sub.1-C.sub.6-alkyl, or R.sup.1 is C.sub.1-C.sub.6-alkyl substituted by a saturated or unsaturated 5- or 6-membered heterocycle containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen, the heterocycle optionally substituted by a group selected from C.sub.1-C.sub.4-alkyl, halogen, and benzyl; R.sup.2 and R.sup.3 together with the nitrogen form a saturated or unsaturated 5- or 6-membered heterocyclic ring optionally containing nitrogen or oxygen as an additional heteroatom, the heterocyclic ring thereof substituted by a group selected from phenyl, benzyl, and diphenylmethyl, each of these groups optionally mono- or di-substituted by one or two groups selected from CF.sub.3, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, phenyl, benzyl, halogen, and OH, or R.sup.2 and R.sup.3 together with the nitrogen form a saturated or unsaturated 5- or 6-membered heterocyclic ring optionally containing nitrogen or oxygen as an additional heteroatom, the heterocyclic ring thereof linked via a single bond, a methylene-bridge, or spiro-connected to a saturated or unsaturated heterocyclic group containing one or two heteroatoms selected from oxygen and nitrogen, the heterocyclic group optionally mono- or di-substituted by a group selected from CF.sub.3, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, phenyl, benzyl, halogen, .dbd.O, and OH, or R.sup.2 and R.sup.3 together with the nitrogen form a saturated or unsaturated bi- or tricyclic heterocyclic ring-system optionally containing nitrogen or oxygen as an additional heteroatom, the heterocyclic ring-system being optionally substituted by a group selected from CF.sub.3, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, phenyl, benzyl, halogen, .dbd.O, and OH; and A is C.sub.1-C.sub.6-alkylene, C.sub.2-C.sub.6-alkenylene, or C.sub.2-C.sub.6-alkynylene, or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) according to claim 1, wherein: R.sup.1 is C.sub.1-C.sub.4-alkyl substituted by a group selected from OH, C.sub.1-C.sub.4-alkoxy, --OCONHC.sub.1-C.sub.4-alkyl, --OCONHC.sub.1-C.sub.4-alkyl, --NHSO.sub.2C.sub.1-C.sub.4-alkyl, and --NHCOC.sub.1-C.sub.4-alkyl, or R.sup.1 is C.sub.1-C.sub.4-alkyl substituted by a saturated or unsaturated 6-membered heterocycle containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen; R.sup.2 and R.sup.3 together with the nitrogen form a saturated or unsaturated 5- or 6-membered heterocyclic ring optionally containing nitrogen as an additional heteroatom, the heterocyclic ring thereof substituted by a group selected from phenyl, benzyl, diphenylmethyl, pyridinyl, pyrimidinyl, benzimidazolonyl, and 3,4-methylenedioxibenzyl, each of these groups optionally mono- or di-substituted by a group selected from CF.sub.3, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, halogen, and OH; and A is C.sub.1-C.sub.4-alkylen- e or C.sub.2-C.sub.4-alkenylene, or a pharmaceutically acceptable salt thereof.

3. The compound of formula (I) according to claim 1, wherein: R.sup.1 is ethyl substituted by a group selected from OH, OCH.sub.3, OCH.sub.2CH.sub.3, --OCONHCH.sub.3, --OCONHCH.sub.2CH.sub.3, --NHSO.sub.2CH.sub.3, --NHSO.sub.2CH.sub.2CH.sub.3, --NHCOCH.sub.3, --NHCOCH.sub.2CH.sub.3, morpholinyl, piperazinyl, and piperidinyl; R.sup.2 and R.sup.3 together with the nitrogen form a 6-membered saturated or unsaturated heterocyclic ring optionally containing nitrogen as an additional heteroatom, the heterocyclic ring thereof substituted by a group selected from phenyl, pyridinyl, pyrimidinyl, benzimidizalonyl, and phenyl mono- or di-substituted by a group selected from CF.sub.3, CH.sub.3, OCH.sub.3, F, and Cl; A is C.sub.1-C.sub.4-alkylene or C.sub.2-C.sub.4-alkenylene, or a pharmaceutically acceptable salt thereof.

4. The compound of formula (I) according to claim 1, wherein: R.sup.1 is ethyl substituted by a group selected from OH, OCH.sub.3, --OCONHCH.sub.2CH.sub.3, --NHSO.sub.2CH.sub.3, --NHCOCH.sub.3, morpholinyl, and piperidinyl; R.sup.2 and R.sup.3 together with the nitrogen form a 6-membered saturated or unsaturated heterocyclic ring optionally containing nitrogen as an additional heteroatom, the heterocyclic ring thereof substituted by a group selected from pyridinyl, phenyl, and phenyl mono- or di-substituted by a group selected from CF.sub.3, CH.sub.3, OCH.sub.3, F, and Cl; and A is ethylene, propylene, butylene, or butenylene, or a pharmaceutically acceptable salt thereof.

5. The compound of formula (I) according to claim 1, wherein: R.sup.1 is ethyl substituted by a group selected from OH, OCH.sub.3, --OCONHCH.sub.2CH.sub.3, --NHSO.sub.2CH.sub.3, --NHCOCH.sub.3, morpholinyl, and piperidinyl R.sup.2 and R.sup.3 together with the nitrogen form a heterocyclic ring selected from the group consisting of piperazine, piperidine, and tetrahydropyridine, the heterocyclic ring thereof substituted by a group selected from pyridinyl, phenyl, and phenyl mono- or di-substituted by a group selected from CF.sub.3, CH.sub.3, and Cl; and A is ethylene, butylene, or butenylene, or a pharmaceutically acceptable salt thereof.

6. The compound of formula (I) according to claim 1, wherein: R.sup.1 is ethyl substituted by a group selected from OH, OCH.sub.3, --OCONHCH.sub.2CH.sub.3, and --NHSO.sub.2CH.sub.3; R.sup.1 and R.sup.3 together with the nitrogen form a piperazine ring, the piperazine ring thereof substituted by a group selected from trifluoromethylphenyl, methylphenyl, dimethylphenyl, and chlorophenyl; and A is ethylene, butylene, or butenylene, or a pharmaceutically acceptable salt thereof.

7. The compound of formula (I) according to claim 1, wherein R.sup.1 is a C.sub.1-C.sub.4-alkyl group.

8. The compound of formula (I) according to claim 1, wherein A is C.sub.1-C.sub.4-alkylene, C.sub.2-C.sub.4-alkenylene, or C.sub.2-C.sub.4-alkynylene.

9. A compound selected from the group consisting of: (a) 1-(2-methoxyethyl)-3-(4-{4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}buty- l)-1,3-dihydro-2H-benzimidazol-2-one; (b) 1-{4-[4-(2,3-dimethylphenyl)-1-p- iperazinyl]butyl}-3-(2-hydroxyethyl)-1,3-dihydro-2H-benzimidazol-2-one; (c) 2-[2-oxo-3-(4-{4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}butyl)-2,3- -dihydro-1H-benzimidazol-1-yl]ethyl-ethylcarbamate; (d) 1-(2-methoxyethyl)-3-(2-{4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}ethy- l)-1,3-dihydro-2H-benzimidazol-2-one; (e) 1-{[2-[4-(2,3-dimethylphenyl)-1-- piperazinyl]ethyl}-3-(2-methoxyethyl)-1,3-dihydro-2H-benzimidazol-2-one; (f) 1-{2-[4-(3-chlorophenyl)-1-piperazinyl]ethyl}-3-(2-hydroxyethyl)-1,3-- dihydro-2H-benzimidazol-2-one; (g) 2-[2-oxo-3-(2-{4-[3-(trifluoromethyl)ph- enyl]-1-piperazinyl}ethyl)-2,3-dihydro-1H-benzimidazol-1-yl]ethyl-ethylcar- bamate; (h) 2-(3-{2-[4-(2,3-dimethylphenyl)-1-piperazinyl]ethyl}-2-oxo-2,3- -dihydro-1H-benzimidazol-1-yl)ethyl-ethylcarbamate; (i) N-[2-(3-{2-[4-(2,3-dimethylphenyl)-1-piperazinyl]ethyl}-2-oxo-2,3-dihydro- -1H-benzimidazol-1-yl)ethyl]methanesulfonamide; (j) N-[2-(3-{(2Z)-4-[4-(3-methylphenyl)-1-piperazinyl]-2-butenyl}-2-oxo-2,3-d- ihydro-1H-benzimidazol-1-yl)ethyl]methanesulfonamide; and (k) N-[2-(3-{(2E)-4-[4-(3-chlorophenyl)-1-piperazinyl]-2-butenyl}-2-oxo-2,3-d- ihydro-1H-benzimidazol-1-yl)ethyl]methanesulfonamide, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising an effective amount of a compound of formula (I) according to one of claims 1 to 9 and a pharmaceutical carrier, diluent, or excipient.

11. A method for treatment or prophylaxis of anxiety disorders and affective disorders, in a host in need of such treatment or prophylaxis, which method comprises administering the host an effective amount of a compound according to one of claims 1 to 9.

12. A method for treatment or prophylaxis of treatment of a disease selected from the group consisting of depression, psychosis, schizophrenia, eating disorders, sexual disorders, Parkinson's disease, and stroke and traumatic brain injury, in a host in need of such treatment or prophylaxis, which method comprises administering the host an effective amount of a compound according to one of claims 1 to 9.