MXPA96002979A - Heterociclic compounds therapeuti - Google Patents

Abstract

The present invention relates to the compounds of the formula (I), wherein R and R 1 are hydrogen, C 1-4 alkyl or are attached or linked to form a ring, A is a cycloalkyl or alkyl-cycloalkyl group, n is an integer from 0 to 3, W is an optionally substituted 5-6-membered heterocyclic ring, or W is an optionally substituted aryl, heteroaryl, aryloxy or thiophenoxy group, or W is a group -SO2NR6R7 -NHC (O) R6R7o-C ( O) NHR6R7, which are useful in the treatment of clinical conditions for which a receptor agonist is indicated "similar to 5-HT"

Description

THERAPEUTIC HETEROCICLIC COMPOUNDS FIELD OF THE INVENTION The present invention relates to new chemical compounds, their preparation, pharmaceutical formulations containing them and their use in medicine, particularly in the prophylaxis and treatment of migraine.

BACKGROUND OF THE INVENTION The receptors that have a mediating action on the actions of 5-hydroxytryptamine (5-HT) have been identified in mammals both in the periphery and in the brain. Currently, as many as seven classes of the 5-HT receptor are proposed (Hoyer et al., Pharmacol. Rev., 46, 157-203, 1994), although only the so-called classes 5-HTj, 5HT2 > 5-HT3, and 5-HT4 have established physiological roles. European Patent Specification 0313397 discloses a class of 5-HT agonists which selectively acts on a particular subtype of the 5-HT receptor, and are effective therapeutic agents for the treatment of clinical conditions in which a selective agonist for this Type of Ref. 22843 receiver is indicated. For example, the receptor in question has a mediating action in the selective cranial arterial vasoconstriction and in the inhibition of the estradiotation of the plasma protein in the dura mater caused by the activation of the Vth nerve (trigeminal). The compounds described in the European specification are therefore beneficial in the treatment or prophylaxis of the conditions in which these actions are indicated, for example, migraine, a condition associated with, and / or with neurogenic inflammation-induced dilation of inflammation. the cranial vasculature. However, it is within the scope of the oldest application that the target tissue can be any tissue where the action is mediated by 5-HT receptors. of the type referred to above. EP-A-0486666 discloses a class of compounds that have exceptional activity at the 5-HT receptor. mentioned above and excellent absorption following oral dosing. These properties make the compounds particularly useful for certain medical applications, notably the prophylaxis and treatment of migraine, severe, recurrent headache, associated with dilated carotid arteries and histamine release, and the associated headache with vascular disorders, here referred to collectively as "migraine" DETAILED DESCRIPTION OF THE INVENTION A class of compounds has now been discovered which not only demonstrated improved metabolic stability and agonism of the 5HT receptor. necessary, but also exhibit a potentially selective inhibition of neurogenic inflammation and the routes or pathways of the nerves responsible for the transmission of headache. The compounds also exhibit partial agonism at the 5HT receptor. and therefore may have reduced side effects compared to 5HT receptor agonists. previously known. Accordingly, according to a first aspect of the present invention, there is provided a compound of the formula (I): where R and R are each independently hydrogen or alkyl with C, or R and R are attached or linked to form an azetidine ring; A is cycloalkyl with C "_, or C. C-alkyl-, cycloalkyl; n is an integer from 0 to 3; W is a five or six element ring containing from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the ring is optionally substituted by one or more substituents independently selected from alkyl with CI_? > cycloalkyl with C "_fi, carbonyl or sulfonyl and optionally the ring is fused to a phenyl ring; or W is an aryl, heteroaryl, aryloxy or thiophenoxy group containing from 1 to 8 carbon atoms, the group is optionally substituted by one or more substitutes independently selected from alkyl with -IA »phenyl, amino or mono- or di- -alkylamino with C. ,, and the heteroaryl group containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or W is a group -SO ^ NR R, -NHC (0) R6R7 or -C (0) NHR6R7 wherein R6 and R are independently selected from hydrogen, alkyl with C? _4 optionally substituted by an aryl or alkoxy group with r W-4 ' and the physiologically functional salts, solvates and derivatives thereof; with the proviso that the compound is not 3- [cis-lN, N-dimethylamino) cyclobutan-3-yl] -5- (1,2,4-triazol-1-ylmethyl) -H-indole or 3- [ rans-1-N, N-dimethylamino) cyclobutan-3-yl] -5- (1, 2,4-triazol-1-ylmethyl) -H-indole.

The compounds of the formula (I) wherein A is cycloalkyl with C "_, are particularly suitable. Preferably, R and R 1 are each independently hydrogen or alkyl with C,,. In suitable compounds of Formula (I) W is a five or six element ring containing from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, the ring is optionally substituted by one or more substituents independently selected from alkyl with C,,, cycloalkyl with C, fi) carbonyl or sulfonyl and optionally the ring is fused to a phenyl ring; or W is a group independently of hydrogen or alkyl with C,,. Particularly suitable compounds of formula (I) include those in which: R and R are each independently hydrogen or alkyl with C,,; A is cycloalkyl with C "_; n is an integer from 0 to 3; W is a ring of five or six elements containing from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, the ring is optionally substituted by one or more substituents independently selected from alkyl with C -? _, Cycloalkyl with C ~ _fi, carbonyl or sulfonyl and optionally the ring is fused to a phenyl ring; or W is a group S0"NR are independently hydrogen or alkyl with C,,; and the salts, solvates and physiologically functional derivatives thereof; with the proviso that the compounds are not 3- [cis-1 - (N, N-dimethylamino) cyclobutan-3-yl] -5- (1,2,4-triazol-1-ylmethyl) -H-indole or 3- [trans ~ l- (N, N-dimethylamino) cyclobutan-3-yl] -5- (1, 2,4-triazol-1-ylmethyl) -H-indole The compounds of the formula (I) wherein A is cycloalkyl with C ~ or C, they are particularly suitable, with the compounds wherein A is cycloalkyl with C, which are preferred. According to this, in a second aspect the present. invention provides a compound of the formula (Ia): where Ra and Ra are each independently hydrogen or alkyl with C._,; n is an integer from 0 to 3; Wa is a ring of five or six elements containing from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, the ring is optionally substituted by one or more substituents independently selected from C 1-4 alkyl 'cycloalkyl with C, _Q , carbonyl or sulfonyl and optionally the ring is fused to a phenyl ring, 8 9 8 9 or Wa is a SO "NR R group wherein R and R are independently hydrogen or C 1-4 alkyl and the salts, solvates and physiologically functional derivatives thereof; with the proviso that the compound is not 3- [cis-1 - (N, N-dimethylamino) cyclobutan-3-yl] -5- (1,2,4-triazol-1-ylmethyl) -H-indole or 3- [trans-1- (N, N-dimethylamino) cyclobutan-3-yl] -5- (l, 2,4-triazol-l-ylmethyl) -H-indole W in formula (I) or Wa in formula (la) includes the following groups (i), (ii), (iii), (iv), (v), (vi), (vii), (viii) or (ix): wherein R 2, R 3, and R 4 are hydrogen or alkyl with C 1-4 't R > 5 is hydrogen or MNDR10DR11, in d, ond, e DR10 and DRll are .hi.d.rogeno or alkyl with C,,; E is -C = or N; F is N when E is -C = or F is = C- when E is N; X is -0-, -S-, -NH- or -CH2 ~; And it's oxygen or sulfur; Z is -NH- or -S-; and B is cycloalkyl with C3_ "and the chiral center * in formula (i) or (ii) is in its (S) or (R) form or is a mixture thereof in any proportions; Suitably X is -0-. The additional, suitable W or Wa groups are those in which Y is oxygen. Preferred groups W and Wa are those of formulas (i) and (ii). A particularly preferred group W or Wa is that of the formula (i) wherein 2 X is -0-, Y is oxygen and R is hydrogen. Examples of the preferred compounds of the invention include: 4- [3-trahs-3-aminocyclobutyl) -lH-indol-5-ylmethyl] - (4S) oxazolidin-2-one. 4 ~ [3- (trans-3-aminocyclobutyl) -lH-indol-5-ylmethyl] - (4S) oxazolidin-2-one acetate. 4- [3- (cis-3-aminocyclobutyl) -lH-indol-5-ylmethyl] - (4S) oxazolidin-2-one acetate. 4- [3- (trans-3-dimethylamino-cyclobutyl) -lH-indol-5-ylmethyl] - (4S) oxazolidin-2-one. 5- (5,5-dimethyl) -3- i 2- [3-trans-3-di-ethylamino-cyclobutyl) -lH-indol-5-yl] ethyl} imidazolidin-2,4-dione. 3- • 2- [3- (trans-3-dimethylaminocyclobutyl) -lH-imidazolidin-2,4-dione. 3-12- [3- (trans-3-aminocyclobutyl) -lH-indol-5-yl] ethyl-5,5-dimethylimidazolidin-2,4-dione. 2- -i 2- [3- (trans-3-dimethylaminocyclobutyl) -lH-indol-5-yl] ethyl "phthalamide. 3- • [2- [3- (trans-3-dimethylaminocyclobutyl) -lH-indol-5-yl] ethyl} -3-azaspiro [5,5] undecan-2,4-dione. N-methyl- [3- (trans-3-dimethylaminocyclobutyl) -lH-indol-5-yl] methanesulfonamide. 4- [3- (trans-3-dimethylaminocyclobutyl) -lH-indol-5-ylmethyl] - (4R) oxazolidin-2-one. 4- [3- (trans-3-dimethylaminocyclobutyl) -lH-indol-5-ylmethyl] -3-methyl (4S) -oxazolidin-2-one. 5,5-dimethyl-3- [3- (trans-3-dimime and lami-nocyclobuyl) -lH-indol-5-ylmethyl] imidazolidin-2,4-dione. 3- [3- (trans-3-dimethylaminocyclobutyl) -lH-indol-5-ylmethyl] imidazolidin-2,4-dione. 5- [3- (trans-3-dimethylaminocyclobutyl) -lH-indol-5-ylmethyl] oxazolidin-2-one. 4- [3- (trans-3-dimethylamino-cyclobut-1-ylmethyl) -lH-indol-5-ylmethyl] - (4S) oxazolidin-2-one. 4- [3- (trans-3-methylaminocyclobutyl) -lH-indol-5-ylmethyl] - (4S) oxazolidin-2-one. 4- [3- (trans-3-dimethylaminocyclobutyl) -lH-indol-5-ylmethyl] -3-methyl (4R) -oxazolidin-2-one. 3- (trans) -3-dimethylaminocyclobutyl) -lH-indol-5-yl-acetamide. 4- [3- (cis-3-dimethylaminocyclobutyl-lH-indol-5-ylmethyl] - (4S) oxazolidin-2-one., 5-f-enoxy-3- (trans-3-aminocyclobutyl) -lH-indole. 5-phenoxy-3- (trans-3-dimethylaminocyclobutyl) -lH-indole. N-benzyl-3- (trans-3-dimethylaminocyclobutyl) -lH-indol-5-yl-acetamide. 5-N-benzylcarboxamido-3- (trans-3-dimethylamino-cyclobutyl) -JH-indole. 3-methyl-5- [3- (trans-3-dimethylaminocyclobutyl) -indol-5-yl] -l, 2,4-oxadiazole. 3 ~ methyl-5- [3- (trans-3-dimethylaminocyclobutyl) -indol-5-ylmethyl] -l, 2,4-oxadiazole. 3-methyl-5- [3-trans-3-dimethylaminocyclobutyl) -indol-5-ylmethyl] -l, 2,4-triazole. (S) -2- (5- (2-Oxo-4-oxazolidinylmethyl) -lH-indol-3-yl) cyclopropylamine. 5-car bo xami d o-3- (_tr_ans_-3-d ime t i 1 ami noc ic 1 or bu t i 1) * lH-indole.

The physiologically acceptable salts are particularly suitable for medical applications because of their wider aqueous solubility relative to the original, ie basic, compounds. Such salts must clearly have a physiologically acceptable anion. Suitable physiologically acceptable salts of the compounds of the present invention include those derived from acetic, hydrochloric, hydrobromic, phosphoric, malic, maleic, fumaric, citric, sulfuric, lactic, or tartaric acids. The succinate and chloride salts are particularly preferred for medical purposes. Salts having a physiologically unacceptable anion are within the scope of the invention as intermediates useful for the preparation of physiologically acceptable salts and / or for use in non-therapeutic situations, for example, in vitro. According to a third aspect of the present invention, there is provided a compound of the formula (I) or (a) or a physiologically acceptable salt, solvate, or derivative thereof which is physiologically functional, for use as a therapeutic agent, specifically as a receptor agonist "similar to 5-HT," for example, as a carotid vasoconstrictor or as an inhibitor of neurogenic inflammation in the prophylaxis and treatment of migraine. As indicated, however, the target organs for the present compounds, other than the carotid vasculature, are within the scope of the present invention. The amount of a compound of the formula (I) or (a), or a salt or solvate thereof, which is required to achieve the desired biological effect, will depend on a number of factors such as the specific compound, the use for which it is proposed, the means of administration, and the patient. A daily dose for the treatment of migraine can be expected to be considered in the range of 0.01 to 5 mg per kilogram of body weight. Unit doses may contain from 1 to 100 mg of a compound of formula (I) or (a), for example, ampoules or ampoules for injection may contain from 1 to 10 mg and orally administrable unit dosage formulations such as The tablets or capsules may contain from 1 to 100 mg. Such unit doses may be administered one or more times per day, separately or in multiples thereof. An intravenous dose can be expected to be considered in the range of 0.01 to 0.15 mg / kg and typically could be administered as an infusion from 0.0003 to 0.15 mg per kilogram per minute. The infusion solutions suitable for this purpose can contain from 0.01 to 10 mg / ml. When the active compound is a salt or solvate of a compound of the formula (I) the dose is based on the cation (for the salts) or an unsolvated compound. When referring hereinafter to the "compound (s) of the formula (I) or (a)" it will be understood that they include the salts and solvates thereof physiologically acceptable. According to a fourth aspect of the present invention, therefore, pharmaceutical compositions comprising, as the active ingredient, at least one compound of the formula (I) or (a) and / or a salt or solvate thereof are provided. pharmacologically acceptable, together with at least one pharmaceutical carrier or excipient. These pharmaceutical compositions can be used in the prophylaxis or treatment of clinical conditions for which a receptor agonist "similar to 5-HT," is indicated, for example, migraine. The carrier must be pharmaceutically acceptable to the patient and must be compatible with, that is, not have a detrimental effect on, the other ingredients in the composition. The carrier can be a solid or liquid and is preferably formulated with at least one compound of the formula (I) or (a) as a unit dose formulation, for example, a tablet which can contain from 0.05 to 95% in weight of the active ingredient. If desired, other physiologically active ingredients can also be incorporated into the pharmaceutical compositions of the invention. Possible formulations include those suitable for oral, buccal, parenteral (e.g., subcutaneous, intramuscular, or intravenous), rectal, topical or intranasal administration. The most suitable means of administration for a particular patient will depend on the nature and severity of the condition being treated and on the nature of the active compound, but, where possible, oral administration is preferred. Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, sachets, or tablets, each containing a predetermined amount of the active compound.; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions. Formulations suitable for sublingual or buccal administration include the pills comprising the active compound and, typically, a seasoned base, such as sugar and acacia or tragacanth, and the tablets comprising the active compound in an inert base, such as gelatin. and glycerin or sucrose and acacia. Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood of the proposed patient. Although such solutions are preferably administered intravenously, they can also be administered by subcutaneous or intramuscular injection. Formulations suitable for rectal administration are preferably provided as unit dosage suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter. Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. Carriers or carriers suitable for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof. The active ingredient is typically present in such formulations at a concentration of 0.1 to 15% w / w. The formulations of the invention can be prepared by any suitable method, typically by uniformly and intimately mixing the active compound (s) with the finely divided liquid or solid carriers or carriers, or both, in the required proportions and then, if necessary, shape the resulting mixture into the desired shape. For example, a tablet can be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a lubricating binder, inert diluent, or surface active dispersing agent, or by molding an intimate mixture of the ingredient. active pulverized and the inert liquid diluent. Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in an amount of water sufficient to give the desired concentration and then rendering the resulting solution sterile and isotonic. Accordingly, according to a fifth aspect of the present invention, there is provided the use of a compound of the formula (I) or (a) in the preparation of a medicament for the prophylaxis or treatment of a clinical condition for which a receptor agonist "similar to 5-HT." is indicated, for example, migraine. According to a sixth aspect, a method is provided for the prophylaxis or treatment of a clinical condition in a mammal, for example, a human being, for which a receptor agonist "similar to 5-HT" is indicated, for example, migraine, which comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or (a) or a physiologically acceptable salt, solvate, or physiologically functional derivative thereof. In a further aspect, the invention provides a process for the preparation of a compound of the formula (I) by reacting a compound of the formula (II) wherein n and W are as defined herein above, with a compound of the formula (III) wherein A is as defined above herein and Z is a benzyloxycarbonyl group, to give a compound of formula I wherein R and R are both hydrogen. The reaction is typically carried out by heating the compounds to a non-extreme temperature suitably in the range of 50 to 100 ° C and preferably to about 80 ° C in the presence of an aqueous mineral acid for example sulfuric acid and then stirring the benzyloxycarbonyl group by reflux in a system of a polar solvent, for example formic acid in methanol, in the presence of a catalyst such as palladium on carbon. The compounds of the formula (la) can be prepared by reacting a compound of the formula (II) where W is Wa with a compound of the formula (III) wherein A is cyclobutyl. Standard N-alkylation methods can be used to convert the compounds of the formula (I) or (Ia) wherein R and R are hydrogen to the corresponding compounds wherein R and / or R are alkyl The compounds of the formula (I) or (Ia) wherein R = R = alkyl with ^ -A can be prepared from the corresponding compound wherein R = R = H by the well-known N, N-dialkylation methods for those skilled in the art, for example, by treatment with the appropriate aldehyde in the presence of a reduction system, for example, sodium cyanoborohydride-acetic acid, in a polar solvent, such as methanol. The compounds of the formula (I) or (la) wherein R or R * = alkyl with C-_, can be prepared from the corresponding compound wherein R = R = H by N-benzylation using benzaldehyde and a reducing agent suitable, for example sodium borohydride, in a polar solvent such as ethanol, followed by N-alkylation using a suitable agent, such as the appropriate dialkylsulfate, typically in the presence of a base, for example anhydrous potassium carbonate, in a polar aprotic solvent, such as DMF, and finally N-debenzylation, typically by catalytic hydrogenation using, for example Pd / C in a polar solvent such as ethanol. The compounds of the formula (III) can be prepared from the appropriate 3-methylenecycloalkan-1-carboxylic acid (J. Amer. Chem. Soc. 1959, 81, p2723) by the reaction with diphenylphosphorylazidate and benzyl alcohol as described in EP-A-0366059. Alternatively, t-butyl alcohol, or 4-nitrobenzyl alcohol can be used. The reaction can be carried out in an aromatic solvent, for example ene, benzene, xylene or pyridine. Chlorinated solvents such as chloroform and 1,2-dichloroethane, and polar aprotic solvents, such as glyme and dimethylformamide are also suitable. The intermediate carbamate can also be prepared by the reaction of the aforementioned acid to form the corresponding acyl azide and the rearrangement to form the isocyanate. This isocyanate can then be reacted with an alcohol to form the carbamate. The compounds of the formula (III) are prepared from the intermediate carbamates by a hydroformylation reaction (also known as the Oxo reaction) with hydrogen gas and carbon monoxide gas in the presence of a transition metal catalyst. suitable. The rhodium, ruthenium, cobalt or platinum catalysts can be used. Chlorotris (triphenylphosphine) rhodium (I) and carbonylhydridotris (triphenylphosphine) rhodium (I) are the preferred catalysts. Suitable pressures of hydrogen are in the range of 1-100 atmospheres and a pressure of about 20 atmospheres is preferred. The carbon monoxide pressure is suitably in the range of 1-100 atmospheres and preferably is approximately 10 atmospheres. The hydroformylation reaction can be carried out in an aromatic solvent, for example ene, xylene or benzene; a non-aromatic hydrocarbon, for example hexane, heptane or a petroleum fraction; or in a dipolar aprotic solvent such as dimethylformamide. Toluene is the preferred solvent. The reaction can be carried out at a non-extreme temperature, suitably in the range of 20-100 ° C, and preferably carried out at about 70 ° C. The compounds of the formula (III) are believed to be novel and accordingly, in an eighth aspect, the present invention provides the novel intermediates of the formula (III). The hydrazines of the formula (II) can be prepared according to the methods of Cripps et al., In J. Amer. Chem. Soc. 8_1_ (1959) p2723 and as described in the patent EP-A-0486666. Additional methods for the preparation of these hydrazines are described in the following Examples given here. For the hydrazines of the formula (II) wherein W is a group of the formula (v) the heterocyclic portion can be constructed using the methodology described in Lin et al., J. Org. Chem., (1979), 44, p4160-4164. A typical reaction scheme for the preparation of a compound of the formula (I) is as follows: Where Z = benzoyloxy carbonyl An alternative route to synthesize the compounds of the formula (I) or (la) is to react a compound of the formula (II) with a compound of the formula (IV) wherein BOC represents a tertiary butoxycarbonyl group, to give a compound of the formula (I) wherein R = R = H and optionally converting this compound to a compound of the formula (I) wherein R and / or R = alkyl with C-_, by standard alkylation techniques as described herein above. The reaction is suitably carried out in the presence of an aqueous mineral acid, for example sulfuric acid at a non-extreme temperature, typically in the range of 50 to 100 ° C and preferably approximately 80 ° C. The compounds of the formula (IV) can be prepared as follows. An amide of the formula (X) they can be prepared by joining 3-benzyloxycyclo- acid. known α1-carboxylic acid, M. Maxim et al. Chem. 'Ber. 1957, 90, 1425 with the hydrochloride of N, 0-dimethyl-hydroxylamine and er through the acid chloride or by the use of amide-binding agents such as dicyclohexyl carbodiimide, N, N'-carbonyl diimidazole and the diphenyl phosphorosazidate. The bonding can also be effected by the use of an activated ester or by means of a mixed anhydride. The use of the acid chloride is preferred. The acid chloride can be prepared using thionyl chloride, phosphorous pentachloride or oxalyl chloride, but thionyl chloride is preferred. Suitable solvents for the binding include pyridine, toluene or acetonitrile or chlorinated solvents such as dichloromethane in the presence of a base, for example pyridine. Dichloromethane is preferred. An amine of the formula (IX) it can be prepared from the compound of the formula (X) by hydrogenolysis of the benzyloxy group using a transition metal catalyst and a hydrogen source to form an intermediate alcohol. This alcohol is converted into a separation group, for example by conversion into its tosylate or mesylate derivative, and then reacted with a source of azide ion to form the azide. Reduction of the azide using a transition metal catalyst and a hydrogen source forms the amine of the formula (IX). Typical catalysts for the hydrogenolysis step include palladium on carbon, palladium on carbon hydroxide, palladium black and platinum oxide. Palladium hydroxide on carbon is preferred. Suitable hydrogen sources include hydrogen gas at a pressure of 1 to 100 atmospheres, ammonium formate and formic acid. The preferred source of hydrogen is hydrogen gas at 15 atmospheres. The reaction is suitably carried out in an organic solvent such as ethanol, methanol, ethyl acetate or acetic acid and is preferably carried out in ethanol. The formation of the tosylate or mesylate derivative can be effected using β-toluenesulfo-nyl chloride or methanesulfonyl chloride in the presence of a base such as pyridine, triethylamine or 4-dimethyl-aminopyr idine. Suitable solvents include pyridine, dichloromethane and toluene. The use of p-toluenesulfonyl chloride in pyridine is preferred. Sodium azide is the preferred source of the azide ion and the reaction is suitably carried out in a polar aprotic solvent, for example dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone at a suitably elevated temperature in the range of 40-170 ° C. Preferably the reaction is carried out in dimethylformamide at about 80 ° C. The reduction of azide is effected by the use of a transition metal catalyst such as palladium on carbon, palladium hydroxide on carbon, palladium black or platinum oxide in a suitable solvent for example an alcohol such as ethanol or methanol, which contains a mineral acid such as hydrochloric acid or an organic acid such as acid acetic. Hydrogen sources include hydrogen gas at a pressure of 1 to 100 atmospheres, ammonium formate and formic acid. The reduction is preferably carried out using palladium hydroxide on carbon in ethanol containing acetic acid under 1 atmosphere of hydrogen. The t-butoxycarbonyl enol ether of the formula (IV) is prepared from the amine of the formula (IX) by protecting the amine group, for example as its t-butyloxycarbonyl derivative, using a suitable reagent. The N, N'-dimethylhydroxylamide portion is then reduced to the aldehyde using a hydride reducing agent. The Wittig reaction of the aldehyde with a suitable reagent provides the compound of the formula (IV). The protection step can be carried out using reagents such as di-butyldicarbona-to or N- (butoxycarbonyloxy) succinimide in the presence of a solvent. Suitable solvents are organic solvents such as dichloromethane, toluene and dioxane. The reaction is typically carried out in the presence of an amine catalyst such as 4-dimethylaminopyridine. The reduction of the N, N'-dimethylhydroxylamide portion is typically carried out using, for example, lithium aluminum hydride, which is preferred, or the diisobutylaluminum hydride in an organic solvent. Suitable solvents include toluene, tetrahydrofuran and diethyl ether. Tetrahydrofuran is the preferred solvent and the reduction is preferably carried out at a temperature of about 0 ° C. The Wittig reaction is carried out using, for example, methoxymethyltriphenylphospho-nium bromide in the presence of a strong base but methoxymethyltriphenylphosphonium bromide and a strong base are preferred. Suitable bases are n-butyl lithium, sodium hydride, sodium amide or potassium butoxide, which is preferred. The reaction is typically carried out in a solvent. Suitable solvents are ethereal solvents, for example tetrahydrofuran or glyme, or polar aprotic solvents such as dimethylformamide. Tetrahydrofuran is the preferred solvent and the reaction is preferably carried out at 0-100 ° C and preferably at about 80 ° C. The intermediate compounds of the formula (IV) are believed to be novel and in accordance with a further aspect, the present invention provides compounds of the formula (IV).

The compounds of the formula (la) are prepared by reacting a compound of the formula (IV) wherein A is cyclobutyl with a compound of the formula (II) wherein W is Wa. A typical reaction scheme is as follows R 1 Reagents: (i) SOCl2 / HN (OMe) Me, (ii) Pd / C / H2, (iii) TsCl / pyridine, (iv) NaN3 / DMF; (v) Pd / C / H2; (vi) (B0C) 20; (vii) LiAlH4; (viii) Fen3PCH2OMe / KO Bu; (ix) AcOH 25% eq.

The compounds wherein A is a cyclopropyl group can be prepared suitably by reacting a compound of the formula (V) NHBOC wherein BOC represents a tertiary butoxycarbonyl group with a hydrazine of the formula (II). The intermediate compounds of the formula (V) are believed to be novel and accordingly, in a further aspect, the present invention provides the compounds of the formula (V). A typical reaction scheme is as follows: (*) Reagents: (i) N2CHC02Et / (RhOAc) 2, (ii) K0H / H20, (iii) DPPA / tBuOH / FenMe, (iv) BH3 / THF / H202 / 0H-, (v) DMSO / (COC1) The aldehyde of the formula (V) can be prepared by the oxidation of the alcohol (*). Although this alcohol has been described in U.S. Pat. No. 4988703, no indication has been previously given as to the stereochemistry. Now methods have been discovered by means of which alcohol (*) can be prepared in its pure trans form. Accordingly, the Curtius reaction of 2-ethylene-cyclopropane-cyclic acid, according to the methods described above for the preparation of the compounds of the formula (III), gives the carbamate product. In this case, the preferred alcohol is t-butyl alcohol and the trans-N-t-butoxycarbonyl-2-ethenylcyclopropylamine is isolated. The trans-ethenyl compound thus isolated is now converted to the terminal alcohol by a hydroboration reaction with oxidation of the intermediate borane by the hydrogen peroxide. Typical reagents include borane solvent complexes, or boron trifluoride boron hydrate-sodium borohydride. The use of the borane-tetrahydrofuran complex in tetrahydrofuran is preferred. The oxidation of the alcohol (*) to the aldehyde (V) can be effected by organic or inorganic oxidants. Organic oxidants include oxalyl chloride / dimethyl sulfoxide, inorganic oxidants include the chromium, manganese and molybdenum complexes. Mixed catalyst / organic material systems such as tetrapropylammonium perruthenate / N-methyl-morpholine N-oxide are also suitable. The preferred oxidizing system is oxalyl chloride / dimethyl sulfoxide (known as Swern oxidation). Suitable solvents include chlorinated and non-chlorinated organic solvents. Dichloromethane is preferred.

An alternative scheme for the synthesis of the compounds of the formula (I) or (Ia) wherein one of R or R is hydrogen with the other which is the alkyl with '1-4 is as follows Reagents: (i) (EtO ^ CHpTsOH, C ") NaH / RI, (w) 1% H SO 80 °, (iv) Pd (OH) 2/10% HCOOH eOH Reflux The invention will now be described, by way of illustration only, by the following examples: The aldehyde of the formula (III) can be protected as a dialkyl acetal derivative wherein the alkyl group can be C, -C, - and can be alicyclic or cyclic. Diacetal is preferred. The protection can be effected by the reagents such as trialkyl ortho-themothyes or dialkoxypropanes in the presence of an acid catalyst such as organic or mineral acids or Lewis acids. Triethyl orthoformate is preferred in the presence of α-toluene sulphonic acid. The acetal can be alkylated using a base and an appropriate alkylating agent. Suitable alkylating agents include alkyl halides, alkyl sulfonates and dialkyl sulfates. Methyl iodide is the preferred alkylating agent. Suitable solvents for the reaction include polar aprotic solvents, ether solvents and alcohols. The dimethylformamide is preferred. The alkylated acetal can now be reacted with a hydrazine of the formula (II) as described above and the carbamate protecting group is removed to give the monoalkylated product.

Example 1: 4- [3- (trans-3-aminocyclobutyl) -5-indolylmethyl) - (4S) -oxazolidin-2-one acetate and 4- [3- (cis-3-aminocyclobutyl) -5-indolylmethyl) - (4S) - oxazolidin-2-one (a) cis and trans N-Methoxy-N-methyl-3-benzyloxy-cyclobutane-1-carboxamide (1) To the 3-benzyloxy cyclobutane-1-carboxylic acid (8.23 g, 39.95 mmol) is added thionyl chloride (50 ml) and dimethylformamide (2 drops). The reaction is refluxed for 2 h then the thionyl chloride is removed on a rotary evaporator. The acid chloride is dissolved in dichloromethane (50 ml) and cooled to 0 ° C. The hydrochloride of N, 0-dimethyl hydroxylamia (4.29 g, 44 mmol) was followed by pyridine 9.71 g, 100 mmol). The reaction is allowed to warm to t.a. and it stirs all night. The volatiles were removed on a rotary evaporator and the residue was taken up in 10% aqueous hydrochloric acid and extracted with ethyl acetate. The extracts are washed with water and dried over sodium sulfate. Column chromatography gave the product (7.7 g, 31 mmol, 77%) as a clear oil. EMAR for C14H? GN03 > calculated 249.13649, found 249.1354. (b) cis and trans 3-hydroxy-N-methoxy-N-methyl-cyclobutan-1-carboxamide The benzyl ether (7.7 g, 30.9 mmol) in ethanol (250 ml) is hydrogenated over 10% palladium hydroxide on carbon (1 g) at 15 atm H ". The product is purified by column chromatography to give 4.02 g, 25.2 mmol, 82%. EMAR for C? H13N03, calculated 159.08954, found 159.0892. (c) cis and trans 3-Azido-N-methoxy-N-methylcyclobutane-1-carboxamide To the alcohol (4.02 g, 25.2 mmol) in pyridine (40 ml) at 0 ° C is added p-toluenesulfonyl chloride (5.29 g, 27.7 mmol) and the reaction is stirred for 16 hours. The volatiles were removed on a rotary evaporator and the residue was taken up in ethyl acetate (150 ml) and washed with 3% aqueous hydrochloric acid in saturated brine (2 x 100 ml), saturated aqueous sodium bicarbonate. (50 ml) and dried over sodium sulfate. Chromatography gave 7.47 g, 23.1 mmoles, 92% of the tosylated compound which was used i directly for the next step. To the tosylate in dimethylformamide (40 ml) is added sodium azide (1.49 g, 23 mmol) and the reaction is heated at 80 ° C for 4 hours. An additional amount of sodium azide (0.75 g, 11.5 mmol) is added and heating is continued for 2 h. The cooled reaction is poured into water (200 ml) and extracted with ethyl acetate. The extracts are dried over sodium sulfate. Column chromatography gave the product (4.1 g, 22.3 mmol, 88%) as an oil. EMAR for C-H ^ O ^; calculated 184.09603, found 184.977. (d) cis and trans 3-Amino-N-methoxy-N-methylcyclobutane-1-carboxamide The azide (4.1 g, 22.3 mmol) in ethanol (60 ml) and acetic acid (2 ml) is hydrogenated (1 atm H ") over 10% palladium on carbon (100 mg). Column chromatography gave the product (1.28 g, 8.1 mmol, 36%) as an oil. HRMS for C.H .. -N "0 ,,: calculated 158.10553, found 158.1033. (e) cis and trans-3-butoxycarbonylamino-N-methoxy-N-methyl-1-cyclobutane carboxamide To the amine (1.28 g, 8.1 mmol) and 4-dimethyl aminopyridine in dichloromethane (20 ml) is added the di-butylcarbonate (3.54 g, 16.2 mmol) in one portion and the reaction is stirred for 16 hours. Water (50 ml) is added and the reaction is stirred for 30 minutes. The dichloromethane is separated and dried over sodium sulfate. Column chromatography gave the product as an oil (1.46 g, 5.66 mmol, 70%). Computed microanalysis: C 55.81, H, 8.53, N, 10.85, found C, 55.62, H, 8.87, N, 10.49. (f) cis and trans 3-t-butoxycarbonylamino-cyclobutan-1-carboxaldehyde Methoxymethylamide (258 mg, 1 mmol) in tetrahydrofuran (5 ml) at -50 ° C is added diisobutyl aluminum hydride (1.1 mmol of a 1 M solution in toluene) and the reaction is allowed to warm to 0 ° C for 30 minutes, then water (20 ml) is added. The mixture is extracted with ethyl acetate and the extracts are dried over sodium sulfate. Column chromatography gave the pure product. Microanalysis calculated C 60.30, H 8.84, N 7.04, found C 60.30, H 8.87, N 7.02. (g) cis and trans N-t-butoxycarbonyl-3- (2-methoxyethenyl) cyclobutan-1-amine.

To the methoxymethyltriphenyl phosphonium bromide / sodium amide (0.23 mmole) tetrahydrofuran (5 ml) is added and the reaction is stirred for 30 min. The aldehyde (30 mg, 0.151 mmol) in tetrahydrofuran (0.5 ml) is added dropwise and the reaction is heated at 80 ° C for 4 h. The cooled reaction mixture is poured into water (20 ml) and extracted with ethyl acetate (2 x 20 ml). The extracts are dried over sodium sulfate. Column chromatography gave the product (14.3 mg, 0.063 mmol, 42%) as an oil (h) 4- [3 - (trans-3-aminocyclobutyl) -5-indolylmethyl) - (4S) -oxazolidin-2-one acetate and 4 - [3- (cis-3-aminocicl.obbutyl) -5-indolylmethyl] _ (4S) -oxazolidin-2-one.

To the appropriate hydrazine (310 mg, 1.5 mmol) in 1% aqueous sulfuric acid (10 ml) is added the methyleneol ether (r ** 1 mmol) and the reaction is heated at 80 ° C for 6 hours. The reaction is cooled and washed with ethyl acetate. The acid layer is saturated with sodium chloride and extracted with tetrahydrofuran, the extracts are dried over sodium sulfate. Column and HPLC chromatography gave the trans product (gum). EMAR calculated for C, -H, nN O ,, calculated 285.14773 found the i and ¿285.1477 and the product cis p.f. 180-181 ° C, calculated EMAR 285.14773 found 285.1458.

Example 2: Trans-4- [3- (3- (dimethylaminocyclobutyl) -5-indolylmethyl] - (S) -l, 3-oxazolidin-2-one (a) Trans-N ~ (benzyloxycarbonyl) -cyclobutamine-3 -acetaldehyde Trans-N- (benzyloxycarbonyl) -3-methylenecyclobutaneamine (18g, 83mmol) (prepared as described in EP-A-0366059) and tris (triphenylphosphine) rhodium chloride (400mg, 0.43mmol) ) are heated at 70 ° C in toluene (250 ml) under 100 atmospheres of C0: H ~ (1: 1 mixture for 18 hours). The solvent is evaporated under reduced pressure and the residue is chromatographed on silica eluting with 25% ethyl acetate in cyclohexane. First eluate product (r.f. 0.25) mixture of the branched chain aldehydes cis and trans. Second eluted product (r.f. ro 0.1) mixture of the straight chain cis and trans aldehydes, the trans isomer was crystallized from ether as white needles (m.p. = 66.67 ° C). Microanalysis for C.4H. -NO-, Calculated C 68.02, H 6.88, N 5.67, Found C, 67.92, H 6.90, N 5.63. (b) 4- [3- (trans-3-aminocyclobutyl) -lH-indol-5-ylmethyl- (4S) -oxazolidin-2-one The appropriate hydrazine (6.3 g, 30 mmol) and the trans ~ N ~ (benzyloxycarbonyl) cyclobutanamine-3-acetaldehyde (6.3 g, 25.5 mmol) are heated at 80 ° C for 7 hours in 1% sulfuric acid (ac) ( 100 ml) and ethanol (150 ml). The reaction mixture is evaporated in vacuo and brine is added. Extraction with ethyl acetate gave the crude product (10.5 g, 83%) MS (FAB) 420 (M + 1) +. The product of the above is refluxed in methanol-10% formic acid with palladium hydroxide on carbon (1 g) for 7 hours. The solvent is removed in vacuo and brine is added. The solution is then washed with ethyl acetate and then made basic (pH 10-12) with dilute ammonium hydroxide solution. Extraction with THF gave the crude product which was purified by flash chromatography (2:14:84 NH3> ET0H3) (2 g, 28%) MS (FAB) 286 (M + 1) +. (c) Trans-4- [3- (3-dimethylaminocyclobutyl) -5-indoylmethyl] - (S) -l, 3-oxazolidin-2-one Formaldehyde (0.18 ml, 2.22 mmol) in methanol (5 ml) is added to the product of step (b) (250 mg, 0.88 mmol), acetic acid (0.26 ml, 4.55 mmol) and sodium cyanoborohydride (70 mg, 1.17). mmoles) in methanol (15 ml) and stirred at room temperature under a nitrogen atmosphere overnight. Water is added and the mixture is washed with ethyl acetate. The aqueous phase is then adjusted to pH 10 with potassium carbonate and saturated with sodium chloride. Extraction with ethyl acetate gave a sticky gum to which is chromatographed on silica eluting with a solution of 0.88 NH ~ 1% in methanol (r.f. '*' 0.4) to give a colorless white powder. Elemental analysis for C? 8 23N3 ° 2 ° * 35 CHC13 Calculated C 62.05, H 6.63, N 11.83 Found C 62.21, H 6.76, N, 11.55, p.f = becomes gummy at 77-78 ° C. This solvated compound can be dried in vacuo at 80 ° C to provide the anhydrous compound of Example 4 The following compounds were made by selecting the appropriate starting materials and following the method described in Example 2.

Example 20: Alternative synthesis for 4- [3- (trans-3-aminocyclobutyl) -5-indolylmethyl] - (4S) -oxazolidin-2-one; Compound of Example 1 The trans ~ N- (benzyloxycarbonyl) -cyclobutamine ~ 3-acetaldehyde (1 g, 4 mmol) and hydrazine (1.2 g, 5.8 mmol) are heated at 80 ° C in 1% aqueous sulfuric acid (50 ml) for 6 hours. After cooling the solid is removed by filtration and dried under vacuum. Crude is used for the next stage, m.p. = 95-100 ° C. The indole protected with Cb (500 mg, 1.2 mmol) and palladium hydroxide on carbon (50 mg, 0.36 mmol) are refluxed in 10% formic acid in methanol (25 ml) for 3 hours. The catalyst is removed by filtration and the solvent is evaporated under reduced pressure. Brine is added to the residue and the pH is adjusted to 11 with a 0.88 ammonium solution. The milky solution is extracted with tetrahydrofuran, dried over MgSO, and evaporated under vacuum to give the free base as a foam. EMAR Calculated 285.1477. Found 285.1485.

Example 21: (+) - 5- [3-trans-3-dimethylaminocyclobutyl) - lH-indol-5-ylmethyl] -oxazolidin-2-one (a) 5-benzyl-2-oxazolidinone - Sl - The 2,3-epoxypropylbenzene (60 g, 448 mmol) and the potassium cyanate (70 g, 364 mmol) are refluxed in DMF (600 ml) and water (300 ml) for 4 hours. The solvent is evaporated in vacuo and water is added. The aqueous phase is then extracted with ethyl acetate, dried (MgSO,) and evaporated. Recrystallization from ethyl acetate gave the product (28.2 g, 36%) m.p. 106-107 ° C MS (El) 177 (M +), 10 133, 86. (b) 5- (4-nitrobenzyl) -2-oxazolidinone 4-Benzyl-2-oxazolidinone (5 g, 28 mmol), 15 potassium nitrate (2.9 g, 29 mmol) and p-iodotoluene (0.5 g, 2 mmol) are stirred in trifluoroacetic acid (50 ml) overnight. The mixture is then poured onto ice and extracted with ethyl acetate. This is 20 wash with a sodium bicarbonate solution, dry (MgSO,) and evaporate. Flash chromatography (ethyl acetate / hexane 70:30) gave the product (2.2 g, 35%) m.p. 150-151 ° C, MS (ES) 223 (M + 1) + 25 (c) 5- (4-aminobenzyl) -2- or xazolidinonj 4- (4-Nitrobenzyl) -2-oxazolidone (9.9 g, 45 mmol) and 10% palladium on charcoal (900 mg) are stirred under an atmosphere of hydrogen in methanol (200 ml) and 2.5 N aqueous HCl (50 ml). ml) at room temperature for 4 hours. The reaction mixture is filtered and evaporated. Water is added and the solution washed with ace¬ 10 ethyl acetate. The aqueous phase is then made basic with a diluted NaOH solution and extracted with THF to give the crude product (6.2 g, 72%) P.f. 135-138 ° C MS (EI) 192 (M +), 106. 15 The 5- (4-aminobenzyl) -2-oxazolidinone (1.7 g, 8.9 mmol) is dissolved in HCl c. (2 ml) and water (7.5 ml) and then cooled to below 5 ° C. A solution of sodium nitrite (0.61 g, 7 mmol) in water (7.7 ml) is added 20 then drip. Then the solution is stirred to? > 5 ° C for 20 minutes. This is then added slowly to a cooled solution (below 5 ° C) of sodium sulfite (3.4 g, 27 mmol) in water (15 ml). The solution is 25 stir for 20 minutes before allowing it to warm to room temperature and then slowly warm to 60 ° C. Then add HCl c. (3 ml) and heated to 60 ° C, continuing overnight. The solution is then diluted with water (15 ml) and ethanol (30 ml). The trans-N- (benzyloxycarbonyl) cyclobutanamine-3-acetaldehyde (1.5 g, 6 mmol) is then added and the mixture is heated at 80 ° C for 7 hours. Partial evaporation followed by extraction with THF gave the crude product which was purified by flash chromatography (methanol / chloroform 5:95) (1.7 g, 46%) MS (FAB) 420 (M + 1) +. The product of this step is then treated by the methods described in example 2 to provide (_ + - 5- [3- (trans-3-dimethyl-aminociclobutyl) -lH-indol-5-ylmethyl] oxazolidin- 2- ona Example 22: 4- [3-trans-3-methylaminocyclobutyl) -lH-indol-5-ylmethyl] - (4S) -oxazolidin-2-one (a) Trans-N- (benzyloxycarbonyl) cyclobutanamine-3-acetaldehyde diethyl acetal.

The trans-N- (benzyloxycarbonyl) cyclobutamine-3-acetaldehyde (1 g, 4 mmol), triethyl orthoformate (1.35 mL, 8 mmol) and p-toluene sulfonic acid (100 mg) are refluxed in ethanol for 3 hours. hours. The reaction mixture is evaporated in vacuo and purified by flash chromatography (ethyl acetate / cyclohexanone 10:90) to give a colorless oil (1.2 g, 94%). (b) Trans-N-benzyloxycarbonyl-N-methylcyclobutan- 10 amide-3-acetaldehyde diethyl acetal The trans-N- (benzyloxycarbonyl) cyclobutanamine-3-carboxaldehyde diethyl acetal (1.2 g, 3.7 mmol) in dry DMF (10 ml) is added dropwise to a cold hydride suspension. of sodium (60% in oil) (165 mg, 4.1 15 mmol) in dry DMF (10 ml). After the addition to the mixture is complete, it is allowed to stir at 10 ° C for 1/2 hour. Then methyl iodide (0.23 ml, 3.7 mmol) in dry DMF (5 ml) is added dropwise. To the mix Then it is allowed to warm to room temperature and stir for 2 hours. The reaction is then poured onto ice and extracted with ether. Flash chromatography (ethyl acetate / cyclohexane 10:90) gave the product 25 as a colorless oil (lg, 83%).

The product of this step is then treated by the methods described in Example 2 to provide 4- [3- (trans-3-methylamino-cyclobutyl) -lH-indol-5-ylmethyl] - (4S) oxazolidin- 2- ona Example 23: 5-N-benzylcarboxamido-3-trans-3-dimethylaminocyclobutyl) -lH-indole (a) 3- (trans-3-dimethylaminocyclobutyl) lH-indol-5-carboxylic acid.

The 5-carboxamido-3- (trans-3-dimethylaminocyclobutyl) -lH-indole (0.4 g, 1.6 mmol), prepared using the methods described in Example 2, is refluxed in a 10 M NaOH solution (15 g). ml) and methanol (10 ml) for 7 hours. The resulting solution is cooled in ice and neutralized with dilute HCl. This solution is then evaporated to dryness in vacuo and methanol is added. The sodium chloride is removed by filtration and the solution is evaporated to give the crude product. (b) 5-N-benzylcarboxamido-3-trans-3-dimethyl-aminociclobutyl) -lH-indole Crude 3- (trans-3-dimethylaminociclobutyl) -lH-indol-5-carboxylic acid (0.4 g, 1.6 mmol), 0- (lH-benzotriazol-1-yl) -N, N tetrafluoroborate, NN-tetramethyluronium (0.57 g, 1.8 mmol), benzylamine (0.18 ml, 1.6 mmol) and triethylamine (0.25, 1.8 mmol) are stirred at room temperature in dry DMF (15 ml) for 5 hours. The reaction is quenched or the temperature is rapidly reduced with water and extracted with ethyl acetate. This is dried (MgSO,) and evaporated to give the crude product which is purified by flash chromatography (NH ", MeOH, CHC13 1:10:89 0.88) (175 mg, 32%) MS (EI) 347 (M + ).

Example 24: 2- i 2- [3- (trans-3-dimethylaminocyclobutyl) -lH-indol-5-yl] ethyl phthalamide The intermediate product protected with Cbz, prepared by the methods described in example 2, (0.5 g, 1.6 mmol), the boron trifluoride etherate (2 ml, 16 mmol) and ethyl mercaptan (3.4 ml, 46 mmol) are subjected to reflux for 48 hours. The mixture is then evaporated in vacuo and brine is added. The pH is then adjusted to a value of 10-12 with a diluted NaOH solution. Extraction with THF gave the crude product which is chromatographed on silica eluting with 0.88 NH3 / MeOH 1:99. (190 mg, 33%) MS (FAB) 360 (M + 1) +. The product from this step is then treated by the methods described in Example 2 to provide 2- (2-2- [3- (trans-3-dimethylaminocyclobutyl) -lH-indol-5-yl] ethyl phthalamide.

Example 25: 3- [trans-3-dimethylaminocyclobutyl] -lH-indol-5-yl acetamide (a) 4-hydrazinophenyl-acetic acid hydrochloride To a solution containing conc. HCl (76 ml) and 4-amino-phenylacetic acid (10 g: 66 mmol) at 4 ° C is added a solution of sodium nitrite (4.56 g, 55 mmol) in water (10 ml) by drip, while maintaining the temperature from 0 to 4 ° C. The mixture is stirred for 30 minutes and added to a cooled (0 ° C) solution of SnCl 2 (74.5 g, 331 mmol) in conc. HCl. (50 ml). The mixture is left at room temperature overnight to warm it. The precipitate formed is filtered and washed with water (50 ml), aq. 50% (50 ml), water (50 ml) and ether (2 x 50 ml). The solid 10 dried in vacuo to give the product 13 g. P.f. 220-223 ° C decomposition. E.M. 166 (M +) 151, 135, 121 NMR [360 Mz, H] ppm 3.5 (s, 2H), 6.9 (d, 2H), 7.1 (d, 2H), 10.7 (s amp.). 15 (b) 3- [trans ~ N- (benzyloxycarbonyl) -3-aminocyclobutyl] -lH-indol-5-yl acetic acid.

To 4-hydrazinophenylacetic HCl in sulfuric acid 20 rich ac. to 1% (75 ml) is added trans-N- (benzyloxycarbonyl) cyclobutanamide-3-acetaldehyde (5 g, 20 mmol). The mixture is heated at 90 ° C for 7 hours. The semisolid formed is filtered and washed with H "2S? 4 at 1% 25 and water. The solid is then taken up in ethyl acetate and washed with water. The organic phase is dried (MgSO,). The product is obtained as a sticky solid. Production: 6.5 g (74%) 5 (c) 3- [trans-N- (benzyloxycarbonyl) -3-amino-cyclobutyl] -lH-indol-5-ylacetamide.

To a solution of 3- [trans-N- (benzyloxycarbonyl) cyclobutanamine] -lH-indol-5-yl acetic acid. 10 (0.5 g, 1.38 mmol) in DMF (5 ml) is added the tetrafluoroborate of 0- (3,4-dihydro-4-oxo-1,2,3-benzotriazine-3-yl) N, N, N, N -tetramethyluronium [TBTU] (0.44 g, 1.38 mmole) and Et N (0.21 ml, 1.52 mmole). Then it bubbles 15 the anhydrous ammonia through the solution for 1 hour at room temperature with ice cooling when necessary. The mixture is stirred overnight at room temperature. The solvent is evaporated under vacuum.

The residue is chromatographed on silica using MeOH (10%) / chloroform (89%) / 880 NH "(11%). Production 0.28 g (56%) MS 269, 253, 182 NMR [360MH3, H1] 2.49 (t, 4H), 3.3 (m, 2H), 25 3.55 (m, 1H), 4.11 (m, 1H); 5.0 (m, 3H), 6.78 (s amp., 1H), 6.98 (dd, 1.6 Hz, 8.5 Hz, 1H), 7.3 (m, 9), 7.7 (d, 6.8 Hz, 1H). The product of this step is then treated by the methods described in Example 2 to provide 3- [trans-3-dimethylaminocyclobuyl] -lH-indol-5-yl acetamide.

Example 26: N-benzyl-3- [trans-3-dimethylaminocyclobutyl] -lH-indol-5-yl acetamide. (a) N-benzyl-3- [trans-3- (benzyloxycarbonyl-amino) cyclobutyl] -lH-indol-5-yl-ace-amide To a solution of 3- [trans ~ N- (benzyloxycarbonyl) -3-aminocyclobutyl] indol-5-yl acetic acid (1 g, 2.76 mmol) in DMF (5 ml) was added TBTU (0.97 g, 3.04 mmol), Et3N (0.42 ml, 3.04 mmol) and benzylamine (0.33 ml, 3.04 mmol). The mixture is stirred overnight at room temperature. The solvent is evaporated under vacuum and the residue is chromatographed on silica, 5% MeOH / 94% CHC13 / 1% 880 NH3 to give the oil a faint yellow color. Production: 0.81 g (80%) EM 468 (M + l), 392, 333.

The product from this step is then treated by the methods described in Example 2 to provide N-benzyl-3- [trans-3-dimethylaminocyclobutyl] -lH-indol-5-yl acetamide.

Example 27: 3-methyl-5- [3- (trans-3-dimethylamino-cyclobutyl) -lH-indol-5-ylmethyl] -l, 2,4-oxadiazole (a) N - [(dimethylamino) ethylidene] -3- [trans-3- (benzyloxycarbonylamino) cyclobutyl] -lH-indol-5-ylacetamide.

To a solution containing 3- [trans ~ N-benzyloxycarbonyl-3-aminocyclobutyl] indole-5-yl acetamide (4.68 g, 13 mmol) in toluene (10 ml) is added N, N-dimethyl acetamide dimethyl acetal (40 ml) . The mixture is then heated at 120 ° C for 2 hours under Dean & Stark The solution becomes very dark. The solvent is evaporated under vacuum to give N- [(dimethylamino) ethanylidene] -3- [trans-3-benzyloxycarbonylamino) cyclobutyl] -lH-indol-5-ylacetamide. Production: 5.7 g raw. (b) 5- "3- [N- (benzyloxycarbonyl) -trans-3-dimethylaminocyclobutyl] -lH-indol-5-yl ^ -3-methyl-1, 2,4-oxadiazole To a mixture containing hydroxylamine HCl, (10 mg, 1.6 mmol) 5N NaOH (0.2 mL), p-dioxane (3 mL) and 70% acetic acid (10 mL) is added amidine (500 mg, 1.6 mmol) and the mixture is heated at 120 ° C for 1 1/2 hours. The solvent is evaporated under vacuum and the residue is chromatographed using silica and 40% EtOAc / 60% cyclohexane to give the product. Production: 150 mg (31%) as a foam EM 417 (M + 1) 296 The product of this step was then treated by the methods described in Example 2 to provide 3-methyl-5- [3- (trans. 3- dimethylaminocyclobutyl) -lH-indol-5-ylmethyl] -1,4, -oxadiazole.

Example 28: 3-methyl-5- [3- (trans-3-dimethylamino-cyclobutyl) -lH-indol-5-ylmethyl] l, 2,4-triazole (a) To a solution of the amidine, prepared as in example 35 (a) above, (3 g, 6.99 mmol) in 70% aqueous acetic acid (100 ml), hydrazine hydrate 10.9 ml, 8.30 mmol is added. ). The mixture is stirred at 90 ° C for 5 hours. The mixture is concentrated under reduced pressure and diluted with water (100 ml). The aqueous phase is extracted with ethyl acetate (2 x 50 ml). The organic phase is dried (MgSO,) and evaporated. The residue is chromatographed using 10% of MeOH / 89% CHC13 /% NH3 to give an oil. Production: 200 mg EM 416 (M + 1), 415 (M +) 326 The product from this step is then treated by the methods described in Example 2 to provide 3-methyl-5- [3- (trans-3- dimethylaminocyclobutyl) -lH-indol-5-ylmethyl] -1,2,4-triazole.

Example 29: (S) -2- (5- (2-Oxo-4-oxazolidinylmethyl) -lH-indol-3-yl) cyclopropylamine a) ethyl 2-ethenylcyclopropanecarboxylate Butadiene (200 ml, Aldrich) condensed to -70 ° C is transferred to a glass coated autoclave vessel and ethyl diazoacetate (20 g, 0.175 moles, Aldrich) and rhodium acetate dimer (0.3 g, Aldrich) are added. The suspension is stirred in a sealed autoclave for 24 hours at room temperature. The content is diluted with 2% diethyl ether in pentane and passed through a pad of silica (50 g). The pad is washed with a small amount of ethanol and with additional ether-pentane. The eluate containing the ethanol is treated separately. The organic phases are concentrated under reduced pressure (^ 5 °) and subjected to a bulb of trajectory or short path for a distillation in the bulb (90-105 ° C to 12 mm) to give 15 the product as a colorless liquid (14.6 8). (b) 2-ethylenecyclopropanecarboxylic acid The above ester (11.79 g, 84.21 mmol) is dissolved in tetrahydrofuran (THF) (16 ml) and treated with potassium hydroxide (7.32 g) in water (75 ml) and heated under gentle reflux for 5 hours. The reaction mixture is 25 concentrate and the residue dissolves in water.

This is made with concentrated hydrochloric acid until pH 4 and the emulsion is extracted with diethyl ether. The organic phase is dried, concentrated and the residual oil is distilled (100-120 ° to 3 mm) to give the product as a * colorless liquid (8.7 g). (c) trans-Nt-Butoxycarbonyl-2-ethenylcyclopropaneamine The above acid (8.66 g, 77.4 mmol) is dissolved in anhydrous toluene (40 ml), cooled to 0 °, treated with dry triethylamine (11.9 ml) and then, dropwise, with diphenyl-15-phosphoryl azide (23.4 g, Aldrich) in toluene (25 ml). The solution is heated to 80 'and maintained at 80-85 ° for 45 minutes. Anhydrous t-butanol (36 ml) and toluene (10 ml) are rapidly added and the solution is heated to 102 °. 20 for 6 hours. The reaction mixture is allowed to cool and is diluted with diethyl ether, washed with IN orthophosphoric acid (100 ml), saturated aqueous sodium bicarbonate and brine, dried and concentrated.

The residual oil is purified by chromatography (silica: 350 g; hexane: ethyl acetate 95: 5) to give the product as a colorless oil (3.91 g). (d) trans-N-t-Butoxycarbonyl-2- (2-hydroxy-ethyl) cyclopropylamine The above alkene (3.91 g, 21.37 mmol) in anhydrous THF (20 ml) is cooled to 0 ° and 10 deals with the borane complex: THF (42.7 ml, IT in THF, Aldrich). It is stirred at 0 ° C for 2.5 hours then it is allowed to reach room temperature, it is cooled again to -5 ° C and treated sequentially with hydroxide. 15 aqueous sodium 6N (24.8 ml) and 30% aqueous hydrogen peroxide (7.53 ml). The mixture is stirred at room temperature for 10 minutes then treated with excess solid potassium carbonate and extracted with ethyl acetate.

Ethyl (3 x 100 ml). The organic phase is washed once with aqueous orthophosphoric acid, aqueous sodium bicarbonate, brine and dried. The solvent is removed and the residual oil is subjected to chromatography (silica: 300 g; 25% methanol from 1% to 4% in dichloromethane) to give the product as an oil which crystallized during standing at 3 ° (4.1 g). (e) trans-N-t-Butoxycarbonyl-2- (2-oxo-ethyl) -5-cyclopropylamine Oxalyl chloride (175 ml) in dry dichloromethane (DCM (8 ml)) is cooled to -65 ° C and treated with dimethyl sulfoxide (316 mg) in 10 DCM (1 ml) and after 10 minutes the above alcohol (394 mg, 1.96 mmol) in DCM (2 ml) is added. After 1 hour at -65 ° Triethylamine (1.1 ml) is added and the reaction is allowed to reach 0 ° and diluted with 15 diethyl ether (25 ml). The organic phase is washed with water, with IN orthophosphoric acid, with saturated aqueous sodium bicarbonate, and brine and dr The solvents are removed to give the product as a colored oil 20 dim yellow (349 mg). (f) (S) -2- (5- (2-Oxo-4-oxazolidinylmethyl) -lH-indol-3-yl) cyclopropylamine 25 To the above aldehyde (349 mg, 1.75 mmol) is treated with water: acetic acid 3: 1 (25 ml) and (S) -4- (2-oxo-4-oxazolidinylmethyl) phenylhydrazine (440 mg, 2.12 mmol) ). The mixture is heated under nitrogen at 80-85 ° for 5 hours. The reaction mixture is concentrated, added DCM, ethanol, 880 ammonia (85: 15: 1) and concentrate again. The residue is subjected to chromatography (silica: 50 g, DCM, ethanol, ammonia (85: 15: 1) and the component is isolated (Rf: 0.10, silica-DCM, methanol, ammonia (90: 10: 1). The latter is subjected to purification (x2) by preparative HPLC (Zorbax Cfi, MeCN-NH.OAc ac 0.1M) to give the title compound as a yellow foam in the form of an acetate salt 7.45 (1H, s, 2-H); 7.70 (1H, s, NH); 10.57 (1H, s, NH indole). Exact mass; 271.13208 (C15H17N302) EXAMPLES OF PHARMACEUTICAL FORMULATION In the following Examples, the "active ingredient" can be any compound of the formula (I) or (a) and / or a salt, physiologically acceptable solvate, or the derivative thereof which is physiologically functional. (1) Formulations of Tablet (i) Oral Mg / tablet A B Active ingredient 2.5 2.5 Avicel 13 Lactose 100.5 69.5 Starch (corn) 9 Starch 5 glycolate and sodium Povidone 3 3 Magnesium stearate 1 1 125 85 Formulations A to C can be prepared by wet granulation of the first six ingredients with povidone, followed by the addition of magnesium stearate and compression. (ü) Oral Mg / Tablet Active ingredient 2.5 Hydroxypropyl methyl cellulose (HPMC) 35 Polycarbophil 51.5 Magnesium stearate 1 90 The formulation can be prepared by direct compression of the mixed ingredients. (2) Capsule Formulations (i) Powder Mg / Capsule D E Active ingredient 2.5 2.5 Lactose 175.5 - Starch (1500 NF) 45 139.5 Starch and sodium glycolate - 6 Magnesium stearate 225 150 Formulations D and E can be prepared by mixing the ingredients and filling the two-part hard gelatin capsules with the resulting mixture. (ii) Liquid filling Mg / Capsule F G Active ingredient 2.5 2.5 Macrogol 4000 BP 222.5 Lecithin - 110 Peanut oil - 112.5 225 225 The formulation F can be prepared by melting the Macrogol 4000 BP, dispersing the active ingredient in the melt and filling the 2-part hard gelatin capsules therewith. The formulation G can be prepared by dispersing the active ingredient in the lecithin and the peanut oil and filling the elastic, soft gelatin capsules with the dispersion. (iii) Controlled release Mg / tablet Active ingredient 2.5 Avicel 145.5 Lactose 62 Triethyl citrate 3 Ethyl cellulose 12 225 The formulation can be prepared by mixing and extruding the first four ingredients and converting into spheres and drying the extruded material. The drpills were coated with ethyl cellulose as a membrane controlling the release and filled into two-part hard gelatin capsules. (3) Intravenous injection formulation in weigh Active ingredient hydrochloric acid c.s. up to pH 7 (Citrate buffer) Water for injections up to 100% The active ingredient is received in the citrate buffer and sufficient hydrochloric acid is added to effect the solution and adjust the pH to 7. The resulting solution is compounded to its volume and filtered through a micropore filter in ampoules or ampoules of sterile glass, which are sealed and overlapped.

Biological tests Saphenous Rabbit Vein Test The compounds of the formula (I) prepared in Synthetic Examples 1 to 17 were each tested for their activity as agonists for the "5-HT-like" receptor which has a mediating effect on the contraction of the Smooth muscle, by the following method. The left and right lateral saphenous veins of New Zealand White Rabbits (2.4-2.7 kg) which have been sacrificed by intravenous injection of pentobarbitone sodium (60 mg / kg) are obtained. The circular segments (3-5 mm wide) prepared from each vessel are converted into a suspension between two wire hooks and immersed in 20 ml organ baths containing the Kreb solution (pH 7.4) of the following composition (mM): NaCl 118.41, NaHCO3 25.00, KC1 4.75, KH2P04 1.19, MgSO4 1.19, glucose 11.10 and CaCl »2.50. Cocaine (30 μM) was present in the Kreb solution throughout the experiment to prevent the absorption of the amines by the neurons of the sympathetic system. The Kreb solution is maintained at 37 ° C and is continuously gassed with carbon dioxide 5% / oxygen 95%. Increases in isometric tissue strength were measured using Grass FT03C force displacement transducers and recorded on a Gould BD-212 pen or pen recorder. A force of 1.0 g was applied to each preparation and reset twice for a subsequent period of 30 minutes. During this period, the tissues were exposed to pargyline (500 μM) to irreversibly inhibit monoamine oxidase and phenoxybenzamine (0.1 μM) to inactivate α-adrenoceptors. At the end of 30 minutes, the inhibitors were removed by several changes of the Kreb solution of the organ bath. The agonist activity was evaluated by simulated additions of the test compound, its concentration is increased in increments of 0.5 log1n units until additional additions did not cause an additional change in tissue strength. In each experiment, the activity of the test compound was compared to the activity of 5-HT. The activity was expressed in terms of p (A, «] (-log. ~ [M] where M is the molar concentration of the agonist required to produce half the maximum effect.) Where the compounds were found to being antagonists, the results were expressed as pKb The results obtained for the compounds of Synthetic Examples 1 to 19 and 21 to 28 are shown in Table 1.

Table 1 Example pA50 (< X) pKb 1 (trans) 6.42 (0.78) Table (1) Cont.) 1 (cis) 5.8 (0.76) 3 5.72 4 5.72 (0.09) 5 6.05 6 5.57 7 6.77 8 7.18 9 5.03 10 5.25 11 4.95 12 6.23 13 4.85 (0.38) 14 6.25 (0.52) 15 5.15 (0.29) 16 < 6.5 17 6.62 18 6.02 19 5.73 21 5.44 (0.16) 22 6.15 (0.72) 23 5.90 24 5.21 (0.48) 25 4.78 Table 1 (Cont.) 26 5.41 27 3.12 28 5.18 B Calf Caudate Assay The compounds of the formula (I) prepared in the Synthetic Examples 1 were further tested to verify their activity as agonists for the "5-HT-like receptor" which has a mediating effect on the contraction of the smooth muscles by the next method. Membranes were prepared from the homogeneous materials of the core of the calf caudate.

Competition studies were carried out in the union with 3. 5nM [3 H] -5HT (ca. 25Ciml-1) in the presence of 15 L of mesulergine and 15 tM of 8-OH-DPAT, using 5 mg wet weight of ml of the membranes in a total volume of 1 ml per tube. The union data were fitted to a four-parameter logistic function to obtain the estimates of the These were converted to pK values using the Cheng-Prussof equation.

The results obtained for the compounds of Synthetic Examples 1 and 2 are shown in Table 2.

Table 2 Example Activity P [A5Q] 1 7.8 2 7.05 It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following

Claims (18)

R E I V I N D I C A C I O N E S A compound of the formula (I) characterized because R and R are each independently hydrogen or alkyl with C, or R and R are attached or linked to form an azetidine ring; A is cycloalkyl with C-, or C 3-3 alkyl-C, cycloalkyl; n is an integer from 0 to 3; W is a ring of five or six elements containing from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the ring is optionally substituted by one or more substituents independently selected from alkyl with cycloalkyl with C "_", Carbonyl or sulfonyl and optionally the ring is fused to a phenyl ring; or W is an aryl, heteroaryl, aryloxy or thiophenoxy group containing from 1 to 8 carbon atoms, the group is optionally substituted by one or more substituents independently selected from C.sub.1, phenyl, amino or mono- or di- -alkylamino with C, ,, and the heteroaryl group containing from 1 to 4 heteroatoms is independently selected from nitrogen, oxygen and sulfur; or W is a group -S02NR R -NHC (0) R R f? 1 r 7 or -C (0) NHR R wherein R and R are independently selected from hydrogen, alkyl with '1-4 optionally substituted by an aryl or C 1-4 alkoxy group and the salts, solvates and derivatives that are physiologically functional thereof; with the proviso that the compound is not 3- [cis-1 N, N-dimethylamino) cyclobutan-3-yl] -5- (1, 2,4-triazol-1-ylmethyl) -H-indole or 3- [ trans-1-N, N-imethylamino) cyclobutan-3-yl] 5- (1, 2,4-triazol-1-ylmethyl) -H-indole.
1. 2. A compound of the formula (I) characterized in that: R and R are each independently hydrogen or alkyl A is cycloalkyl with C 3-6 'n is an integer from 0 to 3; is a ring of five or six elements containing from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, the ring is optionally substituted by one or more substituents independently selected from alkyl with C, C, cycloalkyl, carbonyl or sulfonyl and optionally the ring is fused to a phenyl ring; or W is a group S0"NR are independently hydrogen or alkyl with C,,; and salts, solvates and derivatives that are physiologically functional thereof; with the proviso that the compound is not 3- [cis-1 - (N, N-dimethylamino) cyclobutan-3-yl] -5- (1,2,4-triazol-1-ylmethyl) -H-indole or 3- [trans-l- (N, N-dimethylamino) cyclobutan-3-yl] -5- (1, 2,4-triazol-1-ylmethyl) -H-indole. A compound of the formula (la) characterized because: Ra and Ra are each independently hydrogen or alkyl with C.; n is an integer from 0 to 3; Wa is a five or six element ring containing from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, the ring is optionally substituted by one or more substituents independently selected from C1_alkyl, cycloalkyl with C "_ft, carbonyl or sulfonyl and optionally the ring is fused to a phenyl ring, 8 9 8 9 or Wa is a group S0"NR R wherein R and R are independently hydrogen or alkyl with C,,; the salts, solvates and derivatives thereof which are physiologically functional; with the proviso that the compound is not 3- [cis-1 - (N, N-dimethylamino) cyclobutan-3-yl] -5- (1,2,4-triazol-1-ylmethyl) -H-indole or 3- [trans-1- (N, N-dimethylamino) cyclobutan-3-yl] -5- (1, 2,4-triazol-1-ylmethyl) -H-indole.
2. 4. A compound of the formula (I) or (la). according to any of claims 3 characterized in that W or Wa is selected from groups (i), (ii), (iii), (iv), (v), (vi), (vii), (viii) or (ix): 2 3 4 where R, R, and R are hydrogen or C 1-4 alkyl R is hydrogen or NR R where R 10 11 and R are hydrogen or C 1-4 alkyl is E -C or N; F is N when E is -C = or F is = C- when E is N; X is -0-, -S-, -NH- or -CH2 ~; And it's oxygen or sulfur; Z is -NH- or -S-; and B is cycloalkyl with C "_R and the chiral center * in formula (i) or (ii) is in its (S) or (R) form or is a mixture thereof in any proportions;
3. 5. A compound of the formula (I), characterized in that it is selected from the group consisting of: 4- [3- (trans-3-aminocyclobutyl) -lH-indol-5-ylme] - (4S) oxazolidin-2-one. 4- [3-trans-3-aminocyclobutyl) -lH-indol-5-ylme] - (4S) oxazolidin-2-one acetate. 4- [3- (cis-3-aminocyclobutyl) -lH-indol-5-ylme] - (4S) oxazolidin-2-one acetate. 4- [3- (trans-3-dimeaminocyclobutyl) -lH-indol-5-ylme] - (4S) oxazolidin-2-one. 5- (5, 5-dime) -3- - £ 2- [3-_tran_s-3-dimeaminocyclobutyl) -lH-indol-5-yl] e 3"imidazolidin-2,4-dione." 3- "12- [ 3- (trans-3-dimeaminocyclobutyl) -lH-indol-5-yljetyl'-imidazolidin-2,4-dione. 3- . { 2- [3- (trans-3-aminocyclobutyl) -lH-indol-5-yl] ej- - 5,5-dimeimidazolidin-2,4-dione. 2- • £ 2- [3- (trans-3-dimeaminocyclobutyl) -lH-indol-5-yl] -e} phthalamide. 3-- 2- [3- (trans-3-dimeaminocyclobutyl) -lH-indol-5-yl] -e J "-3-azaspiro [5,5] undecan-2,4-dione, N-me- [3 - (trans-3-dimeaminocyclobutyl) -lH-indol-5-yl] methanesulfonamide, 4- [3- (trans-3-dimeaminocyclobutyl) -lH-indol-5-ylme] - (4R) oxazolidin-2-one. 4- [3- (tr_an_s-3-dimeaminocyclobutyl) -lH-indol-5-ylme] -3-me (4S) -oxazolidin-2-one., 5,5-dime-3- [3- (trans-3 -dimeaminocyclobutyl) -lH-indol-5-ylme] imidazolidin-2,4-dione, 3- [3- (trans-3-dimeaminocyclobutyl) -lH-indol-5-ylme] -imidazolidin-2,4-dione. 5- [3- (trans-3-dimeaminocyclobutyl) -lH-indol-5-ylme] -oxazolidin-2-one.
4. 4- [3- (trans-3-dimeamino-cyclobut-1-ylme) -lH-indol-5-ylme] - (4S) oxazolidin-2-one. 4- [3- (trans-3-meaminocyclobutyl) -lH-indol-5-ylme] - (4S) oxazolidin-2-one. 4- [3- (trans-3-dimeaminocyclobutyl) -lH-indol-5-ylme] -3-me (4R) -oxazolidin-2-one. 3- (trans) -3-dimeaminocyclobutyl) -lH-indol-5-yl acetamide. 4- [3- (cis-3-dimeaminocyclobutyl-lH-indol-5-ylme] - (4S) oxazolidin-2-one.) 5-phenoxy-3- (trans-3-aminocyclobutyl) -lH-indole. phenoxy-3- (trans-3-dimeaminocyclobutyl) N-benzyl-3- (trans-3-dimeaminocyclobutyl) -lH-indol-5-yl acetamide 5-N-benzylcarboxamido-3- (trans-3-dimeaminocyclobutyl) -lH-indole, 3-me-5- [3- (trans-3-dimeaminocyclobutyl) indol-5-yl] -1,2,4-oxadiazole, 3-me-5- [3- (trans-3- dimeaminocyclobutyl) indol-5-ylme] -l, 2,4-oxadiazole, 3-me-5- [3-trans-3-dimeaminocyclobutyl) indol-5-ylme] -l, 2,4-triazole. (S) -2- (5- (2-Oxo-4-oxazolidinylme) -lH-indol-3-yl) cyclopropylamine. 4- [3- (trans-3-dimeaminocyclobutyl) -lH-indol-5-ylme] -3-me (4R) oxazolidin-2-one.
5. 5-carboxamido-3- (trans-3-dimeaminocyclobutyl) -lH-indole.
6. 6. A compound according to claim 5, characterized in that it is 4- [3- (trans-3-dimeaminocyclobutyl) -lH-indol-5-ylme] -4 (S) oxazo-lidin-2-one or an acceptable salt physiologically, solvate or derivative thereof which is physiologically functional.
7. 7. A compound of formula (I) or (con) in accordance with any of claims 1 to 6 or a physiologically acceptable salt, solvate, 0 derived therefrom which is physiologically functional, for use as a therapeutic agent.
8. 8. A compound of the formula (I) or (Ia) according to any of the claims 1 to 6, for use in the prophylaxis and / or treatment of a clinical condition for which a receptor agonist "similar to 5-HT," is indicated.
9. 9. A compound of the formula (I) or (Ia) according to any of claims 1 to 6, for use in the prophylaxis and / or treatment of migraine.
10. 10. A pharmaceutical composition, characterized in that it comprises as active ingredient at least one compound of the formula (I) or (la), according to any of claims 1 to 6 and / or a pharmaceutically acceptable salt or solvate thereof, together with the less a pharmaceutically acceptable carrier or excipient.
11. 11. The use of a compound of the formula (I) or (la) according to any of claims 1 to 6 in the preparation of a medicament for the prophylaxis or treatment of a clinical condition for which an "like" receptor agonist at 5-HT "is indicated.
12. 12. The use according to claim 11, wherein the clinical condition is migraine.
13. 13. A method for the prophylaxis or treatment of a clinical condition in a maniferous, for example, a human being, for which a receptor agonist "similar to 5-HT." Is indicated, characterized in that it comprises administering a compound of the formula (I) or (la) according to any one of claims 1 to 6 in an effective amount.
14. 14. A method according to claim 13, characterized in that the clinical condition is migraine.
15. 15. A process for the preparation of a compound of the formula (I), the process is characterized in that it comprises: a) reacting a compound of the formula (II) wherein W and n are as defined in claim 1, with a compound of the formula (III) wherein Z is a benzyloxycarbonyl group and then removing the benzyloxycarbonyl group to give a compound of the formula (I) wherein R 3 = R = H and optionally converting this compound to a compound of the formula (I) wherein R and / or R is alkyl with C,, by N-alkylation; b) reacting a compound of the form 10 mule (II) with a compound of the formula (IV) where BOC is the butoxy carbonyl ter¬ 20 to give a compound of the formula (I) wherein R = R = H and optionally convert this compound to a compound of the formula (I) wherein R and / or R is alkyl with C, _, by N -alkylation; C) when it is desired to prepare a compound wherein A is a cyclopropyl group, react a compound of the formula (II) with a compound of the formula (V) wherein BOC is the tertiary butoxycarbonyl to give a compound of the formula (I) wherein R - R = H and optionally converting this compound is a compound of the formula (I) wherein R and / or R is alkyl with C, , by N-alkylation.
16. 16. An intermediate compound of the formula (III) characterized in that A and Z are as defined herein above.
17. 17. An intermediate compound of the formula (IV) characterized in that A is as defined here above.
18. 18. An intermediate compound of the formula (V) NHBOC characterized in that BOC is as defined here above.