MXPA99008300A - 2-substituted benzoyl-cycloalkyl-1-carboxylic acid derivatives - Google Patents

Abstract

2-(substituted benzoyl)-cycloalkyl-1-carboxylic acids of formula (I) wherein E is a C1-C4 alkylene chain in which a carbon atom is optionally substituted;each of R and R1, being the same or different, is hydrogen, halogen, hydroxy, trifluoromethyl, cyano, nitro, phenyl, benzyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, SOR4 or SO2R4;R2 is hydrogen or -N(R7R8) in which each of R7 and R8 is, independently, hydrogen, C1-C6 alkyl, benzyl, phenyl, hydroxy, C1-C6 alkoxy, benzyloxy or one of R7 and R8 is hydrogen and the other is COR9;R3 is hydroxy, C1-C6 alkoxy, phenoxy, benzyloxy or a group -N(R12R13);and pharmaceutically acceptable salts thereof, have kynurenine-3-hydroxylase enzyme inhibitor activity.

Description

ACID DERIVATIVES 2-BENZ0IL-SUBST1TUID0S- CICLOALQUIL-1-CARBOXILICO The present invention relates to derivatives of 2- (substituted with benzoyl) -cycloalkyl-1-carboxylic acid, to a process for their preparation, to pharmaceutical compositions containing them and to their use in therapy. The compounds of the invention act as inhibitors of kynurenine-3-hydroxylase (KYN-OH), an enzyme which forms part of the metabolic pathway of kynurenine. It is well known that through the pathway of kynurenine, the metabolism of tryptophan gives rise to the formation of 3-hydroxykynurenine (3-OHKYN) and quinolinic acid (QUIN), on the one hand, and cinuric acid (KYNA), on the other hand, as shown in Figure 1.

(The legend for Figure 1 must be found on the last page of the experimental part of the specification). KYNA is endowed with neuroprotective properties (J. Neurosci, 1990, 10, 2965-2973), whereas QUIN is a potent neurotoxin which has been implicated in the pathogenesis of a variety of neurological disorders (Life Sci., 1984, 35, 19-32; REF: 031252 Nature, 1986, 321, 168-171; Science, 1983, 219, 316-318). Increased concentrations of QUIN have also been indicated as responsible for the neurological disorders that accompany many inflammatory diseases and infections, including Acquired Immunodeficiency Syndrome (AIDS) (Ann Neurol 1991, 29, .202-209). One of the main strategies, directed to the alteration of the KYNA / QUIN balance that blocks the production of 2-OHKYN and QUIN and that increases the production of KYNA, results in the inhibition of key enzymes of the cinurenine pathway (KYN ), among which cinurenine-3-hydroxylase is of primary importance. Consequently, there is a need in the therapy of compounds capable of inhibiting this enzyme. The compounds of the present invention respond to such need. Accordingly, the present invention provides compounds of 2- (substituted with benzoyl) -cycloalkyl-1-carboxylic acid of the formula (I) wherein E is an alkylene chain of 1 to 4 carbon atoms, wherein one carbon atom is optionally substituted by = CH2, one or two alkyl groups of 1 to 4 carbon atoms or one or two halogen atoms; each of R and R 1 f which are the same or different, is hydrogen, halogen, hydroxy, trifluoromethyl, cyano, nitro, phenyl, benzyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio from 1 to 6 carbon atoms, S0R or S02R4 in which R is alkyl of 1 to 6 carbon atoms or -N (R5R6) in which R5 and R6 is, independently, hydrogen, alkyl of 1 to 6 carbon atoms , formyl or alkanoyl of 2 to 6 carbon atoms; R2 is hydrogen or -N (R7Rs) in which each of R7 and Rs is, independently, hydrogen, alkyl of 1 to 6 carbon atoms, benzyl, phenyl, hydroxy, alkoxy of 1 to 6 carbon atoms, benzyloxy or one of R7 and Re is hydrogen and the other is COR9 in which R9 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl or R9 is a group -N (R? 0Rn) wherein each of Ri0 and Rn is independently hydrogen or alkyl of 1 to 6 carbon atoms; R3 is hydroxy, alkoxy of 1 to 6 carbon atoms, phenoxy, benzyloxy or a group -N (R? 2Ri3) wherein Rx z and R13 are as R7 and Rs as defined above, or one of R12 and Ri3 is hydrogen and the other is a group S02R9 in which R9 is as defined above; and pharmaceutically acceptable salts thereof. The alkyl and alkoxy groups can be branched or straight groups. E as an alkylene chain of 1 to 4 carbon atoms is preferably an alkylene chain of 1 to 2 carbon atoms, in particular a methylene group (-CH2 ~). When such an alkylene chain is substituted, it is preferably replaced by a group = CH2 or one or two halogen atoms, in particular fluorine or one or two methyl groups. Representative examples of alkyl groups of 1 to 6 carbon atoms include alkyl groups of 1 to 4 carbon atoms such as methyl, ethyl, n- and isopropyl, n-, iso-, sec- and tert-butyl. Representative examples of the alkoxy groups of 1 to 6 carbon atoms include alkoxy groups of 1 to 4 carbon atoms such as methoxy and ethoxy.

Representative examples of alkylthio groups of 1 to 6 carbon atoms include alkylthio groups of 1 to 4 carbon atoms such as methylthio and ethylthio. Representative examples of alkanoyl groups of 1 to 6 carbon atoms include alkanoyl groups of 1 to 4 carbon atoms such as acetyl and propionyl. Representative examples of alkoxycarbonyl groups of 1 to 6 carbon atoms include alkoxycarbonyl groups of 1 to 4 carbon atoms such as methoxycarbonyl and ethoxycarbonyl. A halogen atom is fluorine, bromine, chlorine or iodine; in particular chlorine or fluorine. Pharmaceutically acceptable salts of the compounds of the invention include the acid addition salts with inorganic acids, for example nitric, hydrochloric, hydrobromic, sulfuric, perchloric and phosphoric or organic acids, eg, acetic, trifluoroacetic, propionic, glycolic, lactic , oxalic, alonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylic and salts with inorganic bases, for example alkali metal, especially bases of sodium and potassium or alkaline earth metal, especially calcium or magnesium bases, or with organic bases, for example acyclic or cyclic amines, preferably methylamine, ethylamine, diethylamine, triethylamine or piperidine. The compounds of the invention have asymmetric carbon atoms and therefore can exist either as racemic mixtures or as individual optical isomers (enantiomers). In addition, the compounds of the invention may also be E- or Z- isomers or mixtures of E-, Z- thereof. Accordingly, the present invention also includes within its scope all possible isomers and their mixtures and both the metabolites and pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of the invention. Preferred compounds of the invention are the compounds of the formula (I) wherein: E is a group -CH2- or a group (CH2) z ~, optionally substituted by = CH2, one or two halogen atoms or one or two alkyl groups of 1 to 4 carbon atoms; each of R and Ri, which are the same or different, is hydrogen, halogen, hydroxy, trifluoromethyl, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, SOR4, S02R4 in which R4 is alkyl of 1 to 4 carbon atoms or -N (R5Re) in which each of R4 and R5 is, independently, hydrogen, alkyl of 1 to 4 carbon atoms or formyl; R 2 is hydrogen or -N (R 7 R 8) in which each of R 7 and β is, independently, hydrogen, alkyl of 1 to 4 carbon atoms, benzyl, phenyl, hydroxy, alkoxy of 1 to 4 carbon atoms or benzyloxy, or one of R7 and R1 is hydrogen and the other is COR9 in which R9 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, phenyl or R9 is a group -N (R? 0Rn ) in which Rio and Rn is, independently, hydrogen or alkyl of 1 to 4 carbon atoms; R3 is hydroxy, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxylamino or a group -N (R? 2Ri3) wherein one of R? 2 and R? 3 is hydrogen and the other is hydrogen, alkyl of 1 to 4 carbon, benzyl, phenyl or a S02R9 group in which R9 is phenyl; and pharmaceutically acceptable salts thereof. The most preferred compounds according to the invention are the compounds of the formula (I) wherein: E is methylene, optionally substituted by = CH2, one or two halogen atoms or one or two alkyl groups of 1 to 4 carbon atoms; each of R and Rl7 which are the same or different, is hydrogen or halogen; R2 is hydrogen; R3 is hydroxy, alkoxy of 1 to 4 carbon atoms, hydroxylamino or a group -N (R? 2R? 3) wherein one of Ri2 and R13 is hydrogen and the other is hydrogen, alkyl of 1 to 4 carbon atoms, benzyl, phenyl or a group S02R9 in which R9 is phenyl; and the pharmaceutically acceptable salts thereof. The most preferred compounds according to the invention are the compounds of the formula (I) wherein: E is methylene, optionally substituted by = CH2, one or two halogen atoms or one or two alkyl groups of 1 to 4 carbon atoms carbon; R and Ri are both halogen; R2 is hydrogen; R3 is hydroxy, alkoxy of 1 to 4 carbon atoms, hydroxylamino or a group -N (R? 2R? 3) wherein one of Rx z and Ri3 is hydrogen and the other is hydrogen, alkyl of 1 to 4 carbon atoms, benzyl, phenyl or a group S02R9 in which R9 is phenyl; and the pharmaceutically acceptable salts thereof. Examples of the preferred compounds of the invention are the following: 2- (3-chlorobenzoyl) -cyclopropane-1-carboxylic acid; 2- (3-fluorobenzoyl) -cyclopropane-1-carboxylic acid; 2- (3-bromobenzoyl) -cyclopropane-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -cyclopropane-1-carboxylic acid; 2- (3,4-difluorobenzoyl) -cyclopropane-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -1-amino-cyclopropane-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -3-methylene-cyclopropane-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -3,3-dimethyl-cyclopropane-l-carboxylic acid; 2- (3,4-dichlorobenzoyl) -3,3-difluoro-cyclopropane-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -3-methyl-cyclopropane-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -cyclopentane-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -cyclopropane-1-carboxamide; 2- (3,4-dichlorobenzoyl) -cyclopropane-1-N-methylcarboxamide; 2- (3,4-dichlorobenzoyl) -cyclopropane-1-N-benzylcarboxamide; 2- (3,4-dichlorobenzoyl) -cyclopropane-1-N-phenylcarboxamide; 2- (3,4-dichlorobenzoyl) -cyclopropane-1-hydroxamic acid; 2- (3,4-dichlorobenzoyl) -cyclopropane-1-N-phenylsulfonylcarboxamide; 2- (3,4-dichlorobenzoyl) -cyclobutane-1-carboxylic acid; and if it is the case, the alkyl esters of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms thereof; either as the individual E- or Z-isomer and / or as the individual optical isomer or as a mixture thereof, where appropriate, the pharmaceutically acceptable salts thereof. A further objective of the present invention is also to provide a 2-benzoyl-substituted-cycloalkyl-1-carboxylic acid compound of the formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance active, in particular as an inhibitor of the enzyme kynurenine-3-hydroxylase. The object of the present invention is also the use of a compound of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use as an inhibitor of the enzyme cinurenina- 3-hydroxylase. The present invention also provides a method for the treatment of a mammal, including a human, in need of a kynurenine-3-hydroxylase inhibitor, such method comprising administering thereto a therapeutically effective amount of a compound of the formula I), as defined above, or a pharmaceutically acceptable salt itself. The compounds of the invention and salts thereof can be obtained, for example, by a process comprising: a) reacting a compound of the formula (II) wherein R and Ri are as defined above, with a compound of the formula (III) wherein R 2 is as defined above and R 3 is alkoxy of 1 to 6 carbon atoms, to obtain a compound of the formula (I) wherein R 3 is alkoxy of 1 to 6 carbon atoms and E is an alkylene group (- CH2-) of 1 carbon atom unsubstituted; or b) reacting a compound of the formula (IV) where E is as defined above; R12 is alkyl of 1 to 6 carbon atoms and X is halogen; with a compound of the formula (V) wherein R and Ri are as defined above, to thereby obtain a compound of the formula (I) wherein R3 is alkoxy of 1 to 6 carbon atoms and R2 is hydrogen; or c) deacylating a compound of the formula (Vi wherein R and Ri are as defined above and BOC means tert-butoxycarbonyl, to thereby obtain a compound of the formula (I) wherein R2 is -NHCOR9 in which R9 is tert-butoxy and R3 is methoxy and is an unsubstituted 1 carbon atom alkylene chain; and, if it is desired to convert a compound of the formula (I) into another compound of the formula (I), and / or, if desired, convert a compound of the formula (I) into a salt thereof, and / or , if desired, converting a salt of a compound of the formula (I) to a free compound of the formula (I), and / or, if desired, separating a mixture of isomers of a compound of the formula (I) in the individual isomers. The above procedure variants a), b) and c) are analogy procedures which can be carried out according to methods well known in the art. The reaction of a compound of the formula (II) with a compound of the formula (III) can be carried out, for example, in a suitable solvent such as, for example, diethyl ether, in the presence of a metal complex suitable, for example palladium (II) diacetate, at a temperature ranging from about -78 ° C to room temperature, for a time ranging from about 1 hour to about 24 hours. In a compound of the formula (IV) the halogen atom X is preferably chlorine or bromine. The reaction of a compound of the formula (IV) with a compound of the formula (V) can be carried out according to the known methods; for example, following the procedure reported in: Sommerville L.F., Organic Synthesis, Coll. Vol. 2, 81, (1943); Child R.G. Arzneim.-Forsch- / Drug Res., 30, 695-702, (1980); Quallich G.J., J. Org. Chem., 55, 4971-4973 (1990); Thyes M., J. Med. Chem., 26, 800-807 (1983); Hester J.B., J. Med. Chem., 34, 308-315 (1991); and De Saaqui- Sannes, Pharm. Acta Helv., 66, 7, 189-192 (1991). For example, this reaction can be carried out in the presence of a Lewis acid catalyst • suitable, in an inert solvent such as, for example, dichloromethane or 1,2-dichloroethane, or in an appropriate aromatic hydrocarbon such as, for example, chlorobenzene, nitrobenzene or in an excess of a compound of the formula (V) same; optionally in the presence of a co-solvent, for example nitromethane. A suitable Lewis acid may be, for example, anhydrous aluminum trichloride, anhydrous zinc dichloride, typically anhydrous aluminum trichloride. The deacylation of a compound of the formula (VI) can be carried out by treatment with a suitable deacylating agent, for example hydrazine hydrate, in a suitable solvent, for example anhydrous methanol. The reaction can be carried out at a temperature ranging from about 0 to about 30 ° C, for a time between about 0.5 and about 24 hours. Also, the optional conversion of a compound of the formula (I) into another compound of the formula (I) can be carried out according to known methods. For example, the hydrolysis of a compound of the formula (I) wherein R3 is alkoxy of 1 to 6 carbon atoms to obtain a compound of the formula (I) wherein R3 is hydroxy can be carried out according to methods well known in the art. For example, this reaction can be carried out in an alkaline, aqueous or hydroalcoholic solution, for example sodium hydroxide, at a concentration ranging from 0.01 to 12 N, at a temperature ranging from -20 ° C to reflux temperature or acid hydrolysis, for example, using an aqueous solution of hydrohalic acids, typically hydrochloric acid, in a suitable solvent, for example acetic acid, at a temperature ranging from about 0 ° C to the reflux temperature. A compound of the formula (I) wherein R 3 is hydroxy, can be converted into another compound of the formula (I) wherein R 3 is alkoxy of 1 to 6 carbon atoms, phenoxy or benzyloxy, by means of conventional alkylation methods , for example by treatment with a suitable alkylating agent, preferably an iodine derivative, in the presence of a base, for example potassium bicarbonate, in a suitable solvent, for example dimethylformamide, at a temperature ranging from about 0 ° C to approximately 60 ° C. A compound of the formula (I) wherein R3 is hydroxy, can be converted into another compound of the formula (I), wherein R3 is -N (R7Rs) by means of conventional methods, for example the methods usually employed in the chemistry of the peptides. In particular, a compound of the formula (I) wherein Ri is an N (R7R8) wherein R7 and R8 are both hydrogen, can be converted into a compound of the formula (I) wherein R- and R8 are each one independently, alkyl of 1 to 6 carbon atoms, benzyl or phenyl, by alkylation processes known in the literature. The optional salification of a compound of the formula (I) as well as the conversion of a salt into the free compound and the separation of a mixture of isomers in the individual isomers can be carried out by conventional methods. As stated above, the compounds of the invention have asymmetric carbon atoms and may have E / Z isomerism. Accordingly, these can be synthesized either as a mixture of isomers and then the desired isomer is separated by conventional techniques, or the synthesis can be carried out by stereospecific methods, known to obtain an individual, isomeric compound. A compound of the formula (II), as defined above, can be obtained, for example, by reacting a compound of the formula (VII) wherein R and Ri are as defined above, with diazomethane, for example, in a suitable solvent such as, for example, diethyl ether, at a temperature ranging from -78 ° C to room temperature, for a time ranging from 1 and 24 hours. The compounds of the formula (III) and (VII) are known compounds or can be prepared according to the known procedures. A compound of the formula (IV) can be obtained by a multi-step process comprising the reaction of a compound of the formula (VIII) / (VIII1 COOR.: OORli wherein R 2 and E are as defined above, with an alkaline agent to obtain a compound of the formula (IX) wherein R12 and E are as defined above. A compound of the formula (IX) can then be reacted with a halogenating agent to obtain a compound of the formula (IV) as defined above. The reaction of a compound of the formula (VIII) to obtain a compound of the formula (IX) can be made by basic hydrolysis, i.e. using an alcoholic solution of an alkali metal hydroxide, typically a solution of potassium hydroxide in a suitable alcoholic medium, ie methanol , at a suitable temperature, for example between 0 and 55 ° C, for a suitable time, for example 2-24 hours. The reaction of a compound of the formula (IX) to obtain a compound of the formula (VI) can be carried out in a suitable halogenating agent, ie oxalyl chloride or bromide or thionyl chloride, typically oxalyl chloride, in the presence or absence of a solvent, at a suitable temperature, for example 0-40 ° C, for a suitable time, for example 1-6 hours.

The compounds of the formula (V) and (III) are known compounds. A compound of the formula (VI) can be obtained by a multi-step process comprising the oxidation of acid of a compound of the formula (X) wherein R and Ri are as defined above, to obtain a compound of the formula (XI) where R and Ri are as defined above. The acid oxidation of a compound of the formula (X) can be carried out, for example, by using a solution of dimethyl sulfoxide (DMSO) of concentrated hydrobromic acid, for example 48% aqueous hydrobromic acid.

The reaction can be carried out at a temperature ranging from about 25 to about 100 ° C, for a time between about 2 and about 48 hours. A compound of the formula (XI) can then be converted to a compound of the formula (XII) wherein R and Ri are as defined above, by treatment with a suitable hypnotic acid derivative in the presence of a suitable acylating agent, for example acetic anhydride. The reaction can be carried out at a temperature ranging from about 50 to about 200 ° C, for a time between about 0.5 and about 24 hours. A compound of the formula (XII), if desired, can be converted to its isomer of the formula (Xlla) The conversion of a compound of the formula (XII) into a compound of the formula (Xlla) can be carried out using a suitable hydrohalic acid solution, for example 48% aqueous brimhydric acid saturated with anhydrous hydrobromic acid gas, to a suitable temperature, for example between about -20 and about 25 ° C, for a suitable time, for example 15 minutes to 24 hours. Cyclopropanation of a compound of the formula (XII) or (Xlla) provides a compound of the formula (XIII) and (XlIIa), respectively wherein R and Rx are as defined above The reaction can be carried out by treating a compound of the formula (XII) or (Xlla), respectively, with an ethereal solution of diazomethane. The reaction can be carried out at a temperature ranging from about -78 to about 25 ° C, for a time between about 2 and about 48 hours. A compound of the formula (XIII) or (XlIIa) is then converted to a compound of the formula (XIV) or (XlVa), respectively where R and Ri are as defined above. The reaction can be carried out by treatment with dimethylaminopyridine (DMAP) in methanol. The reaction can be carried out at a temperature ranging from about 0 to about 50 ° C, for a time between about 10 minutes and 48 hours.

Subsequent reaction of a compound of the formula (XIV) or (XlVa) with di-t-butyl carbonate and DMAP in a suitable solvent, for example anhydrous dichloromethane, provides a compound of the formula (VI), which can be represented by the two isomeric compounds, respective of the formula (XV) and (XVa) where R and Ri are as defined above. The reaction can be carried out at a temperature ranging from about 0 to about 50 ° C, for a time between about 1 and 24 hours. The isomeric compounds of the formula (XV) and (XVa), for convenience, are represented herein as a compound of the formula (VI). The compounds of formula (X) and the above hippuric acid derivatives are known compounds.

When groups which can interfere with the reaction are present in the compounds of the invention and the intermediary thereof, they can be protected before the reaction takes place and can then be deprotected at the end of the reaction. For example, the hydroxy, amino and / or carboxy groups can be protected and then deprotected according to common known techniques of peptide chemistry. The compounds of the invention are co active or inhibitors of kynurenine 3-hydroxylase enzyme and therefore are useful in the prevention and / or treatment of neuropathological processes, related to disordered production of quinolinic acid and / or 3-hydroxykynurenine due to excessive activation of a neuro-transmission mediated by excitatory amino acid receptors and / or oxidative stress. Examples of such neuropathological processes are neurodegenerative pathologies, for chorea example Huntington, Alzheimer's disease, Parkinson's disease, olivopontocerebellar atrophy, various dementias Alzheimer including similar dementia the syndrome caused by Acquired Immunodeficiency Syndrome (AIDS), dementia for multiple infarctions, cerebral amyotrophic lateral sclerosis, cerebral ischemia, cerebral hypoxia, spinal and head trauma and epilepsy. In this manner, a human or animal in need of an inhibitor of the enzyme kynurenine-3-hydroxylase can be treated by means of a method which comprises administering thereto a therapeutically effective amount of a compound of the invention or a salt thereof. of the same. Therefore the condition of the human or animal can be improved. The efficacy of the compounds of the invention in the inhibition of kynurenine 3-hydroxylase enzyme was evaluated for example in mitochondrial extract rat liver following the method subsequently reported according to the procedure described in "Analytical Biochem. (1992 ), 205, 257-262", with minor modifications. The test for cinurenine-3-hydroxylase is based on the enzymatic synthesis of tritiated water during the hydroxylation reaction. The radiolabeled water was quantified after the selective adsorption of the isotopic substrate and its metabolite with charcoal • activated. The mitochondrial extract from rat liver was used as the enzyme preparation for this assay.

The assay for the activity of cinurenine-3-hydroxylase is carried out at 37 ° C for a time of 30 minutes. The reaction mixture of a total volume of 30 μl was composed of 44 μg of the suspended extract, 100 mM Tris / Cl buffer "pH 8.1, 10 mM EDTA, 100 mM KCl, 0.8 mM NADPH, 0.025 mM L -cinnurenine, 0.3 μCi of L- (3, 5-3H) cinurenica (10 Ci / mmoles) and 3 μl of different concentration of inhibitor solutions.After incubation, the reaction was terminated by the addition of 300 μl of 7.5% (P / v) activated charcoal, remolineado and centrifuged for 7 minutes. An aliquot of 75 .mu.l of supernatant was transferred to an Optiplate and 200 ul of scintillation liquid was added. the optiplates were remolinearon and radioactivity was counted in a scintillation counter The results obtained, which have been reported in the following Table 1, demonstrate the efficacy of a representative compound of the invention (E) -2- (3,4-dichlorobenzoyl) -cyclopropane-1-carboxylic acid ( internal code PNU-165853).

Table 1 Inhibition of KYN-3-0H Compound IC50 PNU-165853 0.18 μM The dosage level, suitable for administration to a mammal, for example to humans, depends on the age, weight, conditions of the patient and the route of administration; for example, the dosage adopted for oral administration, for example for the representative compound of the invention PNU 165853, can vary from about 10 to about 500 mg pro dose, from 1 to 5 times a day. The compounds of the invention can be administered in a variety of dosage forms, for example, orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, for example intramuscularly, or by intravenous and / or intrathecal and / or intraspinal injection or infusion. The invention also includes pharmaceutical compositions comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient (which may be a carrier or a diluent). The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form. For example, the solid, oral forms may contain, together with the active compound, diluents, for example lactose, dextrose, sucrose, sucrose, cellulose, corn starch or potato starch; lubricants, for example silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols; binding agents for example, starches, gum arabic, gelatin, methylcululose, carboxymethylcellulose or polyvinyl pyrrolidone, disaggregation agents, for example, a starch, alginic acid, alginates or sodium starch glycolate, effervescent mixtures; pigments, sweeteners, wetting agents such as lecithin, polysorbates, lauryl sulfates; and in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. The pharmaceutical preparations can be prepared in known manner, for example, by mixing, granulating, tabletting, sugar coating or film coating processes.

Liquid dispersions for oral administration can be, for example, syrups, emulsions and suspensions. The syrups may contain as carrier, for example, sucrose or sucrose with glycerin and / or mannitol and / or sorbitol. The suspensions and the emulsions may contain as a carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain together with the active compound, a pharmaceutically acceptable carrier, for example sterile water, olive oil, ethyl oleate, glycols, for example propylene glycol, and if desired, a suitable amount of hydrochloride. of lidocaine. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably these may be in the form of sterile, aqueous, isotonic saline solutions or these may contain propylene glycol as a carrier. The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, for example cocoa buffer, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. The following examples illustrate but do not limit the invention.

Example 1 Preparation of 3,4-dichlorobenzoyl chloride A suspension of 3,4-dichlorobenzoic acid (10 g, 52.35 mmol) in thionyl chloride (50 ml) was heated at reflux for 12 hours under magnetic stirring and a nitrogen atmosphere. The thionyl chloride was removed under vacuum and the solid was washed with anhydrous benzene (3 x 50 ml) and dried under reduced pressure (0.1 mm / Hg), giving 10.9 g of 3,4-dichlorobenzoyl chloride (100%). . The following products can be prepared analogously: 3-chlorobenzoyl chloride; 3-fluorobenzoyl chloride; and 3-bromobenzoyl chloride.

Example 2 Preparation of 3,4-dichlorophenyl-α-diazo-methyl ketone A solution of 3,4-dichlorobenzoyl chloride (10.9 g, 52.35 mmol) in anhydrous benzene (55 ml) was added over 1 hour to a magnetically stirred solution. of diazomethane (370 ml containing 287.9 mmoles of diazomethane) was maintained at a temperature between -10 ° C and -15 ° C, under a nitrogen atmosphere. After 3 hours at -15 ° C, the resulting pale yellow solid was filtered under reduced pressure and washed with anhydrous ethyl ether (2 x 50 ml). 10.9 g of 3,4-dichlorophenyl-α-diazo-methyl-ketone (97.8%) were obtained (mp 94.5-95.5 ° C): IR (CHC13; vmax: 2110 cm "1) .The following products can be prepared from Analogous manner: 3-chlorophenyl-α-diazo-methyl ketone; 3-fluorophenyl-α-diazo-methyl-ketone; and 3-bromophenyl-α-diazo-methyl-ketone.

Example 3 Preparation of t-butyl (E) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylate and (Z) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylate of t- butyl Butyl To a suspension containing dichloromethane (30 ml), t-butyl acrylate (5.96 ml, 40.71 mmol) and Pd (II) (OAc) 2, maintained under magnetic stirring and an argon atmosphere, was added a solution of 3,4-dichlorophenyl-a- diazo methyl ketone (2.5 g, 11.63 mmol) in dichloromethane (200 ml) for 8 hours. After 3 hours at room temperature, the dichloromethane was removed under reduced pressure and the mixture was subjected to flash chromatography. Elution with light oil / diethyl ether 90:10 gave (E) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid t-butyl ester (1 g, 27%). After elution with light oil / diethyl ether 80:20, (t) butyl (Z) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylate (0.4, 11%) was recovered.

RMN-1 !! (CDC13) [(E) -t-Butyl-2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylate]: d 1.3-1.7 (m, 11H, COOt-Bu, 3-CH2); 2.3-2.5 (m, 1H, 2-CH, J = 7 Hz); 2.9-3.1 (, 1H, 4-CH, J = 7 Hz); 7.5 (d, 1H, 5'-CH, J = 7.5 Hz); 7.9 (dd, 1H, 6'-CH, J0 = 8.5 Hz, Jm = 2 Hz); 8.2 (d, 1H, 2'-CH, Jm = 2 Hz) 13 C-NMR (CDCl 3) [(E) -t-butyl-2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylate): d 18.02; 24.68; 25.83; 28.06; 127.14; 130.06; 130.67; 133.27; 136.27; 137.92; 174.36; 195.04.

NMR-XH (CDCl3) [(Z) -t-Butyl-2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylate]: d 1.3-1.7 (m, 10H, COOt-Bu, 3- (H) CH); 1.7-1.9 (, 1H, 3- (H) CH, J = 7 Hz); 2.3-2.4 (m, 1H, 2-CH, J = 7 Hz); 2.7-2.8 (dd, 1H, 4-CH, J = 8 Hz); 7.5 (d, 1H, 5'-CH, J = 7.5 Hz); 7.8 (dd, 1H, 6'-CH, J0 = 8.5 Hz, Jffi = 2 Hz); 8.1 (d, 1H, 2'-CH, Jm = 2 Hz). 13 C-NMR (CDC13) [(Z) -t-Butyl-2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylate]: d 12.17; 24.08; 26.09; 27.72; 81.11; 127.29; 130.26; 130.73; 133.15; 136.91; 137.52; 168.75; 192.23.

The following products can be prepared analogously: (E) t-butyl-2- (3-chlorobenzoyl) -cyclopropyl-1-carboxylate; (E) t-Butyl-2- (3-fluorobenzoyl) -cyclopropyl-1-carboxylate; (E) t-Butyl-2- (3-bromobenzoyl) -cyclopropyl-1-carboxylate; (Z) t-butyl-2- (3-chlorobenzoyl) -cyclopropyl-1-carboxylate; (Z) t-Butyl-2- (3-fluorobenzoyl) -cyclopropyl-1-carboxylate; and (Z) t-butyl-2- (3-bromobenzoyl) -cyclopropyl-1-carboxylate.

Example 4 Preparation of (E) -2- (3,4-dichlorobenzoyl) -cyclopropy1-1-carboxylic acid To a solution of (E) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylate of t- butyl (0.297 g, 0.943 mmol) in ethyl acetate (25 ml), maintained under magnetic stirring, 37% hydrochloric acid (5 ml) was added. After 2 hours at room temperature, the mixture was diluted with water (5 ml). The organic phase was separated, washed with brine (2 x 5 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting mixture was then purified by flash chromatography using dichloromethane / 10% methanol as eluent. The (E) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid (56.8 mg, 41.3%) was obtained.

RMN-1 !! (CDC13) [(E) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid]: d 1.6-1.8 (t, 2H, 3-CH2, J = 6 Hz); 2.3-2.5 (m, 1H, 2-CH, J = 7 Hz); 3.1-3.2 (m, 1H, 4-CH, J = 7 Hz); 7.5 (d, 1H, 5'-CH, J = 7.5 Hz); 7.9 (dd, 1H, 6'-CH, J0 = 8.5 Hz, Jm = 2 Hz); 8.2 (d, 1H, 2'-CH, Jm = 2 Hz). 13 C-NMR (CDCl 3) [(E) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid]: d 18.02; 24.68; 25.83; 127.14; 130.06; 130.67; 133.27; 136.37; 137.92; 174.36; 195.04.

The following products can be prepared analogously: (E) -2- (3-chlorobenzoyl) -cyclopropyl-1-carboxylic acid; (E) -2- (3-fluorobenzoyl) -cyclopropyl-1-carboxylic acid; and (E) -2- (3-bromobenzoyl) -cyclopropyl-1-carboxylic acid.

Example 5 Preparation of (Z) -2- (3,4-dichlorobenzoyl) -cyclopropy1-1-carboxylic acid To a solution of (Z) t-butyl-2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylate (0.06 g, 0.188 mmol) in ethyl acetate (5 ml), maintained under magnetic stirring, 37% hydrochloric acid (1 ml) was added. After 2 hours at room temperature, the mixture was diluted with water (5 ml). The organic phase was separated, washed with brine (2 x 5 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting mixture was then purified by flash chromatography using dichloromethane / methanol 0 * 15% as eluent. The (Z) 2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid (15 mg, 30.8%) was obtained.

NMR-XH (CDC13) [(Z) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid]: d 1.3-1.7 (t, 2H, 3- (H) CH, J = 6 Hz); 1.7-1.9 (m, 1H, 3- (H) CH); 2.3-2.5 (m, 1H, 2-CH); 2.6-2.8 (, 1H, 4-CH); 7.4-7.5 (d, 1H, 5'-CH); 7.6-7.8 (m, 1H, 6'-CH); 8.2 (d, 1H, 2'-CH). 13 C-NMR (CDC 13) [(Z) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid]: d 13.96; 24.08; 26.09; 127.79; 130.30; 130.69; 133.14; 136.63; 138.30; 171.15; 194.23.

The following products can be prepared analogously: (Z) -2- (3-chlorobenzoyl) -cyclopropyl-1-carboxylic acid; (Z) -2- (3-fluorobenzoyl) -cyclopropyl-1-carboxylic acid; (Z) -2- (3-bromobenzoyl) -cyclopropyl-1-carboxylic acid; and (Z) -2- (3,4-difluorobenzoyl) -cyclopropyl-1-carboxylic acid.

Example 6 Preparation of (E) (IR, 2R) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1- (1R-a-phenylglycinyl) carboxamide and (E) (lS, 2S) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1- (lR-a-phenylglycinyl) -carboxamide (E) -2- (3,4-dichlorobenzoyl) -cyclopropyl- 1-carboxylic acid (0.175 g, 0.68 mmol) was dissolved in oxalyl chloride (6 ml) and left at room temperature for 2 hours, under magnetic stirring and an argon atmosphere. The oxalyl chloride was removed by rotary evaporation and the corresponding 2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid chloride, dissolved in anhydrous dioxane (1.5 ml), was added to a dioxane solution (3.5 ml. ) containing R- (-) -genilglicinol (0.093 g, 0.68 mmol) and triethylamine (0.1 ml, 0.7 mmol), maintained under magnetic stirring and an argon atmosphere at 10 ° C.

After 1 hour at 10 ° C, the reaction mixture was treated with 37% hydrochloric acid (1 ml) and ethyl acetate (10 ml). The organic phase was separated, washed with water (3 x 10 ml), with brine (1 x 10 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to medium pressure chromatography on a Lobar column of silica gel (60-43 μm) using light petroleum / ethyl acetate 30:70 as eluent and two amides were separated. According to literature1, the first amide eluted, ([a] D20 = -102.6, c = 0.5 CHC13) can be assigned as (E) - (IR, 2R) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-) lR-a-phenylglycinyl) -carboxamide and the second amide, ([a] D20 = +56, c = 1 CHCl3), as (E) - (lS, 2S) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-) lR-a-phenylglycinyl) -carboxamide (86%). 1 (a) G. Helmchen. G. Nill, D. Flockerzi,. Schühle, M.S.K. Youssef, Angew Chem. Int. Ed. Engl. 18, 1979, 62-63. (b) G. Helmchen, G. Nill, D. Flockerzi, M.S.K. Youssef, Angew, Chem. Int. Ed. Engl. , 18, 1979, 63-65. (c) G. Helmchen. G. Nill., Angew Chem. Int. Ed. Engl. , 18, 1979, 65-66.

NMR-aH (CDC13) [(E) - (IR, 2R) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1- (lR-a-phenylglycinyl) -carboxamide]: d 1.4-1.5 (t, 2H , 3- (H) CH); 1.5-1.6 (m, 1H, 3- (H) CH); 2.3-2.5 (m, 1H, 2-CH); 2.9-3.2 (m, 1H, 4-CH and OH); ); 3.8-3.9 (d, 1H, a-CH2OH)); 5.0-5.1 (m, 1H, a-CH); 6.9-7.0 (broad d, 1H, NH); 7.2-7.4 (m, 5H, a-C6Rs) 7.2-7.4 (m, 1H, 5'-CH, J = 7.5 Hz); 7.9 (dd, 1H, 6 '-CH, JG = 8.5 Hz, Jm = 2 Hz); 8.2 (d, 1H, 2'-CH, Jm = 2 Hz). 13 C-NMR (CDCl 3) [(E) - (IR, 2R) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1- (1R-a-phenylglycinol) carboxamide]: d 18.07; 25.54; 26.84; 29.64; 56.21; 66.29; 126.67; 127.31; 127.96; 130.25; 130.78; 133.46; 136.52; 138.07; 138.69; 170.72; 195.97.

NMR ^ H (CDC13) [(E) - (1S, 2S) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1- (lR-a-phenylglycinyl) -carboxamide]: d 1.4- 1.5 (m, 1H , 3- (H) CH); 1.5-1.6 (m, 1H, 3- (H) CH); 2.35-2.45 (m, 1H, 2-CH); 2.9-3.1 (m, 1H, 4-CH and OH); 3.8-3.9 (d, 1H, a-CH2OH)); 4.9-5.0 (m, 1H, a-CH); 6.9-7.0 (broad d, 1H, NH); 7.1-7.3 (m, 5H, a-C6H5); 7.4 (d, 1H, 5'-CH, J = 7.5 Hz); 7.6-7.7 (dd, 1H, 6'-CH, J0 = 8.5 Hz, Jm = 2 Hz); 7.9 (d, 1H, 2'-CH, Jm-2 Hz). 13 C-NMR (CDC13) [(E) - (1S, 2S) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1- (1R-a-phenylglycinyl) carboxamide]: d 18.04; 25.44; 26.87; 29.64; 56.22; 66.29; 126.70; 127.31; 127.96; 128.88; 130.25; 130.74; 133.43; 136.49; 138.03; 138.76; 170.66; 195.92.

Example 7 Preparation of (E) (IR, 2R) -2-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid To a solution of (E) (IR, 2R) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1 - (1R-α-phenylglycinyl) -carboxamide (50 mg, 0.123 mmol) in dioxane (3.5 ml), maintained under magnetic stirring, 37% hydrochloric acid (1.5 ml) was added and the mixture was left at 50 ° C for 7 hours. After cooling, the reaction mixture was diluted with ethyl acetate (40 ml). The organic phase was washed with water (6 x 3 ml), brine (1 x 4 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to flash chromatography using dichloromethane / methanol 0 * 10 as eluent. The (E) (IR, 2R) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid was produced, ([a] D20 = -86, c = 0.36, CHC13) (20 mg, 75% ).

NMR ^ H (CDC13) [(E) acid (IR, 2R) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid]: d 1.5-1.7 (t, 2H, 3-CH2, J = 6 Hz); 2.3-2.5 (m, 1H, 2-CH); 3.0-3.2 (m, 1H, 4-CH, J = 7 Hz); 7.4-7.5 (d, 1H, 5'-CH, J = 7.5 Hz); 7.7-7.9 (dd, 1H, 6'-CH, J0 = 8.5 Hz); 7.9-8.1 (s, 1H, 2'-CH). 13 C-NMR (CDCl 3) [(E) acid (IR, 2 R) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid]: d 18.62; 25.01; 26.22; 127.21; 130.16; 130.82; 133.52; 136.25; 138.28; 178.11; 194.59.

Example 8 Preparation of (E) (1S, 2S) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid. To a solution of (E) (1S, 2S) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1- (1R-a-phenylglycinyl) -carboxamide (50 mg, 0.123 mmol) in dioxane (3.5 ml), maintained under magnetic stirring, 37% hydrochloric acid (1.5 ml) was added and the mixture was left at 50 ° C for 7 hours. After cooling, the reaction mixture was diluted with ethyl acetate (40 ml). The organic phase was washed with water (6 x 3 ml), brine (1 x 4 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to flash chromatography using dichloromethane / methanol 0 * 10 as eluent. The (E) - (lR, 2R) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid was produced, (([a] D20 = +77, c = 0.65, CHC13) (13 mg, 49%).

NMR-1H (CDC13) [(E) (1S, 2S) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid]: d 1.6-1.8 (t, 2H, 3-CH2, J = 7 Hz); 2.3-2.5 (, 1H, 2-CH, J = 7 Hz); 3.1-3.2 (m, 1H, 4-CH, J = 7 Hz); 7.5 (d, 1H, 5'-CH, J = 7.5 Hz); 7.8 (dd, 1H, 6'-CH, J0 = 7.5 Hz, Jm = 1.5 Hz); 8.1 (s, 1H, 2'-CH, Jm = 1.5 Hz). 13 C-NMR (CDCl 3) [(E) (1 S, 2 S) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid]: d 18.48; 24.68; 26.23; 127.25; 130.24; 130.86; 133.57; 136.38; 138.25; 177.61; 194.45.

Example 9 Preparation of (E) -1-methoxycarbonyl-cyclopropane-2-carboxylic acid A solution of potassium hydroxide (0.354 g, 6.32 mmol) in dry methanol (4 ml) was dropped into an ester solution in one hour. dimethyl ester of (E) 1, 2-cyclopropanedicarboxylate (1 g, 6.32 mmol) in dry methanol (4 ml), maintained under magnetic stirring at room temperature. The resulting solution was heated at 55 ° C for 12 hours and then poured into water (10 ml). After acidification with 10% hydrochloric acid, the aqueous phase was extracted with ethyl acetate (10 x 10 ml). The organic extracts were washed with brine (1 x 10 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to yield an oil which was purified by flash chromatography. Elution with dichloromethane / methanol (95: 5) gave the pure title compound (0.556 g, 61%).

NMR-2H (CDC13); d: 1.5 (t, 2H, 2-CH2, J = 8 Hz); 2.1-2.3 (m, 2H, 1-CH and 3-CH); 3.7 (5, 3H, COOCH3); 10.35 (broad s, 1H, COOH). 13 C NMR (CDCl 3); d: 14.94; 21.71; 22.24; 51.88; 171.74; 176.60.

The following compounds were prepared analogously: (E) -l-methoxycarbonyl-cyclobutane-2-carboxylic acid, (E) -l-methoxycarbonyl-cyclopentane-2-carboxylic acid, (E) -l-methoxycarbonyl-cyclohexane- 2-carboxylic acid (E) -l-methoxycarbonyl-3-methylene-cyclopropane-2-carboxylic acid, (E) -l-methoxycarbonyl-3-methyl-cyclopropane-l-carboxylic acid, (E) -l-methoxycarbonyl acid 3, 3-dimethyl-cyclopropane-1-carboxylic acid, and (E) -l-methoxycarbonyl-3, 3-difluoro-cyclopropane-1-carboxylic acid.

Example 10 Preparation of (E) -1-methoxycarbonyl-cyclopropane-2-carboxylic acid chloride A solution of (E) -1-methoxycarbonyl-cyclopropane-2-carboxylic acid (0.556 g, 3.857 mmol) in oxalyl chloride (20 ml) was stirred under an atmosphere of argon at room temperature for 3 hours, then the solution was stirred. concentrated under vacuum for 2 hours and the oily residue containing the title compound was used in the next step without further purification.

In an analogous manner, the following products were prepared: (E) -l-methoxycarbonyl-cyclobutane-2-carboxylic acid chloride; (E) -l-methoxycarbonyl-cyclopentane-2-carboxylic acid chloride; (E) -l-methoxycarbonyl-cyclohexane-2-carboxylic acid chloride; (E) -l-methoxycarbonyl-3-methylene-cyclopropane-2-carboxylic acid chloride; (E) -l-methoxycarbonyl-3-methyl-cyclopropane-2-carboxylic acid chloride; (E) -l-methoxycarbonyl-3, 3-dimethyl-cyclopropane-2-carboxylic acid chloride; and (E) -l-methoxycarbonyl-3, 3-difluoro-cyclopropane-2-carboxylic acid chloride.

Example 11 Preparation of (E) methyl 2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylate To a magnetically stirred solution of (E) -l-methoxycarbonyl-cyclopropane-2-carboxylic acid chloride (0.627 g, 3.857 mmol) in 1,2-dichlorobenzene (10 ml), portion was added to portion A1C13 (1542 g, 1.57 mmole) under an argon atmosphere at 0 ° C. The resulting solution was stirred 10 minutes at 0 ° C then heated at 55 ° C for 2 hours. The reaction mixture was quenched by the addition of ice water (10 ml) and 10% hydrochloric acid (10 ml), the mixture obtained in this way was extracted with ethyl acetate (4 x 25 ml); The combined organic phases were washed with brine (1 x 10 ml), dried over anhydrous sodium sulfate, concentrated in vacuo. The oily residue was purified by flash chromatography: eluting with light petroleum-ethyl acetate 100: 0 to 85:15 to thereby give the title compound as an oil (0.610 mg, 58%).

NMR ^ H (CDC13): d: 1.6 (dd, 2H, 2-CH2, J = 6.9 Hz); 2.35-2.45 (m, 1-CH); 3.1-3.2 (m, 1H, 3-CH); 3.7 (s, 3H, COOCH3); 7.55 (d, 1H, 6'-CH, J0 = 8 Hz); 7.85 (dd, 1H, 5'-CH, J0 = 8Hz, Jm = 2 Hz); 8.05 (dd, 1H, 2'-CH, Jm = 2 Hz). 13 C NMR (CDCl 3): d: 17.78; 24.39; 25.49; 51.86, 127.00; 129.87, 130.44; 133.04; 136.25; 137.56; 171.88; 194.23.

Analogously, the following products were prepared: 2- (3,4-dichlorobenzoyl) -cyclobutyl-1-carboxylate of (E) -ethyl; 2- (3,4-dichlorobenzoyl) -cyclopentyl-1-carboxylate of (E) -methyl; 2- (3,4-dichlorobenzoyl) -cyclohexyl-1-carboxylate of (E) -methyl; 2- (3,4-dichlorobenzoyl) -3-methylene-cyclopropane-l-carboxylate of (E) -methyl; 2- (3,4-dichlorobenzoyl) -3-methyl-cyclopropane-l-carboxylate of (E) -methyl; 2- (3,4-dichlorobenzoyl) -3,3-difluoro-cyclopropane-1-carboxylate 2- (3,4-dichlorobenzoyl) -3,3-dimethyl-cyclopropane-l-carboxylate of (E) -methyl and (E) -methyl.

Example 12 Preparation of (E) 2- (3, 4-dichlorobenzoyl) -cyclopropane-1-carboxylic acid To a magnetically stirred solution of (E) -methyl 2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylate) (70 mg, 0.244 mmol) in dry dioxane (3.5 ml) was added a solution of sodium hydroxide (19.5 mg, 0. 488 mmoles) in water (1.5 ml). After 2 hours at room temperature, the mixture was diluted with water (10 ml) and extracted with dichloromethane (2 x 2 ml). The aqueous layer was acidified with 10% hydrochloric acid, then extracted with ethyl acetate (4 x 5 ml), the combined organic phases were washed with brine (1 x 5 ml), dried over anhydrous sodium sulfate and dried. concentrated under vacuum to obtain the title compound (50 mg, 79%) as a white solid.

NMR ^ H (Acetone-dβ): d: 1.6 (m, 2H, 2-CH 2); 2.35-2.45 (m, 1-CH) 3.25 (m, 1H, 3-CH); 7.75 (d, 1H, 6'-CH, J0 = 8 Hz); 8.05 (dd, 1H, 5'-CH, J0 = 8 Hz, Jm = 2 Hz); 8.2 (d, 1H, 2'-CH, Jm = 2 Hz). 13 C-NMR (CDC13): d: 18.16; 25.05; 26.38; 128.79; 130.91, 131. 87; 133.55; 137.91; 173.01; 195.48.

In an analogous manner, the following products were prepared: (E) -2- (3,4-dichlorobenzoyl) -cyclobutyl-1-carboxylic acid; (E) -2- (3,4-dichlorobenzoyl) -cyclopentyl-1-carboxylic acid; (E) -2- (3,4-dichlorobenzoyl) -cyclohexyl-1-carboxylic acid. 2- (3,4-dichlorobenzoyl) -3-methylene-cyclopropane-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -3-methyl-cyclopropane-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -3,3-dimethyl-cyclopropane-l-carboxylic acid; and 2- (3,4-dichlorobenzoyl) -3,3-difluoro-cyclopropane-1-carboxylic acid.

Example 13 Preparation of 3,4-dichlorophenylglyoxal To a stirred solution of 3,4-dichloroacetophenone (1mmol) in DMSO (3ml), 48% aqueous hydrobromic acid (3mmol) was added slowly.

The solution was stirred in an open flask at 55 ° C. When the starting material was consumed (24 hours), the solution was emptied on ice. The crude product was extracted with Et = Ac, the solution was washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The titled arylglyoxal was recovered in an essentially pure form. The following products can be prepared analogously: 3-chlorophenylglyoxal; 3-fluorophenylglyoxal; 3-bromophenylglyoxal; and 3, 4-difluorophenylglyoxal.

Example 14 Preparation of (Z) -2-phenyl-4- (3,4-dichlorobenzoylmethylene) -oxazol-5-one A mixture of 3,4-dichlorophenylglyoxal (1 mmol), dry, powdered hippuric acid (1 mmol), Freshly fused sodium acetate, powdered (1 mmol) and high grade acetic anhydride, was heated on a hot, electric plate with constant stirring in an apparatus equipped with a calcium chloride tube. As soon as the material has completely liquified, the flask was transferred to a steam bath and heated for two hours; during this time a part of the product separates as crystals. At the end of the heating, ethyl alcohol is added slowly in the flask, while keeping the temperature below 30 ° C. After allowing the reaction mixture to stand overnight, the crystalline product is filtered off with suction. The pure azlactone is collected as a white solid.

In an analogous manner, the following products were prepared: (Z) -2-phenyl-4- (3-chlorobenzoylmethylene) -oxazol-5-one; (Z) -2-phenyl-4- (3-fluorobenzoylmethylene) -oxazol-5-one; (Z) -2-phenyl-4- (3-bromobenzoylmethylene) -oxazol-5-one; and (Z) -2-phenyl-4- (3,4-difluorobenzoylmethylene) -oxazol-5-one.

Example 15 Preparation of (Z) -2- (3,4-dichlorobenzoyl) -5-phenyl-6-oxo-4-azaspiro [2, 4] -hept-4-en-7-one. A solution of (Z) -2-phenyl-4- (3,4-dichlorobenzoylmethylene) -oxazol-5-one (1 mmol) in anhydrous methylene was treated with an ethereal solution of diazomethane (10 mmol), under magnetic stirring. The mixture was allowed to stand at room temperature overnight, treated with anhydrous calcium chloride to destroy the excess diazomethane, filtered and concentrated under vacuum. The resulting oil was purified by flash chromatography. Elution with light petroleum-ethyl acetate gave the pure title derivative.

The following derivatives were prepared analogously: (Z) -2- (3,4-difluorobenzoyl) -5-phenyl-6-oxo-4-azaspiro- [2,4] -hept-4-en-7-one; (Z) -2- (3-chlorobenzoyl) -5-phenyl-6-oxo-4-azaspiro- [2,4] -hept-4-en-7-one; (Z) -2- (3-fluorobenzoyl) -5-phenyl-6-oxo-4-azaspiro- [2,4] -hept-4-en-7-one; and (Z) -2- (3-bromobenzoyl) -5-phenyl-6-oxo-4-azaspiro- [2, 4] -hept-4-en-7-one.

Example 16 Preparation of 2- (3,4-dichlorobenzoyl) -1-benzamidocyclopropane-1-carboxylate of (Z) -methyl. DMAP (1 mmol) was added to a suspension of (Z) -2- (3,4-dichlorobenzoyl) -5-phenyl-6-oxo-4-azaspiro [2, 4] -hept-4-en-7- one (1 mmol) in absolute methanol and the resulting mixture was stirred magnetically at room temperature for 35 minutes. The methanol was removed under vacuum, the crude product was treated with a 1: 1 mixture of dichloromethane and 5% aqueous citric acid. The organic phase was collected and the aqueous phase was extracted with an additional amount of dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated to give the title compound.

The following derivatives were prepared analogously: 2- (3, 4-difluorobenzoyl) -1-benzamidocyclapropane-1-carboxylate of (Z) -methyl; 2- (3-Chlorobenzoyl) -1-benzamidocyclopropane-1-carboxylate of (Z) -methyl; 2- (3-Fluorobenzoyl) -1-benzamidocyclopropane-1-carboxylate of (Z) -methyl; and 2- (3-bromobenzoyl) -1-benzamidocyclopropane-1-carboxylate of (Z) -methyl; Example 17 Preparation of 2- (3,4-dichlorobenzoyl) -1- (N-benzoyl-N-t-butoxycarbonylamino) -cyclopropane-1-carboxylate of (E) -methyl. Di-t-butyl dicarbonate (2 mmol) and DMAP (1 mmol) were added to a suspension of 2- (3,4-dichlorobenzoyl) -1-benzamidocyclopropane-1-carboxylate.

(Z) -methyl (1 mmol) in anhydrous dichloromethane and the resulting mixture was kept under magnetic stirring under a nitrogen atmosphere at room temperature for two hours. After evaporation of the solvent, the crude reaction product was dissolved in dichloromethane, washed with 5% citric acid, brine and dried over anhydrous sodium sulfate. Evaporation of the solvent yielded the pure title compound.

The following derivatives were prepared analogously: 2- (3,4-dichlorobenzoyl) -1- (N-benzoyl-N-t-butoxycarbonylamino) -cyclopropane-1-carboxylate of (Z) -methyl; 2- (3,4-difluorobenzoyl) -1- (N-benzoyl-N-t-butoxycarbonylamino) -cyclopropane-1-carboxylate of (Z) -methyl; 2- (3-chlorobenzoyl) -1- (N-benzoyl-N-t-butoxycarbonylamino) -cyclopropane-1-carboxylate of (Z) -methyl; 2- (3-Fluorobenzoyl) -1- (N-benzoyl-N-t-butoxycarbonyla ino) -cyclopropane-1-carboxylate of (Z) -methyl; and 2- (3-bromobenzoyl) -1- (N-benzoyl-N-t-butoxycarbonylamino) -cyclopropane-1-carboxylate of (Z) -methyl; Example 18 Preparation of 2- (3,4-dichlorobenzoyl) -1-t-butoxycarbonylamino-cyclopropane-1-carboxylate of (Z) -methyl. Hydrazine hydrate (10 mmol) was added to a magnetically stirred suspension of 2- (3,4-dichlorobenzoyl) -1- (N-benzoyl-Nt-butoxycarbonylamino) -cyclopropane-1-carboxylate of (Z) -methyl in methanol anhydrous at room temperature. The stirring was continued for one hour after which it was evaporated, while the bath temperature was maintained with water below 30 ° C. The residue was then chromatographed with flash (eluent: chloroform-methanol, 9: 1) to give the title compound.

The following derivatives were prepared analogously: 2- (3, 4-dicluorobenzoyl) -1-t-butoxycarbonylamino-cyclopropane-1-carboxylate of (Z) -methyl; 2- (3-Chlorobenzoyl) -1-t-butoxycarbonylamino-cyclopropane-1-carboxylate of (Z) -methyl; 2- (3-Fluorobenzoyl) -1-t-butoxycarbonylamino-cyclopropane-1-carboxylate of (Z) -methyl; and 2- (3-bromobenzoyl) -1-t-butoxycarbonylamino-cyclopropane-1-carboxylate of (Z) -methyl.

Example 19 Preparation of (Z) -methyl 2- (3,4-dichlorobenzoyl) -1-amino-cyclopropane-1-carboxylate 12 N hydrochloric acid was added to a solution of 2- (3,4-dichlorobenzoyl) -1 -t-Butoxycarbonylamino-cyclopropane-1-carboxylate from (Z) -methyl in ethyl acetate and the resulting mixture was stirred magnetically at room temperature for 30 minutes. The reaction mixture was then neutralized with saturated sodium hydrogen carbonate, the organic phase was separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvent gave the title methyl ester.

The following derivatives were prepared analogously: 2- (3-chlorobenzoyl) -1-amino-cyclopropane-1-carboxylate (Z) -methyl; 2- (3-bromobenzoyl) -1-amino-cyclopropane-1-carboxylate (Z) -methyl; 2- (3-fluorobenzoyl) -1-amino-cyclopropane-1-carboxylate of (Z) -methyl; and 2- (3,4-difluorobenzoyl) -1-amino-cyclopropane-l-carboxylate of (Z) -methyl.

Example 20 Preparation of (Z) -2- (3,4-dichlorobenzoyl) -1-amino-cyclopropane-1-carboxylic acid Monohydrate of lithium hydroxide was added IN to a solution of 2- (3, -dichlorobenzoyl) -1-amino-cyclopropane-1-carboxylate of (Z) -methyl in dioxane and the resulting mixture was kept under magnetic stirring at room temperature overnight. The reaction mixture was then evaporated to dryness, the residue was diluted with water and neutralized with IN hydrochloric acid. Ion exchange chromatography on Dowex 50x2 200 and elution with 10% pyridine yielded the title compound.

The following derivatives were prepared analogously: (Z) -2- (3,4-difluorobenzoyl) -1-amino-cyclopropane-1-carboxylic acid; (Z) -2- (3-chlorobenzoyl) -1-amino-cyclopropane-1-carboxylic acid; (Z) -2- (3-fluorobenzoyl) -1-amino-cyclopropane-1-carboxylic acid; and (Z) -2- (3-bromobenzoyl) -1-amino-cyclopropane-1-carboxylic acid.

By agitating in an analogous manner the alkyl esters described in all the above examples, the respective free 1-carboxylic acids can be obtained.

Example 21 Preparation of (E) -2-phenyl-4- (3,4-dichlorobenzoylmethylene) -oxazol-5-one. A suspension of (Z) -2-phenyl-4- (3,4-dichlorobenzoylmethylene) -oxazol-5-one in 48% hydrobromic acid, maintained at 0 ° C and maintained under magnetic stirring, was saturated with acid gas Anhydrous hydrobromic acid for 30 minutes and left in a refrigerator overnight. The product was poured into crushed ice and the solid (E) -azlactone was filtered, washed with ice water and dried over phosphorus pentoxide.

The following derivatives were prepared analogously: (E) -2-phenyl-4- (3-chlorobenzoylmethylene) -oxazol-5-one; (E) -2-phenyl-4- (3-fluorobenzoylmethylene) -oxazol-5-one; (E) -2-phenyl-4- (3-bromobenzoylmethylene) -oxazol-5-one; and (E) -2-phenyl-4- (3,4-difluorobenzoylmethylene) -oxazol-5-one; Example 22 Preparation of (E) -2- (3,4-dichlorobenzoyl) -5-phenyl-6-oxo-4-azaspiro- [2, 4] -hept-4-en-7-one. A solution of (E) -2-phenyl-4- (3,4-dichlorobenzoylmethylene) -oxazol-5-one (1 mmol) in anhydrous dichloromethane was treated with an ethereal solution of diazomethane (10 mmol) under magnetic stirring. The mixture was allowed to stand at room temperature overnight, treated with anhydrous calcium chloride to destroy the excess diazomethane, filtered and concentrated under vacuum. The resulting oil was purified by flash chromatography. Elution with light petroleum-ethyl acetate gave the pure title derivative.

The following derivatives were prepared analogously: (E) -2- (3,4-difluorobenzoyl) -5-phenyl-6-oxo-4-azaspiro- [2,4] -hept-4-en-7-one; (E) -2- (3-chlorobenzoyl) -5-phenyl-6-oxo-4-azaspiro- [2,4] -hept-4-en-7-one; (E) -2- (3-fluorobenzoyl) -5-phenyl-6-oxo-4-azaspiro- [2,4] -hept-4-en-7-one; and (E) -2- (3-bromobenzoyl) -5-phenyl-6-oxo-4-azaspiro- [2,4] -hept-4-en-7-one.

EXAMPLE 23 Preparation of 2- (3,4-dichlorobenzoyl) -1-benzamidocyclopropane-1-carboxylate (E) -methyl ester DMAP (1 mmol) was added to a suspension of (E) -2- (3, -dichlorobenzoyl) 5-phenyl-6-oxo-4-azaspiro- [2, 4] -hept-4-en-7-one (1 mmol) in absolute methanol and the resulting mixture was stirred magnetically at room temperature for 30 minutes. The methanol was removed under vacuum, the crude product was treated with a 1: 1 mixture of dichloromethane and 5% aqueous citric acid. The organic phase was collected and the aqueous phase was extracted with an additional amount of dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated to give the title compound.

The following derivatives were prepared in an analogous manner: 2- (3,4-difluorobenzoyl) -1-benzamidocyclopropane-1-carboxylate of (E) -methyl; 2- (3-Chlorobenzoyl) -1-benzamidocyclopropane-l-carboxylate of (E) -methyl; 2- (3-Fluorobenzoyl) -1-benzamidocyclopropane-l-carboxylate of (E) -methyl; and 2- (3-bromobenzoyl) -1-benzamidocyclopropane-l-carboxylate of (E) -methyl.

Example 24 Preparation of 2- (3,4-dichlorobenzoyl) -1- (N-benzoyl-Nt-butoxycarbonylamino) -cyclopropane-1-carboxylate of (E) -methyl. Di-t-butyl dicarbonate (10 mmol) was added. and DMAP (0.2 mmol) to a suspension of (E) -methyl 2- (3,4-dichlorobenzoyl) -1-benzamidocyclopropane-l-carboxylate (1 mmol) in anhydrous tetrahydrofuran and the resulting mixture was maintained under magnetic stirring in a nitrogen atmosphere at room temperature for 22 hours. After evaporation of the solvent, the crude reaction product was dissolved in dichloromethane, washed with 5% citric acid, brine and dried over anhydrous sodium sulfate. Evaporation of the solvent produced a residue which was subjected to flash chromatography: elution with light petroleum ether-ethyl acetate gave the pure title compound.

The following derivatives were prepared analogously: 2- (3,4-dichlorobenzoyl) -1- (N-benzoyl-N-t-butoxycarbonylamino) -cyclopropane-1-carboxylate of (E) -methyl; 2- (3,4-difluorobenzoyl) -1- (N-benzoyl-N-t-butoxycarbonylamino) -cyclopropane-1-carboxylate of (E) -methyl; 2- (3-Chlorobenzoyl) -1- (N-benzoyl-N-t-butoxycarbonylamino) -cyclopropane-1-carboxylate of (E) -methyl; 2- (3-Fluorobenzoyl) -1- (N-benzoyl-N-t-butoxycarbonylamino) -cyclopropane-1-carboxylate of (E) -methyl; and 2- (3-bromobenzoyl) -1- (N-benzoyl-N-t-butoxycarbonylamino) -cyclopropane-1-carboxylate of (E) -methyl.

Example 25 Preparation of (E) -methyl 2- (3,4-dichlorobenzoyl) -1-t-butoxycarbonylamino-cyclopropane-1-carboxylate. Hydrazine hydrate (10 mmol) was added to a magnetically stirred suspension of 2- (3,4-dichlorobenzoyl) -1- (N-benzoyl-Nt-butoxycarbonylamino) -cyclopropane-1-carboxylate of (E) -methyl in methanol anhydrous at room temperature. Agitation was continued for 15 minutes after which the solvent was evaporated in a rotary evaporator while maintaining the bath temperature with water below 30 ° C.

The residue was then chromatographed with flash (eluent: chloroform-methanol, 9: 1) to give the title compound.

The following derivatives were prepared analogously: (3- (3, 4-difluorobenzoyl) -1-t-butoxycarbonylamino-cyclopropane-1-carboxylate of (E) -methyl; 2- (3-Chlorobenzoyl) -1-t-butoxycarbonylamino-cyclopropane-1-carboxylate of (E) -methyl; 2- (3-Fluorobenzoyl) -1-t-butoxycarbonylamino-cyclopropane-1-carboxylate of (E) -methyl; and 2- (3-bromobenzoyl) -1-t-butoxycarbonylamino-cyclopropane-1-carboxylate of (E) -methyl.

Example 26 Preparation of (E) -methyl 2- (3,4-dichlorobenzoyl) -1-amino-cyclopropane-1-carboxylate 12 N hydrochloric acid was added to a solution of 2- (3,4-dichlorobenzoyl) -1 -t-Butoxycarbonylamino-cyclopropane-1-carboxylate of (E) -ethyl in ethyl acetate and the resulting mixture was stirred magnetically at room temperature for 30 minutes. The reaction mixture was then neutralized with saturated sodium hydrogen carbonate, the organic phase was separated and the aqueous layer was extracted with ethyl acetate.

The combined organic phase was washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvent gave the title methyl ester.

The following derivatives were prepared analogously: 2- (3-chlorobenzoyl) -1-amino-cyclopropane-1-carboxylate (E) -methyl; 2- (3-bromobenzoyl) -1-amino-cyclopropane-1-carboxylate (E) -methyl; 2- (3-Fluorobenzoyl) -1-amino-cyclopropane-1-carboxylate of (E) -methyl; and 2- (3,4-difluorobenzoyl) -1-amino-cyclopropane-1-carboxylate of (E) -methyl.

Example 27 Preparation of (E) -2- (3,4-dichlorobenzoyl) -1-amino-cyclopropane-1-carboxylic acid. Lithium hydroxide monohydrate was added 1N to a solution of (E) -methyl 2- (3,4-dichlorobenzoyl) -1-amino-cyclopropane-1-carboxylate in dioxane and the resulting mixture was kept under magnetic stirring at room temperature overnight. The reaction mixture was then evaporated to dryness, the residue was diluted with water and neutralized with hydrochloric acid.

IN Ion exchange chromatography on Dowex 50x2 200 and elution with 10% pyridine yielded the title compound.

The following derivatives were prepared analogously: (E) -2- (3,4-difluorobenzoyl) -1-amino-cyclopropane-1-carboxylic acid, • (E) -2- (3-chlorobenzoyl) -1- acid amino-cyclopropane-l-carboxylic acid; (E) -2- (3-fluorobenzoyl) -1-amino-cyclopropane-1-carboxylic acid; and (E) -2- (3-bromobenzoyl) -1-amino-cyclopropane-1-carboxylic acid.

EXAMPLE 28 Preparation of 2- (3,4-difluorobenzoyl) -cyclopropane-1-carboxylate of (E) -methyl A solution of monomethyl ester of E-cyclopropane-1,2-dicarboxylate acid (1 g, 6.9 mmol) in - Oxalyl chloride (20 ml) was stirred under an Argon atmosphere for 2 hours then concentrated in vacuo.

To a solution of the resulting residue in o-dichlorobenzene (4 ml), under magnetic stirring and an Argon atmosphere at 0 ° C, aluminum chloride portion (2.76 g, 38.5 mmol) was added portionwise over 30 '. After fifteen minutes the reaction mixture was heated at 60 ° C for 90 'and then emptied into ice cold 3N hydrochloric acid. The aqueous layer was extracted with ethyl acetate (4 x 50 ml). The organic phases were combined, washed with brine (1 x 50 ml), dried over sodium sulfate and concentrated in vacuo. The oil residue was purified on silica gel by means of flash chromatography. Using light petroleum and light petroleum / ethyl acetate 95: 5 as eluent; 602 mg of 2- (3,4-difluorobenzoyl) -cyclopropane-1-carboxylate of (E) -methyl were collected (36% yield).

NMR-aH (CDC13) d: 1.6-1.7 (m, 2H, 3-CH2); 2.3-2.4 (m, 1H, 1-CH) 3.0-3.1 (m, 1H, 2-CH); 3.7 (5, 3H, COOCH3); 7.2-7.4 (m, 1H, 5'-CH); 7.8-7 9 (m, 2H, 6'-CH 2'-CH). 13 C-NMR (CDC13) d: 17.9, 24.53; 25.68; 52.15; 117.35; 117.71; 125.31; 134.09; 147.84 (d); 151.13 (d); 152.83 (d): 156.24 (d) 172.32; 194.36. The following compounds can be prepared in an analogous manner: 2- (3,4-dichlorobenzoyl) -3-methylene-cyclopropane-l-carboxylate of (E) -methyl, m.p. = 81 ° C NMR ^ H (CDC13) d: 3.1-3.2 (, 1H, 1-CH); 3.7-3.8 (m, 4H, 2-CH COOCH3); 5.5-5.7 (d, 2H, 3-exomethylene); 7.6 (d, 1H, 5'-CH, J0 = 8.5 Hz); 7.7 (dd, 1H, 6'-CH, JQ = 8.4 Hz Jm = 2 Hz); 8.1 (d, 1H, 2'-CH, Jm = 2Hz). 13 C NMR (CDCl 3) d: 25.65; 29.96; 52.18; 105.25; 127.36; 130.21; 130.70; 133.30; 136.00; 137.96; 169.51; 190.82 2- (3,4-dichlorobenzoyl) -3,3-dimethyl-cyclopropane-l-carboxylate of (E) -methyl. p.f. = 59-60 ° C NMR-XH (CDCl 3) d: 1.2 (s, 3H, 3a-CH 3); 1.3 (t, 3H, COOCH2CH3); 1.4 (s, 3H, 3β-CH 3); 2.5 (d, 1H, 1-CH, JtranS = 5.7 Hz); 3.0 (d, 1H, 2-CH, Jtrans = 5.7 Hz); 4.0-4.2 (, 2H, COOCH2CH3); 7.4 (d, 1H, 5'-CH, J0 = 8.4 Hz); 7.7 (dd, 1H, 6'-CH, J0 = 8.4 Hz Jm = 2 Hz); 7.9 (d, 1H, 2'-CH, Jm = 2Hz) 13 C NMR (CDCl 3) 6: 14.16; 19.93; 20.20; 33.29; 33.59; 38.50; 60.78; 127.06; 130.01; 130.64; 133.27; 137.40; 137.58; 170.28; 193.47. 2- (3,4-dichlorobenzoyl) -3-methyl-cyclopropane-l-carboxylate of (E) -methyl.

NMR-aH (CDC13) d: 1.1-1.2 (d, 3H, 3-CH3); 2.0-2.2 (m, 1H, 3-CH); 2.4-2.6 (m, 1H, 2-CH); 3.0-3.3 (m, 1H, 1-CH); 3.7 (s, 3H, COOCH3, 7.5 (d, 1H, 5'-CH, J0 = 8.4 Hz), 7.8-7.9 (dd, 1H, 6'-CH, J0 = 8.4 Hz Jm = 2 Hz); 8.1 (d, 1H, 2'-CH, Jm = 2Hz). 2- (3,4-dichlorobenzoyl) -cyclopentane-1-carboxylate of (E) -methyl.

NMR ^ H (CDCl 3) d: 1.6-2.2 (m, 6H, cyclopentane); 3.3-3.4 (m, 1H, 1-CH); 3.6 (s, 3H, COOCH3); 3.9-4.1 (m, 1H, 2-CH); 7.5 (d, 1H, 5 '-CH, J0 = 8.7 Hz); 7.7 (dd, 1H, 6'-CH, J0 = 8.3 Hz Jm = 2 Hz); 8.0 (d, 1H, 2'CH, Jm = 2Hz). 13 C NMR (CDCl 3) d: 25.73; 30.49; 31.36; 46.16; 49.47; 51.86; 127.56; 130.56; 130.65; 133.29; 136.05; 137.61; 175.37; 198.80. 2- (3,4-dichlorobenzoyl) -cyclobutane-1-carboxylate of (E) -methyl.

NMR-2H (CDCl 3) d: 2.1-2.3 (m, 4H cyclobutane); 3.4-3.6 (m, 1H, 1-CH); 3.6 (s, 3H, COOCH3); 4.0-4.4 (m, 1H, 2-CH); 7.4 (d, 1H, 5'CH, J0 = 8.7 Hz); 7.7 (dd, 1H, 6'-CH, J0 = 8.3 Hz Jm = 2 Hz); 8.0 (d, 1H, 2'-CH, Jm = 2 Hz).

Example 29 Preparation of (E) -2- (3,4-difluorobenzoyl) -cyclopropane-1-carboxylic acid To a solution of methyl (E) -2- (3,4-difluorobenzoyl) -cyclopropane-1-carboxylate ( 522 mg, 2.17 mmoles) in dioxane (7 ml), maintained under magnetic stirring, an aqueous solution (3 ml) of potassium hydroxide (182.5 mg, 3.26 mmol) was added. The resulting solution was stirred at room temperature for 20 ', then diluted with water (30 ml). The aqueous layer was extracted with ethyl acetate (3 x 10 ml), acidified with 3N hydrochloric acid and extracted with ethyl acetate (3 x 20 ml). These latter organic phases were combined, washed with brine (1 x 10 ml), dried over sodium sulfate and concentrated in vacuo. 471 mg of (E) -2- (3,4-difluorobenzoyl) -cyclopropane-1-carboxylic acid were collected as a white solid (96% yield) m.p. = 81-82 ° C. 1 H-NMR (CDCl 3 + CD 3 OD) d: 1.6-1.7 (, 2H, 3-CH 2); 2.4-2.5 (m, 1H, 1-CH); 3.1-3.3 (m, 1H, 2-CH); 7.2-7.4 (m, 1H, 5'-CH); 7.7 (m, 2H, 6'-CH 2'-CH); 9.7 (broad s, 1H, COOH). 13 C-NMR (CDC13 + CD30D) d: 18.27; 24.38; 26.15; 38.97; 117.45; 117.80; 125.39; 133.91; 147.88 (d); 151.24 (d); 152.86 (d); 156.36 (d); 177.96; 194.07.

The following compound can be prepared analogously: (E) -2- (3,4-dichlorobenzoyl) -3-methylene-cyclopropane-1-carboxylic acid. p.f. = 184 ° C desc.

NMR ^ H (CDCl 3 + CD 3 OD) d: 3.1-3.2 (m, 1H, 1-CH); 3.7-3.8 (, 4H, 2-CH); 5.5-5.8 (m, 2H, 3-exomethylene, COOH); 7.6 (d, 1H, 5'-CH, J0 = 8.5 Hz); 7.8 (dd, 1H, 6'-CH, J0 = 8.4 HzJm = 2Hz); 8.1 (d, 1H, 2'-CH, Jm = 2Hz). 13 C-NMR (CDC13 + CD30D) d: 25.94; 30.29; 105.57; 127.47; 130. 42; 130.89; 133.55; 136.06; 138.33; 172.74; 191.29.

(E) -2- (3,4-dichlorobenzoyl) -3,3-dimethyl-cyclopropane-1-carboxylic acid. p.f. 148-150 ° C.

NMR ^ H (CDC13 + CD30D) d: 1.1 (s, 3H, 3a-CH3); 1.5 (s 3 H, 3β-CH 3) 2.6 (d, 1 H, 1-CH, Hz); 3.2 (d, 1H, 2-CH, JtranS = 5.7 Hz); 4.6 (broad s, 1H, COOH); 8.0 (d, 1H, 5'-CH, J0 = 8.4 Hz); 8.2 (dd, 1H, 6'-CH, J0 = 8.4 J "= 2Hz); 8.5 (d, 1H, 2'-CH, Jm = 2 Hz). 13 C-NMR (CDC13 + CD30D) d: 19.94; 20.21; 27.89, 28.30; 33.44; 38.72; 127.09; 130.01; 130.69; 133.28; 137.37; 137.64; 172.95; 193.78.

(E) 2- (3,4-dichlorobenzoyl) -3-methyl-cyclopropane-l-carboxylic acid. p.f. = 129 ° C NMR - ^ - H (Acetone D6) d: 1.0-1.1 (dd, 3H, 3-CH3); 2.0-2.2 (m, 1H, 3-CH); 2.2-2.3 (m, 1H, 2-CH); 3.1-3.2 (m, 1H, 1-CH); 7.5 (d, 1H, 5'-CH, J0 = 8.4 Hz); 7.9-8.0 (dd, 1H, 6'-CH, J0 = 8.4 Hz Jm = 2 Hz); 8.0-8.1 (d, 1H, 2'-CH, Jm = 2 Hz); 9.0 (broad s, 1H, COOH).

NMR-13, (Acetone-De) d: 11.03; 27.23; 28.81; 33.30; 128. 71; 130.83; 131.82; 133.45; 137.66; 138.71; 173.17, 193.85.

(E) 2- (3,4-dichlorobenzoyl) -cyclobutane-1-carboxylic acid p.f. = 129-131 ° C NMR ^ H (CDC13 + CD30D) d: 2.1-2.4 (m, 4H cyclobutane); 3.5-3.7 (m, 1H, 1-CH); 4.1-4.3 (m, 1H, 2-CH); 4.9 (broad s, 1H, COOH); 7.5 (d, 1H, 5'-CH, J0 = 8.4 Hz); 7.7 (dd, 1H, 6'-CH, J0 = 8.4 Hz Jn = 2 Hz); 8.0 (d, 1H, 2'-CH, Jm-2 Hz). 13 C-NMR (CDCl 3 + CD 3 CD) d: 22.19; 23.23; 38.97; 44.30; 127.92; 130.84; 131.21; 133.71; 135.06; 138.23; 177.01; 197.63.

(E) -2- (3,4-dichlorobenzoyl) -cyclopentane-1-carboxylic acid m.p. = 86 ° C (dec.) NMR ^ H (Acetone-D6) d: 1.6-2.2 (m, 6H, cyclopentane); 3. 3-3.4 (m, 1H, 1-CH); 4.0-4.1 (m, 1H, 2-CH); 7.7 (d, 1H, 5'-CH, J0 = 8.7 Hz); 7.9 (dd, 1H, 6'-CH, J0 = 8.3 Hz Jm = 2 Hz); 8.1 (d, 1H, 2'-CH Jm = 2 Hz). 13 C-NMR (Acetone-D6) d: 25.73; 30.49; 31.36; 46.16; 49. 47; 127.56; 130.56; 130.65; 133.29; 136.05; 137.61; 177. 07; 198.80.

EXAMPLE 30 Preparation of (E) -2- (3,4-dichlorobenzoyl) -cyclopropane-1-carboxamide 3.5 g (12.82 mmoles) of (E) -methyl-2- (3,4-dichlorobenzoyl) -cyclopropane- were dissolved. 1-carboxylate in dioxane (50 ml) and treated with 30% NH 4 OH (140 ml) for 3 days at room temperature. The residue after evaporation was crystallized with i-propyl ether to give 1.6 g of (E) -2- (3,4-dichlorobenzoyl) -cyclopropane-1-carboxamide (51%). p.f. 188-191 ° C The following compounds can be prepared analogously: (E) -2- (3,4-dichlorobenzoyl) -cyclopropane-1-N-methylcarboxamide m.p. 127-129 ° C; (E) -2- (3,4-dichlorobenzoyl) -cyclopropane-1-hydroxamic acid m.p. 61-62 ° C; (E) -2- (3,4-dichlorobenzoyl) -cyclopropane-1-N-benzylcarboxamide m.p. 151-153 ° C; (E) -2- (3,4-dichlorobenzoyl) -cyclopropane-1-N-phenylcarboxamide m.p. 156-157 ° C; (E) -2- (3,4-dichlorobenzoyl) -cyclopropane-1-N-phenylsulfonylcarboxamide, m.p. 172-173 ° C; Example 31 A capsule, each weighing 0.23 g and containing 50 mg of the active substance, can be prepared as follows: Composition for 500 capsules: acid. (E) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid 25 g Lactose 80 g Corn starch 5 g Magnesium stearate 5 g This formulation can be encapsulated in two two-piece hard gelatin capsules, each one with each capsule weighing 0.23 g.

Example 32 Intramuscular injection of 50 mg / ml An injectable, pharmaceutical composition can be prepared by dissolving 50 g of (E) -2- (3,4-dichlorobenzoyl) -cyclopropyl-1-carboxylic acid in sterile propylene glycol (1000 ml) and Can seal in ampoules of 1-5 ml.

Legend for Figure 1 IDO = Indolaminaoxygenase KYN = Cinurenina KYN-OH = Cinurenina-3-hydroxylase KYNA = Kinurénico acid 3-OHAA = Acid 3-hydroxy anthranilic KYNase = Cinureninasa QUIN = Acid quinolínico 3-HAO = deoxigenasa of acid 3-hidroxi Antranyl KAY = Cinurenin Amino Transferase 3-OHKYN = 3-Hydroxy-Cinurenine It is noted that in relation to this date, the best method known to 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, the content of the following claims is claimed as property.

Claims (14)

1. A compound, characterized in that it is a 2- (benzoyl-substituted) -cycloalkyl-1-carboxylic acid of the formula (I) wherein E is an alkylene chain of 1 to 4 carbon atoms, wherein one carbon atom is optionally substituted by = CH2, one or two alkyl groups of 1 to 4 carbon atoms or one or two halogen atoms; each of R and Ri, which are the same or different, is hydrogen, halogen, hydroxy, trifluoromethyl, cyano, nitro, phenyl, benzyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio from 1 to 6 carbon atoms, SOR4 or S02R4 in which R4 is alkyl of 1 to 6 carbon atoms or -N (R5R6) in which R5 and R6 is, independently, hydrogen, alkyl of 1 to 6 carbon atoms , formyl or alkanoyl of 2 to 6 carbon atoms; R2 is hydrogen or -N (R7R8) in which each of R7 and R8 is independently hydrogen, alkyl of 1 to 6 carbon atoms, benzyl, phenyl, hydroxy, alkoxy of 1 to 6 carbon atoms, benzyloxy or one of R7 and R8 is hydrogen and the other is C0R9 in which R9 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl or R9 is a group -N (R? or Rn) wherein each of Rio and Rn is, independently, hydrogen or alkyl of 1 to 6 carbon atoms; R 3 is hydroxy, alkoxy of 1 to 6 carbon atoms, phenoxy, benzyloxy or a group -N (R 2 R 3) wherein R 2 and R 13 are as R 7 and R 8 as defined above, or one of R 2 and R13 is hydrogen and the other is a group S02R9 in which R9 is as defined above; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, characterized in that, in the formula E is a group -CH2- or a group (CH2) 2-, optionally substituted by = CH2, or one or two halogen atoms or - one or two alkyl groups of 1 to 4 carbon atoms; each of R and R, which are the same or different, is hydrogen, halogen, hydroxy, trifluoromethyl, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, SOR, S02R4 in which R4 is alkyl of 1 to 4 carbon atoms or -N (R5R6) in which each of R5 and R6 is, independently, hydrogen, alkyl of 1 to 4 carbon atoms or formyl; R2 is hydrogen or -N (R7R8) in which each of R7 and R8 is independently hydrogen, alkyl of 1 to 4 carbon atoms, benzyl, phenyl, hydroxy, alkoxy of 1 to 4 carbon atoms or benzyloxy, or one of R7 and R8 is hydrogen and the other is COR9 in which R9 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, phenyl or R9 is a group -N (R? 0Rn ) in which Rio and Rn is, independently, hydrogen or alkyl of 1 to 4 carbon atoms; R3 is hydroxy, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxylamino or a group -N (R2R? 3) wherein one of RX 2 and R13 is hydrogen and the other is hydrogen, alkyl of 1 to 4 carbon atoms , benzyl, phenyl or a group S02R9 in which R9 is phenyl; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 or 2, characterized in that, in the formula (I), E is methylene, optionally substituted by = CH2, one or two halogen atoms or one or two alkyl groups of 1 to 4 carbon atoms; each of R and Ri, which are the same or different, is hydrogen or halogen; R2 is hydrogen; R3 is hydroxy, alkoxy of 1 to 4 carbon atoms, hydroxylamino or a group -N (R12R? 3) wherein one of RX 2 and R13 is hydrogen and the other is hydrogen, alkyl of 1 to 4 carbon atoms, benzyl , phenyl or a group S02R9 in which R9 is phenyl; or a pharmaceutically acceptable salt thereof.

4. A compound according to any of the preceding claims characterized in that, in the formula (I): E is methylene, optionally substituted by = CH2, one or two halogen atoms or one or two alkyl groups of 1 to 4 carbon atoms; R and Ri are both halogen; R2 is hydrogen; R3 is hydroxy, alkoxy of 1 to 4 carbon atoms, hydroxylamino or a group -N (R? 2R? 3) wherein one of R? 2 and Ri3 is hydrogen and the other is hydrogen, alkyl of 1 to 4 carbon atoms carbon, benzyl, phenyl or a group S02R9 in which R9 is phenyl; or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1, characterized in that it is selected from 2- (3-chlorobenzoyl) -cyclopropane-1-carboxylic acid; 2- (3-fluorobenzoyl) -cyclopropane-1-carboxylic acid; 2- (3-bromobenzoyl) -cyclopropane-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -cyclopropane-1-carboxylic acid; 2- (3,4-difluorobenzoyl) -cyclopropane-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -1-amino-cyclopropane-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -3-methylene-cyclopropane-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -3-methyl-cyclopropane-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -3,3-dimethyl-cyclopropane-l-carboxylic acid; and 2- (3,4-dichlorobenzoyl) -3,3-difluoro-cyclopropane-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -3-methyl-cyclopropane-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -cyclopentene-1-carboxylic acid; 2- (3,4-dichlorobenzoyl) -cyclopropane-1-carboxamide; 2- (3,4-dichlorobenzoyl) -cyclopropane-1-N-methylcarboxamide; 2- (3,4-dichlorobenzoyl) -cyclopropane-1-N-benzylcarboxamide; 2- (3,4-dichlorobenzoyl) -cyclopropane-1-N-phenylcarboxamide; 2- (3,4-dichlorobenzoyl) -cyclopropane-1-hydroxamic acid; 2- (3,4-dichlorobenzoyl) -cyclopropane-1-N-phenylsulfonylcarboxamide; 2- (3,4-dichlorobenzoyl) -cyclobutane-1-carboxylic acid; and, if appropriate, the alkyl esters of 1 to 6 carbon atoms and pharmaceutically acceptable salts thereof; either as an individual E or Z isomer and / or as an individual optical isomer or as a mixture thereof.

6. A compound according to claim 5, characterized in that it is in the form of an alkyl ester of 1 to 4 carbon atoms.

7. A compound according to claim 1, characterized in that it is for use in a method of treating the human or animal body by therapy.

8. A compound according to claim 7, characterized in that it is for use as an inhibitor of the enzyme kynurenine-3-hydroxylase.

9. A compound according to claim 7, characterized in that it is for use in the prevention and / or treatment of a neuropathological procedure.

10. A compound according to claim 9, characterized in that the pathological procedure is a neurodegenerative pathology selected from Huntington's chorea, Alzheimer's disease, Parkinson's disease, olivopontocerebellar atrophy, dementia different from Alzheimer's, including dementia similar to the syndrome caused by the Syndrome of Acquired Immunodeficiency (AIDS), dementia due to multiple infarctions, cerebral amyotrophic lateral sclerosis, cerebral ischemia, cerebral hypoxia, spinal and head trauma and epilepsy.

11. The use of a compound according to claim 1 in the preparation of a medicament for use as an inhibitor of the enzyme kynurenine-3-hydroxylase.

12. A method for the treatment of a mammal in need of a kinurenine-3-hydroxylase inhibitor, the method is characterized in that it comprises administering thereto a therapeutically effective amount of a compound according to claim 1.

13. A pharmaceutical composition, characterized in that it comprises a compound according to claim 1 and a pharmaceutically acceptable carrier and / or a diluent.

14. A process for the preparation of a compound according to claim 1, the process is characterized in that it comprises a) reacting a compound of the formula (II) wherein R and Ri are as defined above, with a compound of the formula (III) R. -R, Y (III) CH, wherein R 2 is as defined in claim 1 and R 3 is alkoxy of 1 to 6 carbon atoms, to obtain a compound of the formula (I) wherein R 3 is alkoxy of 1 to 6 carbon atoms and E is a group alkylene (-CH2-) of 1 unsubstituted carbon atom; or reacting a compound of the formula (IV) wherein E is as defined in claim 1; R 2 is alkyl of 1 to 6 carbon atoms and X is halogen; with a compound of the formula (V) wherein R and Ri are as defined in claim 1, to thereby obtain a compound of the formula (I) wherein R3 is alkoxy of 1 to 6 carbon atoms and R2 is hydrogen; or deacylating a compound of the formula (VI) R wherein R and Ri are as defined in claim 1 and BOC means tert-butoxycarbonyl, to thereby obtain a compound of the formula (I) wherein R2 is -NHCORg in which R9 is tert-butoxy and R3 is methoxy and E is an unsubstituted 1 carbon atom alkylene chain; and, if it is desired to convert a compound of the formula (I) to another compound of the formula (I), and / or if desired, and / or if desired, esterify a compound of the formula (I) to form a alkyl ester of 1 to 6 carbon atoms thereof, and / or, if desired, converting a compound of the formula (I) into a salt thereof, and / or, if desired, converting a salt of a compound of the formula (I) in a free compound of the formula (I), and / or, if desired, separating a mixture of isomers of a compound of the formula (I) in the individual isomers.