WO1998040344A1

WO1998040344A1 - 2-substituted benzoyl-cycloalkyl-1-carboxylic acid derivatives

Info

Publication number: WO1998040344A1
Application number: PCT/EP1998/000883
Authority: WO
Inventors: Mario Varasi; Antonio Giordani; Paolo Pevarello; Roberto Pellicciari; Carmela Speciale
Original assignee: Pharmacia & Upjohn S.P.A.
Priority date: 1997-03-11
Filing date: 1998-02-16
Publication date: 1998-09-17
Also published as: PL335601A1; EA199900809A1; HUP0001023A2; TW407146B; NO994386D0; JP2001514634A; GB9705031D0; CA2283184A1; ZA981972B; KR20000076096A; IL131676A0; HUP0001023A3; CN1252049A; NO994386L; EP0973720A1; AU6497998A

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

2-SUBSTITUTED BENZOY -CYC OALKYL-1-CARBOXY IC ACID DERIVATIVES

The present invention relates to 2- (substituted^" benzoyl)- cycloalkyl-1-carboxylic acid derivatives, 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 kynurenine pathway, tryptophan metabolism gives rise to the formation of 3- hydroxykynurenine (3-OHKYN) and quinolinic acid (QUIN), on the one side, and kynurenic acid (KYNA) , on the other side, as shown in Figure 1. (The legend to Figure 1 is to 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; Nature, 1986,321,168-171; Science, 1983,219,316-318).

Increased concentrations of QUIN have also been indicated as responsible for neurological disorders accompanying many infections and inflammatory diseases including Acquired Immunodeficiency Syndrome (AIDS) (Ann. Neurol . 1991,29,202- 209) .

One of the main strategies, aimed at altering the KYNA/QUIN balance blocking 3-OHKYN and QUIN production and increasing KYNA production, entails inhibition of key enzymes of the kynurenine (KYN) pathway, among which Kynurenine-3 -hydroxylase is of primary importance. Consequently, there is a need in therapy of compounds able of inhibiting this enzyme.

The compounds of the present invention fulfill such a need.

Accordingly, the present invention provides 2- (substituted benzoyl) -cycloalkyl-1-carboxylic acid compounds of formula (I)

wherein E is a C₁-C₄ alkylene chain, in which a carbon atom is optionally substituted by =CH₂, one or two C^C^ alkyl groups or one or two halogen atoms; each of R and R₁₇ being the same or different, is hydrogen, halogen, hydroxy, trifluoromethyl , cyano, nitro, phenyl, benzyl, C^Cg alkyl, C^Cg alkoxy, C₁-C₆ alkylthio, SOR₄ or S0₂R₄ in which R₄ is C₁-C₆ alkyl or -N(R₅R₆) in which each of R₅ and R_r is, independently, hydrogen, CACg alkyl, formyl or C -C«- alkanoyl ; R₂ is hydrogen or -N(R₇R₈) in which each of R₇ and R_s is, independently, hydrogen, C-_L-Cg alkyl, benzyl, phenyl, hydroxy, C^Cg alkoxy, benzyloxy or one of R₇ and R₈ is hydrogen and the other is C0R₉ in which R₉ is hydrogen, C-^-Cg alkyl, C-_L-Cg alkoxy, phenyl or R₉ is a group -N(R₁₀R_ι:L) in which each of R₁₀ and R_lλ is independently hydrogen or C Cg alkyl; R₃ is hydroxy, C-_L-Cg alkoxy, phenoxy, benzyloxy or a group -N(R₁₂R₁₃) wherein R₁₂ and R₁₃ are as R₇ and R₈ as defined above, or one of R₁₂ and R₁₃ is hydrogen and the other is a S0₂R₉ group in which R₉ is as defined above; and pharmaceutically acceptable salts thereof . The alkyl and alkoxy groups may be branched or straight groups . E as a C_λ-C₄ alkylene chain is preferably a C^C;, alkylene chain, in particular a methylene (-CH₂-) group. When such alkylene chain is substituted, it is preferably substituted by a =CH₂ group or one or two halogen atoms, in particular fluorine or one or two methyl groups.

Representative examples of C_x-C₆ alkyl groups include C₁-C₄ alkyl groups such as methyl, ethyl, n- and iso-propyl, n- , iso- , sec- and tert-butyl. Representative examples of _j^-Cg alkoxy groups include C_λ - C, alkoxy groups such as methoxy and ethoxy.

Representative examples of C₁-C₆ alkylthio groups include C₁-C₄ alkylthio groups such as methylthio and ethylthio. Representative examples of C-^Cg alkanoyl groups include C₁-C₄ alkanoyl groups such as acetyl and propionyl .

Representative examples of C-_L-Cg alkoxycarbonyl groups include C₁-C₄ alkoxycarbonyl groups 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 acid addition salts with inorganic, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric acids or organic, e.g. acetic, trifluoroacetic , propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylic acids, and salts with inorganic, e.g. alkali metal, especially sodium or potassium bases or alkaline-earth metal, especially calcium or magnesium bases, or with organic bases, e.g. acyclic or cyclic amines, preferably methylamine, ethylamine, diethlamine, triethylamine or piperidine. The compounds of the invention have asymmetric carbon atoms and therefore they can exist either as racemic mixtures or as individual optical isomers (enantiomers) . Moreover the compounds of the invention can also be E- or Z- isomers or E-, Z- mixtures thereof.

Accordingly the present invention also include within its scope all the possible isomers and their mixtures and both the metabolites and the pharmaceutically acceptable bio-precursors

(otherwise known as pro-drugs) of the compounds of the invention.

Preferred compounds of the invention are the compounds of formula (I) wherein:

E is a -CH₂- or a -(CH₂)₂- group, optionally substituted by =CH₂, one or two halogen atoms or one or two C_x-C₄ alkyl groups; each of R and R_x , being the same or different, is hydrogen, halogen, hydroxy, trifluoromethyl , cyano, nitro, C_x-C₄ alkyl, C-_L-Qi alkoxy, C₁-C₄ alkylthio, S0R₄ , S0₂R₄ in which P₄ is CAOj alkyl or -N(R₅R₆) in which each of R₅ and R₆ is, independently, hydrogen, C₁-C₄ alkyl or ormyl ; R₂ is hydrogen or -N(R₇R₈) m which each of R₇ and R₈ is, independently, hydrogen, C_X-C_Λ alkyl, benzyl, phenyl, hydroxy, C-_L-C₄ alkoxy or benzyloxy, or one of R₇ and R₈ is hydrogen and the other is C0R₉ in which R₉ is hydrogen, C₁-C₄ alkyl, A-^ alkoxy, phenyl or R₉ is a group -N(R₁₀R₁₁) in which R₁₀ and R_X1 is, independently, hydrogen or C₁-C₄ alkyl;

R₃ is hydroxy, C-_L-C_J alkoxy, benzyloxy, hydroxylamino or a group -N(R₁₂R₁₃) wherein one of R₁₂ and R₁₃ is hydrogen and the other is hydrogen, C_X- C alkyl, benzyl, phenyl or a S0₂R₉ group in which R₉ is phenyl; and the pharmaceutically acceptable salts thereof.

More preferred compounds according to the invention are the compounds of formula (I) wherein: E is methylene, optionally substituted by =CH₂, one or two halogen atoms or one or two C^^ alkyl groups; each of R and R_λ , being the same or different, is hydrogen or halogen; R₂ is hydrogen;

R₃ is hydroxy, C^C,, alkoxy, hydroxylamino or a group -N(R₁₂R₁₃) wherein one of R₁₂ and R₁₃ is hydrogen and the other is hydrogen, ^_^- ^ alkyl, benzyl, phenyl cr a S0₂R₉ group in which

R₉ is phenyl; and the pharmaceutically acceptable salts thereof.

Most preferred compounds according to the invention are the compounds of formula (I) wherein:

E is methylene, optionally substituted by =CH₂, one or two halogen atoms or one or two C_]_-C₄ alkyl groups; R and R₁ are both halogen;

R₂ is hydrogen;

R₃ is hydroxy, C - C₄ alkoxy, hydroxylamino or a group -N(R₁₂R₁₃) wherein one of R₁₂ and R₁₃ is hydrogen and the other is hydrogen, C-_L - C, alkyl, benzyl, phenyl or a S0₂R₉ group in which R₉ is phenyl; and the pharmaceutically acceptable salts thereof.

Examples of 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) -l-amino-cyclopropane- 1-carboxylic acid; 2- (3 , 4 -dichlorobenzoyl) -3 -methylene-cyclopropane- 1-carboxylic acid; 2- (3 , 4 -dichlorobenzoyl) -3 , 3 -dimethyl-cyclopropane- 1-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) -eyelopentane- 1-carboxylic acid; 2- (3 , 4 -dichlorobenzoyl) -cyclopropane-1-carboxamide ; 2- (3 , 4-dichlorobenzoyl) -cyclopropane-1-N-methyl-carboxamide 2- (3 , 4 -dichlorobenzoyl) -cyclopropane- 1-N-benzyl -carboxamide , 2- (3 , 4-dichlorobenzoyl) -cyclopropane-1-N-phenyl -carboxamide , 2- (3 , 4 -dichlorobenzoyl ) -cyclopropane-1-hydroxamic acid; 2 - (3 , 4-dichlorobenzoyl) -cyclopropane-1-N-phenylsulfonyl- carboxamide ; 2- (3 , 4-dichlorobenzoyl) -cyclobutane-1-carboxylic acid; and, if the case, the C^-Cg , preferably C₁-C₄, alkyl esters thereof; either as single E- or Z- isomer and/or as single optical isomer or as a mixture thereof and, when appropriate, the pharmaceutically acceptable salts thereof. A further object of the present invention is also to provide a 2 -substituted benzoyl-cycloalkyl-1-carboxylic acid compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as an active therapeutic substance, in particular as kynurenine-3 -hydroxylase enzyme inhibitor.

Object of the present invention is also the use of a compound of formula (I) , as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as kynurenine-3 -hydroxylase enzyme inhibitor.

The present invention also provides a method of treating a mammal, including human, in need of a kynurenine-3 -hydroxylase inhibitor, such method comprising adminstering thereto a therapeutically effective amount of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof .

The compounds of the invention and the salts thereof can be obtained, for instance, by a process comprising: a) reacting a compound of formula (II)

wherein R and R_x are as defined above, with a compound of formula (III)

wherein R₂ is as defined above and R₃ is C^Cg alkoxy, to obtain a compound of formula (I) wherein R₃ is CAC₆ alkoxy and E is an unsubstituted C_x-alkylene (-CH₂-) group; or b) reacting a compound of formula (IV)

wherein E is as defined above; R₁₂ is C-_L-Cg alkyl and X is halogen; with a compound of formula (V)

wherein R and R_± are as defined above, thus obtaining a compound of formula (I) wherein R₃ is C-_L-Cg alkoxy and R₂ is hydrogen; or c) deacylating a compound of formula (VI)

wherein R and R_x are as defined above and BOC means tert- butoxycarbonyl , thus obtaining a compound of formula (I) wherein R₂ is -NHC0R₉ in which R₉ is tert-butoxy and R₃ is methoxy and E is an unsubstituted C alkylene chain; and, if desired converting a compound of formula (I) into another compound of formula (I), and/or, if desired, converting a compound of formula (I) into a salt thereof, and/or, if desired, converting a salt of a compound of formula (I) into a free compound of formula (I), and/or, if desired, separating a mixture of isomers of a compound of formula (I; into the single isomers. The above process-variants a) , b) and c) are analogy processes which can be carried out according to well know methods in the art.

The reaction of a compound of formula (II) with a compound of formula (III) can be carried out, for example, in a suitable solvent such as, e. g. diethyl ether, in the presence of a suitable metal complex, e.g palladium (II) diacetate, at a temperature ranging from about -78°C to room temperature, for a time ranging from about 1 hours to about 24 hours. In a compound of formula (IV) the halogen atom X is preferably chlorine or bromine . The reaction of a compound of formula (IV) with a compound of formula (V) can be carried out according to 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 performed in the presence of a suitable Lewis acid catalyst, in an inert solvent such as, e.g., dichloromethane or 1 , 2-dichloroethane , or m an appropriate aromatic hydrocarbon such as, e.g., chlorobenzene , nitrobenzene or in an excess of a compound of formula (V) itself; optionally in the presence of a co- solvent, e.g. nitromethane .

A suitable Lewis acid may be, e.g. anhydrous aluminium trichloride, anhydrous zinc dichloride, typically anhydrous aluminium trichloride. Deacylation of a compound of formula (VI) can be accomplished by treatment with a suitable deacylating agent, e.g. nydrazme hydrate, in a suitable solvent, e.g. anhydrous methanol . The reaction may 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 formula (I) into another compound of formula (I) can be carried out according to known methods .

For example, hydrolysis of a compound of formula (I) wherein R₃ is C_x-Cg alkoxy to obtain a compound of formula (I) wherein R₃ is hydroxy can be carried out according to well known methods in the art. For instance, this reaction can be performed in an aqueous or hydroalcoholic alkali solution, for example sodium hydroxide, at a concentration ranging between 0.01 and 12N, at a temperature ranging from -20 °C to reflux temperature or by acid hydrolysis, for instance, using an aqueous solution of hydroholic acids, typically hydrochloric acid, in a suitable solvent, e.g. acetic acid, at a temperature ranging from about 0°C to reflux temperature.

A compound of formula (I) wherein R₃ is hydroxy, can be converted in another compound of formula (I) wherein R₃ is C-^Cg alkoxy, phenoxy or benzyloxy, by conventional alkylating methods, e.g. by treatment with a suitable alkylating agent, preferably a iodo derivative, in the presence of a base, e.g. potassium bicarbonate, in a suitable solvent, e.g. dimethylformamide , at a temperature ranging from about 0°C to about 60 °C. A compound of formula (I) wherein R₃ is hydroxy, can be converted into another compound of formula (I) , wherein R₃ is -N(R₇R₈) by conventional methods, e.g. methods employed usually in the chemistry of peptides. In particular, a compound of formula (I) wherein R₃ is a N(R₇R₈) wherein R~ and R₃ are both hydrogen can be converted into a compound of formula (I) wherein R₇ and R₈ are, each independently, C^Cg alkyl, benzyl or phenyl, by alkylative procedures known in the literature. The optional salification of a compound of formula (I) as well as the conversion of a salt into the free compound and the separation of a mixture of isomers into the single isomers may be carried out by conventional methods.

As stated above, the compounds of the invention have asymmetric carbon atoms and can have E/Z isomerism. Accordingly, they can be synthesized either as a mixture of isomers and then the desired isomer is separated by conventional techniques, or synthesis can be carried out by known stereospecific processes to obtain a single isomeric compound. A compound of formula (II) , as defined above can be obtained, for instance, by reacting a compound of formula (VII)

wherein

R and R are as defined above, with diazomethane , for example, in a suitable solvent such as, e.g. diethyl ether, at a temperature varying between -78°C and room temperature, for a time ranging between 1 and 24 hours. Compounds of formula (III) and (VII) are known compounds or can be prepared according to known procedures .

A compound of formula (IV) can be obtained by a multi-step process comprising the reaction of a compound of formula (VIII)

wherein R₁₂ and E are as defined above, with an alkali agent to obtain a compound of formula (IX)

wherein R₁₂ and E are as defined above.

A compound of formula (IX) can then be reacted with a halogenating agent to obtain a compound of formula (IV) as defined above.

The reaction of a compound of formula (VIII) to obtain a compound of formula (IX) can be accomplished by basic hydrolysis, i.e using an alcoholic solution of an alkali metal hydroxide, typically a potassium hydroxide solution in suitable alkoholic medium, i.e. methanol, at a suitable temperature, e.g. between 0 and 55°C, for a suitable time, e.g. 2-24 hours. The reaction of a compound of formula (IX) to obtain a compound of formula (VI) can be accomplished in a suitable halogenating agent, i.e. oxalyl chloride or bromide or thionyl chloride, typically oxalyl chloride, in the presence or the absence of a solvent, at a suitable temperature, e.g. 0-40°C, for a suitable time, e.g. 1-6 hours.

The compounds of formula (V) and (VIII) are known compounds. A compound of formula (VI) can be obtained by a multi-step process comprising acid oxidation of a compound of formula (X)

wherein R and R₁ are as defined above, to obtain a compound of formula (XI)

wherein R and R_x are as defined above.

Acid oxidation of a compound of formula (X) can be accomplished for instance by using a dimethylsulfoxide (DMSO) solution of concentrated hydrobromic acid, e.g. aqueous 48% hydrobromic acid .

The reaction may 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 formula (XI) can be then converted into a compound of formula (XII)

wherein R and R_x are as defined above, by treatment with a suitable hyppuric acid derivative in the presence of a suitable acylating agent, e.g. acetic anhydride. The reaction may 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 formula (XII) , if desired, can be converted into its isomer of formula (Xlla)

The conversion of a compound of formula (XII) into a compound of formula (Xlla) can be accomplished using a suitable hydrohalic acid solution, e.g. 48% aqueous hydrobromic acid saturated with anhydrous hydrogen bromide gas, at a suitable temperature, e.g. between about -20 and about 25°C, for a suitable time, e.g. 15 minutes to 24 hours. Cyclopropanation of a compound of formula (XII) or (Xlla) provides a compound of formula (XIII) and (Xllla) , respectively

wherein R and R_λ are as defined above.

The reaction can be accomplished by treatment of a compound of formula (XII) or (Xlla), respectively, with an ethereal solution of diazomethane . The reaction can be carried out at a temperature ranging from about -78 and about 25°C, for a time between about 2 and about 48 hours.

A compound of formula (XIII) or (Xllla) is then converted into a compound of formula (XIV) or (XlVa) , respectively

wherein R and R_λ are as defined above The reaction can be accomplished by treatment with dimethylaminopyridme (DMAP) m methanol The reaction may 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 formula (XIV) or (XlVaj with di-t-butyl-carbonate and DMAP m a suitable solvent, e g anhydrous dichloromethane provides a compound of formula 'VI) , which can be represented by the respective two isomeric compounds of formula (XV) and (XVa)

wherein R and R_x 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 formula (XV) and (XVa) , for convenience, are herein represented as a compound of formula (VI) . The compounds of formula (X) and the above hyppuric acid derivatives are known compounds.

When in the compounds of the invention and the intermediate thereof groups are present which may interfere with the reaction they may be protected before the reaction takes place and then deprotected at the end of the reaction. For instance, hydroxy, amino and/or carboxy groups may be protected and then deprotected according to the common techniques known from the peptide chemistry.

The compounds of the invention are active as kynurenine-3 - hydroxylase enzyme inhibitors and therefore are useful in the prevention and/or treatment of neuropathological processes, related to a deranged production of quinolinic acid and/or 3- hydroxykynurenine due to excessive activation of neuro- transmission mediated by excitatory amino acid receptors and/or oxidative stress. Examples of such neuropathological processes are neurodegenerative pathologies including, e.g. Huntington's chorea, Alzheimer's disease, Parkinson's disease, olivoponto cerebellar atrophy, non-Alzheimer's dementias, including the dementia like syndrome caused by Acquired Immunodeficiency Syndrome (AIDS) , multi-infarctual dementia, cerebral amyotrophic lateral sclerosis, cerebral ischemia, cerebral hypoxia, spinal and head trauma and epilepsy.

A human or animal in need of a kynurenine-3 -hydroxylase enzyme inhibitor can thus be treated by a method which comprises the administration thereto of a therapeutically effective amount of a compound of the invention or a salt thereof . The condition of the human or animal can thereby be improved .

The efficacy of the compounds of the invention in the inhibition of the enzyme kynurenine-3 -hydroxylase was evaluated e.g., in rat liver mitochondrial extract following the method reported below, according to the procedure described in "Analytical Bioche . (1992), 205, 257-262", with minor modifications . The assay for kynurenine 3 -hydroxylase is based on the enzymatic synthesis of tritiated water during the hydroxylation reaction. Radiolabeled water was quantified following selective adsorption of the isotopic substrate and its metabolite with activated charcoal. Rat liver mitochondrial extract was used as enzymatic preparation for this assay.

The assay for kynurenine 3 -hydroxylase activity was carried out at 37°C for a time o 30 min . The reaction mixture of a total volume of 30μl was constituted of 44 μg of suspended extract, 100 mM Tris/Cl^' buffer pH 8.1 , 10 mM EDTA, 100 mM KCl, 0.8 mM NADPH, 0.025 mM L-Kynurenine , 0.3 μCi L- (3 , 5 -³H) Kynurenine (10 Ci/mmol) and 3 μl of different concentration of inhibitor solutions. After the incubation, the reaction was terminated by the addition of 300 μl of 7.5% (W/v) activated charcoal, vortexed and centπfuged for 7 mm.. A 75 μl aliquot of supernatant was transferred to optiplate and 200 μl of liquid scintillation added. The optiplates were vortexed and the radioactivity counted in a scintillation counter.

The obtained results, which have been reported m 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

The dosage level, suitable for administration to a mammal, e.g. to humans, depends on the age, weight, conditions of the patient and on the administration route, for example, the dosage adopted for oral administration, for instance for the representative compound of the invention PNU 165853, may range from about 10 to about 500 mg pro dose, from 1 to 5 times daily.

The compounds of the invention can be administered m a variety of dosage forms, e.g orally, m the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally m the form of suppositories; parenterally, e.g. mtramuscolarly, or by intravenous and/or mtrathecal and/or mtraspmal injection or infusion. The invention includes also pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient (which can 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, e.g. lactose, dextrose, saccharose, sucrose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gum, gelatin, methylcellulose , carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates , laurylsulphates ; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes. The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol . The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for intramuscolar injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desidered, a suitable amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, acqueous, isotonic saline solutions or they may contain as a carrier propylene glycol .

The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa butter, 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 refluxed for 12 hours under magnetic stirring and a nitrogen atmosphere. 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%) .

Analogously, the following products can be prepared: 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 h to a magnetically stirred solution of diazomethane (370 ml containing 287.9 mmol of diazomethane) , maintained at a temperature between -10°C and -15°C, under 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 were obtained (97.8%) (m.p. 94.5-95.5 °C) ; IR (CHC1₃;

V_max: 2110 cm^"1)

Analogously, the following products can be prepared:

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 A-dichlorobenzoyl ) -cyclopropyl- l-carboxylate and t-butyl (Z) 2- (3.4 -dichlorobenzoyl ) - cyclopropyl -1 -carboxylate .

To a suspension containing dichloromethane (30 ml), t- butylacrylate (5.96 ml, 40.71 mmol) and Pd ( II) (OAc) ₂, maintained under magnetic stirring and argon atmosphere, a solution of 3 , 4-dichlorophenyl-α-diazo-methyl ketone (2.5 g; 11.63 mmol) in dichloromethane (200 ml) was added during 8 h. After 3 h at room temperature, dichloromethane was removed under reduced pressure and the mixture was submitted to flash chromatography. Elution with light petroleum/diethyl ether 90:10 afforded t-butyl (E) -2 - (3 , 4-dichlorobenzoyl ) -cyclopropyl- 1-carboxylate (1 g; 27%) . Following elution with light petroleum/diethyl ether 80:20 t-butyl (Z)-2-(3,4- dichlorobenzoyl) -cyclopropyl-1-carboxylate (0.4, 11%) was recovered.

^XH-NMR (CDC1₃) [ (E) -t-butyl-2 - (3 , 4 -dichlorobenzoyl) -cyclopropyl - 1-carboxylate]: δ 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 (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, J_m=2 Hz); 8.2 (d, 1H, 2' -CH, J_m=2 Hz) .

¹³C-NMR (CDC1₃) [(E) -t-butyl-2- (3, 4-dichlorobenzoyl) - cyclopropyl-1-carboxylate]: δ 18.02; 24.68; 25.83; 28.06; 127.14; 130.06; 130.67; 133.27; 136.27; 137.92; 174.36; 195.04.

^Η- R (CDCI₃) [(Z) -t-butyl-2- (3, 4-dichlorobenzoyl) -cyclopropyl - 1-carboxylate]: δ 1.3-1.7 (m, 10H, COOt-Bu, 3-(H)CH); 1.7-1.9 (m, 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=8.4 Hz); 7.5 (d, 1H, 5'-CH, J=7.5 Hz); 7.8 (dd, 1H, 6'-CH, J₀=8.5 Hz, J_m=2 Hz) ; 8.1 (d, 1H, 2'-CH, J„.=2 Hz) .

¹³C-NMR (CDCI₃) [(Z) -t-butyl-2- (3, 4-dichlorobenzoyl) - cyclopropyl -1-carboxylate]: δ 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.

Analogously, the following products can be prepared:

(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 Q_f (E) -2- (3.4-dichlorobenzoyl) -cyclopropyl -1- carboxylic acid.

To a solution of t-butyl (E) -2- (3 , 4-dichlorobenzoyl) - cyclopropyl -1-carboxylate (0.297 g, 0.943 mmol) in ethyl acetate (25 ml) , maintained under magnetic stirring, 37% hydrochloric acid (5 ml) was added. After 2 h 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 under vacuum. The resulting mixture was then purified by means of flash chromatography using dichloromethane/methanol 0÷10% as eluent . (E) -2- (3 , 4 -dichlorobenzoyl) -cyclopropyl -1-carboxylic acid (56.8 mg; 41.3%) were obtained.

^XH-NMR (CDC1₃) [(E) -2- (3, 4-dichlorobenzoyl) -cyclopropyl- 1- carboxylic acid]: δ 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, J_m=2 Hz); 8.2

(d, 1H, 2' -CH, J_ra=2 Hz) .

¹³C-NMR (CDC1₃) [(E) -2- (3, 4-dichlorobenzoyl) -cyclopropyl -1- carboxylic acid]: δ 18.02; 24.68; 25.83; 127.14; 130.06; 130.67; 133.27; 136.37; 137.92; 174.36; 195.04.

Analogously, the following products can be prepared: (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 Q_f (Z) -2- (3 , 4-dichlorobenzoyl) -cyclopropyl -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 h 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 under vacuum. The resulting mixture was then purified by means of flash chromatography using dichloromethane/methanol 0÷15% as eluent . (Z) 2- (3,4- dichlorobenzoyl) -cyclopropyl -1-carboxylic acid (15 mg; 30.8%) was obtained.

^XH-NMR (CDC1₃) [(Z) -2- (3, 4-dichlorobenzoyl) -cyclopropyl- 1- carboxylic acid]: δ 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 (m, 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) .

¹³C-NMR (CDC1₃) [(Z) -2- (3, 4-dichlorobenzoyl) -cyclopropyl- 1- carboxylic acid]: δ 13.96; 24.08; 26.09; 127.79; 130.30; 130.69; 133.14; 136.63; 138.30; 171.15; 194.23.

Analogously, the following products can be prepared: (Z) -2- (3 -chlorobenzoyl) -cyclopropyl- 1-carboxylic acid; (Z) -2- (3 -fluorobenzoyl) -cyclopropyl-l-carboxylic acid; (Z) -2- (3 -bromobenzoyl) -cyclopropyl- 1-carboxylic acid; and (Z) -2- (3 , 4 -difluorobenzoyl) -cyclopropyl-l-carboxylic acid. Example 6

Preparation of (E) (1R, 2R) -2- (3 , 4-dichlorobenzoyl) -cyclopropyl - 1- (lR-α-phenylglycinoyl) -carboxamide and (E) (IS .2S) -2- (3 , 4 - dichlorobenzoyl) -cyclopropyl-1- (lR-α-phenylglycinoyl) - carboxamide .

(E) -2- (3 , 4-dichlorobenzoyl) -cyclopropyl-l-carboxylic acid (0.175 g, 0.68 mmol) was dissolved in oxalylchloride (6 ml) and left at room temperature for 2 h, under magnetic stirring and argon atmosphere. Oxalylchloride was removed by rotary evaporation and the corresponding 2- (3 , 4-dichlorobenzoyl ) - cyclopropyl-l-carboxylic acid chloride, dissolved in anhydrous dioxane (1.5 ml), was added to a dioxane (3.5 ml) solution containing R- ( - ) -phenylglycinol (0.093 g, 0.68 mmol) and triethylamine (0.1 ml, 0.7 mmol), maintained under magnetic stirring and argon atmosphere at 10°C. After 1 h 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 under vacuum. The residue was submitted to medium pressure chromatography on a silica gel Lobar column (60-43 μm) using light petroleum/ethyl acetate 30:70 as eluent and two amides were separated. According to the literature , the first amide eluted, ([ ]_D ²⁰ = -102.6, c = 0.5 CHC1₃) , can be assigned as (E, - (lR,2R)-2- (3, 4 -dichlorobenzoyl) -cyclopropyl-1-) lR-α- phenylglycinoyl) -carboxamide and the second one, ([o]_D = +56, c = 1 CHC1₃) , as (E) - (IS, 2S) -2- (3, 4-dichlorobenzoyl) -cyclopropyi- 1- ) lR-α-phenylglycinoyl) -carboxamide (86%) .

' (a) G Helmchen, G Nill, D. Floc erzi, W Schuhle, M.S.K. Youssef, Angew Chem Int Ed Engl , 18, 1979, 62-63 (b) G Helmchen, G Nill, D Flockerzi, M.S K Youssef, wgew Chem Int Ed Engl , 18, 1979, 63-65 (c) G Helmchen. G. Nύ\„ Angew Chem Int Ed Engl , 18, 1979, 65-66 ^XH- MR (CDCI₃) [(E) - (1R,2R) -2- (3 , 4 -dichlorobenzoyl ) -cyclopropyl - 1- (lR-α-phenylglycinoyl) -carboxamide]: δ 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, α-CH₂0H) ) ; 5.0-5.1 (m, 1H, -CH) ; 6.9-7.0 (bd, 1H, NH) ; 7.2-7.4 (m, 5H, a-C₆H₅) ; 7.2-7.4 (m, 1H, 5'-CH, J= 7.5 Hz); 7.9 (dd, 1H, 6'-CH, J_σ=8.5 Hz, J_m=2 Hz); 8.2 (d, 1H, 2'-CH, J_m=2 Hz) .

¹³C-NMR (CDCI₃) [(E) - (1R,2R) -2- (3, 4-dichlorobenzoyl) - cyclopropyl-1- (lR-α-phenylglycinoyl) carboxamide] : δ 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 (CDCI₃) [(E) - (IS, 2S) -2- (3, 4-dichlorobenzoyl) -cyclopropyl- 1- (lR-α-phenylglycinoyl) -carboxamide]: δ 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, α-CH₂0H) ) ; 4.9-5.0 (m, 1H, α-CH); 6.9-7.0 (bd, 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, J_m=2 Hz); 7.9 (d, 1H, 2'-CH, J_m=2 Hz).

¹³C-NMR (CDCI₃) [(E) - (IS, 2S) -2- (3, 4-dichlorobenzoyl) - cyclopropyl-1- (lR-α-phenylglycinoyl) carboxamide] : δ 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) (1R, 2R) -2-dichlorobenzoyl) -cyclopropyl- 1- carboxylic acid.

To a solution of (E) (1R, 2R) -2- (3 , 4-dichlorobenzoyl) - cyclopropyl-1- (lR-α-phenylglycinoyl) -carboxamide (50 mg, 0.123 mmol) in dioxane (3.5 ml), maintained under magnetic stirring, 37% hydrochloric acid was added (1.5 ml) and the mixture was left at 50°C for 7 h. 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 under vacuum. The residue was submitted to flash chromatography using dichloromethane/methanol O÷IO as eluent . (E) (1R, 2R) -2- (3 , 4 - dichlorobenzoyl) -cyclopropyl-l-carboxylic acid, ([oc]_D = -86, c = 0.36, CHC1₃) was yielded (20 mg, 75%) .

^- MR (CDC1₃) [(E) (1R, 2R) -2- (3 , 4-dichlorobenzoyl) -cyclopropyl- l-carboxylic acid]: δ 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) .

¹³C-NMR (CDC1₃) [(E) (1R,2R) -2- (3, 4-dichlorobenzoyl) - cyclopropyl - 1-carboxylic acid]: δ 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) (IS , 2S) -2- (3.4 -dichlorobenzoyl ) -cyclopropyl - 1-carboxylic acid.

To a solution of (E) (IS, 2S) -2- (3 , 4-dichlorobenzoyl ) - cyclopropyl-1- (lR-α-phenylglycinoyl ) -carboxamide (50 mg, 0.123 mmol) in dioxane (3.5 ml), maintained under magnetic stirring, 37% hydrochloric acid was added (1.5 ml) and the mixture was left at 50°C for 7 h. 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 under vacuum. The residue was submitted to flash chromatography using dichloromethane/methanol O÷IO as eluent . (E) - (1R, 2R) -2- (3 , 4- dichlorobenzoyl) -cyclopropyl-l-carboxylic acid, ( ([α]_D = +77, c = 0.65, CHC1₃) was yielded (13 mg, 49%).

^Η-NMR (CDC1₃) [(E) (IS, 2S) -2- (3, 4-dichlorobenzoyl) -cyclopropyl- l-carboxylic acid]: δ 1.6-1.8 (t, 2H, 3-CH₂, J=7 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); 7.8 (dd, 1H, 6'-CH, J₀=7.5 Hz, J_m=l .5 Hz); 8.1 (s, 1H, 2 ' -CR , J_m=1.5 Hz).

¹³C-NMR (CDCI₃) [(E) (IS, 2S) -2- (3, 4-dichlorobenzoyl) -cyclopropyl - 1-carboxylic acid]: δ 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) -l-methoxycarbonyl-cyclopropane-2 -carboxylic acid,

A solution of potassium hydroxide (0.354 g, 6.32 mmol) in dry methanol (4 ml) was dropped in one hour to a solution of

(E) 1 , 2-cyclopropandicarboxylate dimethyl ester (1 g, 6.32 mmol) in dry methanol (4 ml) , maintained under magnetic stirring at room temperature. The resulting solution was heated to 55°C during 12 hours and then was 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 under vacuum to yield an oil that was purified by flash-chromatography . Elution with dichloromethane/methanol (95:5) afforded the pure title compound (0.556 g; 61%).

^XH-NMR (CDC1₃) ; δ: 1.5 (t, 2H, 2-CH₂, J=8 Hz); 2.1-2.3 (m, 2H, 1-CH and 3-CH); 3.7 (s, 3H, COOCH₃); 10.35 (bs, 1H, COOH) . ¹³C-NMR (CDCI₃) ; δ: 14.94; 21.71; 22.24; 51.88; 171.74; 176.60.

Analogously the following compounds were prepared: (E) -l-methoxycarbonyl-cyclobutane-2-carboxylic acid, (E) -l-methoxycarbonyl-cyclopentane-2-carboxylic acid, (E) -1 -methoxycarbonyl-cyclohexane- 2 -carboxylic acid,

(E) - 1 -methoxycarbonyl -3 -methylene-cyclopropane- 2 -carboxylic acid,

(E) -1 -methoxycarbonyl -3 -methyl-cyclopropane-1-carboxylic acid, (E) -1 -methoxycarbonyl -3 , 3 -dimethyl -cyclopropane-1-carboxylic acid, and

(E) -1 -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 oxalylchloride (20 ml) was stirred under an argon atmosphere at room temperature for 3 hours, then the solution was concentrated under vacuum for 2 hours and the oily residue containing the titled compound was used in the next step without further purification.

Analogously, 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) - 1 -methoxycarbonyl -3 -methylene-cyclopropane-2 -carboxylic acid chloride; (E) -l-methoxycarbonyl-3-methyl-cyclopropane-2-carboxylic acid chloride;

(E) -1 -methoxycarbonyl -3 , 3 -dimethyl -cyclopropane-2 -carboxylic acid chloride and

(E) -1 -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) -1 -methoxycarbonyl - cyclopropane- 2 -carboxylic acid chloride (0.627 g, 3.857 mmol) in 1, 2-dichlorobenzene (10 ml), AlCl₃ (1.542 g, 11.57 mmol) was added portionwise under an argon atmpsphere at 0°C. The resulting solution was stirred 10 minutes at 0°C then warmed to 55°C for 2 hours. The reaction mixture was quenched by addition of ice-water (10 ml) and 10% hydrochloric acid (10 ml) . the mixture so obtained was extracted with ethyl acetate (4 x 25 ml) ; the combined organic phases were washed with brine (1 x 10 ml), dried over an. sodium sulfate, concentrated under vacuum. The oily residue was purified by flash-chromatography : elutionwith light petroleum-ethyl acetate 100:0 to 85:15 thus affording the titled compound as an oil (0.610 mg, 58%) .

^XH-NMR (CDC1₃) : δ: 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, J_D=8 Hz); 7.85 (dd, 1H, 5'-CH, J₀=8Hz, J_m=2 Hz); 8.05 (dd, 1H, 2' -CH, J =2 Hz) . ¹³C-NMR (CDCI₃) : δ : 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:

(E) -methyl 2- (3 , 4-dichlorobenzoyl) -cyclobutyl- 1-carboxylate ;

(E) -methyl 2- (3 , 4-dichlorobenzoyl) -cyclopentyl-1-carboxylate ;

(E) -methyl 2- (3 , 4-dichlorobenzoyl) -cyclohexyl -1-carboxylate ;

(E) -methyl -2- (3 , 4-dichlorobenzoyl) -3-methylene-cyclopropane-l - carboxylate;

(E) -methyl -2- (3 , 4 -dichlorobenzoyl) -3 -methyl-cyclopropane-1 - carboxylate ;

(E) -methyl -2- (3 , 4-dichlorobenzoyl) -3 , 3-dimethyl-cyclopropane-l - carboxylate and (E) -methyl-2- (3 , 4-dichlorobenzoyl) -3,3 -difluoro-cyclopropane- 1- carboxylate .

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), a solution of sodium hydroxide (19.5 mg, 0.488 mmol) in water (1.5 ml) was added. After 2 hours at room temperature, the mixture was diluted with water (10 ml and extracted with dichloromethane (2 x 2 ml ) . The acqueous 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 an. sodium sulfate and concentrated under vacuum to obtain the titled compound (50 mg,

79%) as a white solid. ^XH-NMR (Acetone-d₆) : δ: 1.6 (m, 2H, 2-CH₂) ; 2.35-2.45 (m, 1-CH) ; 3.25 (m, 1H, 3-CH); 7.75 (d, 1H, 6'-CH, J_Q=8 Hz); 8.05 (dd, 1H, 5'-CH, J₀=8 Hz, J_m=2 Hz); 8.2 (d, 1H, 2'-CH, J_m=2 Hz).

¹³C-NMR (CDC1₃) : δ : 18.16; 25.05; 26.38; 128.79; 130.91, 131.87; 133.55; 137.91; 173.01; 195.48.

Analogously 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-l-carboxylic acid; 2- (3 , 4-dichlorobenzoyl) -3 -methyl -cyclopropane- 1-carboxylic acid;

2- (3 , 4-dichlorobenzoyl) -3 , 3 -dimethyl-cyclopropane -1-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 (1 mmol) in DMSO (3 ml) , 48% aqueous hydrobromic acid (3 mmol) 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 poured into ice. The crude product was extracted into 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. Analogously, the following products can be prepared: 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-dιchlorophenylglyoxal (1 mmol), powdered dry hyppuric acid (1 mmol), powdered freshly fused sodium acetate

(1 mmol) and high-grade acetic anhydride, is heated on an electric hot plate with constant shaking m an apparatus fitted with a calcium chloride tube. As soon as the material has liquefied completely, the flask is 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 into the flask, while maintaining the temperature below 30°C. After allowing the reaction mixture to stand overnight, the crystalline product is filtered with suction, . The pure azlactone is collected as a white solid.

Analogously the following products were prepared: (Z) -2-Phenyl-4- (3 -chlorobenzoyl ethylene) -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 exces diazomethane, filtered and concentrated under vacuum. The resultant oil was purified by flash-chromatography . Elution with light petroleum-ethyl acetate afforded the pure titled derivative .

Analogously the following derivatives were prepared: (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 (Z) -Methyl 2- (3 , 4 -dichlorobenzoyl) -1- benzamidocyclopropane- 1-carboxylate .

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 magnetically stirred at room temperature for 35 minutes. Methanol was removed under vacuum, the crude product was treated with a mixture 1:1 of dichloromethane and 5% aq. 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 an. sodium sulfate and concentrated to give the titled compund.

Analogously the following derivatives were prepared:

(Z) -Methyl 2- (3 , 4 -difluorobenzoyl) -1-benzamidocyclopropane-l- carboxylate ; (Z) -Methyl 2- (3-chlorobenzoyl) -1-benzamidocyclopropane-l- carboxylate ;

(Z) -Methyl 2- (3 -fluorobenzoyl) -1-benzamidocyclopropane-l- carboxylate; and

(Z) -Methyl 2- (3 -bromobenzoyl) -1-benzamidocyclopropane-l- carboxylate .

Example 17

Preparation of (Z) -Methyl 2- (3 , 4-dichlorobenzoyl) -1- (N-benzoyl-

N-t -butoxycarbonylamino) -cyclopropane- 1-carboxylate . Di- t-butyl dicarbonate (2 mmol) and DMAP (1 mmol) were added to a suspension of (Z) -Methyl 2- (3 , 4-dichlorobenzoyl) -1- benzamidocyclopropane- 1-carboxylate (1 mmol) in anhydrous dichloromethane and the resulting mixture was kept under magnetic stirring in 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 titled compound.

Analogously the following derivatives were prepared:

(Z) -Methyl 2- (3 , 4-dichlorobenzoyl) -1- (N-benzoyl-N-t- butoxycarbonylamino) -cyclopropane- 1-carboxylate ;

(Z) -Methyl 2- (3 , 4-difluorobenzoyl) -1- (N-benzoyl-N-t- butoxycarbonylamino) -cyclopropane- 1-carboxylate ;

(Z) -Methyl 2- (3-chlorobenzoyl) -1- (N-benzoyl-N-t- butoxycarbonylamino) -eyelopropane- 1 -carboxylate ;

(Z) -Methyl 2- (3 -fluorobenzoyl) -1- (N-benzoyl-N-t- butoxycarbonylamino) -cyclopropane-1-carboxylate ; and

(Z) -Methyl 2- (3 -bromobenzoyl) -1- (N-benzoyl-N-t- butoxycarbonylamino) -cyclopropane-1-carboxylate .

Example 18

Preparation of (Z) -Methyl 2- ( .4 -dichlorobenzoyl) -1-t- butoxycarbonylamino-cyclopropane- 1-carboxylate .

Hydrazine hydrate (10 mmol) was added to a magnetically stirred suspension of (Z) -Methyl 2- (3 , 4 -dichlorobenzoyl) -1- (N-benzoyl - N-t-butoxycarbonylamino) -cyclopropane- 1-carboxylate in anhydrous methanol at room temperature. Stirring was continued for one hour after which the solvent was evaporated, while maintaining the temperature of the water bath below 30°C. The residue was then flash-chromatographed (eluent: chloroform- methanol ; 9:1) to afford the titled compound.

Analogously the following derivatives were prepared:

(Z) -Methyl 2- (3,4 -difluorobenzoyl) -1-t-butoxycarbonylamino- cyclopropane-1-carboxylate ;

(Z) -Methyl 2- (3-chlorobenzoyl) -1- t-butoxycarbonylamino- cyclopropane-1 -carboxylate ;

(Z) -Methyl 2- (3 -fluorobenzoyl) -1- t-butoxycarbonylamino- cyclopropane- 1 -carboxylate ; and (Z) -Methyl 2- (3 -bromobenzoyl) -1-t-butoxycarbonylamino- cyclopropane-1-carboxylate . 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 (Z) -Methyl 2- (3 , 4-dichlorobenzoyl) -1-t-butoxycarbonylamino-cyclopropane-l- carboxylate in ethyl acetate and the resulting mixture was magnetically stirred at room temperature for 30 minutes. The reaction mixture was then neutralised with saturated sodium hydrogen carbonate, the organic phase separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase were washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvent gave the titled methyl ester .

Analogously the following derivatives were prepared: (Z) -Methyl 2- (3-chlorobenzoyl) -1-amino-cyclopropane-l- carboxylate ; (Z) -Methyl 2- (3 -bromobenzoyl ) -1-amino-cyclopropane-l- carboxylate;

(Z) -Methyl 2- (3 -fluorobenzoyl) -1-amino-cyclopropane-l- carboxylate; and

(Z) -Methyl 2- (3 , 4-difluorobenzoyl) -1-amino-cyclopropane- 1-carboxylate .

Example 20

Preparation of (Z) -2- (3 , 4 -dichlorobenzoyl) -1-amino- cyclopropane- 1-carboxylic acid.

I N Lithium hydroxide monohyrate was added to a solution of

(Z) -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 diluted with water and neutralised with 1 N hydrochloric^" acid. Ion exchange chromatography on Dowex 50x2 200 and elution with 10% pyridine yielded the titled compound.

Analogously the following derivatived were prepared:

(Z) -2- (3 , 4 -difluorobenzoyl) -1-amino-cyclopropane-l-carboxylic acid;

(Z) -2- (3-chlorobenzoyl) -1-amino-cyclopropane-l-carboxylic acid;

(Z) -2- (3 -fluorobenzoyl) -1-amino-cyclopropane-l-carboxylic acid; and

(Z) -2- (3 -bromobenzoyl) -1-amino-cyclopropane-l-carboxylic acid.

Analogously starting from the alkyl esters described in all the preceding 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, kept at 0°C and maintained under magnetic stirring, was saturated with anhydrous hydrogen bromide gas 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 phosphorous pentoxide .

Analogously the following derivatives were prepared: (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 excess diazomethane, filtered and concentrated under vacuum, the resultant oil was purifird by flash-chromatography . elution with light petroleum-ethyl acetate afforded the pure titled derivative.

Analogously the following derivatives were prepared: (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 (E) -Methyl 2- (3 , 4-dichlorobenzoyl ) -1- benzamidocyclopropane-1-carboxylate.

DMAP (1 mmol) was added to a suspension of (E)-2-(3,4- dichlorobenzoyl) -5-phenyl-6-oxo-4-azaspiro-[2 , 4]-hept-4-en-7- one(l mmol) in absolute methanol and the resulting mixture was magnetically stirred at room temperature for 30 minutes. Methanol was removed under vacuum, the crude product was treated with a mixture 1:1 of dichloromethane and 5% aq . 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 an. sodium sulfate and concentrated to give the titled compound.

Analogously the following derivatives were prepared:

(E) -Methyl 2- (3 , 4 -difluorobenzoyl) -1-benzamidocyclopropane-l- carboxylate;

(E) -Methyl 2- (3-chlorobenzoyl) -1-benzamidocyclopropane-l- carboxylate; (E) -Methyl 2- (3- fluorobenzoyl) -1 -benzamidocyclopropane-1- carboxylate; and

(E) -Methyl 2- (3 -bromobenzoyl) -1-benzamidocyclopropane-l- carboxylate .

Example 24

Preparation of (E) -Methyl 2- (3 , 4-dichlorobenzoyl) -1- (N-benzoyl- N-t-butoxycarbonylamino) -cyclopropane-1-carboxylate . Di-t-butyl dicarbonate (10 mmol) and DMAP (0.2 mmol) were added to a suspension of (E) -Methyl 2- (3 , 4 -dichlorobenzoyl) - 1- benzamidocyclopropane- 1-carboxylate (1 mmol) in anhydrous tetrahydrofuran and the resulting mixture was kept 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 yielded a residue which was submitted to flash chromatography: elution with light petroleum ether-ethyl acetate afforded the pure titled compound.

Analogously the following derivatives were prepared: (E) -Methyl 2- (3 , 4 -dichlorobenzoyl) -1- (N-benzoyl-N- t- butoxycarbonylamino) -cyclopropane-1-carboxylate ;

(E) -Methyl 2- (3 , 4-difluorobenzoyl ) -1- (N-benzoyl -N-t- butoxycarbonylamino) -cyclopropane - 1 -carboxylate ; (E) -Methyl 2- (3-chlorobenzoyl) -1- (N-benzoyl-N-t- butoxycarbonylamino) -cyclopropane- 1-carboxylate ; (Z) -Methyl 2- (3 -fluorobenzoyl ) -1- (N-benzoyl-N- t- butoxycarbonylamino) -cyclopropane -1 -carboxylate ; and (E) -Methyl 2- (3 -bromobenzoyl) -1- (N-benzoyl -N-t- butoxycarbonylamino) -cyclopropane- 1-carboxylate .

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 (E) -Methyl 2- (3 , 4 -dichlorobenzoyl ) -1- (N-benzoyl - N-t-butoxycarbonylamino) -cyclopropane-1-carboxylate in anhydrous methanol at room temperature. Stirring was continued for 15 minutes after which the solvent was evaporated on a rotary evaporator while maintaining the temperature of the water bath below 30°C. The residue was then flash- chromatographed (eluent: chloroform-methanol ; 9:1) to afford the titled compound. Analogously the following derivatives were prepared: (E) -Methyl 2- (3 , 4 -difluorobenzoyl) -1-t-butoxycarbonylamino- cyclopropane- 1-carboxylate ; (E) -Methyl 2- (3 -chlorobenzoyl) -1-t-butoxycarbonylamino- cyclopropane- 1-carboxylate ;

(E) -Methyl 2- (3 -fluorobenzoyl) -1-t-butoxycarbonylamino- cyclopropane-1-carboxylate ; and

(E) -Methyl 2- (3 -bromobenzoyl) -1-t-butoxycarbonylamino- cyclopropane- 1 -carboxylate .

Example 26

Preparation of (E) -Methyl 2- (3 , 4 -dichlorobenzoyl) -l-amino- cyclopropane- 1 -carboxylate 12 N Hydrochloric acid was added to a solution of (E) -Methyl 2-

(3 , 4-dichlorobenzoyl ) -1-t-butoxycarbonylamino-cyclopropane-l- carboxylate in ethyl acetate and the resulting mixture was magnetically stirred at room temperature for 30 minutes. The reaction mixture was then neutralised with saturated sodium hydrogen carbonate, the organic phase separated and the aqueous layer was extracted with ethyl acetate . The combined organic phase were washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvent gave the titled methyl ester.

Analogously the following derivatives were prepared:

(E) -Methyl 2- (3-chlorobenzoyl) -1-amino-cyclopropane-l- carboxylate ;

(E) -Methyl 2- (3 -bromobenzoyl) -1-amino-cyclopropane-l- carboxylate;

(E) -Methyl 2- (3 -fluorobenzoyl) -1-amino-cyclopropane-l- carboxylate; and

(E) -Methyl 2- (3 , 4 -difluorobenzoyl) - l-amino-cyclopropane- 1-carboxylate .

Example 27

Preparation of (E) -2- (3 , 4-dichlorobenzoyl) - 1 -amino- cyclopropane- 1-carboxylic acid.

1 N Lithium hydroxide monohyrate was added to a solution of (E) -Methyl 2- (3 , 4-dichlorobenzoyl) -1-amino-cyclopropane-l- 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 diluted with water and neutralised with 1 N hydrochloric acid. Ion exchange chromatography on Dowex 50x2 200 and elution with 10% pyridine yielded the titled compound.

Analogously the following derivatived were prepared:

(E) -2- (3 , 4 -difluorobenzoyl) -1-amino-cyclopropane- 1-carboxylic acid;

(E) -2- (3-chlorobenzoyl) -l-amino-cyclopropane- 1-carboxylic acid;

(E) -2- (3 -fluorobenzoyl) -1-amino-cyclopropane-l-carboxylic acid; and

(E) -2- (3 -bromobenzoyl) -1-amino-cyclopropane-l-carboxylic acid.

Example 28

Preparation of (E) -Methyl , 2- (3 , 4 -difluorobenzoyl) - cyclopropane- 1-carboxylate

A solution of E-cyclopropane-1 , 2 -dicarboxylate acid monomethyl ester (1 g, 6.9 mmol) in oxalylchloride (20 ml) was stirred under Argon atmosphere during 2 hours then concentrated under vacuum. To a solution of the resulting residue in o- dichlorobenzene (4 ml) , under magneting stirring and Argon atmosphere at 0°C, aluminium chloride (2.76 g, 38.5 mmol) was added portion wise during 30'. After fifteen minute the reaction mixture was heated at 60°C for 90' and then poured into ice-hydrochloric acid 3N. The aqueous layer was extracted with ethyl acetate (4x50 ml) . The organic phases were combined washed with brine (1x50 ml), dried over sodium sulphate and concentrated under 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 methyl (E) -Methyl, 2- (3 , 4-difluorobenzoyl) -cyclopropane- 1-carboxylate were collected (yield 36%) .

^XH-NMR (CDC1₃) δ: 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 (s, 3H, COOCH₃) ; 7.2-7.4 (m, 1H, 5'- CH) ; 7.8-7.9 (m, 2H, 6'-CH 2'-CH).

¹³C-NMR (CDCI₃) δ: 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.

Analogously the following compounds can be prepared: (E) -Methyl, 2- (3 , 4-dichlorobenzoyl) -3 -methylene-cyclopropane-1- carboxylate . m.p.= 81°C

^XH-NMR (CDCI₃) δ: 3.1-3.2 (m, 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, J₀=8.4 Hz J_m=2 Hz); 8.1 (d, 1H, 2' -CH, J„=2Hz) . ¹³C-NMR (CDCI₃) δ: 25.65; 29.96; 52.18; 105.25; 127.36; 130.21; 130.70; 133.30; 136.00; 137.96; 169.51; 190.82.

(E) -Methyl , 2- (3 , 4-dichlorobenzoyl) -3,3 - dime thy 1- cyclopropane - 1-carboxylate. m.p.= 59-60°C

^XH-NMR (CDCl₃)δ: 1.2(s, 3H, 3α-CH₃) ; 1.3 (t, 3H, COOCH₂CH₃) ; 1.4

(s, 3H, 3β-CH₃) ; 2.5 (d, IH, 1-CH, J_trans =5.7 Hz) ; 3.0 (d, IH, 2-CH, J_trans= 5.7 Hz) ; 4.0-4.2 (m, 2H, COOCH₂CH₃) ; 7.4 (d, IH,

5'-CH, J₀=8.4 Hz) ; 7.7 (dd, IH, 6'-CH, J₀=δ .4 Hz J_m=2 Hz) ; 7.9

(d, IH, 2' -CH, J_m=2Hz) .

¹³C-NMR (CDCI₃) δ: 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.

(E) -Methyl, 2- (3 , 4-dichlorobenzoyl) -3-methyl-cyclopropane-l- carboxylate .

^XH-NMR (CDCI₃) δ: 1.1-1.2 (d, 3H, 3-CH₃) ; 2.0-2.2 ( , IH, 3- CH) ; 2.4-2.6 (m, IH, 2-CH) ; 3.0-3.3 (m, IH, 1-CH) ; 3.7 (s,3H, COOCH₃; 7.5 (d, IH, 5'-CH, J₀=8.4 Hz) ; 7.8-7.9 (dd, IH, 6' -CH, J₀=8.4 Hz J_m=2 Hz) ; 8.0-8.1 (d, IH, 2'-CH, J_m=2Hz) .

(E) -Methyl , 2- (3 , 4-dichlorobenzoyl) -cyclopentane- 1-carboxylate .

^^"H-NMR (CDCI₃) δ: 1.6-2.2 (m, 6H, cyclopentane); 3.3-3.4 (m, IH,

1-CH); 3.6 (s, 3H, COOCH₃) ; 3.9-4.1 (m, IH, 2-CH); 7.5 (d, IH, 5'-CH, J₀=8.7 Hz); 7.7 (dd, IH, 6'-CH, J₀=8.3 Hz J_m=2 Hz); 8.0 (d, IH, 2'CH, J_m=2Hz) . ¹³C-NMR (CDCI₃) δ: 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.

(E) -Methyl, 2- (3 , 4-dichlorobenzoyl) -cyclobutane -1 -carboxylate .

^XH-NMR (CDCI₃) δ: 2.1-2.3 (m, 4H cyclobutane); 3.4-3.6 (m, IH,

1-CH); 3.6 (s, 3H, COOCH₃) ; 4.0-4.4 (m, IH, 2-CH); 7.4 (d, IH,

5'CH, J₀=8.7 Hz); 7.7 (dd, IH, 6'-CH, J₀=8.3 Hz J_m=2 Hz); 8.0 (d, IH, 2' -CH, J_m=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 mmol) 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 during 20' then was diluted with water (30 ml) . The aqueous layer was extracted with ethyl acetate (3x10 ml), acidified with hydrochloric acid 3N and extxracted with ethyl acetate (3x20 ml) . These last organic phases are combined, washed with brine (1x10 ml) , dried over sodium sulphate and concentrated under vacuo . 471 mg of (E) -2- (3 , 4-difluorobenzoyl ) - cyclopropane- 1- carboxylic acid as a white solid were collected (yield 96%) . m.p. = 81-82°C

^XH-NMR (CDCl₃+CD₃OD)δ: 1.6-1.7 (m, 2H, 3-CH₂); 2.4-2.5 (m, IH, 1-CH); 3.1-3.3 (m, IH, 2-CH); 7.2-7.4 (m, IH, 5'-CH); 7.7 ( , 2H, 6' -CH 2' -CH) ; 9.7 (bs, IH, COOH) .

¹³C-NMR (CDC1₃+CD₃0D) δ: 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.

Analogously the following compound can be prepared: (E) -2- (3 , 4-dichlorobenzoyl) -3 -methylene-cycloρropane-1- carboxylic acid. m.p.= 184°C dec.

^-N R (CDCI₃+CD₃OD) δ: 3.1-3.2 (m, IH, 1-CH) ; 3.7-3.8 (m, 4H, 2- CH) ; 5.5-5.8 (m, 2H, 3 -exomethylene , COOH) ; 7.6 (d, IH, 5' -CH, J₀=8.5 Hz) ; 7.8 (dd, IH, 6' -CH, J₀=8.4 HzJm=2Hz) ; 8.1 (d, IH, 2' -CH, J_m=2Hz) .

¹³C-NMR (CDCI₃+CD₃OD) δ: 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, m.p. 148-150°C.

^XH-NMR (CDCI₃ + CD₃OD) δ: 1.1 (s, 3H, 3α-CH₃) ; 1.5 (s, 3H, 3β-CH₃) ; 2.6 (d, IH, 1-CH, J_trans = 5.7 Hz) ; 3.2 (d, IH, 2-CH, J_trans=5.7 Hz) ; 4.6 (bs, IH, COOH) ; 8.0 (d, IH, 5' -CH, J₀=8.4 Hz) ; 8.2 (dd, IH, 6' -CH, J₀=8.4 J_m=2Hz) ; 8.5 (d, IH, 2' -CH, J_m=2 Hz) .

¹³C-NMR (CDC1₃+CD₃0D) δ: 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- 1-carboxylic acid. m.p. = 129°C

^XH-NMR (Acetone D₆) δ: 1.0-1.1 (dd, 3H, 3-CH₃) ; 2.0-2.2 (m, IH, 3-CH) ; 2.2-2.3 (m, IH, 2-CH) ; 3.1-3.2 (m, IH, 1-CH) ; 7.5 (d, IH, 5' -CH, J₀=8.4 Hz) ; 7.9-8.0 (dd, IH, 6' -CH, J₀=8.4 Hz J_m=2 Hz) ; 8.0-8.1 (d, IH, 2' -CH, J_m=2 Hz) ; 9.0 (bs, IH, COOH) .

¹³C-NMR (Acetone-Dg) δ: 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 m.p.= 129-131°C

^XH-NMR (CDCI₃+CD₃OD) δ: 2.1-2.4 (m, 4H cyclobutane); 3.5-3.7 ( , IH, 1-CH); 4.1-4.3 (m, IH, 2-CH); 4.9 (bs, IH, COOH); 7.5 (d, IH, 5'-CH, J₀=8.4 Hz); 7.7 (dd, IH, 6'-CH, J₀=8.4 Hz J_m=2 Hz); 8.0 (d, IH, 2'-CH, J„=2 Hz) .

¹³C-NMR (CDCI₃+CD₃OD) δ: 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 . )

^XH-N R (Acetone-D_g) δ: 1.6-2.2 (m, 6H, cyclopentane); 3.3-3.4 (m, IH, 1-CH); 4.0-4.1 (m, IH, 2-CH); 7.7 (d, IH, 5'-CH, J₀=8.7 Hz); 7.9 (dd, IH, 6'-CH, J₀=8.3 Hz J_m=2 Hz); 8.1 (d, IH, 2'-CH J_m=2 Hz) . ¹³C-NMR (Acetone-Dg) δ: 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

3.5g (12.82 mmol) of (E) -Methyl -2- (3 , 4-dichlorobenzoyl) - cyclopropane- 1-carboxylate were dissolved in dioxane (50 ml) and treated with 30% NH₄OH (140 ml) for 3 days at room temperature .

The residue after evaporation was crystallized from i-propyl ether to give 1.6g of (E) -2- (3 , 4-dichlorobenzoyl) -cyclopropane - 1-carboxamide (51%) .

M.P. 188-191°C

Analogously the following compounds can be prepared:

(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

Capsule, each weighing 0.23 g and containing 50 mg of the active substance can be prepared as follows: Composition for 500 capsules: (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 incapsulated in two hard gelatin capsules of two pieces, each with each capsule weighing 0.23 g.

Example 32 Intramuscular injection of 50 mg/ml

A pharmaceutical injectable composition can be manifactured dissolving 50 g (E) -2- (3 , 4-dichlorobenzoyl) -cyclopropyl-l- carboxylic acid in sterile propyleneglycol (1000 ml) and sealed in 1-5 ml ampoules.

Legend to Figure 1

IDO = Indolamineoxigenase

KYN = Kynurenine

KYN-OH = Kynurenine-3 -hydroxylase

KYNA = Kynurenic acid

3-OHAA = 3 -hydroxy anthranilic acid

KYNase = Kynureninase

QUIN = Quinolinic acid

3-HAO = 3 -hydroxy anthranilic acid deoxygenase

KAT = Kynurenine amino transferase

3-OHKYN = 3 -Hydroxy-kynurenine