Title of Invention

N-ACYLAMINOBENZENE DERIVATIVES AS SELECTIVE MONOAMINE OXIDASE B INHIBITORS

Abstract

This invention relates to N-acylamino aryl derivatives of the general formula (I), wherein R<SUP>1</SUP> is halogen, halogen-(C<SUB>1</SUB>-C<SUB>6</SUB>)-alkyl, cyano, C<SUB>1</SUB>-C<SUB>6</SUB>-alkoxy or halogen-(C<SUB>1</SUB>-C<SUB>6</SUB>)-alkoxy; R<SUP>21</SUP>, R<SUP>22</SUP>, R<SUP>23</SUP> and R<SUP>24</SUP> independently from each other are selected from the group consisting of hydrogen, (C<SUB>1</SUB>-C<SUB>6</SUB>)-alkyl, halogen, halogen-(C<SUB>1</SUB>-C<SUB>6</SUB>)-alkyl, hydroxy, C<SUB>1</SUB>-C<SUB>6</SUB>-alkoxy or -CHO; R<SUP>3</SUP> is hydrogen or C<SUB>1</SUB>-C<SUB>3</SUB>-alkyl; R<SUP>4</SUP>, R<SUP>5</SUP> independently from each other are selected from the group consisting of hydrogen, C<SUB>1</SUB>-C<SUB>1</SUB>-alkyl, C<SUB>1</SUB>-C<SUB>6</SUB>-alkoxy or -COO(C<SUB>1</SUB>-C<SUB>6</SUB>)alkyl; or R<SUP>4</SUP> and R<SUP>5</SUP> form together with the C-atom to which they are attach a C<SUB>3</SUB>-C<SUB>7</SUB>-cycloalkyl ring; R<SUP>6</SUP> is -CO-NR<SUP>7</SUP>R<SUP>8</SUP>; -COO(C<SUB>1</SUB>-C<SUB>6</SUB>)-alkyl, -CN, -NR<SUP>2</SUP> or -NHC(O)R; R<SUP>7</SUP> and R<SUP>8</SUP> independently from each other are selected from the group consisting of hydrogen, C1-C6-alkyl, NH<SUB>2</SUB> or hydroxy; R is hydrogen or C<SUB>1</SUB>-C<SUB>6</SUB>-alkyl; n is 0, 1, 2 or 3. X is -CHRO, -OCHR, -CH<SUB>2</SUB>S-, -SCH<SUB>2</SUB>-, -CH<SUB>2</SUB>CH<SUB>2</SUB>-, -CH=CH- or -C&#8801;C-; and to pharmaceutically active acid addition salts thereof. It has been found that the compounds of general formula (I) are selective monoamine oxidase B inhibitors and they are therefore useful in the treatment of diseases mediated by monoamine oxidase B inhibitors, for example for the treatment of Alzheimer’s disease or senile dementia.

Full Text

This invention relates to N-acylamino aryl derivatives of the general formula wherein R1 is halogen, halogen-(C1-C6)-alkyl, cyano, C1-C6-alkoxy or halogen-(C1-C6)-alkoxy; R , R™, R and R independently from each other are selected from the group consisting of hydrogen, (C1-C6)-aIkyl, halogen, halogen- (C1-C6)-alkyl, hydroxy, C1-C6-alkoxy or -CHO; R3 is hydrogen or Q-C3-alkyl; R4, R5 independently from each other are selected from the group consisting of hydrogen, Q-Q-alkyl, Ci-Q-alkoxy or -CO0(C1-C6)alkyl; or R4 and R5 form together with the C-atom to which they are attach a C3-C7-cycloalkyl ring; R6 is -CO-NR7Rs; -COO(C1-C6)-aIkyI, -CN, -NR2 or -NHC(0)R; R7 and R8 independently from each other are selected from the group consisting of hydrogen, C1-C6-alkyl, NH2 or hydroxy; R is hydrogen or C1-C6-alkyl; n is 0,1,2 or 3. X is -CHRO, -OCHR-, -CH2S-, -SCH2-, -CH2CH2-, -CH=CH- or -OC-; and to pharmaceutically active acid addition salts thereof. It has been found that the compounds of general formula I are selective monoamine oxidase B inhibitors. Monoamine oxidase (MAO, EC 1.4.3.4) is a flavin-containing enzyme responsible for the oxidative deamination of endogenous monoamine neurotransmitters such as dopamine, serotonin, adrenaline, or noradrenaline, and trace amines, e.g. phenylethyl-amine, as well as a number of amine xenobiotics. The enzyme exists in two forms, MAO-A and MAO-B, encoded by different genes (A. W. Bach et al., Proc. Natl. Acad. Sri. USA 1988, 85,4934-4938) and differing in tissue distribution, structure and substrate specificity. MAO-A has higher affinity for serotonin, octopamine, adrenaline, and noradrenaline; whereas the natural substrates for MAO-B are phenylethylamine and tyramine. Dopamine is thought to be oxidised by both isoforms. MAO-B is widely distributed in several organs including brain (A.M. Cesura and A. Pletscher, Prog. Drug Research 1992,38,171-297). Brain MAO-B activity appears to increase with age. This increase has been attributed to the gliosis associated with aging (C.J. Fowler et al., /. Neural. Transm. 1980,49,1-20). Additionally, MAO-B activity is significantly higher in the brains of patients with Alzheimer"s disease (P. Dostert et al., Biochem. Pharmacol. 1989,38, 555-561) and it has been found to be highly expressed in astrocytes around senile plaques (Saura et al., Neuroscience 1994, 70, 755-774). In this context, since oxidative deamination of primary monoamines by MAO produces NH3, aldehydes and H2O2, agents with established or potential toxicity, it is suggested that there is a rationale for the use of selective MAO-B inhibitors for the treatment of dementia and Parkinson"s disease. Inhibition of MAO-B causes a reduction in the enzymatic inactivation of dopamine and thus prolongation of the availability of the neurotransmitter in dopaminergic neurons. The degeneration processes associated with age and Alzheimer"s and Parkinson"s diseases may also be attributed to oxidative stress due to increased MAO activity and consequent increased formation of H2O2 by MAO-B. Therefore, MAO-B inhibitors may act by both reducing the formation of oxygen radicals and elevating the levels of monoamines in the brain. Given the implication of MAO-B in the neurological disorders mentioned above, there is considerable interest to obtain potent and selective inhibitors that would permit control over this enzymatic activity. The pharmacology of some known MAO-B inhibitors is for example discussed by D. Bentue-Ferrer et al. in CNS Drugs 1996, 6,217-236. Whereas a major limitation of irreversible and non-selective MAO inhibitor activity is the need to observe dietary precautions due to the risk of inducing a hypertensive crisis when dietary tyramine is ingested, as well as the potential for interactions with other medications (D. M. Gardner et al., /. Clin. Psychiatry 1996,57, 99-104), these adverse events are of less concern with reversible and selective MAO inhibitors, in particular of MAO-B. Thus, there is a need for MAO-B inhibitors with a high selectivity and without the adverse side-effects typical of irreversible MAO inhibitors with low selectivity for the enzyme. Object of the present invention therefore is to provide compounds which must have the criteria mentioned above. It has been found that the compounds of formula I of the present invention show the potential to be highly selective MAO-B inhibitors. Subjects of the present invention are further a process for the manufacture of compounds of formula I as well as the use of the compounds of formula I in the control or prevention of diseases mediated by monoamine oxidase B inhibitors, and, respectively, their use for the production of corresponding medicaments. The following definitions of general terms used in the present patent application apply irrespective of whether the terms in question appear alone or in combination. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an," and "the" include plural forms unless the context clearly dictates otherwise. The term "C1-C6-alkyl" ("lower alkyl") used in the present application denotes straight-chain or branched saturated hydrocarbon residues with 1 to 6 carbon atoms, preferably with 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, and the like. Accordingly, the term "C1-C3-alkyl" means a straight-chain or branched saturated hydrocarbon residue with 1 to 3 carbon atoms. The term "halogen" denotes fluorine, chlorine, bromine and iodine. "Halogen-(C1-C6)-alkyr or "halogen-(CrG6)-aIkoxy" means the lower alkyl residue or lower alkoxy residue, respectively, as defined herein substituted in any position with one or more halogen atoms as defined herein. Examples of halogenalkyl residues include, but are not limited to, 1,2-difluoropropyI, 1,2-dichIoropropyI, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and 1,1,1-trifluoropropyl, and the like." Halogenalkoxy" includes trifluoromethyloxy. "C1-C6-Alkoxy" means the residue -O-R, wherein R is a lower alkyl residue as defined herein. Examples of alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like. The term"C3-C7-cycloalkyl" denotes a saturated carbocyclic group, containing 3 to 7 carbon atoms. For example, a cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and these groups may optionally be substituted by one or two C1-C4-alkyl substituents, for example methyl or ethyl. "Pharmaceutically acceptable salts" of a compound means salts that are pharmaceutically acceptable, which are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and that possess the desired pharmacological activity of the parent compound. These salts are derived from an inorganic or organic acid or base. If possible, compounds of formula I may be converted into pharmaceutically salts. It should be understood that pharmaceutically acceptable salts are included in the present invention. Among compounds of the present invention certain compounds of formula I are preferred, for example the compounds of formula la. wherein R1 is halogen, halogen-(C1-C6)-alkyl, cyano, C1-C6-alkoxy or halogen-(C1-C6)-alkoxy; R21, R22, R23 and R24 independently from each other are selected from the group consisting of hydrogen and halogen; R3 is hydrogen or C1-C3-alkyl; R4 is hydrogen or C1-C6-aIkyl; R5 is hydrogen or C1-C6-aIkyl; or R4and R5 together form a CrC7-cycloalkyl ring; R6 is -CO-NR7R8; -COOR9; or -CN; R7 and R8 independently from each other are hydrogen, methyl or ethyl; R9 is C1-C6-alkyl; and n is 1, 2 or 3. and pharmaceutically active acid addition salts thereof. Preferred are further those compounds of formula I, wherein X is CH2O, R is fluorine or trifluoromethyl and R6 is -COOCH3, for example the following compounds: N-[4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester, N-[3-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester, N-[4-(4-fluoro-benzyloxy)-phenyI]-maIonamic acid methyl ester, N-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester, N-[4-(2,4-difluoro-benzyloxy)-phenyl]-malonamic acid methyl ester, N-[4-(2-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester, N-[4-(2,4,5-trifluoro-benzyloxy)-phenyl]-malonamic acid methyl ester, N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester, N-[4-(3,5-bis-trifluoromethyl-benzyloxy)-2-fluoro-phenyl]-malonamic acid methyl ester, N-[4-(3-fluoro-benzyloxy)-3-methyl-phenyl]-malonamic acid methyl ester or N-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester. Further preferred are compounds of formula I, wherein X is CH2O and R6 is -CONH2, for example the following compounds: cyclopropane-1,1-dicarboxylic acid amide [4-(3-fluoro-benzyloxy)-phenyl]-amide, N- [4-(3-fluoro-benzyIoxy)-phenyI] -malonamide, N-[4-(3-fluoro-benzyloxy)-phenyl]-2-methyl-malonamide, N- [3-fluoro-4-(3-fluoro-benzyloxy)-phenyl] -malonamide, N- [4-(4-fluoro-benzyloxy)-phenyl] -malonamide, N- [4- (2,4-difluoro-benzyloxy)-phenyl] -malonamide, N- [4-(2,4,5-trifluoro-benzyloxy)-phenyl] -malonamide, N- [4-(2-fluoro-benzyloxy)-phenyl] -malonamide, N-(4-benzyloxy-phenyl)-malonamide, N- [4- (4-chloro-benzyloxy)-phenyl] -malonamide, N- [4-(3-fluoro-benzyloxy)-2-hydroxy-phenyl] -malonamide, N- [2-fluoro-4-(4-fluoro-benzyloxy)-phenyl] -malonamide, N- [4-(3-fluoro-benzyloxy)-3-methyl-phenyl] -malonamide, N-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl] -malonamide or cyclopropane-l,l-dicarboxylic acid amide [2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]- amide. Preferred are compounds of formula I wherein X is -OCH?- and R6 is -NHCOCH3 or -NHCOH. Examples of such compounds are the following: 2-Acetylamino-N- [2-fluoro-4- (4-fluoro-benzyloxy)-phenyl] -acetamide, 2-Acetylamino-N-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-acetamide, N-[2-Fluoro-4-(4-fluoro-benzyloxy)-phenyl]-2-formylamino-acetamideor N-[2-Fluoro-4-(3-fluoro-benzyloxy)-phenyl]-2-formylamino-acetamide. Also preferred are compounds of formula I wherein X is -OCH2- and R6 is —NH2. The following compound is an example thereof: 2-amino-N- [2-fluoro-4-(4-fluoro-benzyloxy)-phenyl] -acetamide. Another preferred group of compounds of formula I are those, wherein X is -CH=CH- and R6 is -COOCH, or -CONH2, for example the followings: N-{4-[2-(4-fluoro-phenyI)-vmyl]-phenyI}-malonamic acid methyl ester, N-{4-[2-(3-fiuoro-phenyl)-vinyI]-phenyl}-malonamide, N-{4- [2-(4-fluoro-phenyl)-vinyl] -phenyl} -malonamide or N-{4-[2-(3-£Iuoro-phenyl)-vinyl]-phenyl}-malonamic acid methyl ester. The compounds of general formula I can be manufactured by reacting a compound of formula with a compound of formula III to obtain a compound of formula and, if desired, converting a compound of formula I into a pharmaceutically acceptable salt. In accordance with the present invention, a possibility to prepare compounds of general formula I is shown in scheme 1: The key intermediates A are accessible through nucleophilic substitution of aromatic nitro compounds containing p-substituted leaving groups with benzylic alcohols or thiols. P- substituted leaving groups can be for example halogens (F, CI, Br, I), tosylates, mesylates or triflates. These substitution reactions can be conducted neat or in inert solvents like for example toluene or xylene. Preferred reaction temperatures are between 50° and 150 °C. Alternatively, compounds A can be prepared by Williamson-ether synthesis, starting from p-nitrophenols and benzylic halides, tosylates, mesylates or triflates. Bases used can be for example alcoholates or carbonates (sodium, potassium or cesium carbonate). Preferred solvents are lower alcohols, acetonitrile or lower ketones at temperatures between 20 °C and reflux temperature. Another approach is the Mitsunobu-coupling of benzylic alcohols with p-nitrophenols. The reaction is done as usual in inert solvents like for example diethyl ether or tetrahydrofuran, using dialkyl-azo-dicarboxylates in presence of phosphines (for example tributyl- or triphenyl-phosphine). The key intermediates A are reduced to the amino-compounds B using catalytic hydrogenation (for example Platinum on charcoal in lower alcohols, ethyl acetate or tetrahydrofurane). An alternative is the reduction of the nitro-group by metals like iron, tin, or zinc in acidic media like diluted hydrochloric acid or acetic acid. Metals can also be replaced by metal salts (for example tin-(II)-chloride). Intermediates B can be acylated by known methods to give the desired compounds I-A.These reactions can be done with acid chlorides and bases (for example trialkykmines, sodium carbonate or potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate), eventually in presence of an acylation catalyst (e.g. 1 to 10 mol% of N,N-dimethyl-4-aminopyridine) in solvents like dichloromethane, ethyl acetate or acetonitrile, preferentially at room temperature. An alternative is the well known coupling of an acid with the amine B using coupling reagents like N,N"-dicyclohexyicarbodiimide (DCC), N-(3-dimethylammopropyl)-N"-emyl-carbodiimide hydrochloride (EDC) or l,l"-carbonyl-diimidazole (CDI) in solvents like dichloromethane, diethyl ether or THF, preferentially at 0 to 40 °C. Intermediates B can also primarily be monoalkylated by known methods (see for example Johnstone et al, /. Chem. Soc. (C) 1969,2233 or Krishnamurthy et al., Tetrahedron Lett. 1982,23,3315) to give compounds D. These are then acylated as previously described to lead to the desired compounds I-B. Compounds with inverted ether or thioether linkers can be obtained by similar reactions, as depicted in scheme la. The key-intermediates A/ are then further transformed into the final products by the reaction sequences already mentioned in scheme 1. Additional functional group manipulations can be done by standard methods on the acylated compounds to obtain all compounds of formula I (for example: functionalising the malonic position by deprotonation and reaction with electrophiles). Alternatively, in accordance with the present invention, compounds B can also be prepared by allkylklation of N-protected p-hydroxyanilines with benzylic halides or by Mitsunobu-coupling of N-protected p-hydroxyanilines with benzylic alcohols (scheme 2) by the methods described previously. Protective groups PG can be for example N-Boc (N-tert.-butoxycarbonyl) or N-acetyl. Deprotection of F leads to the intermediates B. Obviously, compounds with inverted ether and thioether linkers can be prepared by similar reaction sequences, inverting substituent-patterns on the aromatic moieties. Another method to prepare compounds of the type D or I-B involves cross-coupling reactions of arylstannanes (Lam et al., Tetrahedron Lett. 2002,43, 3091), arylboronates (Lam et al., Synlett2000, 5, 674); Chan et aL, Tetrahedron Lett. 1998, 39, 2933) or aryl halides (Buchwald et al., J. Amer. Che?n. Soc. 1996, 118, 7215) with the corresponding amines or amides (scheme 3). Once again, compounds with inverted ether and thioether linkers can be prepared by similar reaction sequences, inverting substituent-patterns on the aromatic moieties. A possibility to prepare compounds I where X is -CH2CH2- or -CH=CH- is shown in scheme 4 . Wittig- or Wittig-Horner reactions between phosphor-ylides and aromatic aldehydes under standard conditions leads to styrene-derivatives G. These intermediates can be reduced to intermediates H or I Usually, reduction of G by Bechamp-type conditions leads to compounds H, which can then be further reduced to compounds I by catalytic hydrogenation. Using harsher hydrogenation conditions, compounds G can be reduced in one step to give compound J. Compounds H or I are then further processed by the methods depicted in scheme 1 to yield the final products I. Another method to prepare compounds of the type G involves nitration of styrene-derivatives. (The compounds of formula I are, as already mentioned above, monoamine oxidase B inhibitors and can be used for the treatment or prevention of diseases in which MAO-B inhibitors might be beneficial. These include acute and chronic neurological disorders, cognitive disorders and memory deficits).Treatable neurological disorders are for instance traumatic or chronic degenerative processes of the nervous system, such as Alzheimer"s disease, other types of dementia, minimal cognitive impairment or Parkinson"s disease. Other indications include psychiatric diseases such as depression, anxiety, panic attack, social phobia, schizophrenia, eating and metabolic disorders such as obesity as well as the prevention and treatment of withdrawal syndromes induced by abuse of alcohol, nicotine and other addictive drugs. Other treatable indications may be reward deficiency syndrome (G.M. Sullivan, International patent application No. WO 01/34172 A2), peripheral neuropathy caused by cancer chemotherapy (G. Bobotas, International Patent Application No. WO 97/33572 Al), or the treatment of multiple sclerosis (R.Y. Harris, International patent application No. WO 96/40095 Al) and other neuroinflammatory diseases. (The compounds of formula I are especially useful for the treatment and prevention of Alzheimer"s disease and senile dementia;) The pharmacological activity of the compounds was tested using the following method: The cDNA"s encoding human MAO-A and MAO-B were transiently transfected into EBNA cells using the procedure described by E.-J. Schlaeger and K. Christensen (Transient Gene Expression in Mammalian Cells Grown in Serum-free Suspension Culture; Cytotechnology, 15: 1-13,1998). After transfection, cells were homogenised by means of a Polytron homogenizer in 20 mM Tris HC1 buffer, pH 8.0, containing 0.5 mM EGTA and 0.5 mM phenylmethanesulfonyl fluoride. Cell membranes were obtained by centrifugation at 45,000 xg and, after two rinsing step with 20 mM Tris HC1 buffer, pH 8.0, containing 0.5 mM EGTA, membranes were eventually re-suspended in the above buffer and aliquots stored at -80 °C until use. MAO-A and MAO-B enzymatic activity was assayed in 96-well-plates using a spectrophotometric assay adapted from the method described by M. Zhou and N. Panchuk-Voloshina (A One-Step Fluorometric Method for the Continuous Measurement of Monoamine Oxidase Activity, Analytical Biochemistry, 253:169-174, 1997). Briefly, membrane aliquots were incubated in 0.1 M potassium phosphate buffer, pH 7.4, for 30 min at 37 °C with or without various concentrations of the compounds. After this period, the enzymatic reaction was started by the addition of the MAO substrate tyramine together with 1 U/ml horse-radish peroxidase (Roche Biochemicals) and 80 uM N-acetyl-3,7,-dihydroxyphenoxazine (Amplex Red, Molecular Probes). The samples were further incubated for 30 min at 37 °C in a final volume of 200 (0.1 and absorbance was then determined at a wavelength of 570 nm using a SpectraMax plate reader (Molecular Devices). Background (non-specific) absorbance was determined in the presence of 10 U.M clorgyline for MAO-A or 10 µM L-deprenyl for MAO-B. IC50 values were determined from inhibition curves obtained using nine inhibitor concentrations in duplicate, by fitting data to a four parameter logistic equation using a computer program. (The compounds of the present invention are specific MAO-B inhibitors) The IC50 values of preferred compounds of formula I as measured in the assay described above are in the range of 1000 nM or less, typically 100 nM or less, and ideally 50 nM or less. In the table above are disclosed some IC50 values (nM) of preferred compounds. (The compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations).The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions. The compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for phases are dried and evaporated to give l.l8g (76%) of a yellowish waxy solid. MS: m/e = 234.3 (M++H). c) N-r4-(3-Fluoro-benzylsulfanyl)-phenvl1-malonarnic acid methyl ester Prepared in analogy to example 20c) from 4-(3-fluoro-benzylsulfanyl)-phenylamine and methyl malonyl chloride. Yellowish solid. Yield = 64%. MS: m/e = 334.2 (M++H). Example 24 N-f4-(3-Fluoro-benzylsulfanyl)-phenyn-malonamide Prepared in analogy to example 3 from N-[4-(3-fiuoro-benzylsultanyl)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield = 47%. Colorless solid. MS: m/e = 319.3 (M++H). Example 25 N-f4-(2,4-Difluoro-benzyloxy)-phenvl]-malonamic acid methyl ester a) 2,4-Difluoro-1- (4-mtro-phenoxymethyl)-benzene Prepared in analogy to example 8 from 4-nitrophenol and 2,4-difluoro-benzylbromide. Colorless solid. Yield = 86%. MS: m/e = 265.1 (M+). b) 4-(2,4-Difluoro-benzyloxy)-phenylamine Prepared in analogy to example 8b) by hydrogenation of 2,4-difluoro-l-(4-nitro-phenoxymethyl)-benzene. Yield = 99%. Brown solid. MS: m/e = 235.1 (M+). c) N-F4-(2,4-Difluoro-ben2yioxy)-phenvll-malonamic acid methyl ester Prepared in analogy to example 20c) from 4-(2,4-difluoro-benzyloxy)-phenylamine and methyl malonyl chloride. Colorless solid. Yield = 99%. MS: m/e = 336.2 (M++H). Example 26 N-[4-(2-Fluoro-benzvloxv")-phenyl1-malonamic acid methyl ester a) l-Fluoro-2- (4-nitrophenoxy. -methvl Vbenzene Prepared in analogy to example 8 from 4-nitrophenol and 2-fluoro-benzylbromide. Colorless solid. Yield = 74%. MS: m/e = 247.1 (M+). b) 4-(2-Fluoro-benzvloxv)-phenvlamine Prepared in analog}"- to example 8b) by hydrogenation of l-fluoro-2-(4-nitrophenoxy)-methyl-benzene. Yield = 99%. Brown oil. MS: m/e = 217.2 (M+). c) N-l"4-(2-Fluoro-benzyloxv)-phenvll-malonamic acid methyl ester Prepared in analogy to example 20c) from 4-(2-fluoro-benzyloxy)-phenylamme and methyl malonyl chloride. Colorless solid. Yield = 70%. MS: m/e = 318.2 (M++H). Example 27 N44-(2,4,5-Trifluoro-benzyioxy)-phenyl1-malonamic acid methyl ester a) l,2,4-Trifluoro-5-(4-mtro-phenoxymethvl)-benzene Prepared in analogy to example 8 from 4-nitrophenol and 2,4,5-trifluoro-benzylbromide. Colorless solid. Yield = 92%. MS: m/e = 283.0 (M+). b) 4-(2,4,5-Trifluoro-benzyloxy)-phenvlamine Prepared in analogy to example 8b) by hydrogenation l,2,4-trifruoro-5-(4-nitro-phenoxymethyl)-benzene. Yield = 97%. Slightly red solid. MS: m/e = 254.1 (M++H). c) N-f4-(2,4,5-Trifluoro-benzyloxy)-phenvll-malonamic acid methyl ester Prepared in analogy to example 20c) from 4-(2,4>5-trifluoro-benzyloxy)-phenylamine and methyl malonyl chloride. Colorless solid. Yield = 91%. MS: m/e = 352.2 (M+-H). Example 28 N- [4- (2,4-Difluoro-benzyloxy)-phenyll -malonamide Prepared in analogy to example 3 from N-[4-(2,4-difluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield = 49%. Colorless solid. MS: m/e = 321.1 (M++H). Example 29 N- f 4- (2 A5-Trifluoro-benzyloxy)-phenyl1 -malonamide Prepared in analogy to example 3 fromN-[4-(2,4,5-trifluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield = 52%. Colorless solid. MS: m/e = 339.2 (M++H). Example 30 N44-(2-Fluoro-benzyloxy)-phenyl]-malonamide Prepared in analogy to example 3 from N-[4-(2-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield = 30%. Colorless solid. MS: m/e = 303.2 (M++H). Example 31 N-{4-fl-(3-Fluoro-phenvl)-ethoxv1-phenvll-malonamide a) l-Fluoro-3-(l-(4-nitrophenoxv)-ethvI)-benzene Prepared in analogy to example 16a) from l-(3-fluoro-phenyl)-ethanol (Balasubramanian et al., Synth. Commun,, 1994, 24 (8), 1049) and 4-nitrophenol. Yellow oil. Yield = 77%. MS: m/e = 261.2 (M+). b) 4-[1- (3-Fluoro-phenyl)-ethoxv] -phenvlamine Prepared in analogy to example 8b) by hydrogenation of l-fluoro-3-(l-(4-nitrophenoxy)-ethyl)-benzene. Yield = 95%. Yellowish oil. MS: m/e = 232.2 (M++H). c)N-{4-ri-(3-Fluoro-phenyl)-ethoxy]-phenyll-malonamic acid methyl ester Prepared in analogy to example 20c) from4-[l-(3-fluoro-phenyl)-ethoxy]-phenylamine and methyl malonyl chloride. Yellowish solid. Yield = 30%. MS: m/e = 332.4 (M++H). d)N-{4-[l-(3-Fluoro-phenyl)-ethoxyl-phenyU-malonamide Prepared in analogy to example 3 from N-{4-[l-(3-fluoro-phenyl)-ethoxy]-phenylj-malonamic acid methyl ester and ammonium hydroxide. Yield = 55%. Colorless solid. MS: m/e = 317.3 (M++H). Example 32 N-(4-Benzyloxv-phenyl)-malonamic acid methyl ester Prepared in analogy to example 20c) from 4-benzyloxyaniline and methyl malonyl chloride. Yellowish solid. Yield = 62%. MS: m/e = 300.2 (M++H). Example 33 N- (4-Benzyloxv-phenyl)-malonamide Prepared in analogy to example 3 from N-(4-benzyloxy-phenyl)-malonamic acid methyl ester and ammonium hydroxide. Yield = 85%. Colorless solid. MS: m/e = 285.1 (M++H). Example 34 N- [4-(4-Chloro-benzvloxv")-phenyn -malonamide a) N-(4-Hvdroxv-phenyl)-malonamide A suspension of 6.0g (18.5mmol) of N-(4-benzyloxy-phenyl)-malonamide in 150ml methanol is treated with 0.8g of palladium 5% on charcoal. Hydrogenation is performed at room temperature and normal pressure overnight. The reaction mixture is then brought to reflux and filtered hot. Cooling of the filtrate yields 3.56g (99%) of the title compound as a colorless solid. MS: m/e = 285.1 (M++H). b) N- [4- (4-Chloro-benzyloxv)-phenvl1 -malonamide Prepared in analogy to example 8 from N-(4-hydroxy-phenyl)-malonamide and 4-chloro-benzylbromide. Colorless solid. Yield = 18%. MS: m/e = 319.1 (M++H). Example 35 N- [4- (3-Fluoro-benzyloxy)-phenyl1 -2-hydrazinocarbonyl-acetamide A suspension of 0.35g (l.lmmol) of N-[4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester in 7ml methanol is treated with 83mg (Ummol) of hydrazine hydrate. The reaction mixture is refluxed for 2h, then another portion of 300mg (6mmol) of hydrazine hydrate is added and reflux is pursued for another 8h. The mixture is cooled and hold overnight in the frig. The precipitate is filtered off and recrystallised from methanol to yield 0.043g (12%) of filthy, colorless needles. MS: m/e = 318.3 (M++H). Example 36 N- [4- (3-Fluoro-benzvloxy)-phenvn -N"-hvdroxy-malonamide A solution of sodium methylate is prepared by dissolving 0.23g (l0mmol) sodium in 10ml methanol. This solution is cooled to 0° and 0.25g (5mmol) of hydroxylamine hydrochloride is added, followed by 0.317g (lmmol) of N-[4-(3-fluoro-benzyloxy)-phenyl] -malonamic acid methyl ester. The mixture is stirred for 2h at room temperature, diluted with 25ml of water and acidified to pH = 3 by addition of citric acid. The precipitate is filtered and recrystallised from ethyl acetate, giving 0.123mg (39%) of a colorless solid. MS: m/e = 319.3 (M++H). Example 37 2-[4-f3-Fluoro-benzyloxv)-phenvlcarbamovll-malonic acid dimethyl ester 0.15g (0.47mmol) of N-[4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester is dissolved in 7ml tetrahydrofuran and cooled to 0°.38mg (lmmol) of sodium hydride (55 to 65% in oil) is added and the mixture stirred for 45minutes at room temperature. After cooling again to 0° a solution of 56mg (0.6mmol) methyl chloroformate in 0.5ml tetrahydrofuran is slowly added with a seringe. The yellowish solution is stirred at room temperature for 2h, treated with about 40ml of water, acidified to pH = 3 by addition of citric acid and extracted 3 times with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated in vacuo yielding 212mg of a yellow gum. Chromatography (silica gel, ethyl acetate / cyclohexane 1:1) gives 62mg (35%) of a slightly yellow solid. MS: m/e = 376.3 (M++H). Example 38 N- [4- f 3-Fluoro-benzvloxy)-2-hydroxy-phenyl1 -malonamide a) 3-(3-Fluoro-benzyloxy)-phenol Prepared in analogy to example 8 from resorcinol and 3-fluoro-ben2yIbromide. Colorless oil. Yield = 7%. MS: m/e = 218.1 (M+). b) 5-(3-Fluoro-benzyloxv)-2-nitro-phenol l.Og (5mmol) of 3-(3-fluoro-benzyloxy)-phenol is dissolved in 10ml acetic acid and cooled to 10°. 0.44g (5mmol) of 65% nitric acid is dissolved in 10ml acetic acid and slowly added to the previous solution. The colored mixture is stirred for 15min. at 10° and for 2h at room temperature. 50ml of water is added and the product extracted 3 times with ethyl acetate. Chromatography (silica gel, dichloromethane / methanol 98:2) yields 0.38g (32%) of the desired product as a yellow solid. MS: m/e = 262.1 (M+ -H). c) 2-Amino-5-(3-fluoro-benzvloxy)-phenol Prepared in analogy to example 8b) by hydrogenation of 5-(3-fluoro-benzyloxy)-2-nitro-phenol. Yield = 95%. Greyish solid. MS: m/e = 234.3 (M++H). d) N-[4-(3-Fluoro-benzyloxv)-2-hydroxy-phenyn-malonamic acid methyl ester Prepared in analogy to example 20c) from 2-amino-5-(3-fluoro-benzyloxy)-phenol and methyl malonyl chloride. Yellowish solid. Yield = 90%. MS: m/e = 334.3 (M++H). e) N- [4- (3-Fluoro-benzyloxv)-2-hvdroxv-phenvn -malonamide Prepared in analogy to example 3 from N-[4-(3-fluoro-benzyloxy)-2-hydroxy- phenyl] -malonamic acid methyl ester and ammonium hydroxide. Yield = 23%. Colorless solid. MS: m/e = 319.4 (M++H). Example 39 N-[2-Fluoro-4-(4-fluoro-berizvloxy)-phenvl] -malonamic acid methyl ester a) l-(2-Fluoro-4-iodo-phenyl)-2,5-dimethyl-lH-pyrrole A solution of 2-fiuoro-4-iodoaniline (25.3 g, 107 mmol), acetonylacetone (14.9 g, 131 mmol) and para-toluenesulfonic acid (203 mg, 1 mmol) in dry toluene was heated under reflux for 1 h with a Dean-Stark tap. After cooling to room temperature the mixture was poured into sodium hydrogen carbonate (saturated). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and then boiled with charcoal. Filtering to remove the charcoal followed by evaporation afforded the title compound (33.2 g, 98%) as a light brown solid. MS: m/e = 315.1 (M++H). b) 1- [2-Fluoro-4-(4-fluoro-benzvloxv)-phenyll-2,5-dimethvI-lH-p\Trole A solution of l-(2-fluoro-4-iodo-phenyl)-2,5-dimethyl-lH-pyrrole (33.18 g, 105 mmol), 4-fluorobenzylalcohol (26.6 g, 211 mmol), cesium carbonate (68.6 g, 211 mmol), cuprous iodide (2.0 g, 11 mmol) and 1,10-phenanthroline (3.8 g, 21 mmol) in toluene (52 mL) was heated at 100 °C in an autoclave for 48 h. After cooling to room temperature, the mixture was filtered and poured into sodium hydroxide (IN). The resulting mixture was extracted with toluene and the organic extracts washed with brine, dried and evaporated. The residue was triturated with boiling hexane to leave the title compound (24.7 g, 75%) as a light brown solid. MS: m/e = 314.1 (3VT+H). c) 2-Fluoro-4-(4-fluoro-benzvloxy)-phenvlarnine (1:1) hydrochloride A solution of the l-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-2,5-dimethyl-lH-pyrrole (23.7 g, 76 mmol), potassium hydroxide (8.5 g, 151 mmol), hydroxylamine HC1 (62.5 g, 899 mmol) in water (125 mL) and propan-2-ol (250 mL) was heated at 100 °C for 36 h. After cooling to room temperature, the mixture was poured into water, and extracted with diethylether. The combined organic layers were then washed with brine, dried and the resulting solution was diluted with HC1 in diethylether. The resulting precipitate was then filtered off to afford the title compound (15.2 g, 74%) as a light brown solid. MS: m/e = 236.0 (M+-C1). d) N42-Fluoro-4-(4-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester The title compound is prepared in analogy to example 1 from 2-fluoro-4-(4-fluoro-ben2yloxy)-phenylamine (1:1) hydrochloride. Light yellow solid. Yield = 95%. MS: m/e = 236.2 (M++H). Aternatively the 2-fluoro-4-(4-fluoro-benzyloxy)-phenylamine (1:1) hydrochloride can be prepared as follows. e) 2-Fluoro-4- (4-fluoro-benzyloxy)-nitrobenzene A solution of 3-fluoro-4-nitrophenol (5.0 g, 32 mmol) and 4-fluorobenzyl bromide (6.3 g, 33 mmol) in acetone (50 mL) containing potassium carbonate (5.3 g, 38 mmol) was heated under reflux for 2 h. After cooling to room temperature the mixture was filtered and evaporated to leave the title compound (7.3 g, 86%) as a light yellow solid. MS: m/e = 265.1 (M++H). f) 2-FIuoro-4-(4-fluoro-benzvloxy)-phenvlamine (1:1) hydrochloride A. solution of 2-fluoro-4-(4-fluoro-benzyIoxy)-nitrobenzene (7.3 g, 27 mmol) in ethyl acetate (160 mL) was hydrogenated in the presence of Pt/C (5%, 1.1 g) at room temperature for 12 h. The mixture was then filtered and HC1 in diethylether was added. The resulting precipitate was filtered off and dried to afford the title compound (7.3 g, 39%) as a white solid. MS: m/e = 236.2 (M+-C1). Example 40 1ST- r2-Fluoro-4- (4-fluoro-benzyloxy")-phenyll -malonamide A. solution of N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl] -malonamic acid methyl ester (150 mg, 0.45 mmol) and ammonium hydroxide (2.0 mL) in THF (1.0 ml) in a sealed tube was heated at 55 °C for 6 h. After cooling to room temperature the mixture was evaporated and the title compound (60 mg, 42%) was purified by trituration from diethylether. MS: m/e = 321.2 (M++H). Example 41 N-r4-(3,5-Bis-trifluoromethvl-benzvloxv)-2-fluoro-phenyll-malonamic acid methyl ester a) 4-(3,5-Bis-trifluoromethvl-benzyloxv)-2-fluoro-nitrobenzene As described for example 39e, 3-fluoro-4-nitrophenol (5 g, 32 mmol) was converted to the title compound (12.2 g, 99%) [using 3,5-bis(trifluoromethyl)benzyl bromide (10.3 g, 33 mmol) instead of 4-fluorobenzyl bromide] which was obtained as a light yellow solid. MS: m/e = 383.0 (M+). b) 4-(3,5-Bis-trifluoromethyl-benzyloxv)-2-fluoro-phenylamine (1:1) hydrochloride As described for example 39f, 4-(3,5-bis-trifluoromethyl-benzyloxy)-2-fluoro-nitrobenzene (12.2 g, 32 mmol) was converted to the title compound (8.3 g, 66%) which was obtained as light pink solid. MS: m/e = 388.2 (M+-H). c) N-[4-(3>5-Bis-trifluoromethvl-benzyloxy)-2-fluoro-phenyn-malonamic acid methyl ester As described for example 39d, 4-(3,5-bis-trifluoromethyl-benzyloxy)-2-fluoro-phenylamine (1:1) hydrochloride (500 mg, 1 mmol) was converted to the title compound (590 mg, 92%) which was obtained as an off-white solid. MS: m/e = 454.2 (M++H). Example 42 N- [4- f 3,5-Bis-trifluoromethvl-benzvloxy)-2-fluoro-phenvl1 -malonamide As described for example 40, N-[4-(3,5-bis-trifluoromethyl-benzyloxy)-2-fluoro-phenylj-malonamic acid methyl ester (250 mg, 0.56 mmol) was converted to the title compound (84 mg, 35%) which was obtained as a white solid after purification by chromatography on silica gel eluting with DCM:MeOH (9:1). MS: m/e = 439.2 (M++H). Example 43 N-[2-Fluoro-4-(4-trifluoromethyl-benzyloxv)-phenvl1-malonamic acid methyl ester a) 2-Fluoro-4-(4-trifluoromethyl-benzvloxv)-nitrobenzene As described for example 39e, 3-fluoro-4-nitrophenol (5 g, 32 mmol) was converted to the title compound (9.9 g, 99%) [using 3-(trifluoromethyl)benzyl bromide (8.0 g, 33 mmol) instead of 4-fluorobenzyl bromide] which was obtained as a light yellow solid. MS: m/e = 315.0 (M+). b) 2-Fluoro-4-f4-trifluoromethyl-benzvloxv)-phenylamine (1:1) hydrochloride As described for example 39f, 2-fluoro-4-(4-trifluoromethyl-benzyloxy)-nitrobenzene (4.9 g, 15 mmol) was converted to the title compound (3.0 g, 60%) which was obtained as a grey solid. c) N-[2-Fluoro-4-(4-trifluoromethvl-benzvloxy)-phenvl1-malonamic acid methyl ester As described for example 39d, 2-fluoro-4-(4-trifluoromethyl-benzyloxy)-phenylamine (1:1) hydrochloride (500 mg, 1 mmol) was converted to the title compound (700 mg, 98%) which was obtained as an off-white solid. MS: m/e = 386.2 (M++H). Example 44 N-f2-Fluoro-4-(4-tTifluoromethyl-benzvloxy)-phenyll-malonamide As described for example 40, N-[2-fluoro-4-(4-trifluoromethyl-benzyloxy)-phenyl]-malonamic acid methyl ester (250 mg, 0.65 mmol) was converted to the title compound (94 mg, 39%) which was obtained as a white solid after purification by chromatography on silica gel eluting with DCM:MeOH (9:1). MS: m/e = 371.2 (M++H). Example 45 N-[4-f3-Fluoro-benzyloxy)-3-methoxy-phenyl1-malonamic acid methyl ester a) 1- C3-Fluoro-benzvloxv)-2-methoxv-4-nitro-benzene Prepared in analogy to example 8 from 4-nitroguaiacol and 3-fluoro-benzylbromide. Colorless oil. Yield = 74 %. MS: m/e = 277.1 (M+). b)4-(3-Fluoro-benzvloxv)-3-methoxv-phenvlamine Prepared in analogy to example Sb) by hydrogenation of l-(3-fluoro-benzyloxy)-2-methoxy-4-nitro-benzene. The crude reaction mixture was used without purification in the next step. c) N-r4-(3-Fluoro-benzvloxy)-3-methoxy-phenyll-malonamic acid methyl ester Prepared in analogy to example 20c) from 4-(3-fluoro-benzyloxy)-3-methoxy-phenylamine and methyl malonyl chloride. Yellowish solid. Yield = 89%. MS: m/e = 348.2 (M++H). Example 46 N-r4-(3-Fluoro-berizyloxy)-3-methoxy-phenvn-malonamide Prepared in analogy to example 3 from N-[4-(3-fluoro-benzyloxy)-3-methoxy-phenylj-malonamic acid methyl ester and 7M ammonia in methanol. Yield = 71 %. Colorless solid. MS: m/e = 333.0 (M++H). Example 47 N-f4-(3-Fluoro-benzvloxv)-3-methyl-phenvll-malonamic acid methyl ester a) l-(3-Fluoro-benzyloxy)-2-methyl-4-nitro-benzene Prepared in analogy to example 8 from 2-methyl-4-nitrophenol and 3-fluoro-benzylbromide. Colorless oil. Yield = 62 %. MS: m/e = 261.1 (M+). b) 4-(3-Fluoro-benzyloxv)-3-methvl-phenylamine Prepared in analogy to example 8b) by hydrogenation of l-(3-fluoro-benzyloxy)-2-methyl-4-nitro-benzene. The crude reaction mixture was used without purification in the next step. c) N-[4-(3-Fluoro-benz^,loxy)-3-methyl-phenyll-malonamic acid methyl ester Prepared in analogy to example 20c) from 4-(3-fluoro-benzyloxy)-3-methyl-phenylamine and methyl malonyl chloride. Colorless solid. Yield = 98%. MS: m/e = 332.0 (M++H). Example 48 N-[4-(3-Fluoro-benzvloxy)-3-methyl-phenyn-malonamide Prepared in analogy to example 3 from N-[4-(3-fluoro-benzyloxy)-3-methyl-phenylj-malonamic acid methyl ester and 7M ammonia in methanol. Yield = 60 %. Colorless solid. MS: m/e = 317.0 (M++H). Example 49 N-f3-Chloro-4-(3-fluoro-benzvloxy)-phenvl]-malonamic acid methyl ester a)2-Chloro-l-(3-fluoro-benzyloxv)-4-nitro-benzene Prepared in analogy to example 8 from 2-chloro-4-nitrophenol and 3-fluoro-benzylbromide. Colorless solid. Yield = 84 %. MS: m/e = 281.0 (M+). b) 3-Chloro-4- (3-fluoro-benzyloxy)-phenylamme Prepared in analogy to example 8b) by hydrogenation of 2-chloro-l-(3-fluoro-benzyloxy)-4-nitro-benzene. The crude reaction mixture was used without purification in the next step. c) N-[3-Chloro-4-(3-fluoro-benzvloxy)-phenyl1-malonamic acid methyl ester Prepared in analogy to example 20c) from 3-chloro-4-(3-fluoro-benzyloxy)-phenylamine and methyl malonyl chloride. Colorless solid. Yield = 78%. MS: m/e = 352.1(M++H). Example 50 N43-Chloro-4-(3-fluoro-benzyloxy)-phenyl1-malonamide Prepared in analogy to example 3 from N-[3-chloro-4-(3-fiuoro-benzyloxy)-) phenyl]-malonamic acid methyl ester and 7M ammonia in methanol. Yield = 100 %. Colorless solid. MS: m/e = 337.1 (M++H). Example 51 Cvclopropane-l,l-dicarboxvlic acid amide f2-fluoro-4-(4-fluoro-benzvloxy)-ph.enyll-amide A mixture of 2-fluoro-4- (4-fluoro-benzyloxy) -phenylamine (1:1) hydrochloride (272 mg, 1 mmol), 1-carboxycyclopropanecarboxamide (129 mg, lmmol), N-(3-dimethylaminopropyl)-N"ethylcarbodiimide hydrochloride (EDCI, 211 mg, 1.1 mmol) and triethylamine (111 mg, 1.1 mmol) in DCM (7 mL) was stirred at rt for 2 h. Then the mixture was poured into water and the mixture extracted with DCM. The combined organic extracts were then dried and evaporated to afford the title compound (130 mg, 38%) as a light brown solid after purification by chromatography on silica gel eluting with ethyl acetate : heptane (1:1 to 3:1). MS: m/e = 347.0 (M++H). N-[2-Fluoro-4-f4-fluoro-benzvIoxy)-phenYn-2,2-dimethvI-malonamic acid methyl ester A mixture of N-[2-fluoro-4- (4-fluoro-benzyloxy) -phenyl] -malonamic acid methyl ester (335 mg, 1 mmol), sodium hydride (55%, 873 mg, 2 mmol) and iodomethane (213 mg, 1.5 mmol) were stirred at room temperature for 3 h. Then the mixture was poured into water and the mixture extracted with ethyl acetate. The combined organic extracts were then dried and evaporated to afford the title compound (83 mg, 23%) as a light yellow solid after purification by chromatography on silica gel eluting with ethyl acetate: heptane (1:1 to 3:1). MS: m/e = 364.1 (M++H). Example 53 N-[2-Fluoro-4-(4-fluoro-benzyloxy)-phenyn-malonamic acid ethyl ester The title compound is prepared in analogy to example 1 from 2-fluoro-4-(4-fluoro-benzyloxy)-phenylamine (1:1) hydrochloride [using ethylmalonyl chloride instead of methylmalonyl chloride]. Light yellow solid. Yield = 84%. MS: m/e = 350.3 (M++H). Example 54 N-r4-(3-Fluoro-benzyloxy)-3-formyl-phenvn-malonamic acid methyl ester a) 2- (3-Fluoro-benzyloxy)-5-nitro-benzaldehyde Prepared in analogy to example 8 from 2-hydroxy-5-nitrobenzaldehyde and 3-fluoro-benzylbromide. Colorless solid. Yield = 95 %. MS: m/e = 275.1 (M+). b) 5-Amino-2-(3-fluoro-benzyloxy)-benzaldehyde Prepared in analogy to example 8b) by hydrogenation of 2-(3-fluoro-benzyloxy)-5-nitro-benzaldehyde. The crude reaction mixture was used without purification in the next step. c) N-[4-(3-Fluoro-benzyloxy)-3-formyl-phenyn-malonamic acid methyl ester Prepared in analogy to example 20c) from 5-amino-2-(3-fluoro-benzyloxy)-benzaldehyde and methyl malonyl chloride. Colorless solid. Yield = 3 %. MS: m/e = 344.1 (M+-H). Example 55 2-Ethyl-N-[4-(3-fluoro-benzyloxy)-phenyl]-malonamide A solution of sodium ethanolate is prepared by dissolving 46mg (2mmol) sodium in 5ml ethanol. 302mg (lmmol) of N-[ 4-(3-fluoro-benzyloxy)-phenyl]-malonamide is added, followed by 343mg (2mmol) of ethyl iodide. The reaction mixture is refluxed for 2.5h, hydrolysed and extracted with ethyl acetate. Chromatography (silica gel; dichloromethane / methanol) yields 45mg (14%) of a colorless solid. MS: rn/e = 331.3 (M++H). Example 56 N-{4-[2-(4-Fluoro-phenvl)-vmvl1-phenvl}-malonamic acid methyl ester a) (4-Nitro-benzvl)-phosphonic acid diethyl ester lOg (46.3mmol) of4-nitroben2ylbromideand 10.03g (60.3mmol) of triethyl phosphite are dissolved in 25ml dimethylformamide. The reaction mixture is held at 155° C for 1.5h, diluted with 20ml water and extracted 3 times with ethyl acetate. The organic phase is dried and concentrated to yield 8.35g (66%) of the crude title compound. MS: m/e = 274.1 (M++H). b) 4- \2-(4-Fluoro-phenyl)-vinvl]- 1-nitro-benzene 2.63g of sodium hydride are added to 50ml of dimethylformamide. The mixture is cooled to 0° C and 16g (58.6mmol) of (4-nitro-benzyl)-phosphonic acid diethyl ester is added portionwise. The solution is stirred at room temperature for 1.5 h, then cooled to -10°. A solution of 6.09g (50mmol)4-fiuoro-benzaldehyde in 10ml dimethylformamide is slowly added to the mixture at —10°. Stirring at room temperature for 45 min followed by additon of 250ml water yields a precipitate which is filtered and recrystallised from ethanol / water 85:15 to yield 10.81g (91%) of a yellow solid. MS: m/e = 243.1 (M+). c) 4- [2- (4-Fluoro-phenvl)-vinyll -phenylamine A solution of 7.3g (30mmol) of 4-[2-(4-fluoro-phenyl)-vinyl]-1-nitro-benzene in 250ml of ethanol is treated with 80ml of aqueous 25% hydrochloric acid. The mixture is heated at 110° C and 5g (42mmol) of tin is added portionwise. After stirring for 3h at 110° C the suspension is cooled to room temperature, neutralised by additon of aqueous sodium hydroxide and extracted 3 times with dichloromethane. Drying over magnesium sulfate and evaporations yields 5.46 g (85%) of a colorless solid. MS: m/e = 214.2 (M++H). d) N-14- [2- (4-Fluoro-phenvl)-vinvll -phenyU-malonamic acid methyl ester Prepared in analogy to example 20c) from 4-[2-(4-fluoro-phenyl)-vinyl]-phenylamine and methyl malonyl chloride. Colorless solid. Yield = 97 %. MS: m/e = 314.0 (M++H). Example 57 N-{4-r2-(4-Fluoro-phenyl)-yinyn-phenvI}-malonamide Prepared in analogy to example 3 from N-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-malonamic acid methyl ester and 7M ammonia in methanol. Yield = 89 %. Colorless solid. MS: m/e = 299.2 (M++H). Example 58 N-(4-r2-(3-Fluoro-phenyl)-vinvn-phenvl}-malonamic acid methyl ester a) 4-f2-(3-Fluoro-phenyl)-vinvn-l-nitro-benzene Prepared in analogy to example 56b) from (4-nitro-benzyl)-phosphonic acid diethyl ester and 3-fluoro-benzaldehyde. Yellow solid. Yield = 82%. MS: m/e = 243.0 (M+). b) 4-[2-(3-Fluoro-phenyl)-vinvl1-phenvlamine 2.41g (lOmmol) of 4-[2-(3-fluoro-phenyl)-vinyl]-l-nitro-benzeneis dissolved in 25ml of ethyl acetate and treated with 240mg of platinum 5% on charcoal. Hydrogenation is performed at room temperature and normal pressure for 4h. The catalyst is filtered off and the filtrate concentrated. The residue is crystallised from diethyl ether / heptane to yield 1.32g (62%) of an orange solid. MS: m/e = 213.1 (M+). c) N-{442-(3-Fluoro-phenyl)-vmyl1-phenvl}-malonamic acid methyl ester Prepared in analogy to example 20c) from 4-[2-(3-fluoro-phenyl)-vinyl]-phenylamine and methyl malonyl chloride. Colorless solid. Yield = 99 %. MS: m/e = 313.9 (M++H). Example 59 N-(4-[2-(3-Fluoro-phenyl)-vinyl]-phenyl}-malonamide Prepared in analogy to example 3 from N-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-malonamic acid methyl ester and 7M ammonia in methanol. Yield = 68 %. Colorless solid. MS: m/e = 299.2 (M++H). Example 60 N-{4-[2-(4-Fluoro-phenvl)-ethvn-phenvll-malonamic acid methyl ester al 4- [2-(4-Fluoro-phenyD-emvl1-phenylamine 3.46g of 4-[2-(4-fluoro-phenyl)-vinyl)-phenylamine is dissolved in 100ml of tetrahydrofuran, treated with 350mg of palladium 10% on charcoal and hydrogenated at room temperature and normal pressure for about 4h. The catalyst is filtered off and the filtrate concentrated to yield 3.46g (99%) of a yellow solid. MS: m/e = 216.9 (M++H). b) N--f4-f2-("4-Fluoro-phenvl")-ethvn-phenvll-malonamic acid methyl ester Prepared in analogy to example 20c) from 4-[2-(3-fluoro-phenyl)-vinyl]-phenylamine and methyl malonyl chloride. Colorless solid. Yield = 99 %. MS: m/e = 316.0 (M++H). Example 61 N-{442-(4-Fluoro-phenyl)-e&yl1-phenyl}-mdonamide Prepared in analogy to example 3 from N-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-malonamic acid methyl ester and 7M ammonia in methanol. Yield = 94 %. Colorless solid. MS: m/e = 301.1 (M++H). Example 62 N-{4-[2-(3-Fluoro-phenvl)-ethvn-phenvll-malonamic acid methyl ester a) 4- [2- (3-Fluoro-phenyl)-ethvn -phenylamine Prepared in analogy to example 60b) by hydrogenation of 4-[2-(3-fluoro-phenyl)-vinyl]-phenylamine. Yellow solid. Yield = 100%. MS: m/e = 215.1 (M+). b) N-{4-[2-(3-Fluoro-phenvl")-ethyll-phenvll-malonamic acid methyl ester Prepared in analogy to example 20c) from 4-[2-(3-fluoro-phenyl)-ethyl]-phenylamine and methyl malonyl chloride. Colorless solid. Yield = 95 %. MS: m/e = 316.0 (M++H). Example 63 N-{4-r2-(4-Methoxv-phenyl)-vinvll-phenyl}-malonamic acid methyl ester a) 4-[2-(4-Methoxv-phenvl)-vinyll-phenvlamine Prepared in analogy to example 56b) from (4-nitro-benzyl)-phosphonic acid diethyl ester and 4-methoxy-benzaldehyde. Yellow solid. Yield = 69%. MS: m/e = 225.9 (M+). b) N-{4-[2-(4-Methoxv-phenvl)-vinvn-phenvl}-malonamic acid methyl ester Prepared in analogy to example 20c) from 4-[2-(4-methoxy-phenyl)-vinyl] -phenylamine and methyl malonyl chloride. Colorless solid. Yield = 66 %. MS: m/e = 326.1 (M++H). Example 64 N-{4-r2-(4-CMoro-phenyl)-ethvl]-phenyl}-malonamic acid methyl ester a) 4-f2-(,4-Chloro-phenyl)-vinyll-l-nitro-benzene Prepared in analogy to example 56b) from (4-nitro-benzyl)-phosphonic acid diethyl ester and 4-chloro-benzaldehyde. Yellow solid. Yield = 95%. MS: m/e = 259.1 (M+). b) 4-[2-(4-Chloro-phenvl)-ethvll-phenvlamine A solution of 5.0g (19.2mmol) 4-[2-(4-chloro-phenyl)-vinyl]-l-nitro-benzene in 100ml ethyl acetate is treated with 200mg of platinum 5% on charcoal. Hydrogenation is performed at room temperature and normal pressure overnight. The catalyst is filtered off and the filtrate evaporated to yield 3.17g (71%) of a slightly yellow solid. MS: m/e = 231.9 (M++H). c) N-{4-[2-(4-Chloro-phenvl)-ethvn-phenyl}-malonamic acid methyl ester Prepared in analogy to example 20c) from 4-[2-(4-chloro-phenyl)-ethyl]-phenylamine and methyl malonyl chloride. Colorless solid. Yield = 99 %. MS: m/e = 332.1 (M++H). Example 65 N- {4- [2- ( 4-Chloro-phenvl)-ethvn -phenvll-malonamide Prepared in analogy to example 3 from N-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-malonamic acid methyl ester and 7M ammonia in methanol. Yield = 65 %. Colorless solid. MS: m/e = 317.1 (M++H). Example 66 2-Arnino-N-r2-fluoro-4-(4-fiuoro-benzvloxy)-phenvll-acetamide (1:1) hydrochloride a) {[2-Fluoro-4-(4-fluoro-benzyloxy)-phenylcarbamoyll-methyl}-carbamic acid tert- butyl ester A mixture of 2-fluoro-4-(4-fluoro-benzyloxy)-phenylamine (1:1) hydrochloride (272 mg, 1 mmol), Boc-glycine (263 mg, 1.5 mmol), N,N"-dicylcohexyIcarbodiimide (206 mg, 1 mmol) and pyridine (127 mg, 1.6 mmol) in ethyl acetate (6 mL) was stirred at room temperature for 3 h. After this time, the reaction mixture wa poured into sodium hydrogen carbonate (saturated), and the mixture extracted with ethyl acetate. The combined organic layers were then washed with brine and dried. Filtration and evaporation afforded the title compound (180 mg, 46%) as a light brown solid after chromatography on silica gel eluting with ethyl acetate: heptane (1:1 to 4:1). MS: m/e = 393.1 (M++H). b) 2-Amino-N-[2-fluoro-4-(4-fluoro-benzvloxv)-phenvl1-acetamide (1:1) hydrochloride A solution of {[2-fluoro-4-(4-fluoro-benzylox7)-phenylcarbamoyl]-methyl}-carbamic acid tert-butyi ester (148 mg, 0.4 mmol) in HC1 dioxane (4 M, 3 mL) was stirred at room temperature for 1 h. The resulting precipitate was filtered off to afford the title compound (112 mg, 90%) as a white solid. MS: m/e = 293.1 (M+-C1). Example 67 (R)-2-Amino-N- f 2-fluoro-4- (4-fluoro-benzvloxv)-phenvn -propionamide As described for example 66a and 66b, 2-fluoro-4-(4-fluoro-benzyloxy)-phenylamine (1:1) hydrochloride (200 mg, 0.7 mmol) was converted to the title compound (127 mg, 39%) [using Boc-D-Ala-OH instead of Boc-glycine] which was obtained as a white solid. MS: m/e = 307.0 (M+-CI). Example 68 2-Amino-N- f 2-fluoro-4- (4-fluoro-benzvloxv)-phenvn -propionamide As described for example 66a and 66b, 2-fluoro-4-(4-fluoro-benzyloxy)-phenylamine (1:1) hydrochloride (200 mg, 0.7 mmol) was converted to the title compound (41 mg, 15%) [using Boc-DL-Ala-OH instead of Boc-glycine] which was obtained as a white solid. MS: m/e = 306.9 (M++H). Example 69 l-r2-Fluoro-4-(4-fluoro-beii2yloxy)-phenylcarbamoyll-2S-methvl-propyl-ammonium; chloride As described for example 66a and 66b, 2-fluoro-4-(4-fluoro-benzyloxy)-phenylarriine (1:1) hydrochloride (200 mg, 0.7 mmol) was converted to the title compound (47 mg, 12%) [using Boc-L-Valine instead of Boc-glycine] which was obtained as a white solid. MS: m/e = 335.2 (M++H). Example 70 2-Acetylamino-N-[2-fluoro-4-(4-fluoro-benzyloxv)-phenvl1-acetamide A solution of 2-amino-N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-acetamide (1:1) hydrochloride (50 mg, 0.15 mmol), acetyl chloride (14.4 mg, 0.18 mmol), triethylamine (31 mg, 0.30 mmol) was stirred at 0 °C for 4 h. Then the mixture was diluted with water and the mixture extracted with DCM. The organic layer was then washed with brine, dried, filtered and evaporated to leave the title compound (50 mg, 99%) as a white solid. MS: m/e = 335.2 (M++H). Example 71 fR)-2-Acetylaxnino-N-r2-fluoro-4-f4-fluoro-benzvloxv)-phenvl1-propionarnide As described for example 70, (R)-2-amino-N-[2-fluoro-4-(4-fluoro-benzyloxy)-phen7l]-propionamide (50 mg, 0.15 mmol) was converted to the title compound (43 mg, 76%) which was obtained as a white solid. MS: m/e = 349.4 (M++H). Example 72 N- f 2-Fluoro-4- (4-fluoro-benzyloxv)-phenyl1 -2-formylamino-acetamide Step 1: A mixture of acetic anhydride (40 mg, 0.39 mmol) and formic acid (22 mg, 0.48 mmol) was stirred at 0 °C and then heated uat 60 °C for 1 h. Step 2: During this time, 2-amino-N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-acetamide (1:1) hydrochloride (50 mg, 0.15 mmol) was extracted with DCM and sodium hydrogen carboante (saturated) and the organic layer evaporated. Then to a mixture of the acetic formic anhydride (Step 1) in dry THF (0.5 mL) was added a solution of the amine (Step 2) in dry THF (1 mL) at room temperature and the resulting mixture stirred for 10 min. Then the reaction mixture was evaporated leave the title compound (44.1 mg, 91%) as a white solid. MS: m/e= 321.1 (M++H). Example 73 (R)-N- [2-Fluoro-4- (4-fluoro-benzvloxv)-phenyll -2-formvIarnino-propionarnide As described for example 72, (R)-2-amino-N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-propionamide (50 mg, 0.15 mmol) was converted to the title compound (16 mg, 30%) which was obtained as a white solid. MS: m/e = 333.1 (M+-H). Example 74 2-Amino-N-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-acetamide hydrochloride (1:1) As described for example 66a and 66b, 2-fluoro-4-(3-fluoro-benzyloxy)-phenylamine (1:1) hydrochloride (500 mg, 2.1 mmol) was converted to the title compound (300 mg, 44%) which was obtained as a white solid. MS: m/e = 293.1 (M+-C1). Example 75 2-Ace1^larrdno-N-[2-fluoro-4-(3-fluoro-benzyloxv)-phenyl1-acetairiide As described for example 70,2-fluoro-4-(3-fluoro-benzyloxy)-phenylamine (1:1) hydrochloride (150 mg, 0.45 mmol) was converted to the title compound (127 mg, 84%) which was obtained as a white solid. MS: m/e = 335.2 (M++H). Example 76 N- f 2-Fluoro-4- (3-fluoro-berizyloxy)-phenvl1-2-formylamino-acetamide As described for example 72,2-fiuoro-4-(3-fluoro-benzyloxy)-phenylamine (1:1) hydrochloride (133 mg, 0.4 mmol) was converted to the title compound (115 mg, 89%) which was obtained as a white solid. MS: m/e = 321.1 (M++H). Example 77 2-Amino-N-f2-fluoro-4-(4-trifluoromemvl-benzvloxy)-phenvl1-acetamide (1:1) hydrochloride As described for example 66a and 66b, 2-fluoro-4-(4-trifluoromethyl-benzyloxy)-phenylamine (1:1) hydrochloride (600 mg, 2.1 mmol) was converted to the title compound (155 mg, 20%) which was obtained as a white solid. MS: m/e = 343.1 (M+-Cl). Example 78 2-Acetylamino-N- [2-fluoro-4- (4-trifluoromethvl-benzyloxy)-phenyll -acetamide As described for example 70,2-fluoro-4-(4-trifluoromethyl-ben2yloxy)-phenylamine (1:1) hydrochloride (120 mg, 0.32 mmol) was converted to the title compound (119 mg, 98%) which was obtained as a white solid. MS: m/e = 385.2 (M++H). Example 79 2-Amino-N-[4-(3,5-bis-trifluoromethyl-benzyloxy)-2-fluoro-phenvn-acetamide(l:l) hydrochloride As described for example 66a and 66b, 4-(3,5-bis-trifluoromethyl-benzyloxy)-2-fluoro-phenylamine (1:1) hydrochloride (500 mg, 1.4 mmol) was converted to the title compound (180 mg, 30%) which was obtained as a white solid. MS: m/e = 411.2 (M+-Cl). Example 80 2-Acetylamino-N-[4-(33-bis-trifluoromemyl-benzyloxy)-2-fluoro-phenyll-acetarnide As described for example 70,4-(3,5-bis-trifluoromethyl-benzyloxy)-2-£luoro-phenylamine (1:1) hydrochloride (130 mg, 0.29 mmol) was converted to the title compound (107 mg, 81%) which was obtained as a white solid. MS: m/e = 453.2 (M++H). Example 81 2-Amino-N- [4- (3-fluoro-benzyloxy)-phenyl1 -acetamide; hydrochloride a) {r4-(3-Fluoro-benzyloxv)-phenvlcarbamoyn-methyl}-carbamic acid tert-butyl ester A mixture of 0.345g (1.59mmol) 4-(3-fluoro-benzyloxy)-phenylamine and 0.278g (1.59mmol) of N-tert-Butyloxyglycine is dissolved in 10ml of ethyl acetate, cooled to 0° and 0.32Sg (1.59mmol) N,N"-dicycIohexyIcarbodiimide is added at once. The resulting slurry is stirred for additional 3h at room temperature and filtered. The filtrate is washed 3 times with saturated sodium carbonate solution, dried and concentrated. The residue is triturated with 20ml diethylether to give 0.353g (59%) of the title compound as a colorless solid.. MS: m/e = 375.4 (M++H). b) 2-Amino-N-r4-(3-fluoro-benzvloxy,)-phenyl1-acetamide; hydrochloride Aslurryof0.166g(0.44mmol) of {[4-(3-fluoro4)enzyloxy)-phenylcarbamoyl]-memyl}-carbamic acid tert-butyl ester in 1ml diethyl ether is treated with 3ml of a saturated solution of gaseous hydrochloric acid in diethyl ether. The mixture is refluxed for 4h, poured on water and made basic by addition of a saturated sodium carbonate solution. Extraction with ethyl acetate yields a yellowish solid which is dissolved in about 1ml of diethyl ether and treated with a few drops of a saturated solution of gaseous hydrochloric acid in diethyl ether. The precipitate is filtered to give 0.051g (37%) of a colorless solid. MS: m/e = 275.2 (M++H). Example A Tablets of the following composition are produced in a conventional manner: Example B Tablets of the following composition are produced in a conventional manner: Example C Capsules of the following composition are produced: The active ingredient having a suitable particle size, the crystalline lactose and the microcrystalline cellulose are homogeneously mixed with one another, sieved and thereafter talc and magnesium stearate are admixed. The final mixture is filled into hard gelatine capsules of suitable size. Example P An injection solution may have the following composition and is manufactured in usual manner: WE CLAIM: 1. Compounds of the general formula wherein R1 is halogen, halogen-(C1-C6)-alkyl] cyano, C1-C6-alkoxy or halogen-(C1-C6)-alkoxy; R21, R22, R23 and R24 independently from each other are selected from the group consisting of hydrogen, (C1-C6-alkyl, halogen, halogen-{C1-C6)-alkyl, hydroxy, C1-C6-alkoxy or-CHO; R3 is hydrogen or C1-C6alkyl; R4, R3 independently from each other are selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C6-alkoxy or -COO(C1-C5)alkyl; or R4 and R5 form together with the C-atom to which they are attach a C3-C7-cycloalkyl ring; R6 is -CO-NR7R8; -COO(C1-C6,)-alkyl, or -NHC(0)R; R7 and R8 independently from each other are selected from the group consisting of hydrogen, C1-C6-alkyl, NH2 or hydroxy, R is hydrogen or C1 -C6-alkyl; n is 0, 1, 2 or 3. X is -CHRO, -OCHR-, -CH2S-, -SCH2-, -CH2CH2-, -CH=CH- or -OC-; and pharmaceutically active acid addition salts thereof. 2. Compounds of the general formula wherein R1 is halogen, halogen-(Ci-Cs)-alkyl, cyano, C1-C6-alkoxy or h.alogen-(Ci-C,s)-aIkoxy; R , R , R and R" independently from each other are selected from the group consisting of hydrogen and halogen; R3 is hydrogen or C1-C3-alkyl; R4 is hydrogen or C1-C6-alkyl; R5 is hydrogen or C1-C6-alkyl; or R4 and R5 together form a C3-C7-cycloalkyl ring; R6 is -CO-NR7R8; -COOR9; or -CN; R7 and R8 independently from each other are hydrogen, methyl or ethyl; R9 is C1-C6-alkyl; and n is 1,2 or 3. and pharmaceutically active acid addition salts thereof. 3. Compounds of formula I according to claim 1, wherein X is CH2O, R1 is fluorine or trifluoromethyl and R6 is -COOCH3. 4. Compounds according to claim 3, which are N-[4-(3-fluoro-ben2yloxy)-phenyl]-malonamic acid methyl ester, N-[3-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester, N-[4-(4-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester, N-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester, N-[4-(2,4-difluoro-benzyloxy)-phenyl]-malonamic acid methyl ester, N-[4-(2-fluoro-benzyloxy)-phenyl]-malonarnic acid methyl ester, N-[4-(2,4,5-trifluoro-benzyloxy)-phenyl]-malonamic acid methyl ester, N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyi]-malonamic acid methyl ester, N-[4-(3,5-bis-trifluoromethyl-benzylox7)-2-fluoro-phenyl]-malonamic acid methyl ester, N-[4-(3-fluoro-benzyloxy)-3-memyl-phenyl]-malonamic acid methyl ester or N-[3-cHoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester. 5. Compounds of formula 1 according to claim 1, wherein X is CH2O and R6 is -CONH2. 6. Compounds according to claim 5, which compounds are cyclopropane- 1,1-dicarboxylic acid amide [4-(3-fluoro-benzyloxy)-phenyI]-arnide, N-[4-(3-fluoro-benzyloxy)-phenyl]-malonamide, N- [ 4-( 3-fluoro-benzyloxy)-phenyl]-2-methyl-malonamide, N- [ 3-fluoro-4-(3-fluoro-benzyloxy)-phenyl] -malonamide, N-[4-(4-fluoro-ben2yloX5")-prienyl]-malonamide, N-[4-(2,4-difluoro-benzyloxy)-phenyl]-malonamide, N- [4-(2,4,5-triuuoro-berizyloxy)-phenyl] -malonamide, N-[ 4-(2-fluoro-benzyloxy)-phenyl]-malonamide, N- (4-benzyloxy-phenyl) -malonamide, N-[4-(4-chloro-ben2yloxy-)-phenyl]-malonamide, N- [4-(3-fluoro-benzyloxy)-2-hydroxy-phenyl] -malonamide, N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-malonamide, N-[4-(3-fluoro-benzyloxy)-3-methyl-phenyl]-malonamide, N-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-malonamideor cyclopropane-1,1-dicarboxylic acid amide [2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]- amide. 7. Compounds of formulal according to claim l,whereinX is -CH2O- andR6 is -NHCOCH3 or -NHCOH. S. Compounds according to claim 7, wherein the compounds are 2-Acetylairiino-N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyI]-acetamide, 2-Acerylamino-N-[2-fiuoro-4-(3-fluoro-ben2yloxy)-phenyl]-acetamide, N- [2-Fluoro-4-(4-fluoro-ben2yloxy)-phenyl] -2-formylamino-acetarnide or N-[2-Fluoro-4-(3-fiuoro-benzyloxy)-phenyl]-2-formylamino-acetamide. 9. Compounds of formula I according to claim 1, wherein X is -CHjO- and R6 is -NH2. 10. A compounds according to claim 9, wherein the compound is 2-amino-N- [ 2-fluoro-4- (4-fluoro-benzyloxy) -phenyl] -acetamide. 11. Compounds of formula I according to claim 1, wherein X is -CH=CH- and R6 is -COOCH3 or -CONH2. 12. Compounds according to claim 11, wherein the compounds are N-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-mdonamic acid methyl ester, N-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-malonamide, N-{4-[2-(4-fluoro-phenyl)-vmyI]-phenyl}-malonamideor N-{4-[2-(3-fluoro-phenyI)-vinyl]-phenyI}-malonamic acid methyl ester. 13. A process for the manufacture of a compound of formula I according to any one of claims 1 to 12, which process comprises reacting a compound of formula with a compound of formula under conditions such as herein described to obtain a compound of formula and, if desired, converting a compound of formula I into a pharmaceutically acceptable salt. 14. A compound of formula 1 according to any one of claims 1 to 12, when manufactured by a process according to claim 13. 15. A composition containing one or more compounds as claimed in any one of claims 1 to 12 and pharmaceutically acceptable excipients.

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