Indian Patents. 220431:3H-QUINAZOLIN-4-ONE DERIVATIVES

Title of Invention	3H-QUINAZOLIN-4-ONE DERIVATIVES
Abstract	ABSTRACT This invnetion relates to 3H-quinazolin-4-one derivatives as defined in the specification and claims, to a process for their preparation, to pharmaceutical compositions comprising them and to their use as selective monoamine oxidase B inhibitors.

Full Text	3H-Ouinazolin-4-one derivatives This invention relates to 3H-quinazolin-4-one derivatives, to a process for their preparation, to pharmaceutical compositions comprising them and to their use as selective monoamine oxidase B inhibitors. In a first aspect the present invention provides a compound of formula I wherein R' is -(CH2)„-C0-NR5R6; -{CH2)„-C00R7; -(CH2)n-NRV; -(CH2)n-CN; -(CH2)n-OR8 or phenyl, which is unsubstituted or substituted by one to three substituents selected from halogen and fluoro(Ci-C6)-aIk}'l; R2 is hydrogen, halogen or CpQ-alkyl; R3 is hydrogen, Ci-Cs-alkyl, Cs-Q-cycloalkyl or benzyl; R4 is halogen, fluoro(Ci-C6)-alkyI, cyano, Ci-Ce-alkoxy or fluoro(Ci-C6)-alkoxy; R5 and R^ are independently from each other hydrogen or Ci-Cg-alkyl; R7 is hydrogen or Ci-Ce-allc)'!; R8 is hydrogen or Q-Cs-alkyl; m is 1, 2 or 3; and n is 0,1 or 2; as well as their pharmaceuticaUy acceptable salts. In another aspect the present invention provides a compound of formula I wherein R' is -(CH2)„-C0-NR'R'; -(CH2)„-C00R^ -(CH2)n^NR'R^ -(CH2)n-CN; ^(CHoJn-OR^ or phenyl, which is unsubstituted or substituted by one to three substituents selected from halogen and fluoro(C]-C6)-aIk}'l; '^ is hydrogen or Ci-Ce-alkyl; R' is hydrogen, Ci-Ce-alkyl, Cs-Cg-cycloalk}'! or benz)i; R^ is halogen, fluaro(Ci-C6)-alk7l, cyano, Ci-Ce-alkoxy or fluoro(Ci-Q)-all;o}:>'; R^ and R^ are independently from each other hydrogen or CrC6-aIk}d; R' is hydrogen or Ci-Ce-alkyl; R^ is hydrogen or Ci-Q-alkyl; Ji is 1,2 or 3; and a is 0,1 or 2; as well as their pharmaceutically ai ceptable salts. It has been found that the compou nds of general formula I are selective monoamine oxid¬ase B inhibitors. Monoamine oxidase (MAO, EC 1. !:.3.4) is a flavin-containing enzyme responsible for the oxidative deamination of endogenaus monoamine neurotransmitters such as dopamine, serotonin, adrenaline, or noradrei aUne, and trace amines, e.g. phenyl ethyl-amine, as weU asanumherofaminexenobiotics. The enzyme exists in two forms, MAO-A and MAO-B, encoded by different genes [Bach :t a!., Proc. Natl. Acad. Sci. USA 85:4934-4938 (1988)] and differing ia tissue distributior, structure and substrate specificity. MAO-A has higher affinity for serotonin, octopamint, adrenaline, and noradrenaline; whereas the natural substrates for MAO-B are phenyli thylamine and tyramine. Dopamine is thought to be oxidised by both isoforms. MAO- 3 is widely distributed in several organs including brain [Cesura and Pletscher, Prog. Dru{ Research 38:171-297 (1992)]. Brain MAO-B activity appears to increase with age. This increase has been attributed to the gliosis associated with aging [Fowler et al., J. Neural. Tn nsm. 49:1-20 (1980)]. Additionally, MAO-B activity is significantly higher in the brains c hibitors may act by both reducin j the formation of oxygen radicals and elevating the levels of monoamines in the brain. Given the implication of MAO-I in the neurological disorders mentioned above, there is considerable interest to obtain p jtent and selective inhibitors that would permit control over this enzymatic activity. The pharmacology of some known IVL'IO-B inhibitors is, e.g., discussed by Bentu^-Ferrer et al. in CNS Drugs 6:217-236 (1996). \'VhereaE a major limita¬tion of irreversible and non-.9ele. :tive MAO inhibitor activit}'is the need to observe dietary :irecautions due to the risk of indi cing a hypertensive crisis when dietary t)TarDine is in¬vested, as well as the potential for nteractions with other medications [Gardner et al., I. lilin. Psychiatry 57:99-104 (1996) , these adverse events are of less concern with reversible md selective MAO inhibitors, in j 'articular of MAO-B. Thus, there is a need for MAO-B inhibitors with a high selectivity a id without the adverse side-effects typical of irreversible MAO inhibitors with low selectivi ty for the enzyme. It has been found that compound i of formula I of the present invention and their pharma-ceuticaHy acceptable salt show the potential to be highly selective MAO-B inhibitors. Sub¬jects of the present invention are : iirther a process for the manufacture of compounds of formula I as well as medicaments based on a compound in accordance with the invention and their manufacture as well as t he use of the compounds in the control or prevention of diseases mediated by monoamine oxidase B inhibitors, and, respectively, for the produc¬tion of corresponding medicamej its. The following definitions of gene -al terms used in the present patent application apply irrespective of whether the terms in question appear aione or in combination. It must be noted that, as used in the specific ition and the appended claims, the singular forms "a", "an," and "the" include plural for ns unless the context clearly dictates otherwise. The term "(Ci-C6)-aIkyr' ("lower alky!") used in the present application denotes straight-chain or branched saturated hyd: ocarbon residues with 1 to 6 carbon atoms, preferably-with 1 to 4 carbon atoms, such a; methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, and the hke. The term "halogen" denotes fluo: ine, chlorine, bromine and iodine. "Halogen-(Ci-C6)-aUcyr' means ■ he lower alkyl residue as defined herein substituted in any position with one or more halog :n atoms as defined herein. Examples of halogen alfcyl resi¬dues include, but are not limited to, 1,2-difluoropropyl, 1,2-dichloropropyI, trifluoro-methyl, 2,2,2-trifIuoroethyl, 2,2,: l-trichloroethyl, and 1,1,1-trifluoropropyl, and the like. "Ci-Cg'Alkoxy" means the residi e -0-R, wherein R is a lower alkyl residue as defined here¬in. Examples of alkoxy radicals i: iclude, but are not limited to, methoxy, ethox}'^, isoprop-oxy, and the like. "Pharmaceutically acceptable sal ts" of a compound means salts that are pharmaceuticaUy acceptable, which are generally iafe, non-toxic, and neither biologically nor otherwise un¬desirable, and that possess the d ;sired pharmacological activit)- of the parent compound. These salts are derived firom an inorganic or organic acid or base. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (sol¬vates) or crystal forms (polymorphs) of the same acid addition salt. In one embodiment the present invention provides a compound of formula I wherein R is , -(CH2)a-CO-NH2. and n is 0 or 1. In one embodiment the present invention provides a compound of formula I wherein R' is -(CH2)ii-CO0R'; v^^herein R' is hydrogen or Ci-Q-alkyl; and n is 0,1 or 2. In another em¬bodiment the present invention provides a compound of formula I wherein R is -(CH2)n-COOR'; wherein R^ is CrCe-alkyl; and n is 0. In one embodiment the present invention provides a compound of formula I wherein R' is -(CH2)n-NH2; and n is 1 or 2. In one embodiment the present invention pro\ides a compound of formula I wherein R' is -(CH2)n-CN; and n is 0,1 or 2. In another embodiment the present invention provides a compound of formula I wherein R* is -CN. In one embodiment the present invention provides a compound of formula I wherein R^ is or phenyl, which is substituted by halogen. In oneembodimenttbepresentinventionprovidesacompoundof formula! wherein R^ is hydrogen or Ci-Q-alkyl. In another embodiment the present invention provides a com¬pound of formula I wherein R^ is hydrogen or methyl. In one embodiment the present invention provides a compound of formula I wherein R is Ci-C6-aIkyI, Cs-Ce-cycloalkji or benzyl. In another embodiment the present invention provides a compound of formula I wherein R is Cj-Cs-cj'cloalkyl. In another embodiment the present invention provides a compound of formula I wherein R is benzyl. In one embodiment the present invention provides a compound of formula I wherein R is halogen; and m is 1. Among compounds of the present invention certain compounds of formula T, or ph.arnia-ceutically acceptable salts thereof, are preferred. Preferred compounds of formula I are those, wherein R' is hydrogen. Also preferred are compounds of formula I, wherein R is CCi-C6)-aIk}d. Especially pre¬ferred are those, wherein R^ is me+bvl Compounds of formula I, wherein R^ is Cs-Cg-c/cloalky) or benz}'l, are also preferred. Preferred compounds of formula I are ftirther those, wherein R^ is KCHzin-CO-NH^R^ wherein R^ and R^ are independently from each other hydrogen or Ci-Cs-alk}'!, and n is 0, 1 or 2. Epecially preferred are those compounds, wherein R^ and R are hydrogen, and n is 0,1 or 2. Even more preferred are compounds of formula I, wherein R' is -{CH2)n-CO-NR R , wherein R^ and R are hydrogen, and n is 0. The following compounds are examples thereof: 2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quina2olin-3-yl]-acetamide, 2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-propionamide, 2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazolin'3-yl]-acetamide, 2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-propionamide, 2-[7-(3-fluoro-benzyioxy)-2-methyl-4-oxo-4H-quinazolin-3-yl]-acetamide, and 2-[2-cyclopropyI-7-(3-fluoro-benzylox>')-4-oxO'4H-qmna2oIin-3-yI]-acetamide. Also preferred are compounds of formula I, wherein R^ is -(CH2)n-0R^, wherein R is hydrogen or Q-Ce-alkyl, and n is 0,1 or 2. Especially preferred are those compounds, wherein R* is methyl and n is 1. Examples thereof are the following compounds: 7-(3-fluoro-benzyloxy)-3-(2-methoxy-ethyl)-3H-quinazolin"4-one, 7-(4-fluoro-benzyloxy)-3-(2-methoxy-ethyl)-3H-quLnazoIin-4-one, and 7-(3-fluoro-benzyloxy)-3-(2-methoxy-ethyl)-2-methyl-3H-quinazoHn-4-one. Further preferred are compounds of formula I, wherein R^ is -(CH2)n-NR^R , wherein R and R are independently from each other hydrogen or Cj-Q-alkyl, and n is 0,1 or 2. Especially preferred within this group of compounds are those, wherein R^ and R are hydrogen, and n is 0^ 1 or 2. The following compounds are examples thereof: 3-(2-aniino-ethyI)-7-(3-fluoro-ben2yIoxy}-3H-quinazoIin-4-one 1:2 hydrochloride, 3-(3-amino-propyl)-7-(3-fluoro-benzyloxy)-3H-quinazolin~4-one 1:2 hydrochloride, 3-(2-ainino-elhyl)-7-(4-fluoro-ben2:)'lox}0-3H-quinazolin-4-one 1:1 hydrochloride, and 2-f7-(3-£[uoro-ben2ylox)')-2-methyl-4-oxo-4fi-qmnazolin-3-yI]-ethyl-ammonium chloride. Preferred compounds of formijla I are especially those, wherein R* is halogen or fluoro(Cj-C5)-a!kyl. More preferably, R^ is fluoro. In another embodiment the present invention provides a compound of formula I selected from 2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazo]in-3-yIj-acetamide, 2-[7-(3-fluaro-benz)'loxy)-4-oxo-4H-quinazolin-3-yl]-propionamide, 2-[7-(4-fluoro-benzylox}')-4-oxo-4H-quinazolin-3-yl]-acetamide, 2-[7-(4-fluoro-benz)'loxy)-4-oxo-4H-quinazo]in-3-yl]-propionamide, 2-[7-(3-fluoro-benzyloxy),-2-methyl"4-oxo-4H-quinazolin-3-yl]-acetamide, 2-[2-cyclopropyl-7-(3-fliJOro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-acetamide, 7-(3-fIuoro-benzyloxy)-3-(2-methox}'-ethyl)-3H'quinazolin-4--one, ~ 7-(4-fluDro-benzyIoxy)-3-(2-methoi:)'-ethyl)-3H-quLnazohn-4~one, 7-(3-fluoro-benzyloxy)-3'(2-methoxy-ethyl)-2-methyi-3H-quinazolin-4-one, 3-(2-aminO'ethyl)-7-(3-fiuoro-benzylox)')-3H-qmna2o!in-4-one 1:2 hydrochloride, 3-(3-amino-propyl)-7-(3-fluoro-benz)'loxy)-3H-quinazolxn-4-one 1:2 hydTOchloride, 3-(2-3mino-ethyl)-7-(4-fluoro-benzyloxy)-3H-quinazolin-4-one 1:1 hydrochloride, and 2-[7-(3-fluoro-benzyloxy)-2-methyl-4-oxo-4H-quinazolin-3-yl]-ethyl-ammonium chloride. In a further aspect the present invention provides a process for the preparation of a compound of formula I and a pharmaceuticaUy acceptable salt thereof comprising reacting a compound of formula IV ( (IV) wherein R^ is hydrogen, Ci-Ce-allcyl, Ca-Cg-cycloalkj'l or benzyl; R^ is halogen, fluoro(Ci-C6)'alkyl, cyano, Ci-Ce-alkoxy or fluoro(Ci-C6)-aIkory; and m is 1, 2 or 3 with a compound of formula V (V) vherein .^' is -(CH2)„-C0-NK^R^; -(CHz)n-COOR^; -(CH2)„-NRV; -(CH2)n-CN; -(CH2)n-0R^; or phenyl, which is unsubstituted or substituted by one to three substituents selected from halogen and fluoro(Ci-C6)-aIi:y'l; R.^ is hydrogen, halogen or Ci-Ce-allcyl; R^ and R^ are independently from each other hydrogen or Q-Q-allcj'!; R^ is hydrogen or Ci-Cs-alkyi; R^ is hydrogen or Ci-Cs-aikyl; and n is 0,1 or 2; and optionally converting the resulting compound of formula I into a pharmaceutically acceptable salt. In one embodiment the compounds of general formula I and their pharmaceutically acceptable salts can be manufactured by reacting a compound of formula II and, if desired, converting a compound of formula I into a pharroaceutically acceptable salt, or alternatively, reacting a compound of formula VI to obtain a compound of formula IV which in turn is reacted with a compound of formula V to obtain a compound of formula I and, if desired, converting a compound of formula I into a pharmaceutically acceptable salt In accordance with the present invention, compounds of general formula I can be pre¬ pared following scheme 1: 2-Amino-4-fluorobenzoic acid VIII is heated in the presence of formam.idine acetate IX which after basification of the reaction medium affords com¬ pounds of type Ila. Subsequent reaction with the sodium salts of ben2ylic alcohols of type X affords compounds of type IVa which are then dissolved in l-methyl-2-pyrrohdone ( (NMP) and treated with sodium hydride and an electrophile of formula V to give com¬pounds of formula I, wherein R^ is hydrogen. Alternatiyel)', compounds of genera] formula J can be prepared according to the following scheme 2: 4-Fluoro-2-nitro-benzonitrile XI is heated in the presence of HBr and the re¬sulting acid XII is esterified with acidic methanol to afford a compound of formula XIII. Subsequent reaction with the sodium salts of benzj'Hc alcohols of type X affords com¬pounds of type XTV, which are then hydrogenated to anilines of formula VI. Treatment with acetamidate hydrochloride of type VII in base (usually sodium methoxide) forms the quinazolinones IV which are then alkylated with compounds of type V to form the target compounds of formula I. Pharmaceutically acceptable salts of compounds of formula I can be maniifactured readily according to methods known per se and taking into consideration the nature of the com¬pound to be converted into a salt. Inorganic or organic acids such as, e.g., hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric add, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceuti¬cally acceptable salts of basic compounds of formula I Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesjun or the like, basic amines or basic amino acids are suitable for the formation of pharmaceu-ticaDy acceptable salts of acidic compounds. The compounds of formula I and their pharmaceutically acceptable salts 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 acut 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 t)'pes 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 metabohc dis¬orders such as obesity as well as the prevention and treatment of withdrawal syndromes induced.by.ahuse of alcohol, nicotine and other addictive drugs. Other treatable indica¬tions maybe reward deficiency syndrome (WO 01/34172), peripheral neuropathy caused by cancer chemotherapy (WO 97/33572), or the treatment of multiple sclerosis {WO 96/40095) and other neuroinflammatory diseases. 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 Schlaeger and Christensen [Cytotechnology, 15:1-13 (1998)]. After transfection, cells were homogeneised by means of a Polytron homogeneiser in 20 mM Tris HCl buffer, pH 8.0, containing 0.5 mM EGTA and 0.5 mM phenylmethanesulfonyi fluoride. Cell membranes were obtained by centrifugation at 45,000 xg and, after two rinsing step with 20 mM Tris HCl 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 spectro-photometric assay adapted from the method described by Zhou and Panchuk-VolosHna [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 pM N-acetyl-3,7,-diliydroxyphenoxazine (Amplex Red, Molecular Probes). The samples were further incubated for 30 min at 37°C in a final volume of 200 [il 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 (iM dorgyline for !MAO-A or 10 pM L-deprenyl for MAO-B. ICso 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 activities of compounds of formula I as measured in the assay described above are in the range of 10 fiM or Jess, typically of ] (iM or less, and ideally 0.3 (iM or less. The compounds of formula I and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical prepa¬rations 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 admimstra-I tion can also be effected rectally, e.g. in the form of suppositories, or parenteraUy, e.g. in the form of injection solutions. The compounds of formula I andpharmaceutically acceptable salts thereof can be pro¬cessed 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, e.g., as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, e.g-, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine cap¬sules. Suitable ca.rriers for the production of solutions and syrups are, e.g., water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble saltsofcompoundsof formula I, but as a rule are not necessary. Suitable carriers for suppositories are, e.g., natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. In addition, the pharmaceutical preparations can contain preservatives, soiubilizers, "' stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances. As mentioned earlier, medicaments containing a compound of formula I or pharmaceuti-caHy acceptable salts thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutical!)' valuable substances into a galenical dosage form together with one or more therapeutically inert carriers. The dosage can vary within wide limits and will, of comrse, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/ kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies betvv'een 0.7-1400 mg per day, preferably between 7 and 700 mg per day. The following examples are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof. The term "room temperature" is abbreviated as "rt". Example 1; 2-[7-(3-FIuoro-benzyloxy)-4-oxo-4H-quinazolin-3-y]]-acetamide a) 7-Fluoro-3H-quinazolin-4-one: Amixture of 2-amino-4-fIuorobenzoic acid (14.6 g, 94 mmol) and formamidine acetate (19.6 g, 18,8 mmol) in 2-methoj:)'ethanol (110 mL) was heated at 130°C for 18 h. After cooling, the mixture was half evaporated and an off-white solid formed. The mixture was diluted with ammonia (25%, 10 mL in 90 mL water) and thesolidfilteredoffand washed with water. The solid was then washed with hexane and dried underhighvacuumtoaffordthetitle compound (12.5 g, 81%) as an off-white solid. MS: m/e = 165.2 (M+H^). h) 7-(3-Fluoro-benzvloxy)-3H-quinazolin-4-one: Sodium (1.8 g, 78.6 mmol) was added portionwise to 3-fluorobenzyl alcohol and the resulting mixture heated at 80-90 °C for 4 h under Argon. The resulting suspension was cooled to rt and 7-fluoro-3H-quinazoliii-4-one (3.2 g, 19.5 mmol) was added and the resulting mixture heated at 130-MCC for 14 h. The solid formed was then dissolved with water (400 mL) and the mixture acidified to pH 3-4 with HCl (4 N). The resulting precipitate was then filtered off, washed with water (100 mL) and diethylether (100 mL). RecrystaUisation from tetrahydrofiiran ; ethylacetate (1:1) afforded the title compound (3.2 g, 61%) as white crystals. MS: m/e = 271.3 (M-hH"^). c) 2-f7-(3-Fluoro-ben2yloxy)-4-oXQ-4H-quinazolin-3-yll"acetamide: A mixture of 7-(3-fiuoro-benzyloxy}-3H-quinazoIin-4-one (200 mg, 0.74 mmol) and sodium hydride (55%, 36 mg, 0.81 mmol) in N-methylpyrolidinone (5 mL) was heated at 60 °C for 1 h. Then bromacetamide (117 mg, 0.85 mmol) was added and the resulting mixture was heated at 80 "C for 1 h. After cooling to rt, water (50 mL) was added and the resulting precipitate was washed with methanol and diethylether and then dried under high vacuum to afford the title compound (200 mg, 83%) as an off-white soHd. MS: m/e = 328.3 (M+IT"). Example 2: 2-[7~(3-FIuoro-benE)')ox7)-4-oxo-4H-qiiinazolin-3-yI]-propionamide As described for example Ic, 7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one (200 mg, 0.74 mmol) was converted to the title compound (190 mg, 75%) (using 2-brompropionamide instead of bromacetamide) which was obtained as a white solid, MS: m/e = 342.3 (M+H"^). Examples: 7-(3'Fluoro-benzyloxy)-3-(2-methoxy-ethyI)-3H-quinazolin-4-one As described for example Ic, 7-(3-fiuoro-benzyIoxy}-3H-quinazolin-4-one (300 mg, 0.74 mmol) was converted to the title compound (165 mg, 68%) [using (2-broinoraethyl)-methyl ether instead of bromacetamide] which was obtained as a white soHd after crystal¬lisation from diethylether : heptane. MS: m/e = 342.3 (M-t-H"^). Example 4: 3-(2-An:uno-ethyl)-7-(3-£luoro-benzyloxy)-3H-quinazoiin-4-one 1:2 hydrochloride a) 2-[7-("3-Fluoro-ben2ylox:y-)-4-oxo-4H-quinazolin-3-yl1-ethvll-carbamic acid tert-butvl ester: As described for example Ic, 7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one (200 mg, 0.74 mmol) was converted to the title compound (175 mg, 57%) [using 2-(Boc-amino)- ethylbromide instead of bromacetamide] which was obtained as a white soHd after crystal-Hsation from diethylether: heptane. MS: m/e = 342.3 (M+H^). h) 3-(2-Aiiiino-etbyl)-7-f 3-fluoro-benzyloxy)-3H-quinazoHn-4-one 1:2 hydrochloride: A mixture of {2-[7-(3-£iuoro-ben2yIoxy)-4-oxo-4H-quinazoIin-3-yI]-ethyI\|-carbamic acid tert-bnty! ester (150 mg, 0.36 mmol) and HCl in dioxane (4 N, 3 mL) was stirred at rt for 72 h. The precipitate was filtered off and washed with diethylether to afford the title com¬pound (120 jBg, 86%) as a white solid. MS: m/e = 314.3 (M+H^). Example 5: [7-(3-Fluoro-benzylosy)-4-oxo-4H-quinazolin-3-yl]-acetic acid ethyl ester As described for example Ic, 7-(3-fluoro-benZ7loxy)-3H-quinazolin-4-one (200 mg, 0.74 mmol) was converted to the title compound (170 mg, 65%) [using ethyl bromoacetate ,^ instead of bromacetamide] which was obtained as a white sohd. MS: m/e = 357.3 (M+H"^). Example 6: Fiuoro-f7-(3-fluoro-benzyioxy)-4-oxo-4H-quinazoIin-3-yI]-acetic acid ethyl ester As described for example Ic, 7-(3-fluoro-benzyloxy)-3H-qmnazolin-4-one (200 mg, 0.74 mmol) was converted to the title compound (100 mg, 36%) [using ethyl bromofluoro-acetate instead of bromacetamide] which was obtained as a white solid after purification by chromatography (SiOi, CH2CI2: 2N NHs/MeOH 99:1 to 9;1) and crj'stallisation fi-om diethylether : heptane. MS: m/e = 375.4 (M+H""). Example 7: 2-[7-(3-Fluoro-benzyloxy)-4-oxo-4H-qmnazolin-3-yl]-propionic acid ethyl ester ( As described for example Ic, 7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one (200 mg, 0.74 mmol) was converted to the title compound (240 mg, 88%) [using ethyl 2'bromo propi¬onate instead of bromacetamide] which was obtained as a colourless oil after purification by chromatography (SiO;, CH2CI2: 2N NHj/MeOH 99:1 to 9:1). MS: m/e = 3713 (M+H+). Example 8: [7-(3-Fluoro-benzyloxy)-4-oxo-4H-qULnazolirL-3-yl]'acetic acid tert-butyl ester As described for example Ic, 7-(3-fiuoro-benzyloxy)-3H-quinazolin-4-one (200 mg, 0.74 mmol) Vfas converted to the title compound (277 mg, 97%) [using tert-butyl-bromacetate instead of bromacetamide] which was obtained as a white solid after purification by chro¬matography (SiOi, CH2CI2:2N NHs/MeOH 99:1 to 9:1). MS: m/e = 385.3 (M+H""). Example 9; 2-[7-(3-FIuorO'benz)']oxf)-4-oxo-4H-quii3azoIm-3-yI]-propionic add tert-butyl ester As described for example Ic, 7-(3-fluQro-benzylox}0-3H-quinazolin-4-one (200 mg, 0.74 inmol) was converted to tbe title compound (245 mg, 83%) [using 2-bromopropionic acid tert-but}d ester instead of bromacetamide] which was obtained as a white solid after puri¬fication by chromatography (SiOj, CH^Ciz: 2N NHj/MeOH 99:1 to 9:1). MS: m/e ~ 385.3 (M+H^). Example 10: 3-(3-Amino-propyl)-7-(3-fluoro-benzyloxy)-3H-quinazoIin-4-one 1:2 hydrochloride a) i3-["7-f3-Fluoro-ben2yloxyV4-oxo-4H-quin3Zolin-3-yl1-propyU-carbamic acid tert-butyl esten As described for example Ic, 7-(3-fluoro-benzyloxy)-3H-quinazoIin-4-one (200 rag, 0.74 mmol) was comrerted to the title compound (312 mg, 99%) [using 3-(Boc-amino)propyl-bromide instead of bromacetamide] which was obtained as a white solid after purification by chromatography (SiOa, CHzCh: 2N NHj/MeOH 99:1 to 9:1). MS: m/e = 428.5 (M+H^). b) 3-f3-Amino-propyl)-7-(3-fluoro-henzvIox)')-3H-quinazoIin--4-one 1:2 hydrochloride: A mixture of {3-[7-(3-fluoro-benzyIoxy)-4-oxo-4H-quinazolin-3-yl]-propyl}-carbamic acid tert-ibutyl ester (275 mg, 0.64 mmol) and HCl in dioxane (4 N, 8 mL) was stirred at rt for 16 h. The precipitate was filtered off and recrystaUised from EtOH : ether to afford the title compound (120 mg, 47%) as a white sohd. MS: m/e = 328.3 (M+H""). Example 11: 3-(3-Fluoro-benzyl)-7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one As described for example Ic, 7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one (200 mg, 0.74 mmol) was converted to the title compound (253 mg, 90%) [using 3-fluorobenzyl bromide instead of bromacetamide] which was obtained as a white solid after purification by chromatography (Si02, CHjCla: 2N NH3/MeOH 99:1 to 9:1). MS: m/e = 379.3 (M+H^). Example 12: 2-[7-(4-Fluoro-benzyloxy)-4-oxo-4H-qumazohn-3-yl]-acetamide a) 7-f4-Fluoro-bgnzvloxv)-3H-quinazolin-4--one: A mixture of sodium hydride (55%, 3r2 ■ g, 73 mmol), 4-fluoroben2yl alcohol (9.2 g, 73 mmol) and 7-fluoro-3H-qmnazohn-4-one (3.0 g, 18 mmol) in DMF (75 mL) was heated at 140 °C for 2 h. The resulting suspension was cooled to rt and the mixture acidified to pH 3 with HCl (cone). The resulting precipi¬tate was then filtered off, washed with water and diethidether. Partial purification by chro- matography on silica gel eluting with ethyl acetate : hexane (2:1) afforded the title com¬pound (3.2 g, 66%) as an off-white sohd. MS: m/e = 271.3 (M+H""). b) 2-[7-(4-Fluoro-benz\4oxy')-4-oxo-4H-quinazQlin-3-vl1-acetamide: As described for example Ic, 7-(4-fluoro-ben2yloxy)-3H-quinazolin-4-one (Example 12a, 200 mg, 0.74 mmol) was converted to the title compound (20 mg, 8%) %) which was obtained as a white solid after purification by HPLC (Waters Xterra RP18 (5 fim x 50 xl9mni3 elating with AcCN/ 0.1%TFAAVater. MS: m/e = 32S.3 (M+H"). Example 13: 2-[7-{4-Fluoro-benzyIoxy)-4-oxo-4H-qmnazoIin-3-yI]-propionamide As described for example Ic, 7-(4-fluoro-benzyloxy)-3H-quinazolin-4-one (400 mg, 1.5 mmol) was converted to the title compound (37 mg, 7%) (using 2-brorr)opropionamide , -instead of bromacetamide) which was obtained as a white solid after purification by HPLC (Waters Xterra RP18 (5 pm x 50 xl9mm) eluting with AcCN/ 0.1%TFA/Vv^ater. MS: m/e = 340.2 iU+it). Example 14: [7-(4-Fluoro-benzyloxy)-4:-oxo-4H-qmnazolin-3-yl]-acetic acid ethyl ester As described for example Ic, 7-(4-fluoro-benzylox)0-3H-quinazohn-4-one (400 mg, 1.5 mmol) was converted to the title compound (83 mg, 16%) (using ethyl bromoacetate instead of bromacetamide) which was obtained as a white solid after purification by HPLC (Waters Xterra RP18 (5 pm x 50 xl9mm) eluting with AcCN/ 0.1%TFAA\'ater. MS: m/e = 357.3 (MH-H^). Example 15: 2-[7-(4-FJuoro-beiizyIoxy)-4-oxo-4H-quinazolin-3-yI]-propiomc acid ethyl ,. ester As described for example Jc, 7-(4-fluoro-benzy]oxy)-3H-qmnazo]in-4-one (400 mg, 1.5 mmol) was converted to the tide compound (32 mg, 6%) (using ethyl-2-bromopropionate instead of bromacetamide) which was obtained as a white solid after purification by HPLC (Waters Xterra RP18 (5 pinx50xI9mn)) eluting with AcCN/0.1%TFAAVater. MS: m/e = 371.3 (M+H"^). Example 16: " 7-(4-Fluoro-benzylox)')-3-(2-methoxy-efhyl)-3H-quinazolin-4-one As described for example 3, 7-(4-fluoro-benzyloxy)-3H-quinazolin-4-one (400 mg, 1.5 mmol) was converted to the title compound (115 mg, 24%) which was obtained as a white solid after purification by HPLC (Waters Xterra RP18 (5 pmx 50 xl9mra) eluting with AcCN/ 0.1%TFA/W'ater. MS: m/e ^ 329.1 (M+H+j. Example 17: 3-(2-Amino--ethyl)-7-{4--fluoro-ben2yloxy)-3H-qmiiazolin-4-one 1:1 hydrochloride a) {2-[7-(4-Fluoro-benzTloxy)-4-oxo-4H-qmnazohr3-3-Yl!-ethvU-carbamic add tert-butyl ester: As described for examplelOa, 7-(4-fluoro-benzyIoxy)-3H-quinazoHn-4-one (300 mg, 1.1 mmol) was converted to the title compound (105 mg, 23%) which was obtained as a white solid after purification by HPLC (Waters Xterra RP18 (5 \|im x 50 xl9mm) eluting with AcCN/ 0.1%TFA/Water. MS: m/e = 414.5 (M+H^). b) 3-(2-Amino-ethyl)-7-(4-fluoro-ben.zyloxy')-3H-qmna2olLn-4-one 1:1 hydrochloride: As described for examplelOb, i2-[7-(4-fiuoro-benzylox)')-4-oxo-4H-quinazoIin-3-yl]-ethyl}-carbamic acid tert-butyl ester (102 mg, Q.25 mmol) was converted to the title compound (84 mg, 97%) which was obtained as a white sohd. MS: m/e = 314.2 (M+H"^). Example 18: 3'[7-(4-Fluoro-benzyloxj')-4-oxo-4H-qumazolin-3-yl]-propionamide As described for example Ic, 7-(4-fluoro-benzyloxy)-3H-quinazolin-4-one (300 mg, 1.1 mmol) was converted to the title compound (72 mg, 19%) (using 3-bromopropionamide instead of bromoacetamide) which was obtained as a white solid after purification by HPLC (Waters Xterra RP18 (5 \im x 50 xl9mm) eluting with AcCN/ 0.1%TFA/W^ater. MS: m/e = 342.1 (M+H""). Example 19: 2-[7-(3-Fluoro-benzyloxy)-2-inethyl-4-oxo-4H-quinazolin-3-yl]-acetamide a) 4-Fluoro-2-nitro-benzoic acid: A mbcture of 4-fluoro-2-nitro-benzonitrile (12.2 g, 73.7 mmol) suspended in HBr (48%, 74.5 mL, 664 mmol) was heated at 130 °C for 6.5 h. After cooling to rt water (1 L) was added and the resulting precipitate was washed with water andhexaneto afford the title compound (11.0 g, 81%) as a hght brown soHd. MS: m/e = 183.9 (M-H). b) 4-Fluoro-2-nitro-benzoic acid methyl ester: A mixture of 4-fluoro-2-nitro-benzoic acid (10.9 g, 58.8mrnol)in methanol (120 mL) containing sulfuric acid (1-8 g, 18.7 mmol) was heated under reflux for 41 h. After cooling to rt the mixture was poured into sodium hydrogen carbonate (sat. 250 mL), and extracted with ethyl acetate (3 x 100 mL). The combined-extractswerewashedwith brine (100 mL) dried and evaporated to leave the_titl.e compound (10.7 g, 91%) as a light brown liquid. MS: m/e = 199.0 (M-H). c) 4-(3-Fluoro-benzyloxy)-2-nitrO"benzQic acid (3-fluoro-beiizyl> ester and 4-f3-fluoro-benzyIoxy)-2-ni^ro-benzoic acid methyl ester: A mixture of 4-fluoro-2-nitro-benzoic acid methyl ester (9.2 g, 46.3 mmol), 3-f!uorobenzyl alcohol (16.7 g, 132.4 mmol) and potas¬sium carbonate (12.8 g, 92.6 mmol) in DMF (210 mL) was heated at 65 °C for 48 h. After cooling to rt, the mixture was poured into water (400 mL), and extracted with diethyl ether (3x 100 mL). The combined extracts were washed with brine (100 mL) dried and evapo¬rated. Purification by chromatograph}'on silica gel eliiting with ethyl acetate :hexane (1:1) afforded the title compound (14.0 g, 76%) as a Hght yellow Hquid. d) 4-f3-FIuorQ-benzvioxy')-2-nitro-ben2oic acid: A mixture of 4-(3-fluoro-benCTloxy")-2- nitro-benzoic acid {3-f!uoro-benzyl) ester and 4-{3-fiuoro-benzyloxy)'2-nitro-benzoic acid methyl ester (14.0 g, 35.0 mmol) inTHF (120mL) and water (120 mL), containing hthium hydroxide monohydrate (2.94 g, 70.1 mmol) was stirred at rt for 48 h. Then the mixture was poured into sodium hydroxide (2 N, 50 mL) and then the mixture extracted with diethyl ether (3x150 mL). The aqueous phase was then adjusted to pH 2 with HCl. Then the mixture was poured into sodium hydroxide (2 N, 50 mL) and the aqueous phase was then adjusted to pH 5.2 with HCl then the mixture extracted with diethyl ether (3 x 100mL).Thecombinedextracts were then washed with brine (100 mL) dried and evapo¬rated to afford title compound (6.6 g, 65%) as a light yellow solid. MS: m/e = 290.0 (M-H). e) 2-Amino-4-f 3-fluoro-benzyloxy)-benzoic acid: A mixture of 4-(3-f!uoro-benzyloxy)-2- nitro-benzoic acid (7.2 g, 24.8 mmol) in ethyl acetate (150 m.L) in the presence of Pt/C (5%, 1.0 g) was hydrogenated at rt and pressure for 3.5 h. The mixture was then filtered and the filtrate was evaporated. The resulting light brown solid was triturated with di- chloromethane (DCM) to afford the title compound (5.2 g, 80%) as an off-white solid. MS: m/e = 260.1 (M~H). Alternatively, a mixture of 4-(3-fluoro-benzyloxy)-2-nitro-benzoic acid (6,6 g, 22.8 mmol) in ethyl acetate (140 mL) in the presence of Pd/C (5%, 1.0 g) was hydrogenated at rt and pressure for 3.5 h. The mixture was then filtered and the filtrate was evaporated. The re-suiting light brown solid was triturated with DCM to afford the title compound (5.1 g, 87%) as an ofF-white solid. f) 7-("3-Fluoro-benzv]oxy1-2-methyl-3H-quinazolin-4-one: To a mixture of 2-amino-4-(3- fluoro-benzyloxy)-benzoic acid (2.0 g, 7.7 mmol) and ethyl acetamidate LI CI (1.9 g, 15.3 mmol) in methanol (30 ml) was added sodium methoxide (5.4 M, 0.S3 g, 15.3 mmol) and the resulting mixture was heated under reflux for 19 h. After this time ethyl acetamidate HCl (1.9 g, 15.3 mmol) and sodium methoxide (5.4 M, 0.83 g, 15.3 mmol) was added and the resulting mixture heated for another 1 h. After cooling to rt the mixture was poured into water (40 mL) and then the resulting precipitate was stirred for 2 h, and filtered off to afford the title compound (2.1 g, 97%) as an off-white solid. MS: m/e = 283.1 (M-H). g) 2-f7-f3-Fluoro-benz\']oxy)-2-methy]-4-oxo-4H-qmnazolir[-3-vn-acetamide: As i described for example 1 c, 7-(3-fluoro-benzyloxy)-2-methyl-3H-quina2ohn-4'One (250 mg, 0.88 mmol) was converted to the title compound (218 mg, 73%) which was obtained as a white solid after trituration with dichloromethane (DCM). MS: m/e = 342.1 (M+H ). Example 20: 7-(3-Fluoro-benz7loxy)-3-(2-methoxy-ethyl)-2-methyl-3H-qmnazoIin-4-one \.s described for example 3, 7-(3-fluoro-benz)"loxy)-2-meth.yl-3H-quinazoliii-4-one (250 ng, 0.88 minol) was converted to the title compound (150 mg, 45%) wbicli was obtained IS a white solid after purification by chromatography (Si02,EtOAc:beptane 1:3 to 2:1). VIS: m/e = 343.1 (M+H^). Example 21: 2-[7-(3-FluoTo-ben2yloxy)-2-methyl-4-oxo-4H-quinazolin-3-yl]-etiiyl-ammonium chloride a) f2-[7-(3-Fiuoro-ben2vloxy')-2-methyl-4-oxo-4H-quinazolin-3-yl1-ethyU-carbamicacid tert-but\'l ester: As described for example 4a, 7-(3-fluoro-benzyIox)')-2-niethyl-3H-quin-azolin-4-one (250 mg, 0.88 mmo!) was converted to the title compound (72 mg, 18%) which was obtained as a white solid after purification by chromatography (Si02, EtOAc:heptane 1:4 to 2:1). MS: m/e = 428.3 (M+H). b) 2-[7-f3-Fluoro-benzvloxy)-2-methyl-4-oxo-4H-quinazolin-3-yn-ethyl-ammoniiim chloride: As described for example 4b, {2-[7-(3-fluoro-benzyloxy}-2-niefhyl-4-oxo-4H-quinazoIin-3-yl]-ethyl}-carbamic acid tert-butyl ester (50 mg, 0.12 mmol) was converted to the title compound (45 mg, 85%) which was obtained as a white solid after purification by cbromatography (SiOj, EtOAcrheptane 1:4 to 2:1). MS: m/e = 328.2 (M+H^). Example 22: 2-[7-(3-Fluoro-benzyloxy)-2-isopropyl-4-oxo-4H-quinazolin-3-yl]-acet-amide a) 7-{3-Fluoro-benzyloxvV2-isopTopyl-3H-qmnazolin-4-one: As described for example 19f, 2-amino-4-(3-fiuoro-benzyIoxy)-benzoic acid (1 g, 3.S mmol) was converted to the title compound (196 mg, 16%) [using ethyl isopropylamidate HCl instead of ethyl acet-amidate HCI] which was obtained as a white soKd after purification by chromatography (SiOi, dicbloromethane:MeOH 95:5 to 85:15). MS: m/e = 330.1 (M+NH4). b) 2-f7-l"3-Fluoro-benzvIoxy)-2-isopropyI-4-oxo-4H-quina2oIin-3-vI1-acetamide: As described for example Ic, 7'(3-fluoro-benz7loxy)-2-isopropyl-3H-quina2oUn-4-one (80 jng, 0-2j6_mm.ol) was converted to the title compound (84 mg, 89%) which was obtained as a white sofid after trituration with dichloromethane. MS: m/e - 370.2 (M+H'"). Example 23: [7-(3-FluorO"beTizylox7)-2-isopropyl-4-ox.o-4H-quinazoiin-3-yl]-aceto-nitrile To a mixture of 2-[7-(3-fluoro-benzyloxy)-2-isopropyI-4-oxo-4H-quma2olin-3-yI]-acet- amide (50 mg, 0.14 mmo!) in dimethylformamide (0.5 mL), dichloromethane (2 mL) was added N-ethyl-N,N-diispropylamine (26.2 mg, 0.2 mmol) and the resulting mixture cooled to -78 °C. Then trifluorosulfonic anhydride (49.6 mg, 0.18 mmol) was added and the reaction mixture allowed to warm up to rt over 30 min. The resulting mixture was then poured ointo sodium hydrogen carbonate (sat. 5 mL), and the mixture extracted with di- ethylether (3x5 mL). The combined extracts were then washed with brine, dried and eva¬ porated to leave a light yellow solid. Purification by chromatography (SiOi, EtOAc:hept- ane 1:1 to 85:15) afforded the tide compound (26 mg, 55%) as a white soJid MS; m/e = ' 352.2 (M+H"^). Example 24: 2-[2-Cyclopropyl-7-(3-fluoro-benzyloxy)~4-oxo-4H-quiiiazolin-3-yl]-acetamide a) 2-CyclopropvI-7-(3-fluoro-benzyloxv"l-3H-quLna2olin-4-one: As described for example 19f, 2-amino-4-(3-fluoro-benzyloxy)-benzoic acid (1.0 g, 3.8 mmol) was converted to the title compound (607 mg, 49%) [using ethyl cyclopropyl-amidate HCl instead of ethyl acetamidate HCl] which was obtained as a white solid after trituration with dieth)dether-MS: m/e = 311.2 (M-l-H^). b) 2-[2-Cvclopropyl-7-(3-fiuoro-benzvloxy)-4-oxO"4H-quinazolin-3-yl1-acetamide: As described for example Ic, 2-cyclopropyl-7-(3-fluoro-ben2yloxy)-3H-quinazoUn-4-one (80 mg, 0.26 mmol) was converted to the title compound (98 mg, 65%) which was obtained as a white solid after purification by chromatography (SiOn, dichioro-methane:MeOH 9S:2 to 9:1). MS: m/e = 368.1 (M-i-H"'). Example 25: 2-CyclopropyI-7-(3-fluoro-benzyloxy)-3-(2-methoxy-ethyl)-3H-quin-azoIin-4-one As described for example 3, 2-cyclopropyl-7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one (150mg, 0.48 mmo]) was converted to the title compound (15 mg, 8%) which was Gb-_ _ tained as a white solid after purification by chromatography (Si02> dichloromethane : MeOH 95:5). MS: m/e = 369.2 (M4-H^). Example 26:[2-CyclopropyI-7-(3-fiuoro-benzy]oxy)-4-oxo-4H-quinazoliii-3-yl]-acetic acid methyl ester As described for example Ic, 2-cydopropyl-7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one (100 mg, 0.3 mmol) was converted to the title compound (33 mg, 27%) [using methyl bromoacetate instead of bromacetamide] which was obtained as a white solid after puri¬fication by chromatography (Si02, EtOAc:heptane 1:9 to 1:1). MS: m/e = 383.3 (M+H""}. Example 27: 2-[2-Benzyl-7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yI]-acetamide a) 2-Benz}d-7-(3-fluoro-benzyloxy)-3H-quin3zolin-4-one: As described for example 19f, 2-amino-4-(3-fluoro--benzyloxy)-benzoic acid (1.0 g, 3.8 mmol) was converted to the title compound (731 mg, 53%) [using ethyl benzylamidateHCl instead of ethyl acetamidate HCl] which "Was obtained as a white solid after trituration with diethylether. MS: m/e = 361.2 (M+H""). h) 2- [2-Ben2yl-7-('3-fluoro-benzy]ox>0-4-oxo-4H-quinazoIin-3-yl1 -acetamide: As described for example Ic, 2-benzyl-7-(3-fluoro-benzyIoxy)-3H-quinazolin-4-one (150 mg, 0.42 mmolj was converted to the title compound (94 mg, 54%) which was obtained as a white solid after purification by chromatography (SiOa, dichlormethane : MeOH 99:1 to 9:1). MS: m/e = 418.2 (M+H""). Example A: Tablets Tablets of the following composition are produced in a conventional manner: ) mg/Tablet Active ingredient 100 Powdered lactose 95 White corn starch 35 Polj-vinylpyrrolidone 8 i Na carboxymethylstarch 10 Magnesium stearate 2 Tabktweighf 250 Example B: Tablets Tablets of the following composition are produced in a conventional manner: mg/Tablet Active ingredient 200 Powdered lactose 100 White corn starch 64 Polyvinylpyrrolidone 12 Na carboxymethylstarch 20 Magnesium stearate 4 Tablet weight 400 Example C: Capsxiles Capsules of the foilowing composition are produced: mg/Capsule Active ingredient 50 Crystalline lactose 60 Microcrystalline cellulose 34 Talc 5 Magnesium stearate 1 Capsule fill weight 150 The active ingredient having a suitable particle size, the crystalline lactose and the microcrj'stalline 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 D: Injection solution An injection solution may have the following composition and is manufactured in usua manner: Active substance 1.0 mg 1 N HCl 20.0 ]xl acetic acid 0.5 mg NaCl 8.0 mg phenol 10.0 mg 1 N NaOH q.s. ad pH 5 H2O q.s. ad 1 ml 1. A compound of formula I wherein R' is -{CH2)n-CO-NR5R6 -(CH2)«-CO0R7 -(CH2)„-NR5R6; -{CH2)„-CN; -(CH2)n-0R^; or phenyl, which is unsubstituted or substituted by one to three substituents selected from halogen and fLuoroCCrCsValk^'l; R^ is hydrogen, halogen or Ci-Q-aUcyl; R' is hydrogen, Ci-Q-alkyl, C3-C6-cyc!oalkyl or benzyl; R^ is halogen, fluoro{CrC6)-alkyt, cyano, Q-Q-alkoxy or fluoro(Ci-Q)-alkox)'; R^ and R^ are independently from each other hydrogen or Cj-Ce-aLkyl; R' is hydrogen or d-Ce-aikyl; R^ is hydrogen or Ci-Q-alk)d; m is 1, 2 or 3; and n is 0,1 01 2; as well as pharmaceutically acceptable salts thereof. 2. The compound of formula I according to claim 1 wberein R1 is -(CH2)n-C0-NIt5R69; -(CH2Jn-COOR7; -(CH2)n-NR5R6 -(CH2)n-CN; -(CH2)n-0R'; or phenyl, which is unsubstituted or substituted by one to three substituents selected from halogen and fluoro{C1-C6)-aIkyl; R2 is hydrogen or C1-C6-alkyl R3 is hydrogen, C2-Cg-alkyl, Cs-Ce-cycloallq'l or benzyl; R' is halogen, fluoro(Ci-C6)-alkyl, cyano, Q-Cfi-alkoxy or fluoro(Ci-C6)-alkox)'; R^ and R^ are independently from each other hydrogen or Ci-Ce-alkyl; R^ is hydrogen or Ci-Ce-alk)'!; R^ is hydrogen or Ci-Ce-alkyI; m is 1, 2 or 3; and n is 0,1 or 2; as well as their pharmaceutically acceptable salts. 3. The compound of formula I according to claim 1 selected from 2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoliii-3-yl]-acetamide, 2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-propionamide, 2-[7-(4-fIuoro-ben2yloxy)-4-oxo-4H-quinazoliii-3-yl]-acetamide, 2-[7-{4-fluoro-benzylox}0-4-oxo-4H-qmnazolin-3-yl]-propionainlde. 2-[7-(3-fluoTO-benzyloxy)-2-methyl-4-oxo-4H-qmnazolin-3-yl]-acetamide, 2-[2-cyclopropy!-7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-ylj-acetamide, 7'(3-fluoro-benzy]oxy)-3-(2-methoxy-etliyl)-3H-quinazolin-4-one, 7-(4-fluoro-benzyloxy)'3-(2-inethox)'-ethyI)-3H-quinazoUn-4-one, 7-(3-fluoro-benzyloxy)"3-(2-methoxji'-ethyl)-2-methyl-3H-qulnazolm-4-one, 3-(2-amiiio-ethyl)-7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one 1:2 hydrochloride, 3-(3-amino-propyl)-7-{3-fLuorO'benz)4oxy)-3H-quina2oIin-4-one 1:2 hydrochloride, _ 3-(2-amiiio-ethyl)-7-(4-fluoro-benzyloxy)-3H-quinazolin-4-one 1:1 hydrochloride, and 2-[7-(3-fluoro-ben2yloxy)-2-methyl-4-oxo-4H-quinazol!n-3-yl]-ethyl-ammonium chloride. 4. A process for the preparation of a compound of foimula I according to claim 1 and a pharmaceutically acceptable salt thereof comprising reacting a compound of formula IV (IV) wherein ■R3 is hydrogen, C1-C6-allcyl, CB-Ce-cycloalkyl or benzyl; R4 is halogen, fluoro(C1-C6)-alkyl, cyano, Ci-Cs-alkoxy or fluoro(C]-C6)-alkox}'; and m is 1, 2 or 3 with a compound of formula V , (V) wherein > R' is -(CH2)n-C0-KR5R6; -(CH2)n-C00R7 -(CH2)n-NR^R^ -(CH2)n-CN; -(CH2)i,-0R^; or phenyl, which is unsubstituted or substituted by one to three substituents selected from halogen and fluoro(C]-C6)-aJkl; R2 is hydrogen, halogen or C1-C6-alkyl; R5 and R are independently from each other hydrogen or CrQ-alk)'!; R7is hydrogen or C1-C6-alkyl; a R is hydrogen or C1-alkyl; and N is , 1 or 2; And optionally converting the resulting compound of formula I into a pharmaceuticaJly acceptable salt. 5. A medicament containing a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients for the treatment and prevention of diseases which are mediated by monoamine oxidase B inhibitors. 6. The medicament according to claim 5 for the treatment and prevention of Alzheimer's disease and senile dementia. 7. A compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, when manufactured by a process according to claim 4. 8. A compound of formula I according to claim 1 as well as a pharmaceutically acceptable salt thereof for the treatment or prevention of diseases.

Full Text

3H-Ouinazolin-4-one derivatives
This invention relates to 3H-quinazolin-4-one derivatives, to a process for their preparation, to pharmaceutical compositions comprising them and to their use as selective monoamine oxidase B inhibitors.
In a first aspect the present invention provides a compound of formula I

wherein
R' is -(CH2)„-C0-NR5R6; -{CH2)„-C00R7; -(CH2)n-NRV; -(CH2)n-CN; -(CH2)n-OR8
or phenyl, which is unsubstituted or substituted by one to three substituents selected
from halogen and fluoro(Ci-C6)-aIk}'l; R2 is hydrogen, halogen or CpQ-alkyl; R3 is hydrogen, Ci-Cs-alkyl, Cs-Q-cycloalkyl or benzyl;
R4 is halogen, fluoro(Ci-C6)-alkyI, cyano, Ci-Ce-alkoxy or fluoro(Ci-C6)-alkoxy; R5 and R^ are independently from each other hydrogen or Ci-Cg-alkyl; R7 is hydrogen or Ci-Ce-allc)'!; R8 is hydrogen or Q-Cs-alkyl; m is 1, 2 or 3; and n is 0,1 or 2; as well as their pharmaceuticaUy acceptable salts.
In another aspect the present invention provides a compound of formula I wherein
R' is -(CH2)„-C0-NR'R'; -(CH2)„-C00R^ -(CH2)n^NR'R^ -(CH2)n-CN; ^(CHoJn-OR^
or phenyl, which is unsubstituted or substituted by one to three substituents selected
from halogen and fluoro(C]-C6)-aIk}'l; '^ is hydrogen or Ci-Ce-alkyl;
R' is hydrogen, Ci-Ce-alkyl, Cs-Cg-cycloalk}'! or benz)i;
R^ is halogen, fluaro(Ci-C6)-alk7l, cyano, Ci-Ce-alkoxy or fluoro(Ci-Q)-all;o}:>'; R^ and R^ are independently from each other hydrogen or CrC6-aIk}d; R' is hydrogen or Ci-Ce-alkyl; R^ is hydrogen or Ci-Q-alkyl;

Ji is 1,2 or 3; and
a is 0,1 or 2;
as well as their pharmaceutically ai ceptable salts.
It has been found that the compou nds of general formula I are selective monoamine oxid¬ase B inhibitors.
Monoamine oxidase (MAO, EC 1. !:.3.4) is a flavin-containing enzyme responsible for the oxidative deamination of endogenaus monoamine neurotransmitters such as dopamine, serotonin, adrenaline, or noradrei aUne, and trace amines, e.g. phenyl ethyl-amine, as weU asanumherofaminexenobiotics. The enzyme exists in two forms, MAO-A and MAO-B, encoded by different genes [Bach :t a!., Proc. Natl. Acad. Sci. USA 85:4934-4938 (1988)] and differing ia tissue distributior, structure and substrate specificity. MAO-A has higher affinity for serotonin, octopamint, adrenaline, and noradrenaline; whereas the natural substrates for MAO-B are phenyli thylamine and tyramine. Dopamine is thought to be oxidised by both isoforms. MAO- 3 is widely distributed in several organs including brain [Cesura and Pletscher, Prog. Dru{ Research 38:171-297 (1992)]. Brain MAO-B activity appears to increase with age. This increase has been attributed to the gliosis associated with aging [Fowler et al., J. Neural. Tn nsm. 49:1-20 (1980)]. Additionally, MAO-B activity is significantly higher in the brains c
hibitors may act by both reducin j the formation of oxygen radicals and elevating the levels of monoamines in the brain.
Given the implication of MAO-I in the neurological disorders mentioned above, there is considerable interest to obtain p jtent and selective inhibitors that would permit control over this enzymatic activity. The pharmacology of some known IVL'IO-B inhibitors is, e.g., discussed by Bentu^-Ferrer et al. in CNS Drugs 6:217-236 (1996). \'VhereaE a major limita¬tion of irreversible and non-.9ele. :tive MAO inhibitor activit}'is the need to observe dietary

:irecautions due to the risk of indi cing a hypertensive crisis when dietary t)TarDine is in¬vested, as well as the potential for nteractions with other medications [Gardner et al., I. lilin. Psychiatry 57:99-104 (1996) , these adverse events are of less concern with reversible md selective MAO inhibitors, in j 'articular of MAO-B. Thus, there is a need for MAO-B inhibitors with a high selectivity a id without the adverse side-effects typical of irreversible MAO inhibitors with low selectivi ty for the enzyme.
It has been found that compound i of formula I of the present invention and their pharma-ceuticaHy acceptable salt show the potential to be highly selective MAO-B inhibitors. Sub¬jects of the present invention are : iirther a process for the manufacture of compounds of formula I as well as medicaments based on a compound in accordance with the invention and their manufacture as well as t he use of the compounds in the control or prevention of diseases mediated by monoamine oxidase B inhibitors, and, respectively, for the produc¬tion of corresponding medicamej its.
The following definitions of gene -al terms used in the present patent application apply irrespective of whether the terms in question appear aione or in combination. It must be noted that, as used in the specific ition and the appended claims, the singular forms "a", "an," and "the" include plural for ns unless the context clearly dictates otherwise.
The term "(Ci-C6)-aIkyr' ("lower alky!") used in the present application denotes straight-chain or branched saturated hyd: ocarbon residues with 1 to 6 carbon atoms, preferably-with 1 to 4 carbon atoms, such a; methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, and the hke.
The term "halogen" denotes fluo: ine, chlorine, bromine and iodine.
"Halogen-(Ci-C6)-aUcyr' means ■ he lower alkyl residue as defined herein substituted in any position with one or more halog :n atoms as defined herein. Examples of halogen alfcyl resi¬dues include, but are not limited to, 1,2-difluoropropyl, 1,2-dichloropropyI, trifluoro-methyl, 2,2,2-trifIuoroethyl, 2,2,: l-trichloroethyl, and 1,1,1-trifluoropropyl, and the like.
"Ci-Cg'Alkoxy" means the residi e -0-R, wherein R is a lower alkyl residue as defined here¬in. Examples of alkoxy radicals i: iclude, but are not limited to, methoxy, ethox}'^, isoprop-oxy, and the like.
"Pharmaceutically acceptable sal ts" of a compound means salts that are pharmaceuticaUy acceptable, which are generally iafe, non-toxic, and neither biologically nor otherwise un¬desirable, and that possess the d ;sired pharmacological activit)- of the parent compound.

These salts are derived firom an inorganic or organic acid or base. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (sol¬vates) or crystal forms (polymorphs) of the same acid addition salt.
In one embodiment the present invention provides a compound of formula I wherein R is , -(CH2)a-CO-NH2. and n is 0 or 1.
In one embodiment the present invention provides a compound of formula I wherein R' is -(CH2)ii-CO0R'; v^^herein R' is hydrogen or Ci-Q-alkyl; and n is 0,1 or 2. In another em¬bodiment the present invention provides a compound of formula I wherein R is -(CH2)n-COOR'; wherein R^ is CrCe-alkyl; and n is 0.
In one embodiment the present invention provides a compound of formula I wherein R' is -(CH2)n-NH2; and n is 1 or 2.
In one embodiment the present invention pro\ides a compound of formula I wherein R' is -(CH2)n-CN; and n is 0,1 or 2. In another embodiment the present invention provides a compound of formula I wherein R* is -CN.
In one embodiment the present invention provides a compound of formula I wherein R^ is or phenyl, which is substituted by halogen.
In oneembodimenttbepresentinventionprovidesacompoundof formula! wherein R^ is hydrogen or Ci-Q-alkyl. In another embodiment the present invention provides a com¬pound of formula I wherein R^ is hydrogen or methyl.
In one embodiment the present invention provides a compound of formula I wherein R is Ci-C6-aIkyI, Cs-Ce-cycloalkji or benzyl. In another embodiment the present invention provides a compound of formula I wherein R is Cj-Cs-cj'cloalkyl. In another embodiment the present invention provides a compound of formula I wherein R is benzyl.
In one embodiment the present invention provides a compound of formula I wherein R is halogen; and m is 1.
Among compounds of the present invention certain compounds of formula T, or ph.arnia-ceutically acceptable salts thereof, are preferred.
Preferred compounds of formula I are those, wherein R' is hydrogen.
Also preferred are compounds of formula I, wherein R is CCi-C6)-aIk}d. Especially pre¬ferred are those, wherein R^ is me+bvl

Compounds of formula I, wherein R^ is Cs-Cg-c/cloalky) or benz}'l, are also preferred.
Preferred compounds of formula I are ftirther those, wherein R^ is KCHzin-CO-NH^R^ wherein R^ and R^ are independently from each other hydrogen or Ci-Cs-alk}'!, and n is 0, 1 or 2. Epecially preferred are those compounds, wherein R^ and R are hydrogen, and n is 0,1 or 2.
Even more preferred are compounds of formula I, wherein R' is -{CH2)n-CO-NR R , wherein R^ and R are hydrogen, and n is 0.
The following compounds are examples thereof:
2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quina2olin-3-yl]-acetamide,
2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-propionamide,
2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazolin'3-yl]-acetamide,
2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-propionamide,
2-[7-(3-fluoro-benzyioxy)-2-methyl-4-oxo-4H-quinazolin-3-yl]-acetamide, and
2-[2-cyclopropyI-7-(3-fluoro-benzylox>')-4-oxO'4H-qmna2oIin-3-yI]-acetamide.
Also preferred are compounds of formula I, wherein R^ is -(CH2)n-0R^, wherein R is hydrogen or Q-Ce-alkyl, and n is 0,1 or 2. Especially preferred are those compounds, wherein R* is methyl and n is 1.
Examples thereof are the following compounds: 7-(3-fluoro-benzyloxy)-3-(2-methoxy-ethyl)-3H-quinazolin"4-one, 7-(4-fluoro-benzyloxy)-3-(2-methoxy-ethyl)-3H-quLnazoIin-4-one, and 7-(3-fluoro-benzyloxy)-3-(2-methoxy-ethyl)-2-methyl-3H-quinazoHn-4-one.
Further preferred are compounds of formula I, wherein R^ is -(CH2)n-NR^R , wherein R and R are independently from each other hydrogen or Cj-Q-alkyl, and n is 0,1 or 2. Especially preferred within this group of compounds are those, wherein R^ and R are hydrogen, and n is 0^ 1 or 2.
The following compounds are examples thereof:
3-(2-aniino-ethyI)-7-(3-fluoro-ben2yIoxy}-3H-quinazoIin-4-one 1:2 hydrochloride, 3-(3-amino-propyl)-7-(3-fluoro-benzyloxy)-3H-quinazolin~4-one 1:2 hydrochloride, 3-(2-ainino-elhyl)-7-(4-fluoro-ben2:)'lox}0-3H-quinazolin-4-one 1:1 hydrochloride, and 2-f7-(3-£[uoro-ben2ylox)')-2-methyl-4-oxo-4fi-qmnazolin-3-yI]-ethyl-ammonium chloride.

Preferred compounds of formijla I are especially those, wherein R* is halogen or fluoro(Cj-C5)-a!kyl. More preferably, R^ is fluoro.
In another embodiment the present invention provides a compound of formula I selected from
2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazo]in-3-yIj-acetamide,
2-[7-(3-fluaro-benz)'loxy)-4-oxo-4H-quinazolin-3-yl]-propionamide,
2-[7-(4-fluoro-benzylox}')-4-oxo-4H-quinazolin-3-yl]-acetamide,
2-[7-(4-fluoro-benz)'loxy)-4-oxo-4H-quinazo]in-3-yl]-propionamide,
2-[7-(3-fluoro-benzyloxy),-2-methyl"4-oxo-4H-quinazolin-3-yl]-acetamide,
2-[2-cyclopropyl-7-(3-fliJOro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-acetamide,
7-(3-fIuoro-benzyloxy)-3-(2-methox}'-ethyl)-3H'quinazolin-4--one, ~
7-(4-fluDro-benzyIoxy)-3-(2-methoi:)'-ethyl)-3H-quLnazohn-4~one, 7-(3-fluoro-benzyloxy)-3'(2-methoxy-ethyl)-2-methyi-3H-quinazolin-4-one, 3-(2-aminO'ethyl)-7-(3-fiuoro-benzylox)')-3H-qmna2o!in-4-one 1:2 hydrochloride, 3-(3-amino-propyl)-7-(3-fluoro-benz)'loxy)-3H-quinazolxn-4-one 1:2 hydTOchloride, 3-(2-3mino-ethyl)-7-(4-fluoro-benzyloxy)-3H-quinazolin-4-one 1:1 hydrochloride, and 2-[7-(3-fluoro-benzyloxy)-2-methyl-4-oxo-4H-quinazolin-3-yl]-ethyl-ammonium chloride.
In a further aspect the present invention provides a process for the preparation of a compound of formula I and a pharmaceuticaUy acceptable salt thereof comprising reacting a compound of formula IV
( (IV)
wherein
R^ is hydrogen, Ci-Ce-allcyl, Ca-Cg-cycloalkj'l or benzyl;
R^ is halogen, fluoro(Ci-C6)'alkyl, cyano, Ci-Ce-alkoxy or fluoro(Ci-C6)-aIkory; and
m is 1, 2 or 3
with a compound of formula V
(V)

vherein
.^' is -(CH2)„-C0-NK^R^; -(CHz)n-COOR^; -(CH2)„-NRV; -(CH2)n-CN; -(CH2)n-0R^;
or phenyl, which is unsubstituted or substituted by one to three substituents selected
from halogen and fluoro(Ci-C6)-aIi:y'l; R.^ is hydrogen, halogen or Ci-Ce-allcyl;
R^ and R^ are independently from each other hydrogen or Q-Q-allcj'!; R^ is hydrogen or Ci-Cs-alkyi; R^ is hydrogen or Ci-Cs-aikyl; and n is 0,1 or 2;
and optionally converting the resulting compound of formula I into a pharmaceutically acceptable salt.
In one embodiment the compounds of general formula I and their pharmaceutically acceptable salts can be manufactured by reacting a compound of formula II

and, if desired, converting a compound of formula I into a pharroaceutically acceptable
salt, or alternatively,
reacting a compound of formula VI

to obtain a compound of formula IV which in turn is reacted with a compound of formula
V to obtain a compound of formula I
and, if desired, converting a compound of formula I into a pharmaceutically acceptable
salt
In accordance with the present invention, compounds of general formula I can be pre¬
pared following scheme 1: 2-Amino-4-fluorobenzoic acid VIII is heated in the presence of
formam.idine acetate IX which after basification of the reaction medium affords com¬
pounds of type Ila. Subsequent reaction with the sodium salts of ben2ylic alcohols of type
X affords compounds of type IVa which are then dissolved in l-methyl-2-pyrrohdone (
(NMP) and treated with sodium hydride and an electrophile of formula V to give com¬pounds of formula I, wherein R^ is hydrogen.

Alternatiyel)', compounds of genera] formula J can be prepared according to the following scheme 2: 4-Fluoro-2-nitro-benzonitrile XI is heated in the presence of HBr and the re¬sulting acid XII is esterified with acidic methanol to afford a compound of formula XIII. Subsequent reaction with the sodium salts of benzj'Hc alcohols of type X affords com¬pounds of type XTV, which are then hydrogenated to anilines of formula VI. Treatment with acetamidate hydrochloride of type VII in base (usually sodium methoxide) forms the quinazolinones IV which are then alkylated with compounds of type V to form the target compounds of formula I.

Pharmaceutically acceptable salts of compounds of formula I can be maniifactured readily according to methods known per se and taking into consideration the nature of the com¬pound to be converted into a salt. Inorganic or organic acids such as, e.g., hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric add, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceuti¬cally acceptable salts of basic compounds of formula I Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesjun or the like, basic amines or basic amino acids are suitable for the formation of pharmaceu-ticaDy acceptable salts of acidic compounds.
The compounds of formula I and their pharmaceutically acceptable salts 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 acut 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 t)'pes 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 metabohc dis¬orders such as obesity as well as the prevention and treatment of withdrawal syndromes induced.by.ahuse of alcohol, nicotine and other addictive drugs. Other treatable indica¬tions maybe reward deficiency syndrome (WO 01/34172), peripheral neuropathy caused by cancer chemotherapy (WO 97/33572), or the treatment of multiple sclerosis {WO 96/40095) and other neuroinflammatory diseases.
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 Schlaeger and Christensen [Cytotechnology, 15:1-13 (1998)]. After transfection, cells were homogeneised by means of a Polytron homogeneiser in 20 mM Tris HCl buffer, pH 8.0, containing 0.5 mM EGTA and 0.5 mM phenylmethanesulfonyi fluoride. Cell membranes were obtained by centrifugation at 45,000 xg and, after two rinsing step with 20 mM Tris HCl 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 spectro-photometric assay adapted from the method described by Zhou and Panchuk-VolosHna [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 pM N-acetyl-3,7,-diliydroxyphenoxazine (Amplex Red, Molecular Probes). The samples were further incubated for 30 min at 37°C in a final volume of 200 [il 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 (iM dorgyline for !MAO-A or 10 pM L-deprenyl for MAO-B. ICso 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 activities of compounds of formula I as measured in the assay described above are in the range of 10 fiM or Jess, typically of ] (iM or less, and ideally 0.3 (iM or less.
The compounds of formula I and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical prepa¬rations 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 admimstra-I tion can also be effected rectally, e.g. in the form of suppositories, or parenteraUy, e.g. in the form of injection solutions.
The compounds of formula I andpharmaceutically acceptable salts thereof can be pro¬cessed 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, e.g., as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, e.g-, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine cap¬sules. Suitable ca.rriers for the production of solutions and syrups are, e.g., water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble saltsofcompoundsof formula I, but as a rule are not necessary. Suitable carriers for suppositories are, e.g., natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical preparations can contain preservatives, soiubilizers, "'
stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.
As mentioned earlier, medicaments containing a compound of formula I or pharmaceuti-caHy acceptable salts thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutical!)' valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
The dosage can vary within wide limits and will, of comrse, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/ kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies betvv'een 0.7-1400 mg per day, preferably between 7 and 700 mg per day.
The following examples are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof. The term "room temperature" is abbreviated as "rt".
Example 1; 2-[7-(3-FIuoro-benzyloxy)-4-oxo-4H-quinazolin-3-y]]-acetamide
a) 7-Fluoro-3H-quinazolin-4-one: Amixture of 2-amino-4-fIuorobenzoic acid (14.6 g, 94 mmol) and formamidine acetate (19.6 g, 18,8 mmol) in 2-methoj:)'ethanol (110 mL) was heated at 130°C for 18 h. After cooling, the mixture was half evaporated and an off-white

solid formed. The mixture was diluted with ammonia (25%, 10 mL in 90 mL water) and thesolidfilteredoffand washed with water. The solid was then washed with hexane and dried underhighvacuumtoaffordthetitle compound (12.5 g, 81%) as an off-white solid. MS: m/e = 165.2 (M+H^).
h) 7-(3-Fluoro-benzvloxy)-3H-quinazolin-4-one: Sodium (1.8 g, 78.6 mmol) was added portionwise to 3-fluorobenzyl alcohol and the resulting mixture heated at 80-90 °C for 4 h under Argon. The resulting suspension was cooled to rt and 7-fluoro-3H-quinazoliii-4-one (3.2 g, 19.5 mmol) was added and the resulting mixture heated at 130-MCC for 14 h. The solid formed was then dissolved with water (400 mL) and the mixture acidified to pH 3-4 with HCl (4 N). The resulting precipitate was then filtered off, washed with water (100 mL) and diethylether (100 mL). RecrystaUisation from tetrahydrofiiran ; ethylacetate (1:1) afforded the title compound (3.2 g, 61%) as white crystals. MS: m/e = 271.3 (M-hH"^). c) 2-f7-(3-Fluoro-ben2yloxy)-4-oXQ-4H-quinazolin-3-yll"acetamide: A mixture of 7-(3-fiuoro-benzyloxy}-3H-quinazoIin-4-one (200 mg, 0.74 mmol) and sodium hydride (55%, 36 mg, 0.81 mmol) in N-methylpyrolidinone (5 mL) was heated at 60 °C for 1 h. Then bromacetamide (117 mg, 0.85 mmol) was added and the resulting mixture was heated at 80 "C for 1 h. After cooling to rt, water (50 mL) was added and the resulting precipitate was washed with methanol and diethylether and then dried under high vacuum to afford the title compound (200 mg, 83%) as an off-white soHd. MS: m/e = 328.3 (M+IT*").
Example 2: 2-[7~(3-FIuoro-benE)')ox7)-4-oxo-4H-qiiinazolin-3-yI]-propionamide
As described for example Ic, 7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one (200 mg, 0.74 mmol) was converted to the title compound (190 mg, 75%) (using 2-brompropionamide instead of bromacetamide) which was obtained as a white solid, MS: m/e = 342.3 (M+H"^).
Examples: 7-(3'Fluoro-benzyloxy)-3-(2-methoxy-ethyI)-3H-quinazolin-4-one
As described for example Ic, 7-(3-fiuoro-benzyIoxy}-3H-quinazolin-4-one (300 mg, 0.74 mmol) was converted to the title compound (165 mg, 68%) [using (2-broinoraethyl)-methyl ether instead of bromacetamide] which was obtained as a white soHd after crystal¬lisation from diethylether : heptane. MS: m/e = 342.3 (M-t-H"^).
Example 4: 3-(2-An:uno-ethyl)-7-(3-£luoro-benzyloxy)-3H-quinazoiin-4-one 1:2 hydrochloride
a) 2-[7-("3-Fluoro-ben2ylox:y-)-4-oxo-4H-quinazolin-3-yl1-ethvll-carbamic acid tert-butvl ester: As described for example Ic, 7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one (200 mg, 0.74 mmol) was converted to the title compound (175 mg, 57%) [using 2-(Boc-amino)-

ethylbromide instead of bromacetamide] which was obtained as a white soHd after crystal-Hsation from diethylether: heptane. MS: m/e = 342.3 (M+H^).
h) 3-(2-Aiiiino-etbyl)-7-f 3-fluoro-benzyloxy)-3H-quinazoHn-4-one 1:2 hydrochloride: A mixture of {2-[7-(3-£iuoro-ben2yIoxy)-4-oxo-4H-quinazoIin-3-yI]-ethyI|-carbamic acid tert-bnty! ester (150 mg, 0.36 mmol) and HCl in dioxane (4 N, 3 mL) was stirred at rt for 72 h. The precipitate was filtered off and washed with diethylether to afford the title com¬pound (120 jBg, 86%) as a white solid. MS: m/e = 314.3 (M+H^).
Example 5: [7-(3-Fluoro-benzylosy)-4-oxo-4H-quinazolin-3-yl]-acetic acid ethyl ester
As described for example Ic, 7-(3-fluoro-benZ7loxy)-3H-quinazolin-4-one (200 mg, 0.74
mmol) was converted to the title compound (170 mg, 65%) [using ethyl bromoacetate ,^
instead of bromacetamide] which was obtained as a white sohd. MS: m/e = 357.3 (M+H"^).
Example 6: Fiuoro-f7-(3-fluoro-benzyioxy)-4-oxo-4H-quinazoIin-3-yI]-acetic acid ethyl ester
As described for example Ic, 7-(3-fluoro-benzyloxy)-3H-qmnazolin-4-one (200 mg, 0.74 mmol) was converted to the title compound (100 mg, 36%) [using ethyl bromofluoro-acetate instead of bromacetamide] which was obtained as a white solid after purification by chromatography (SiOi, CH2CI2: 2N NHs/MeOH 99:1 to 9;1) and crj'stallisation fi-om diethylether : heptane. MS: m/e = 375.4 (M+H"").
Example 7: 2-[7-(3-Fluoro-benzyloxy)-4-oxo-4H-qmnazolin-3-yl]-propionic acid ethyl
ester (
As described for example Ic, 7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one (200 mg, 0.74 mmol) was converted to the title compound (240 mg, 88%) [using ethyl 2'bromo propi¬onate instead of bromacetamide] which was obtained as a colourless oil after purification by chromatography (SiO;, CH2CI2: 2N NHj/MeOH 99:1 to 9:1). MS: m/e = 3713 (M+H+).
Example 8: [7-(3-Fluoro-benzyloxy)-4-oxo-4H-qULnazolirL-3-yl]'acetic acid tert-butyl ester
As described for example Ic, 7-(3-fiuoro-benzyloxy)-3H-quinazolin-4-one (200 mg, 0.74 mmol) Vfas converted to the title compound (277 mg, 97%) [using tert-butyl-bromacetate instead of bromacetamide] which was obtained as a white solid after purification by chro¬matography (SiOi, CH2CI2:2N NHs/MeOH 99:1 to 9:1). MS: m/e = 385.3 (M+H"").

Example 9; 2-[7-(3-FIuorO'benz)']oxf)-4-oxo-4H-quii3azoIm-3-yI]-propionic add tert-butyl ester
As described for example Ic, 7-(3-fluQro-benzylox}0-3H-quinazolin-4-one (200 mg, 0.74 inmol) was converted to tbe title compound (245 mg, 83%) [using 2-bromopropionic acid tert-but}d ester instead of bromacetamide] which was obtained as a white solid after puri¬fication by chromatography (SiOj, CH^Ciz: 2N NHj/MeOH 99:1 to 9:1). MS: m/e ~ 385.3 (M+H^).
Example 10: 3-(3-Amino-propyl)-7-(3-fluoro-benzyloxy)-3H-quinazoIin-4-one 1:2 hydrochloride
a) i3-["7-f3-Fluoro-ben2yloxyV4-oxo-4H-quin3Zolin-3-yl1-propyU-carbamic acid tert-butyl esten As described for example Ic, 7-(3-fluoro-benzyloxy)-3H-quinazoIin-4-one (200 rag, 0.74 mmol) was comrerted to the title compound (312 mg, 99%) [using 3-(Boc-amino)propyl-bromide instead of bromacetamide] which was obtained as a white solid after purification by chromatography (SiOa, CHzCh: 2N NHj/MeOH 99:1 to 9:1). MS: m/e = 428.5 (M+H^).
b) 3-f3-Amino-propyl)-7-(3-fluoro-henzvIox)')-3H-quinazoIin--4-one 1:2 hydrochloride: A mixture of {3-[7-(3-fluoro-benzyIoxy)-4-oxo-4H-quinazolin-3-yl]-propyl}-carbamic acid tert-ibutyl ester (275 mg, 0.64 mmol) and HCl in dioxane (4 N, 8 mL) was stirred at rt for 16 h. The precipitate was filtered off and recrystaUised from EtOH : ether to afford the title compound (120 mg, 47%) as a white sohd. MS: m/e = 328.3 (M+H"").
Example 11: 3-(3-Fluoro-benzyl)-7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one
As described for example Ic, 7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one (200 mg, 0.74 mmol) was converted to the title compound (253 mg, 90%) [using 3-fluorobenzyl bromide instead of bromacetamide] which was obtained as a white solid after purification by chromatography (Si02, CHjCla: 2N NH3/MeOH 99:1 to 9:1). MS: m/e = 379.3 (M+H^).
Example 12: 2-[7-(4-Fluoro-benzyloxy)-4-oxo-4H-qumazohn-3-yl]-acetamide
a) 7-f4-Fluoro-bgnzvloxv)-3H-quinazolin-4--one: A mixture of sodium hydride (55%, 3r2 ■ g, 73 mmol), 4-fluoroben2yl alcohol (9.2 g, 73 mmol) and 7-fluoro-3H-qmnazohn-4-one (3.0 g, 18 mmol) in DMF (75 mL) was heated at 140 °C for 2 h. The resulting suspension was cooled to rt and the mixture acidified to pH 3 with HCl (cone). The resulting precipi¬tate was then filtered off, washed with water and diethidether. Partial purification by chro-

matography on silica gel eluting with ethyl acetate : hexane (2:1) afforded the title com¬pound (3.2 g, 66%) as an off-white sohd. MS: m/e = 271.3 (M+H""). b) 2-[7-(4-Fluoro-benz\4oxy')-4-oxo-4H-quinazQlin-3-vl1-acetamide: As described for example Ic, 7-(4-fluoro-ben2yloxy)-3H-quinazolin-4-one (Example 12a, 200 mg, 0.74 mmol) was converted to the title compound (20 mg, 8%) %) which was obtained as a white solid after purification by HPLC (Waters Xterra RP18 (5 fim x 50 xl9mni3 elating with AcCN/ 0.1%TFAAVater. MS: m/e = 32S.3 (M+H").
Example 13: 2-[7-{4-Fluoro-benzyIoxy)-4-oxo-4H-qmnazoIin-3-yI]-propionamide
As described for example Ic, 7-(4-fluoro-benzyloxy)-3H-quinazolin-4-one (400 mg, 1.5 mmol) was converted to the title compound (37 mg, 7%) (using 2-brorr)opropionamide , -instead of bromacetamide) which was obtained as a white solid after purification by HPLC (Waters Xterra RP18 (5 pm x 50 xl9mm) eluting with AcCN/ 0.1%TFA/Vv^ater. MS: m/e =
340.2 iU+it).
Example 14: [7-(4-Fluoro-benzyloxy)-4:-oxo-4H-qmnazolin-3-yl]-acetic acid ethyl ester
As described for example Ic, 7-(4-fluoro-benzylox)0-3H-quinazohn-4-one (400 mg, 1.5 mmol) was converted to the title compound (83 mg, 16%) (using ethyl bromoacetate instead of bromacetamide) which was obtained as a white solid after purification by HPLC (Waters Xterra RP18 (5 pm x 50 xl9mm) eluting with AcCN/ 0.1%TFAA\'ater. MS: m/e =
357.3 (MH-H^).
Example 15: 2-[7-(4-FJuoro-beiizyIoxy)-4-oxo-4H-quinazolin-3-yI]-propiomc acid ethyl ,. ester
As described for example Jc, 7-(4-fluoro-benzy]oxy)-3H-qmnazo]in-4-one (400 mg, 1.5 mmol) was converted to the tide compound (32 mg, 6%) (using ethyl-2-bromopropionate instead of bromacetamide) which was obtained as a white solid after purification by HPLC (Waters Xterra RP18 (5 pinx50xI9mn)) eluting with AcCN/0.1%TFAAVater. MS: m/e = 371.3 (M+H"^).
Example 16: " 7-(4-Fluoro-benzylox)')-3-(2-methoxy-efhyl)-3H-quinazolin-4-one
As described for example 3, 7-(4-fluoro-benzyloxy)-3H-quinazolin-4-one (400 mg, 1.5 mmol) was converted to the title compound (115 mg, 24%) which was obtained as a white solid after purification by HPLC (Waters Xterra RP18 (5 pmx 50 xl9mra) eluting with AcCN/ 0.1%TFA/W'ater. MS: m/e ^ 329.1 (M+H+j.

Example 17: 3-(2-Amino--ethyl)-7-{4--fluoro-ben2yloxy)-3H-qmiiazolin-4-one 1:1 hydrochloride
a) {2-[7-(4-Fluoro-benzTloxy)-4-oxo-4H-qmnazohr3-3-Yl!-ethvU-carbamic add tert-butyl ester: As described for examplelOa, 7-(4-fluoro-benzyIoxy)-3H-quinazoHn-4-one (300 mg, 1.1 mmol) was converted to the title compound (105 mg, 23%) which was obtained as a white solid after purification by HPLC (Waters Xterra RP18 (5 |im x 50 xl9mm) eluting with AcCN/ 0.1%TFA/Water. MS: m/e = 414.5 (M+H^).
b) 3-(2-Amino-ethyl)-7-(4-fluoro-ben.zyloxy')-3H-qmna2olLn-4-one 1:1 hydrochloride: As described for examplelOb, i2-[7-(4-fiuoro-benzylox)')-4-oxo-4H-quinazoIin-3-yl]-ethyl}-carbamic acid tert-butyl ester (102 mg, Q.25 mmol) was converted to the title compound (84 mg, 97%) which was obtained as a white sohd. MS: m/e = 314.2 (M+H"^).
Example 18: 3'[7-(4-Fluoro-benzyloxj')-4-oxo-4H-qumazolin-3-yl]-propionamide
As described for example Ic, 7-(4-fluoro-benzyloxy)-3H-quinazolin-4-one (300 mg, 1.1 mmol) was converted to the title compound (72 mg, 19%) (using 3-bromopropionamide instead of bromoacetamide) which was obtained as a white solid after purification by HPLC (Waters Xterra RP18 (5 \im x 50 xl9mm) eluting with AcCN/ 0.1%TFA/W^ater. MS: m/e = 342.1 (M+H"").
Example 19: 2-[7-(3-Fluoro-benzyloxy)-2-inethyl-4-oxo-4H-quinazolin-3-yl]-acetamide
a) 4-Fluoro-2-nitro-benzoic acid: A mbcture of 4-fluoro-2-nitro-benzonitrile (12.2 g, 73.7 mmol) suspended in HBr (48%, 74.5 mL, 664 mmol) was heated at 130 °C for 6.5 h. After cooling to rt water (1 L) was added and the resulting precipitate was washed with water andhexaneto afford the title compound (11.0 g, 81%) as a hght brown soHd. MS: m/e = 183.9 (M-H).
b) 4-Fluoro-2-nitro-benzoic acid methyl ester: A mixture of 4-fluoro-2-nitro-benzoic acid (10.9 g, 58.8mrnol)in methanol (120 mL) containing sulfuric acid (1-8 g, 18.7 mmol) was heated under reflux for 41 h. After cooling to rt the mixture was poured into sodium hydrogen carbonate (sat. 250 mL), and extracted with ethyl acetate (3 x 100 mL). The combined-extractswerewashedwith brine (100 mL) dried and evaporated to leave the_titl.e compound (10.7 g, 91%) as a light brown liquid. MS: m/e = 199.0 (M-H).
c) 4-(3-Fluoro-benzyloxy)-2-nitrO"benzQic acid (3-fluoro-beiizyl> ester and 4-f3-fluoro-benzyIoxy)-2-ni^ro-benzoic acid methyl ester: A mixture of 4-fluoro-2-nitro-benzoic acid methyl ester (9.2 g, 46.3 mmol), 3-f!uorobenzyl alcohol (16.7 g, 132.4 mmol) and potas¬sium carbonate (12.8 g, 92.6 mmol) in DMF (210 mL) was heated at 65 °C for 48 h. After

cooling to rt, the mixture was poured into water (400 mL), and extracted with diethyl ether (3x 100 mL). The combined extracts were washed with brine (100 mL) dried and evapo¬rated. Purification by chromatograph}'on silica gel eliiting with ethyl acetate :hexane (1:1) afforded the title compound (14.0 g, 76%) as a Hght yellow Hquid.
d) 4-f3-FIuorQ-benzvioxy')-2-nitro-ben2oic acid: A mixture of 4-(3-fluoro-benCTloxy")-2-
nitro-benzoic acid {3-f!uoro-benzyl) ester and 4-{3-fiuoro-benzyloxy)'2-nitro-benzoic
acid methyl ester (14.0 g, 35.0 mmol) inTHF (120mL) and water (120 mL), containing
hthium hydroxide monohydrate (2.94 g, 70.1 mmol) was stirred at rt for 48 h. Then the
mixture was poured into sodium hydroxide (2 N, 50 mL) and then the mixture extracted
with diethyl ether (3x150 mL). The aqueous phase was then adjusted to pH 2 with HCl.
Then the mixture was poured into sodium hydroxide (2 N, 50 mL) and the aqueous phase
was then adjusted to pH 5.2 with HCl then the mixture extracted with diethyl ether (3 x 100mL).Thecombinedextracts were then washed with brine (100 mL) dried and evapo¬rated to afford title compound (6.6 g, 65%) as a light yellow solid. MS: m/e = 290.0 (M-H).
e) 2-Amino-4-f 3-fluoro-benzyloxy)-benzoic acid: A mixture of 4-(3-f!uoro-benzyloxy)-2-
nitro-benzoic acid (7.2 g, 24.8 mmol) in ethyl acetate (150 m.L) in the presence of Pt/C
(5%, 1.0 g) was hydrogenated at rt and pressure for 3.5 h. The mixture was then filtered
and the filtrate was evaporated. The resulting light brown solid was triturated with di-
chloromethane (DCM) to afford the title compound (5.2 g, 80%) as an off-white solid.
MS: m/e = 260.1 (M~H).
Alternatively, a mixture of 4-(3-fluoro-benzyloxy)-2-nitro-benzoic acid (6,6 g, 22.8 mmol) in ethyl acetate (140 mL) in the presence of Pd/C (5%, 1.0 g) was hydrogenated at rt and pressure for 3.5 h. The mixture was then filtered and the filtrate was evaporated. The re-suiting light brown solid was triturated with DCM to afford the title compound (5.1 g, 87%) as an ofF-white solid.
f) 7-("3-Fluoro-benzv]oxy1-2-methyl-3H-quinazolin-4-one: To a mixture of 2-amino-4-(3-
fluoro-benzyloxy)-benzoic acid (2.0 g, 7.7 mmol) and ethyl acetamidate LI CI (1.9 g, 15.3
mmol) in methanol (30 ml) was added sodium methoxide (5.4 M, 0.S3 g, 15.3 mmol) and
the resulting mixture was heated under reflux for 19 h. After this time ethyl acetamidate
HCl (1.9 g, 15.3 mmol) and sodium methoxide (5.4 M, 0.83 g, 15.3 mmol) was added and
the resulting mixture heated for another 1 h. After cooling to rt the mixture was poured
into water (40 mL) and then the resulting precipitate was stirred for 2 h, and filtered off to
afford the title compound (2.1 g, 97%) as an off-white solid. MS: m/e = 283.1 (M-H).
g) 2-f7-f3-Fluoro-benz\']oxy)-2-methy]-4-oxo-4H-qmnazolir[-3-vn-acetamide: As
i described for example 1 c, 7-(3-fluoro-benzyloxy)-2-methyl-3H-quina2ohn-4'One (250 mg, 0.88 mmol) was converted to the title compound (218 mg, 73%) which was obtained as a white solid after trituration with dichloromethane (DCM). MS: m/e = 342.1 (M+H ).

Example 20: 7-(3-Fluoro-benz7loxy)-3-(2-methoxy-ethyl)-2-methyl-3H-qmnazoIin-4-one
\.s described for example 3, 7-(3-fluoro-benz)"loxy)-2-meth.yl-3H-quinazoliii-4-one (250 ng, 0.88 minol) was converted to the title compound (150 mg, 45%) wbicli was obtained IS a white solid after purification by chromatography (Si02,EtOAc:beptane 1:3 to 2:1). VIS: m/e = 343.1 (M+H^).
Example 21: 2-[7-(3-FluoTo-ben2yloxy)-2-methyl-4-oxo-4H-quinazolin-3-yl]-etiiyl-ammonium chloride
a) f2-[7-(3-Fiuoro-ben2vloxy')-2-methyl-4-oxo-4H-quinazolin-3-yl1-ethyU-carbamicacid tert-but\'l ester: As described for example 4a, 7-(3-fluoro-benzyIox)')-2-niethyl-3H-quin-azolin-4-one (250 mg, 0.88 mmo!) was converted to the title compound (72 mg, 18%) which was obtained as a white solid after purification by chromatography (Si02, EtOAc:heptane 1:4 to 2:1). MS: m/e = 428.3 (M+H*).
b) 2-[7-f3-Fluoro-benzvloxy)-2-methyl-4-oxo-4H-quinazolin-3-yn-ethyl-ammoniiim chloride: As described for example 4b, {2-[7-(3-fluoro-benzyloxy}-2-niefhyl-4-oxo-4H-quinazoIin-3-yl]-ethyl}-carbamic acid tert-butyl ester (50 mg, 0.12 mmol) was converted to the title compound (45 mg, 85%) which was obtained as a white solid after purification by cbromatography (SiOj, EtOAcrheptane 1:4 to 2:1). MS: m/e = 328.2 (M+H^).
Example 22: 2-[7-(3-Fluoro-benzyloxy)-2-isopropyl-4-oxo-4H-quinazolin-3-yl]-acet-amide
a) 7-{3-Fluoro-benzyloxvV2-isopTopyl-3H-qmnazolin-4-one: As described for example 19f, 2-amino-4-(3-fiuoro-benzyIoxy)-benzoic acid (1 g, 3.S mmol) was converted to the title compound (196 mg, 16%) [using ethyl isopropylamidate HCl instead of ethyl acet-amidate HCI] which was obtained as a white soKd after purification by chromatography (SiOi, dicbloromethane:MeOH 95:5 to 85:15). MS: m/e = 330.1 (M+NH4*).
b) 2-f7-l"3-Fluoro-benzvIoxy)-2-isopropyI-4-oxo-4H-quina2oIin-3-vI1-acetamide: As described for example Ic, 7'(3-fluoro-benz7loxy)-2-isopropyl-3H-quina2oUn-4-one (80 jng, 0-2j6_mm.ol) was converted to the title compound (84 mg, 89%) which was obtained as a white sofid after trituration with dichloromethane. MS: m/e - 370.2 (M+H'").

Example 23: [7-(3-FluorO"beTizylox7)-2-isopropyl-4-ox.o-4H-quinazoiin-3-yl]-aceto-nitrile
To a mixture of 2-[7-(3-fluoro-benzyloxy)-2-isopropyI-4-oxo-4H-quma2olin-3-yI]-acet-
amide (50 mg, 0.14 mmo!) in dimethylformamide (0.5 mL), dichloromethane (2 mL) was
added N-ethyl-N,N-diispropylamine (26.2 mg, 0.2 mmol) and the resulting mixture
cooled to -78 °C. Then trifluorosulfonic anhydride (49.6 mg, 0.18 mmol) was added and
the reaction mixture allowed to warm up to rt over 30 min. The resulting mixture was then
poured ointo sodium hydrogen carbonate (sat. 5 mL), and the mixture extracted with di-
ethylether (3x5 mL). The combined extracts were then washed with brine, dried and eva¬
porated to leave a light yellow solid. Purification by chromatography (SiOi, EtOAc:hept-
ane 1:1 to 85:15) afforded the tide compound (26 mg, 55%) as a white soJid MS; m/e = '
352.2 (M+H"^).
Example 24: 2-[2-Cyclopropyl-7-(3-fluoro-benzyloxy)~4-oxo-4H-quiiiazolin-3-yl]-acetamide
a) 2-CyclopropvI-7-(3-fluoro-benzyloxv"l-3H-quLna2olin-4-one: As described for example 19f, 2-amino-4-(3-fluoro-benzyloxy)-benzoic acid (1.0 g, 3.8 mmol) was converted to the title compound (607 mg, 49%) [using ethyl cyclopropyl-amidate HCl instead of ethyl acetamidate HCl] which was obtained as a white solid after trituration with dieth)dether-MS: m/e = 311.2 (M-l-H^).
b) 2-[2-Cvclopropyl-7-(3-fiuoro-benzvloxy)-4-oxO"4H-quinazolin-3-yl1-acetamide: As described for example Ic, 2-cyclopropyl-7-(3-fluoro-ben2yloxy)-3H-quinazoUn-4-one (80 mg, 0.26 mmol) was converted to the title compound (98 mg, 65%) which was obtained as a white solid after purification by chromatography (SiOn, dichioro-methane:MeOH 9S:2 to 9:1). MS: m/e = 368.1 (M-i-H"').
Example 25: 2-CyclopropyI-7-(3-fluoro-benzyloxy)-3-(2-methoxy-ethyl)-3H-quin-azoIin-4-one
As described for example 3, 2-cyclopropyl-7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one (150mg, 0.48 mmo]) was converted to the title compound (15 mg, 8%) which was Gb-_ _ tained as a white solid after purification by chromatography (Si02> dichloromethane : MeOH 95:5). MS: m/e = 369.2 (M4-H^).

Example 26:[2-CyclopropyI-7-(3-fiuoro-benzy]oxy)-4-oxo-4H-quinazoliii-3-yl]-acetic acid methyl ester
As described for example Ic, 2-cydopropyl-7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one (100 mg, 0.3 mmol) was converted to the title compound (33 mg, 27%) [using methyl bromoacetate instead of bromacetamide] which was obtained as a white solid after puri¬fication by chromatography (Si02, EtOAc:heptane 1:9 to 1:1). MS: m/e = 383.3 (M+H""}.
Example 27: 2-[2-Benzyl-7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yI]-acetamide
a) 2-Benz}d-7-(3-fluoro-benzyloxy)-3H-quin3zolin-4-one: As described for example 19f, 2-amino-4-(3-fluoro--benzyloxy)-benzoic acid (1.0 g, 3.8 mmol) was converted to the title compound (731 mg, 53%) [using ethyl benzylamidateHCl instead of ethyl acetamidate HCl] which "Was obtained as a white solid after trituration with diethylether. MS: m/e = 361.2 (M+H"").
h) 2- [2-Ben2yl-7-('3-fluoro-benzy]ox>0-4-oxo-4H-quinazoIin-3-yl1 -acetamide: As described for example Ic, 2-benzyl-7-(3-fluoro-benzyIoxy)-3H-quinazolin-4-one (150 mg, 0.42 mmolj was converted to the title compound (94 mg, 54%) which was obtained as a white solid after purification by chromatography (SiOa, dichlormethane : MeOH 99:1 to 9:1). MS: m/e = 418.2 (M+H"").
Example A: Tablets
Tablets of the following composition are produced in a conventional manner:
) mg/Tablet
Active ingredient 100
Powdered lactose 95
White corn starch 35
Polj-vinylpyrrolidone 8
i Na carboxymethylstarch 10
Magnesium stearate 2
Tabktweighf 250
Example B: Tablets
Tablets of the following composition are produced in a conventional manner:
mg/Tablet
Active ingredient 200

Powdered lactose 100
White corn starch 64
Polyvinylpyrrolidone 12
Na carboxymethylstarch 20
Magnesium stearate 4
Tablet weight 400
Example C: Capsxiles
Capsules of the foilowing composition are produced:
mg/Capsule
Active ingredient 50
Crystalline lactose 60
Microcrystalline cellulose 34
Talc 5
Magnesium stearate 1
Capsule fill weight 150
The active ingredient having a suitable particle size, the crystalline lactose and the microcrj'stalline 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 D: Injection solution
An injection solution may have the following composition and is manufactured in usua manner:
Active substance 1.0 mg
1 N HCl 20.0 ]xl
acetic acid 0.5 mg
NaCl 8.0 mg
phenol 10.0 mg
1 N NaOH q.s. ad pH 5
H2O q.s. ad 1 ml

1. A compound of formula I

wherein
R' is -{CH2)n-CO-NR5R6 -(CH2)«-CO0R7 -(CH2)„-NR5R6; -{CH2)„-CN; -(CH2)n-0R^;
or phenyl, which is unsubstituted or substituted by one to three substituents selected
from halogen and fLuoroCCrCsValk^'l; R^ is hydrogen, halogen or Ci-Q-aUcyl; R' is hydrogen, Ci-Q-alkyl, C3-C6-cyc!oalkyl or benzyl;
R^ is halogen, fluoro{CrC6)-alkyt, cyano, Q-Q-alkoxy or fluoro(Ci-Q)-alkox)'; R^ and R^ are independently from each other hydrogen or Cj-Ce-aLkyl; R' is hydrogen or d-Ce-aikyl; R^ is hydrogen or Ci-Q-alk)d; m is 1, 2 or 3; and n is 0,1 01 2; as well as pharmaceutically acceptable salts thereof.
2. The compound of formula I according to claim 1 wberein
R1 is -(CH2)n-C0-NIt5R69; -(CH2Jn-COOR7; -(CH2)n-NR5R6 -(CH2)n-CN; -(CH2)n-0R';
or phenyl, which is unsubstituted or substituted by one to three substituents selected
from halogen and fluoro{C1-C6)-aIkyl; R2 is hydrogen or C1-C6-alkyl
R3 is hydrogen, C2-Cg-alkyl, Cs-Ce-cycloallq'l or benzyl;
R'* is halogen, fluoro(Ci-C6)-alkyl, cyano, Q-Cfi-alkoxy or fluoro(Ci-C6)-alkox)'; R^ and R^ are independently from each other hydrogen or Ci-Ce-alkyl; R^ is hydrogen or Ci-Ce-alk)'!; R^ is hydrogen or Ci-Ce-alkyI; m is 1, 2 or 3; and n is 0,1 or 2; as well as their pharmaceutically acceptable salts.
3. The compound of formula I according to claim 1 selected from

2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoliii-3-yl]-acetamide,
2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-propionamide,
2-[7-(4-fIuoro-ben2yloxy)-4-oxo-4H-quinazoliii-3-yl]-acetamide,
2-[7-{4-fluoro-benzylox}0-4-oxo-4H-qmnazolin-3-yl]-propionainlde.
2-[7-(3-fluoTO-benzyloxy)-2-methyl-4-oxo-4H-qmnazolin-3-yl]-acetamide,
2-[2-cyclopropy!-7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-ylj-acetamide,
7'(3-fluoro-benzy]oxy)-3-(2-methoxy-etliyl)-3H-quinazolin-4-one,
7-(4-fluoro-benzyloxy)'3-(2-inethox)'-ethyI)-3H-quinazoUn-4-one,
7-(3-fluoro-benzyloxy)"3-(2-methoxji'-ethyl)-2-methyl-3H-qulnazolm-4-one,
3-(2-amiiio-ethyl)-7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one 1:2 hydrochloride,
3-(3-amino-propyl)-7-{3-fLuorO'benz)4oxy)-3H-quina2oIin-4-one 1:2 hydrochloride, _
3-(2-amiiio-ethyl)-7-(4-fluoro-benzyloxy)-3H-quinazolin-4-one 1:1 hydrochloride, and 2-[7-(3-fluoro-ben2yloxy)-2-methyl-4-oxo-4H-quinazol!n-3-yl]-ethyl-ammonium chloride.
4. A process for the preparation of a compound of foimula I according to claim 1 and a pharmaceutically acceptable salt thereof comprising reacting a compound of formula IV
(IV)
wherein
■R3 is hydrogen, C1-C6-allcyl, CB-Ce-cycloalkyl or benzyl;
R4 is halogen, fluoro(C1-C6)-alkyl, cyano, Ci-Cs-alkoxy or fluoro(C]-C6)-alkox}'; and
m is 1, 2 or 3
with a compound of formula V ,
(V)
wherein > R' is -(CH2)n-C0-KR5R6; -(CH2)n-C00R7 -(CH2)n-NR^R^ -(CH2)n-CN; -(CH2)i,-0R^;
or phenyl, which is unsubstituted or substituted by one to three substituents selected
from halogen and fluoro(C]-C6)-aJkl; R2 is hydrogen, halogen or C1-C6-alkyl; R5 and R are independently from each other hydrogen or CrQ-alk)'!;

R7is hydrogen or C1-C6-alkyl;
a
R is hydrogen or C1-alkyl; and
N is , 1 or 2;
And optionally converting the resulting compound of formula I into a pharmaceuticaJly
acceptable salt.
5. A medicament containing a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients for the treatment and prevention of diseases which are mediated by monoamine oxidase B inhibitors.
6. The medicament according to claim 5 for the treatment and prevention of Alzheimer's disease and senile dementia.
7. A compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, when manufactured by a process according to claim 4.
8. A compound of formula I according to claim 1 as well as a pharmaceutically acceptable salt thereof for the treatment or prevention of diseases.

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1222-chenp-2005 correspondence-others.pdf

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Patent Number

220431

Indian Patent Application Number

1222/CHENP/2005

PG Journal Number

30/2008

Publication Date

25-Jul-2008

Grant Date

28-May-2008

Date of Filing

13-Jun-2005

Name of Patentee

F. HOFFMANN-LA ROCHE AG

Applicant Address

Inventors:

#	Inventor's Name	Inventor's Address
1	THOMAS, Andrew, William
2	RODRIGUEZ-SARMIENTO, Rosa, Maria
3	WYLER, Rene

PCT International Classification Number

C07D239/90

PCT International Application Number

PCT/EP2003/013888

PCT International Filing date

2003-12-08

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	02027700.0	2002-12-13	EUROPEAN UNION