Title of Invention	IMIDAZO [4,5-B]QUINOLINE-DERIVATIVES FOR THE TREATMENT OF INFLAMMATORY DISEASES
Abstract	The compounds of formula I In which R1, R2, R3 and A have the meanings as given In the description are novel effective INOS Inhibitors.

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FORM 2 THE PATENT ACT 1970 (39 Of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See Section 10, and rule 13) TITLE OF INVENTION IMIDAZO[4,5-B] QUINOLINE- DERIVATIVES AND THEIR USE AS NO- SYNTHASE INHIBITORS APPLICANT(S) a) Name b) Nationality c) Address ALTANA PHARMA AG GERMAN Company BYK-GULDEN-STRASSE 2, D-78467 KONSTANZ, GERMANY PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed : - IMIDAZO (4,5-B) QUINOLINE-DERIVATIVES AND THEIR USE AS NO-SYNTHASE INHIBITORS Field of application of the Invention The invention relates to novel imidazo [4,5-b] quinoline derivatives, which are used in the pharmaceuti- cal industry for the production of pharmaceutical compositions. Known technical background In the German Patent Application DE 2504252 and in the European Patent Application EP 0125756 3H-imidazo [4, 5-b] pyridine derivatives with anti-ulcer activity are described. Description of the invention It has now been found that the novel imidazo [4,5-b] quinoline derivatives, which are described in greater details below, have surprising, unanticipated and particularly advantageous properties. The invention thus relates to compounds of formula I in which Rl is l-4C-alkoxy; A is l-4C-alkylene ; R2 is hydrogen; halogen ; hydroxyl; nitro; amino ; 1-7C-alkyl; trifluoromethyl; 3-7C-cycloalkyl; 3-7C- cycloalkyl-l-4C-alkyl; l-4C-alkoxy ; completely or predominantly fluorine-substituted l-4C-alkoxy ; l-4C-alkoxy-l-4C-alky; l-4C-alkoxy-14C-alkoxy ; mono-or di-l-4C-alkylaminocarbonyl ; mono- or di-14C-alkylaminosulfonyl ; 1-4C-alkylcarbonylamino ; l-4C-alkylsulfonylamino ; phenyl; phenyl- l-4C-alkyl; phenyl-l-4C-alkoxy ; R21-and/or R22-substituted phenyl; phenyl- 14C-alkyl wherein the phenyl moiety is substituted by R23; Het; R24-substituted Het; Het-l-4C-alkyl ; Het- l-4C-alkyl wherein the Het moiety is substituted by R25; in which R21 is cyano; halogen ; carboxyi ; l-4C-alkyl ; l-4C-alkoxy ; hydroxy-14C-alkyi ; l-4C-alkoxy-l-4C- alkyl ; 3-7C-cycloalkoxy ; 3-7C-cycloalkylmethoxy ; completely or predominantly fluorine- substituted 14C-alkoxy ; aminocarbonyl ; mono-or di-14C-alkylaminocarbonyl ; 1-4C- alkylcarbonylamino ; 14C-alkoxycarbonyl ; aminosulfonyl ; mono-or di-14C-alkylaminosulfonyl; amino; tdfluoromethyl; hydroxy); phenylsulfonylamino ; or phenyl-1-4C-alkoxy; R22 is halogen ; l-4C-alkyl; or 14C-alkoxy ; or wherein R21 and R22 together are a 1-2C-alkylenedioxy group; R23 is halogen ; l-4C-alkyl ; or 14C-alkoxy ; Het represents a mono-or bicyclic single or fused 5 to 10-membered heteroaryl radical containing one to three heteroatoms, each of which is selected from a group consisting of nitrogen, oxygen and sulfur, R24 is halogen; 1-4C-alkyl; or 14C-alkoxy ; R25 is halogen ; l-4C-alkyl; or 14C-alkoxy ; R3 is hydrogen ; halogen ; l-4C-alkyl ; or 14C-alkoxy ; the salts; the N-oxides; and the salts of the N-oxides of these compounds. 1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals. 2 1-7C-Alkyl is a straight-chain or branched alkyl radical having 1 to 7 carbon atoms. Examples are the heptyt isoheptyi (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3, 3-dimethylbutyl), pentyl, isopentyl (3-methylbutyi), neopentyl (2, 2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals. 14C-Alkylene is a straight chain alkylen radical having 1 to 4 carbon atoms. Examples which may be mentioned in this context are the methylene (-CH2-), ethylene (-CH2-CH2-), trimethylene (-CH2-CH2-CH2-) and the tetramethylene (-CHz-CH2-CH2-CH2-) radical. l-4C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned in this context are, for example, the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, iso- propoxy, ethoxy and methoxy radicals. l-2C-AIieylenedioxy represents, for example, the methylenedioxy [-0-CH2-O-] and the ethylenedioxy [-0-CH2-CH2-0-] radicals. 3-7C-Cycloalkyl stands for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cydopropyl, cyclobutyl and cyclopentyl are preferred. 3-7C-Cycloalkoxy stands for cyclopropoxy, cyclobutoxy, cydopentoxy, cyclohexoxy and cydoheptoxy, of which cyclopropoxy, cyclobutoxy and cyclopentoxy are preferred. 3-7C-Cycloalkyl-l-4C-alkyl stands for one of the abovementioned l-4C-alkyl radicals, which is substi- tuted by one of the abovementioned 3-7C-cycloalkyl radicals. Examples which may be mentioned are the cyclopropylmethyl, the cyclohexylmethyl and the cyclohexylethyl radicals. 3-7C-Cycloalkylmethoxy represents cydopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cydohexylmethoxy and cycloheptylmethoxy, of which cydopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred. Halogen within the meaning of the present invention is bromine, chlorine or fluorine. Completely or predominantly fluorine-substituted 14C-alkoxy is, for example, the 2,2, 3,3, 3-pentafluoropropoxy, the perfluoroethoxy, the 1,2, 2-tdfluoroethoxy and in particular the 1,1, 2, 2-tetrafluoroethoxy, the 2,2, 2-trifluoroethoxy, the trifluoromethoxy and the difluoromethoxy radical, of which the difluoromethoxy radical is preferred. "Predominantly "in this connection means that more than half of the hydrogen atoms of the l-4C-alkoxy radical are replaced by fluorine atoms. 1-4C-Alkoxy-14C-alkoxy stands for one of the abovementioned l-4C-alkoxy radicals which is substi- tuted by the same or another of the abovementioned 1-4C-alkoxy radicats. Examples which may be mentioned are the 2-(methoxy)ethoxy (-0-CH2-CH2-0-CH3) and the 2-(ewthoxy)ethoxy radical (-0-CH2- CH2-0-CH-CH3). l-4C-Alkoxy-l-4C-alkyl stands for one of the abovemenGoned 14C-alkyl radicals which is substituted by one of the abovementioned l-4C-alkoxy radicals. Examples which may be mentioned are the 2-methoxyethyl, the 2-ethoxyethyl and the 3-methoxypropyl radical. 3 Hydroxy-1 C-alkyl stands for one of the abovementioned 1-C-alkyl radicals which is substituted by a hydro,, group. Examples which may be mentioned are the 1-hydroxymethyl, the 2-hydroxyethyl and the 3-hydroxyypropyl radical. Mono-or Di-l-4C-aIlsylamino radicals contain in addition to the nitrogen atom, one or two of the abovementioned 14C-alkyl radicals. Preferred are the di-l-4C-alkylamino radicals, especially the di- methylamino, the diethylamino and the diisopropylamino radical. Mono-or Di-l-4C-alkylaminocarbonyl radicals contain in addition to the carbonyl group one of the abovementioned mono-or di-l-4C-alkylamino radicals. Examples which may be mentioned are the N-methyl-the N, N-dimethyl-, the N-ethyl-, the N-propyl-, the N, N-diethyl- and the N-isopropylaminocarbonyl radical. Mono-or Di-l-4C-alkylaminosulfonyl stands for a sulfonyl group to which one of the abovementioned mono-or di-l-4C-alkylamino radicals is bonded. Examples which may be mentioned are the methyl- aminosulfonyl, the dimethylaminosulfonyl and the ethylaminosulfonyl radical. An 1-4C- Alkylcarbonylamino radical is, for example, the propionyiamino [C3H7C (O) NH-] and the acetylamino radical [CH3C (O) NH-]. An l-4C-Alkylsulfonylamino radical is, for example, the propylsulfonyiamino [C3H, S (0) 2NH-] and the methylsulfonylamino radical [CH3S (0) 2NH-]. l-4C-Alkoxycarbonyl is a carbonyl group to which one of the abovementioned l-4C-alkoxy radicals is bonded. Examples are the methoxycarbonyl [CH30-C(0)-] and the ethoxycarbonyl [CH3CH20-C (OH radical. Phenyl-l-4C-alkoxy stands for one of the abovementioned l-4C-alkoxy radicals, which is substituted by the phenyl radical. Examples which may be mentioned are the benzyloxy and the phenethoxy radi- cal. Phenyl-14C-alkyl stands for one of the abovementioned 14C-alkyl radicals, which is substituted by a phenyl radical. Examples which may be mentioned are the phenylethyl and the benzyl radical. N-oxide denotes the N-oxide on the pyridine which is substituted by Rl. Het represents a mono-or bicyclic single or fused 5 to 10-membered heteroaryl radicai ontaining one to three heteroatoms, each of which is selected from a group consisting of nitrogen, oxygen and sulfur, and includes, for example, without being restricted to furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzo-fused analogues thereof, such as, for example, benzofuranyl, indolyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzoxazolyl or quinolinyl, or imidazopyridinyl or imidazopyridazinyl. Preferably, the bicyclic fused 9- or 10 membered heteroaryl radicals, such as, for axample, the banzo-fused analogues (e.g. benzofuranyl, indolyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzoxazoty) or quinoiinyi) or imidazopyridinyl or imidazopyridasinyi, are to be men- tioned, whereby said benzo-fused analogues are particularly preferred. 4 Het-l-4C-alkyl stands for one of the abovementioned l-4C-alkyl radicals, which is substituted by one of the abovementioned Het radicals. Examples which may be mentioned are the Het-ethyl and the Het- methyl radical, particularly, the pyridylethyl and the pyridylmethyl radical. The person skilled in the art is aware on account of his/her expert knowledge that, with regard to the R24-substituted or R25-substituted Het radical, certain combinations of the substituents R24 or R25 with the Het radical would lead to chemically less stable compounds. This can apply, for example, to certain 5-membered Het radicals which are substituted with an electron rich radical, such as, for exam- pie, the l-4C-alkoxy radical might be. With regard to the R24-substituted or R25-substituted Het radi- cal, those compounds according to the invention, in which the combination of the substituent R24 or R25 with the Het radical does not lead to chemically less stable compounds, are therefore preferred. If Het represents a R24-substituted or R25-substituted benzo-fused Het radical, the Het radical is pref- erably substituted on the benzo ring. Exemplary unsubstituted heteroaryl radicals Het which may be mentioned are furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, lH-pyrrol-2-yl, lH-pyrrol-3-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imi- dazol-4-yl, imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isoxazol-4-yl, isoxazol-5-yi, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, [1,2, 3] thiadiazol-4-yl, [1,2, 3] thiadiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-2-yl, pyridazin-4-y), pyridazin-3-yl, pyrazin-2-yl, indol-2-yl, indol-3-yl, benzofuran-2-yl, benzofuran-3-yl, ben-zothiophen-2-yl and benzothiophen-3-yi. Suitable salts for compounds of the formula I - depending on substitution-are all acid addition salts or all salts with bases. Particular mention may be made of the pharmacologically tolerable inorganic and organic acids and bases customarily used in pharmacy. Those suitable are, on the one hand, water- soluble and water-insoluble add addition salts with adds such as, for example, hydrochloric acid, hy- drobromic acid, phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulphosalicylic acid, maieic acad, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, tolue- nesulphonic acid, methanesulphonic acid or 3-hydrogcy-2-naphthoic acid, the acids being employed in salt preparation-depending on whether a mono-or polybasic acid is concerned and depending on which salt is desired- in ah. equimoiar quantitative ratio or one differing therefrom. On the other hand, salts with bases are-depending on substitution-also suitable. As examples of salts with bases are mentioned the lithium, sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium, moglumine or guanidinium salts, here, too, the bases being employed in salt prepa- ration in an equimoiar quantitative ratio or one differing therefrom. Pharmacologically intolerable salts, which can be obtained, for example, as process products during the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically tolerable salts by processes known to the person skilled in the art. According to experts knowledge the compounds of the invention as well as their salts may contain, e. g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore all solvates and in particular all hydrates of the compounds of formula I as well as all solvates and in particular all hydrates of the salts of the compounds of formula 1. 5 Compounds of formula I to be emphasized are those in which Rl is l-4C-alkoxy ; A is 14C-alkylene ; R2 is hydrogen; halogen ; l-7C-alkyl ; trifluoromethyl ; l-4C-alkoxy ; completely or predominantly fluo- rine-substituted l-2C-alkoxy ; phenyl; R21-and/or R22-substituted phenyl; or Het; wherein R21 is l-4C-alkyl ; 14C-alkoxy ; hydroxy- 14C-alkyl ; l-2C-alkoxy-l-2C-alkyl ; completely or predomi- nantly fluorine-substituted l-2C-alkoxy ; R22 is l-4C-alkoxy ; Het represents a bicyclic fused 9-or 10-membered heteroaryl radical containing one to three het-eroatoms, each of which is selected from a group consisting of nitrogen, oxygen and sulfur ; R3 is hydrogen; the salts ; the N-oxides ; and the salts of the N-oxides of these compounds. Preferred compounds of formula I are those wherein either Rl is methoxy ; A is ethylene ; R2 is hydrogen; halogen ; l-4C-alkyl ; l-4C-alkoxy ; R21- and/or R22-substituted phenyl ; or Het ; wherein R21 is l-4C-alkoxy; R22 is l-4C-aikoxy; Het is benzofuranyl; or benzothiophenyl; R3 is hydrogen ; or Rl is methoxy; A is ethylene ; R2 is hydrogen ; halogen; l-4C-alkyl; l-4C-alkox ; R21-substituted phenyi ; or Het ; wherein R21 is hydroxy-l-4C-alkyl ; Het is benzofuranyl ; or benzothiophenyl; R3 is hydrogen; the salts ; the N-oxides ; and the salts of the N-oxides of these compounds. Examples of imidazo[4,5-b]quinoline compounds within he scope of this invention are : 2- [2-(4- methoxypyridin-2-yl)ethyl]-3H-imidazo[4,5-b]quinoline, 2-[2-(4-methoxypyridin-2-yl)ethyl]-7- methyl-3H-imidazo [4,5-b] quinoline, 2-[2-(4-methoxypyridin-2-yl)ethyl]-5-methyl-3H-imidazo [4, 5-b] quinoline, 7-methoxy-2- [2- (4-memoxypyridin-2-yljeihyl]-3H-imidazo [4, 5-bJquinoline, 7- bromo-2- [2-(4-methoxypyridin-2-yl)ethyl]-3H-imidazo[4,5-b]quinoline, 7-(4- hydroxymethylphenyl)-2-[2-(4-methoxypyridin-2-yl)ethyl]-3H-imidazo [4, 5-b] quinoline, 7-benzofuran-2-yl-2-[2-(4-methoxypyridin-2-yl)ethyl]-3H-imidazo [4, 5-b] quinoline, 7- (3,4-dimethoxyphenyl)-2-[2-(4-methoxypyridin-2-yl)ethyl]-3H-imidazo[4,5-b]quinoline, the salts, the N-oxides and the safts of the N-oxides of these compounds. A special embodiment of the compounds of the present invention include those compounds of formula I in which Rl is methoxy. Another special embodiment of the compounds of the present invention include those compounds of formula I in which A is ethylene. A further special embodiment of the compounds of the present invention include those compounds of formula I in which R3 is hydrogen. Still a further special embodiment of the compounds of the present invention include those compounds of formula I in which Rl is methoxy and A is ethylene. Still a further special embodiment of the compounds of the present invention include those compounds of formula I in which Rl is methoxy, R3 is hydrogen and A is ethylene. The compounds of fomnula I according to the invention can, for example, be prepared as described in the following examples according to the following reaction schemes or as known to one of ordinary skill in the art, e. g. in a manner similar or analogous to art-known processes. In reaction scheme 1 the synthesis of compounds of formula 1, in which Rl is l-4C-alkoxy, A is ethyl- ene and R2 and R3 independently of one another have the meanings indicated above, is 6 described, whereby each reaction step can be carried out as specified by way of example in the following exam- pies or analogously or similarly thereto or as known to the person skilled in the art. In a first reaction step the nitro group of the commercially available 4-nitro-2-picoline-N-oxide is ade is ex- changed by a l-4C-alkoxy group. The resulting 4- (l-4C)-alkoxy-2-picoline-N-oxide (compound of for- mula Viril) is then converted via a rearrangement into a compound of formula VI, which is oxidized to give 4-(l-4C)-alkoxy-pyridin-2-carbaldehyde (compound of formula VI). The carbon chain in 2-position of the compounds of formula VI is lengthened, for example, by a con- densation (with a malonic acid derivative) and a subsequent hydrogenation reaction. Alternatively, the carbon chain can be lengthened using a Wittig reaction followed by a hydrogenation reaction. In the last step the methyl 3- (4- (l-4C)-alkoxypyridin-2-yl) propionate (compound of formula) IV) or the corresponding acid (compound of formula Hi) are converted with a 2, 3-diaminoquinoline derivative (compound of formula 11) to give the compounds of formula 1. The synthesis of 4-methoxy-pyridin-2-carbaldehyde (compound of formula VI) is described for example in Ashimori et al, Chem Pharm Bull 38,2446-2458 (1990). The synthesis of 3- (4-methoxypyddin-2-yl) propionic acid (compound of formula ii) is described in the following examples or can be carried out as known to one of ordinary skill in the art. 7 Reaction scheme 1 : a.) NaRl/MH b.) 1. AC20 2. NaOH c.) 4-Methoxy-TEMPO/NaOCI d. ) Monomethyl malonate potassium saltlpiperldinelpyridine e. ) H2/Pd/C (10%) f. ) NaOH g. ) Polyphosphoric acid The compounds of formula 11 are either known or can, for example, be prepared as described in the following examples according to reaction schemes 2 or 3. In reaction schemes 2 and 3 the synthesis of compounds of formula 11 in which R2 and R3 independ- ently of one another have the meanings indicated above is described exemplarily whereby each reac- tion step can be carried out as described by way of example in the following examples or in a manner known to the person skilled in the art or similarly or analogously thereto. In a first reaction step the commercially available mucobromic acid is converted into the nitro contain- ing dialdehyde compounds of formula Xiil, which are transformed with commercially available or by art- known methods synthetically available aniline derivatives of formula XIV, in which R2 and R3 have the meanings given above, into the propenal derivatives of formula XII. These compounds of formula Xil are converted by a ring closure reaction to the corresponding quinoline derivatives of formula Xi. Sub- sequent N-oxide formation reaction gives the corresponding quinoline N-oxide derivatives of formula X which are subjected sequentially to a chlorination reaction, to a substitution reaction of the chlorine atom by an amino radical and to a reduction reaction of the nitro radical to furnish the desired 2, 3- diaminoquinoline derivatives of formula II. Reaction scheme 2: a.) NaN02 b. ) HCI c.) acetic acid d. ) H202 e.) Poof.) NH3g.) MfC/Hz or FeCI31CINH2NH2 Alternatively, compounds of formula IX, in which R2 and R3 independently of one another have the meanings indicated above, can be also prepared according to reaction scheme 3. Commercially avail- able or by art-known methods synthetically available quinoline N-oxide derivatives of 8 formula XV, in which R2 and R3 have the meanings given above, are subjected sequential to a nitration reaction and a chlorination reaction to give desired compounds of formula IX. Reaction scheme 3: a. ) AgN03 b.) POC13 The compounds of formula) can be converted, optionally, into their N-oxides, for example with the aid of hydrogen peroxide in methanol or with the aid of m-chloroperoxybenzoic acid in dichloromethane. The person skilled in the art is familiar on the basis of his/her expert knowledge with the reaction condi- tions which are specifically necessary for carrying out the N-oxidation. It is known to the person skilled in the art that if there are a number of reactive centers on a starting or intermediate compound it may be necessary to block one or more reactive centers temporarily by pro- tective groups in order to allow a reaction to proceed specifically at the desired reaction center. A de- tailed description for the use of a large number of proven protective groups is found, for example, in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The substances according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or sub- jecting it to one of the customary purification methods, such as column chromatography on a suitable support material. Salts are obtained by dissolving the free compound in a suitable solvent (for example a ketone like acetone, methylethylketone, or methylisobutylketone, an ether, like diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol, such as ethanol, isopropanol) which contains the desired acid, or to which the desired acid is then added. The salts are obtained by filtering, reprecipitating, precipitating with a non- solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by basi- fication into the free compounds which, in turn, can be converted into salts. In this manner, pharma- cologically non-tolerable salts can be converted into pharmacologicallytolerable salts. The following examples illustrate the invention in greater detail, without restricting it. Suitably, the con- versions are carried out analogously to methods which are familiar per se to the person skilled in the art, for example, in the manner which is described in the following examples. As well, further com- pounds of formula 1, of which the preparation is explicitly not described, can be prepared in an analo- gous way or in a way which is known by a person skilled in the art using customary preparation meth- ods. Having described the invention in detail and by reference to the embodiments thereof, the scope of the present invention is not limited only to those described embodiments. As it will apparent to persons skilled in the art, modifications, variations and adaptations to the described invention can be 9 made on the base of the disclosure (e. g. the explicite, implicite or inherent disclosure) of the present invention without departing from the spirit and scope of this invention. The compounds, which are mentioned in the examples as well as their salts, their N-oxides and the salts of the N-oxides are preferred compounds of the invention. Examples : Final products: General procedure for the synthesis of compounds 1 to 5: 1 mmol of 3-(4-methoxypyridin-2-yl)propionic acid (mentioned as compound Fl) is added portionwise at 100-110°C to a solution of 1 mmol of the appropriate 2, 3-diaminoquinoline compound (mentioned as compound Al, compound Bl, compound CI, compound Dl or compound El) in 1. 2 g of polyphos- phoric acid. After stirring for 5-10 h at 120-165°C, the reaction mixture is cooled to room temperature, treated with 2 g of ice and neutralized with aqueous 5 N sodium hydroxide solution. The mixture is extracted three times each with 5 mi of dichloromethane. The organic phase are dried using magne- sium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel. The final compounds 1 to 5 are obtained as colourless solids. 1. 2-[2-(4-Methoxypyridin-2-yl)ethyl]-3H-imidazo[4,5-b]quineline EF: C18H16N40 MS : cale. : 304. 3 fnd : 305.1 [MH+] 2. 2-[2-(4-Methoxypyridin-2-yl)ethyl]-7-methyl-3H-imidazo[4,5-b]quinoline EF : C19H18N40 MS : calc. : 318. 4 fhd : 319. 3 [MHI 3. 2- [2-(4-Methoxypyridin-2-yl)ethyl]-5-methyl-3H-imldazo[4,5-b]quinoline EF: C19H18N40 MS: calc. : 318. 4 fnd: 319.3 [MH+] 4. 7-Methoxy-2-[2-(4-methoxypyridin-2-yl)ethyl]-3H-Imidazo[4,5-b]quinoline EF: C19H18N402 MS: calc.: 334.4 fnd: 335.3 [MH+] 5. 7-Bromo-2-[2-(4-methoxypyridin-2-yl)ethyl]-3H-imidazo[4,5-b]quinoline EF: C18H15BrN40 MS: caic. : 383. 2 fnd: 385.2 [MH+] General procedure for the synthesis of compounds 6 to 8: 1 mmol of 7-bromo-2- [2- (4-methoxypyridin-2-yl) ethyl]-3H-imidazo [4,5-b] quinone (compound 5) and 1 mmol of the appropriate commercially available boronic aCd known to the person skilled in the art are dissolved in 32 ml of dioxane. After addition of 3.6 ml of 2N aqueous sodium hydrogencarbonate solu- tion and 50 mg of trans-dichloro-bis- (cyclohexylphosphine) palladium, the reaction mixture is stirred under reflux over night. The resulting precipitate is tittered off, washed with dioxane and stirred in methanol. The solid is collected and dried to give the final compounds 6 to 8 as coloudess crystals. 6. 7-(4-Hydroxymethylphenyl)-2-[2-(4-methoxypyridin-2-yl)ethyl]-3H-imidazo[4,5- blauinoline EF: C2sH22N402 MS: calc. : 410.5 fnd : 411.4 [MH+], 843.0 [2MNa+] 7. 7-Benzofuran-2-yl-2-[2-(4-methoxypyridin-2-yl)ethyl]-3H-imdiazo[4,5-b]quinoline EF: C26H20N4O2 MS: calc. : 420.5 fnd : 421.3 [MH+] 8. 7-(3,4-Dimethoxyphenyl)-2-[2-(4-methoxypyridin-2-yl)ethyl]-3H-imidazo[4,5-b]quinoline EF: C26H24N403 NS : calc: 440. 5 fnd: 441. 4 [MHI Starting compounds: Al. 2,3-Diaminoquinoline Compound Al can be prepared according to K. S. Sharma et al. Synthesis 1981,4, 316-318 and Ochiai, Kaneko et al. Chem. Pharm. Bull. 1959,7, 267,272, 273,275 starting from commercially avail- able quinoline N-oxide. A2. 2. 3-Diamino-8-methylquinoline 0.4 g of palladium on active carbon (5% Pd) is added to a solution of 1.1 g of 2-amino-3-nitro-8- methylquinoline (compound Bl) in 50 mi of methanolRetrahydrofurane 1: 1 and the resulting suspension is hydrated for 1 h. The catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel using dichloromethane/nethanol 10 : 1 to give 0. 79 g of the title com- pound as colourless solid. EF: C10H11N3 TLC : Rf=0. 13 (dichloromethenelmethanol 10: 1) MS : calc. : 173. 2 fnd: 174. 3 [MH+1 A3. 2. 3-Diamino-6-methylquinoline 0. 24 g of palladium on charcoal (10% Pd) is added to a solution of 1. 32 9 of 2-amino-3-nitro-6- methylquinoline (compound B2) in 100 ml of ethanol/tetrahydrofurane 1:1. After hydration for 1. 5 h, the catalyst is filtered off and the filtrate 10 is concentrated in vacuo, the residue is chromatographed on silica gel (dichbromethane/methanol 8 : 1). 1.02 g of the titl compound are obtained as colourless solid. EF: C10H11N3 TLC : Rf = OA3 (dichloromethanelmethanol 10: 1) A4. 2. 3-Diamino-6-methoxyquinoline 10 mg of palladium on charcoal (10% Pd) are added to a solution of 0.64 g of 2-amino-3-nitro-6- methoxyquinoline (compound B3) in 40 mi of methanol/tetrahydrofurane 1:1. After hydration for 0.5 h, the catalyst is filtered off and the filtrate is concentrated in vacuo. 0. 38 g of the title compound are ob- tained as light yellow solid. EF: C10H11NO3 TLC: Rf = 0.36 (dichloromethane/methanol 6: 1) A5. 6-Bromo-2, 3-diaminoquinoline 76 mg of ferric bichloride and 125 mg of charcoal are added successively to a suspension of 0.5 g of 2- amino-6-bromo-3-nitroquinoline (compound B4) in 15 ml of methanol. Under reflux 0. 4 mi of hydrazin- ium hydrate are added dropwise and reflux is continued for 3 h. After cooling to room temperature, the solids are filtered off and the filtrate is concentrated in vacuo. The residue is redissolved in 15 ml of dichloromethane/methanol 1: 1 and extracted three times each with 15 ml of 0.25 M aqueous ethylene diamine tetraacetic acid (EDTA) solution. The organic layer is dried over magnesium sulfate, filtered and evaporated in vacuo to give 0.32 g of the title compound as brown residue. EF: C9H8N3Br TLC: Rf = 0.71 (dichloromethane/methanol 9: 1) MS: calc. : 237. 2 fhd: 238.3 [M~ Bl. 2-Ainine-3-nitro-8-methylquinoline 1. 6 g of 2-chloro-8-methyl-3-nitroquinoline (compound CI) is dissolved in 70 mi of ethanolic ammonia solution and stirred at 130°C for 18 h in an autoclave. After cooling to room temperature, the reaction mixture is concentrated in vacuo and the residue recrystallized from ethyl acetate. 1. 2 g of the title compound are obtained as red solid. EF: C10H9N3O2 TLC: Rf = 0.55 (toluene/acetone 9: 1) MS : cale. : 203. 2 fhd: 204-0 [MH+1 B2. 2-Amine-6-methyl-3-nitroquinoline 2.0 g of 2-chloro-6-methyl-3-nitroquinoline (compound C2) is dissolved in 100 ml of ethanolic ammonia solution and stirred at 130°C for 6 h in an autoclave. After cooling to room temperature, the reaction mixture is concentrated in vacuo and the residue redissolved in 50 ml of ethyl acetate and extracted two times each with 50 ml of halfsaturated aqueous potassium carbonate solution. The organic phase is dried using magnesium sulfate, filtered and evaporated in vacuo. The residue is filtered over silica gel (dichloromethane). 1. 5 g of the title compound are obtained as violet solid. EF: C10H9N3O2 TLC: Rf = 0.20 (dichloromethane) B3.2-Amino-6-methoxv-3-nitroquinoline 0.75 g of 2-chloro-6-methoxy-3-nitroquinoline (compound C3) are dissolved in 70 ml of ethanolic ammonia solution and stirred at 125°C for 6 h in an autoclave. After cooling to room temperature, the re- action mixture is concentrated in vacuo and the residue redissolved in 30 mi of ethyl acetate and ex- tracted two times each with 30 mi of halfsaturated aqueous potassium carbonate solution. The organic phase is dried using magnesium sulfate, filtered and evaporated in vacuo. The residue is filtered over silica gel (dichloromethane/methanol 8: 2). 0.64 g of the title compound are obtained as violet solid. EF: C10H9N3O3 TLC: Rf = 0. 15 (dichloromethane) B4. 2-Amino4-bromo4-nitroquinoline 0.8 g of 2-chloro-6-bromo-3-nitroquinoline (compound C4) are dissolved in 12 ml of ethanolic ammonia solution and stirred at 120°C for 2.5 h in an autoclave. Under cooling in an ice bath, 0.55 g of the title compound precipitate from the reaction mixture as red crystals. 11 EF: C9H6N302Br TLC: Rf = 0.55 (petroleum ether/ethyl acetate 7: 3) MS: calc. : 267.2 fnd: 268.2 [MH+] C9. 2-Chloro-8-methyl-3-nitroquinoline A suspension of 2. 0 g of 3-nitro-8-methyl-quinoline-1-oxide (compound Dl) in 15 ml of phosphorus oxychloride is. stirred at 100°C for 1 h. After cooling to room temperature, the reaction mixture is added to 40 ml of ice water and diluted with 50 ml of ethyl acetate. With the aid of solid potassium carbonate the pH value is adjusted to pH 8 and the mixture is extracted two times each with 30 ml of ethyl ace- tate. The combined organic phases are dried using magnesium sulfate, filtered and evaporated in vacuo. The residue is recrystallized from diethylether to give 1. 3 g of the title compound as violet solid. EF: C10H7N2O2C1 TLC: Rf = 0. 75 (toluene/acetone 9 : 1) MS : calo. : 222. 6 fhd: 223. 0 [MH+] C2. 2-Chloro-6-methyl-3-nitroquinoline A suspension of 0.43 g of6-methyt-3-nitroquinoiine-l-oxide (compound D2) in 4 mi of phosphorus oxy- chloride is stirred at 100°C for 15 min. After cooling to room temperature, the reaction mixture is added to 10 ml of ice water, diluted with 15 mi of dichloromethane and extracted with 20 ml of a halfsaturated aqueous sodium hydrogencarbonate solution. The organic layer is dried using magnesium sulfate, filtered and evaporated in vacuo. The residue is recfystaiiized from diethylether to give 0.44 g of the title compound as violet solid. EF: CioH7N202C ! TLC: Rf = 0. 72 (dichloromethane) MS: calc. : 222.6 fnd: 223.2 [MH+] C3. 2-Chloro-6-methoxv-3-nitroauinoline A suspension of 8.0 g of 6-methoxy-3-nitroquinoline-l-oxide (compound D3) in 80 ml of phosphorus oxychloride is stirred at 100°C for 30 min. After cooling to room temperature, the reaction mixture is added to 500 mi of ice water, diluted with 250 mi of dichloromethane and extracted three times each with 250 ml of a halfsaturated aqueous potassium carbonate solution. The organic layer is dried using magnesium sulfate, filtered and evaporated in vacuo. The residue is recrystallized from diethylether to give 5.6 g of the title compound as violet solid. EF: C10H7N2O3C1 TLC: Rf = 0. 75 (dichloromethane) C4. 2-Bromo-2-chloro3-nitroquinoline A suspension of 1. 0 g of 6-bromo-3-nitroquinoline-l-oxide (compound D4) in 7 ml of phosphorus oxy- chloride is stirred at 120°C for 1.5 h. After cooling to room temperature, the reaction mixture is added to 15 ml of ice water, diluted with 20 ml of ethyl acetate and extracted with 20 ml of a halfsaturated aque- ous sodium hydrogencarbonate solution. The organic layer is dried using magnesium sulfate, filtered and evaporated in vacuo. The residue is recrystallized from diethylether to give 0.82 g of the title com- pound as violet solid. EF: C9H4N202Br MS: calc. : 287.5 fhd: 288/286 [M+l Dl. 3-Nitro-8-methyl-=quinoline-l-oxide 0. 5 mi of benzoyi chloride are added dropwise to a suspension of 1. 4 9 of silver nitrate in 15 ml of di- chloromethane. After 45 min stirring, the precipitate is filtered off and the filtrate is dropped to a solution of 1.0 9 of 8-methylquinoline-l-oxide (compound El) in 15 mi of dichloromethane at 0°C. The reaction mixture is refluxed for 1 h. After cooling to room temperature, the reaction mixture is diluted with 20 ml of dichloromethane and extracted two times each with 50 mi of halfsaturated aqueous sodium hydro- gencarbonate solution. The organic layer is dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is recrystallized from acetonitrile to give 0.65 g of the title compound as yellow crystals. EF: doHaNzOa TLC: Rf = 0. 55 (dichloromethane/methanol 95 : 5) MS: calc. : 204.2 fhd : 205.0 [MH+] D2. 6-Methyl-3-nitroquinoline-l-oxide A solution of 46 g of m-chloroperbenzoic acid in 19 mi of dichloromethane is added dropwise to a solu- tion of 17.6 g of 6-methyl-3-nitroquinoline (compound E2) in 400 ml of dichloromethane. The reaction mixture is stirred for 70 h, diluted with 20 ml of dichloromethane and extracted two times each with 800 ml of halfsaturated aqueous sodium hydrogencarbonate solution. The organic layer is dried over mag- nesium sulfate, filtered 12 and evaporated in vacuo. The residue is chromatographed on silica gel (di- chloromethane/methanol 98: 2). 8.25 g of the title compound are obtained as yellow crystals. EF: C, oHaN204 TLC : Rf = 0.38 (dichloromethanelmethanol 95: 1) MS: calc. : 204.2 fnd : 204. 0 [MHI D3. 6-Methoxy-3-nitroquinoline-l-oxide 19.2 g of benzoyl chloride are added dropwise to a suspension of 46.5 g of silver nitrate in 80 mi of dichloromethane at 15°C. The reaction mixture is stirred at room temperature for 0.5 h and at boiling temperature for 1 h. The precipitate is filtered off and the filtrate is dropped to a solution of 24.0 g of 6- methoxyquinoline-1-oxide (compound E3) in 80 ml of dichloromethane at 10°C. The reaction mixture is refluxed for 1.5 h. After cooling to room temperature, the reaction mixture is diluted with 200 ml of di- chloromathane and extracted two times, each with 200 ml of halfsaturated aqueous sodium hydrogen- carbonate solution. ; The organiWlayer. is dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is recrystaiiized from ethyl-acetate, to give 8. 2 g of the title compound as. yellow crystals. EF: C, OH3N204 TLC: Rf = 0.73 (ethyl acetate) MS: calc. : 220.2 fhd: 220. 0 [MI D4. 6-Bromo-3-nitroquinoline-1-oxide 22. 5 mi of benzoyl chloride are added dropwise t a suspansion of 66. 0 g of silver nitrate in 300 ml of dichloromethane at 0°C. The reaction mixture is stirred at room temperature for 1 h. The precipitate is filtered off and the filtrate is dropped to a solution of 43.1 g of 6-bromoquinoline-l-oxide (compound E4) in 800 ml of dichloromethane at 10°C. The reaction mixture is refluxed for 2 h. After cooling to room temperature, the reaction mixture is extracted two times each with 800 mi of halfsaturated aqueous sodium hydrogencarbonate solution. The organic layer is dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is recrystaiiized from ethyl acetate to give 32.8 g of the five com- pound as yellow crystals. EF: CflH6N203Br TLC: Rf = 0. 76 (dichloromethane/methanol 98: 2) MS: caic. : 269.1 fnd : 268 [M'] El. 8-Methvl-qutnoline-loxfde A solution of 2.45 g of m-chloroperbenzoic acid in 15 ml of dichloromethane is added dropwise to a solution of 1 g of commercially available 8-methylquinoline in 15 ml of dichloromethane. The reaction mixture is stirred over night, diluted with 30 ml of dichloromethane and extracted two times each with 50 mi of halfsaturated aqueous sodium hydrogencarbonate solution. The organic layer is dried over magnesium sutfate, filtered and evaporated in vacuo. The residue is chromatographed on silica gel (dichloromethanelmethanol 98: 2). 1 g of the title compound are obtained as colourless solid. EF: C10H9NO TLC: Rf = 0.38 (dichloromethane/methanol 95: 5) MS: caic. : 159.2 fnd: 160.1 [MH+] E2. 6-Methyl-3-nitroquinoline The title compound is prepared according to. Moriey; Simpson; J. Chem. Soc. 1948,2024,2026. E3. 6-Methoxyquinoline-l-oxide The title compound is commercially available. E4. 6-Bromogulnoline-l -oxide The tile compound is prepared according to Hamana ; Nagayoshi Chem. Pharm. Bull. 1986, 14, 319, 321, 322 ; Chiai ; Okamoto ; Yakugaku Zasshi 1948, 68, 88 ; Chem. Abstr., 1953, 8073. Fl. 3- (4-Methoxypyridin-2-yl)propionic acid 41. 95 g of methyl 3- (4-methoxypyridin-2-yl) propionate (compound F2) are dissolved in 700 mi of tetra- hydrofuran, and 217 mi of IN sodium hydroxide solution are added. The mixture is stirred at RT until no more starting material is detectable (TLC). The mixture is neutralized using 217 mi of 1 N hydrochlo- ric acid solution, evaporated to dryness using a rotary evaporator and dried under high vacuum. The colorless residue is ground and extracted four times with dichloromethane/methanol (9:1). The com- bined extracts 13 are evaporated to dryness. This gives 33.2 g of the title compound as a colorless pow- der of m. p. 131-132°C. The mass spectrum shows the molecular peak MH+ at 182 Da. F2. Methyl [4-methoxypyridin-2-yl)propionate 43.1 g of methyl 3- (4-methoxypyridin-2-yl) acrylate (starting material F3) in 600 ml of methanol are hy- drogenated over 3.0 g of Pd/C (10%) until the starting material has disappeared (TLC). The catalyst is filtered off, and the mixture is then concentrated and dried under high vacuum. This gives 41.95 g of the title compound as a light-yellow oil. The mass spectrum shows the molecular peak MH* at 196 Da. F3. Methyl 34-methoxvovrldin-2-vilacrvlate A mixture of 45 g of 4-methoxypyridine-2-carbaldehyde (Ashimori et al., Chem. Pharm. Bull. 38, 2446- 2458 (1990) ), 75.80 g of pyridine hydrochloride, 102.45 g of monomethyl malonate potassium salt and 4.1 mi of piperidin in 700 ml of pyridine are slowly heated, with stirring, to 120°C. When the evolution of gas starts, the heating source is temporarily removed to stop the reaction from becoming too violent. Once the reaction has subsided, the mixture is stirred at 120°C for a further 2.5 h, and the pyridine is then distilled off under reduced pressure. The residue is partitioned between ethyl acetate/water and the organic phase is washed with water and dried. The residue obtained after concentration is chroma- tographed on a silica gel column using ethyl acetate/petroleum ether 2: 1. This initially gives 43.2 g of the title compound as a yellow oil which crystallizes on standing and then shows a m. p. of80-82°C. The mass spectrum shows the molecular peak MHd at 194 Da. Commercial applicability The compounds according to the invention have valuable pharmacological properties which make them commercially utilizable. They are selective inhibitors of the enzyme inducib ! e nitric oxide synthase. Nitric oxide synthases (NO-syntases, NOSs) are enzymes that generate NO and cdrulline from the amino acid arginin. In certain pathophysiological situations such as arginine depletion ortetrahydro-biopterin depletion the generation of 02 from NO-synthases instead or together with NO has been reported. NO is long known as a signalling molecule in most living organisms including mammals and humans. The most prominent action of NO is ifs smooth muscle relaxing activity, which is caused on the molecular level by the activation of soluble guanylate cyclase. In the last years a lot of other en- zymes have been shown to be regulated by NO or reaction products of NO. There exist three isoforms of NO-synthases which fall into two classes and differ in their physiologic functions and molecular properties. The first class, known as constitutive NO-synthases, comprises of the endothelial NO-synthase and the neuronal NO-synthase. Both is nzymes are expressed constitu- tively in various cell types, but are most prominent in endothelial cells of blood vessel walls (therefore called endothelial NO-synthase, ENOS or NOS-III) and in neuronal cells (therefore called neuronal NO- synthase, nNOS or NOS-I). Activation of these two enzymes is dependent on Ca25/Calmodulin which is generated by transient increases of the intracellular free Ca2+ concentraGon. Activation of constitutive isoforms leads to transient bursts of nitric oxide resulting in nanomolar cellular or tissue NO concentra- tions. The endothelial isoform is involved in the physiologic regulation of blood pressure. NO generated by the neuronal isoform seems to have neurotransmitter function and the neuronal isoform is among other regulator processes involved in memory function (long term potentiation). 14 In contrast to the constitutive isoforms the activation of inducibie NO-synthase (iNOS, NOS-II), the sole membar of the second class, is performed by transcriptional activation of the iNOS-promoter. Proin- flammatory stimuli lead to transcription of the gene for inducible NO-synthase, which is catalytically active without increases in the intracellular Ca2-concentration. Due to the long half live of the inducible NO-synthase and the unregulated activity of the enzyme, high micromolar concentrations of NO are generated over longer time periods. These high NO-concentrations atone or in cooperation with other reactive radicals such as 02-are cytotoxic. Therefore, in situations of microbial infections, iNOS is in- volved in cell killing by macrophages and other immune cells during early nonspecific immune re- sponses. There are a number of pathophysiological situations which among others are characterized by the high expression of inducible NO-synthase and concomitant high NO or Oiconcentrations It has been shown that these high NO concentrations alone or in combination with other radical species lead to tissue and organ damage and are causally involved in these pathophysiologies. As inflammation is characterized by the expression of proinflammatory enzymes, including inducible NO-synthase, acute and chronical inflammatory processes are promising diseases for the therapeutic application of selec- tive inhibitors of inducible NO-synthase. Other pathophysiologies with high NO-production from indue- ible NO-synthase are several forms of shock (septic, hemorrhagic and cytokine-induced). It is dear that nonselective NO-synthase inhibitors will lead to cardiovascular and neuronal side effects due to concomitant inhibition of constitutive NO-synthase isoforms. It has been shown in in-vivo animal models of septic shock that reduction of circulating plasma NO- levels by NO-scavenger or inhibition of inducible NO-synthase restores systemic blood pressure, re- duces organ damage and increases survival (deAngelo Exp. Opin. Pharmacother. 19-29,1999; Redl et al. Shock 8, Suppl. 51,1997; Strand et al. CritCare Med. 26,1490-1499,1998). It has also been shown that increased NO production during septic shock contributes to cardiac depression and myo- cardial dysfunction (Sun et al. J. Mol. Cell Cardiol. 30, 989-997, 1998). Furthermore there are also re- ports showing reduced infarct size after occlusion of the left anterior coronary artery in the presence of NO-synthase inhibitors (Wang et al. Am. J. Hyperttens. 12, 174-182, 1999). Considerable inducible NO-synthase activity is found in human cardiomyopathy and myocarditis, supporting the hypothesis that NO accounts at least in part for the dilatation and impaired contractility in these pathophysiologies (de Belder et al. Br. Heart. J. 4, 426-430, 1995). In animal models of acute or chronic inflammation, blockade of inducible NO-synthase by isoform-selective or nonseledive inhibitors or genetic knock out improves therapeutic outcome. It is reported that experimental arthritis (Connor et al. Eur. J. Pharmacol. 273, 15-24, 1995) and osteoarthntis (Pelle- tier et al. Arthritis & Rheum. 41, 1275-1286, 1998), enperimentat inflammations of the gastro-intestinal tract (Zingarelli et al. Gut 45, 199-209, 1999), experimental glomerulonephritis (Narita et al. Lab. Invest. 72, 17-24, 1995), experimental diabetes (Corbett et al. PNAS 90, 8992-8995, 1993), LPS-induced ex- perimental lung injury is reduced by inhibition of inducible NO-synthase or in iNOS-knock out mice (Kristof et al. Am. J. Crit Care. Med. 158, 1SS3-18S9 1998). A pathophysiological role of indicible NO- synthase derived NO or Os'is aiso discussed in chronic inflammatory diseases such es asthma, bron- chits and COPD. Furthermore, in models omeurodegenerative diseases of the CNS such as MPTP-induced parkinson- ism, amyloid peptide induced Alzheimar s diseass (Ishii et al. FASEB J. 14, 1485-1489, 15 2000), malo- nate induced HunHngton's disease (Connop etai. NeuropharmacoL 35, 459-465, 1996), experimental menengitis (Korytko & Boje Neuropharmacol. 35, 231-237, 1996) and experimental encephalitis (Park- inson et al. J. Mol. Med. 75, 174-186, 1997) a causal participation of NO and inducible NO-synthase has been shown. Increased iNOS expression has been found in the brains of AIDS victims and it is reasonable to assume a role of iNOS in AIDS related dementia (Bagasra et al. J. Neurovirol. 3 153-167,1997). Other studies implicated nitric oxide as a potential mediator of microglia dependent primary demyelina- tion, a hallmark of multiple skierosis (Parkinson et al. J. Mol. Med. 75,174-186,1997). An inflammatory reaction with concomitant expression of inducible NO-synthase also takes place dur- ing cerebral ischemia and roperfusion (ladecola et al. Stroke 27, 1373-1380, 1996). Resulting NO to- gether with 02- from infiltrating neutrophils is thought to be responsible for cellular and organ damage. Also, in models of traumatic brain injury (Mesenge et al. J. Neurotrauma 13,209-214, 1996; Wada et al. Neurosurgery 43, 1427-1436, 1998) NO-synthase inhibitors have been show to posses protective properties. A regulator role for inducible NO-synthase has been reported in various tumor cell lines (Tozer & Everett Clin Oncol. 9.357-264, 1997). On account of their indudble NO-synthase-inhibiting properties, the compounds according to the inven- tion can be employed in human and veterinary medicine and therapeutics, where an excess of NO or Ou'due to increases in the activity of inducible NO-synthase is involved. They can be used without limitation for the treatment and prophylaxis of the following diseases: Acute inflammatory diseases: Septic shock, sepsis, SIRS, hemorrhagic shock, shock states induced by cytokine therapy (IL-2, TNF), organ transplantation and transplant rejection, head trauma, acute lung injury, ARDS, inffammatory skin conditions such as sunburn, inflammatory eye conditions such as uvei- lis, glaucoma and conjunctivitis. Chronic inflammatory diseases of peripheral organs and the CNS : gastroint3Unal inflammatory dis- eases such as Crohn's disease, inflammatory bowel disease, ulcerative colitis, lung inflammatory dis- eases such as asthma and COPD, arthritic disorders such as rheumatoid arthritis, osteoarthritis and gouty arthritis, heart disorders such as cardiomyopathy and myocardiUs, artheroskierosis, neurogenic inflammation, skin diseases such as psoriasis, dermatitis and eczema, diabates, glomerulonephritis ; dementia such as dementias of the Alzheimer's type, vascular dementia, dementia due to a general medical condition, such as QIDS-, Parl6inson°s disas, Huntington s induo3d dementias, QLS, multiple sclerosis ; necrotiang vasculitides such as poiyarteritis nodosa, serum sickness, Wegener's granuloma- tosis, Kawasaki's syndrom; headaches such as migraine, chronic tension headaches, cluster and vas- cular headaches, post-traumatic stress disorders ; pain disorders such as neuropathic pain ; myocardial and cerebral ischemia/reperFusin injury. The compounds may also be useful in the treatment of cancers that express nitric oxide synthase. The invention further relates to a method for the treatment of mammals, including humans, which are suffering from one of the abovementioned illnesses. The method is characterized in that a therapeuti- cally active and pharmacologically effective and tolerable amount of one or more of the compounds according to the invention is administered to the ill mammal. 16 The invention further relates to the compounds according to the invention for use in the treatment and/or prophylaxis of illnesses, especially the illnesses mentioned. The invention also relates to the use of the compounds according to the invention for the production of pharmaceutical compositions which are employed for the treatment and/or prophylaxis of the illnesses mentioned. The invention also relates to the use of the compounds according to this invention for the production of pharmaceutical compositions having an iNOS inhibitory activity. The invention furthermore relates to pharmaceutical compositions for the treatment and/or prophylaxis of the illnesses mentioned, which contain one or more of the compounds according to the invention. The pharmaceutical compositions are prepared by processes which are known per se and familiar to the person skilled in the art. As pharmaceutical compositions, the compounds according to the inven- ton (= active compounds) are either employed as such, or preferably in combination with suitable pharmaceutical auxiliaries and/or exdpients, e. g. in the form of tablets, coated tablets, capsules, cap- lets, suppositories, patches (e. g. as ITS), emulsions, suspensions, gels or solutions, the active com- pound content advantageously being between 0.1 and 95% and where, by the appropriate choice of the auxiliaries and/or excipients, a pharmaceutical administration form (e. g. a delayed release form or an enteric form) exactly suited to the active compound and/or to the desired onset of action can be achieved. The person skilled in the art is familiar with auxiliaries or excipients which are suitable for the desired pharmaceutical formulations on account of his/her expert knowledge. In addition to solvents, gel for- mers, ointment bases and other active compound excipients, for eetampie antioKidants, dispersants, emulsifiers, preservatives, solubilizers, colorants, compleing agents or permeation promoters, can be used. The administration of the pharmaceutical compositions according to the invention may be performed in any of the generally accepted modes of administration available in the art. Illustrative examples of suit- able modes of administration include intravenous, oral, nasal, parenteral, topical, transdermal and rec- tal delivery. Oral and intravenous delivery are preferred. For the treatment of disorders of the respiratory tract, the compounds according to the invention are preferably also administered by inhalation in the form of an aerosol; the aerosol particles of solid, liquid or mixed composition preferably having a diameter of 0.5 to 10 um, advantagously of 2 to 6 pm. Aerosol generation can be carried out, for example, by pressure-driven jet atomizers or ultrasonic at- omizers, but advantageously by propellant-driven metered aerosols or propellant-free administration of micronized active compounds from inhalation capsules. Depending on the inhaler system used, in addition to the active compounds the administration forms additionally contain the required excipients, such as, for example, propellants (e. g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fill- ers (e. g. lactose in the case of powder inhalers) or, if appropriate, further active compounds. 17 For the purposes of inhalation, a large number of apparatuses are available with which aerosols of optimum partide size can be generated and administered, using an inhalation technique which is as right as possible for the patient In addition to the use of adaptors (spacers, expanders) and pear-shaped containers (e. g. Nebulator@, VolumatirD), and automatic devices emitting a puffer spray (Au- tohaler@), for metered aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (e. g. Diskhaler@, Rotadisk@, Turbohaler@ or the inhaler described in European Patent Application EP 0 505 321), using which an optimal administration of active compound can be achieved. For the treatment of dermatoses, the compounds according to the invention are in particular administe- red in the form of those pharmaceutical compositions which are suitable for topical application. For the production of the pharmaceutics 1 compositions, the compounds according to the invention (= active compounds) are preferably mixed with suitable pharmaceutical auxiliaries and further processed to give suitable pharmaceutical formulations. Suitabl 'pharmacautical formulations are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions. The pharmaceutical compositions according to the invention are prepared by processes known per se. The dosage of the active compounds is carried out in the order of magnitude customary for iNOS in- hibitors. Topical application forme (such as ointments) for the treatment of dermatoses thus contain the active compounds in a concentration of, for example, 0.')-99%. The doss for administration by inhala- tion is customary between 0. 1 and 10 mg per day. The customary dose in the case of systemic ther- apy (p. o.) is between 0.3 and 30 mg/kg per day, (i. v.) is between 0. 3 and 30 mg/kg/h. Biological Investigations Measurement of Inducible NO-synthase activity The assay is performed in 96-well microtiter F-plates (Greiner, Frickenhausen, FRG) in a total volume of 100 pi in the presence of 100 nM calmodulin, 226 pM CaC12,477 pM MgCI2 5 pM flavin-adenine- dinucleotide (FAD), 5 pM flavin mononucleotide (FMN), 0.1 mM NADPH, 7 mM glutathione, 10 pM BH4 and 100 mM HEPES pH 7.2. Arginine concentrations are 0.1 pM for enzyme inhibition experiments. 150000 dpm of 13H] arginine are added to the assay mixture. Enzyme reaction is started by the addition of 4 pg of a crude cytosolic fraction containing human inducible NO-synthase and the reaction mixture is incubated for 45 to 60 min at 37°C. Enzyme reaction is stopped by adding 10 NI of 2M MES-buffer pH 5, 0.50 NI of the incubation mixture are transferred into a MADP N65 filtration microtiter plate (Milli- pore, Eschbom, FRG) containing already 50 pi of AG-50W-X8 cation exchange resin (Biorad, Munchen, FRG). The resin in the Na loaded form is pre-equilibrated in water and 70 pi (corresponding to 50 NI dry beads) are pipetted under heavy stirring with a 8 channel pipette into the filtration plate. After pipetting 50 pi of the enzyme reaction mixture onto the filtration plates, the plates are placed on a filtration manifold (Porvair, Shepperton, UK) and the flow through is collected in Pica scintillation plates (Packard, Maiden, CT). The resin in the filtration plates is washed with 75 pi of water (1x50 pi and lx 25 pi) which is also collected in the same piate as the sample. The total flow through of 125 pi is mixed with 175 NI of Microscint-40 scintillation cocktail (Packard) and the scintillation plate is sealed with TopSeal P-foil (Packard). Scintillation plates are counted in a szintillation counter. 18 For the measurement of inducible NO-synthase-inhibiting potencies of compounds increasing concen- trations of inhibitors wera included into the incubation mixture. IC50-values were calculated from the parcent inhibition at given concentrations by nonlinear least square fitting. The inhibitory values determined for the compounds according to the invention follow from the following table A, in which the compound numbers correspond to the example numbers. Table A Inhibition of LINOS activity [measured as -logIC50 (mol/I)] 19 We claims 1. Compounds of formula I Rl is 14C-alkoxy ; A is l-4C-alkylene ; R2 is hydrogen ; halogen ; hydroxyl; nitro ; amino ; 1-7C-alkyl; trifluoromethyl; 3-7C-cydoalkyi; 3-7C- cycloalkyl-l-4C-alkyl; l-4Calkoxy; completely or predominantly fluorine-substituted l-4C-alkoxy ; l-4C-alkoxy-14C-alkyl ; l-4C-alkoxy-l-4C-alkoxy; mono- or di-l-4C-alkylaminocarbonyl ; mono- or di-l-4C-alkylaminosulfonyl ; 1-4C-alkylcarbonylamino; l-4C-alkylsulfonylamino ; phenyl ; phenyl-l-4C-alkyl; phenyl-l-4C-alkoxy; R21- and/or R22-substituted phenyl ; phenyl-l-4C-alkyl wherein the phenyl moiety is substituted by R23; Het; R24-substituted Het; Het-14C-alkyl ; Het- l-4C-alkyl wherein the Het moiety is substituted by R25; in which R21 is cyano ; halogen ; carboxyl ; l-4C-alkyl ; l-4C-alkoxy ; hydroxy-14C-alkyi ; l-4C-alkoxy-l-4C- alkyl; 3-7C-cycloalkoxy; 3-7C-cycloalkylmethoxy; completely or predominantly fluorine- substituted l-4C-alkoxy; aminocarbonyl; mono-or di-l-4C-alkylaminocarbonyl ; 14C- alkylcarbonylamino; l-4C-alkoxycarbonyl ; aminosutfonyi ; mono -or di-l-4C-alkylaminosulfonyl; amino ; trifluoromethyl; hydroxyl; phenylsulfonylamino ; or phenyl-l-4C-alkoxy ; R22 is halogen ; l-4C-alkyl; or 14C-alkoxy ; or wherein R21 and R22 together are a l-2C-alkylenedioxy group; R23 is halogen ; 14C-alkyl; or l-4C-alkoxy ; Het represents a mono-or bicydic single or fused 5 to 10-membered heteroaryl radical containing one to three heteroatoms, each of which is selected from a group consisting of nitrogen, oxygen and sulfur, R24 is halogen ; l-4C-alkyl; or 14C-alkoxy ; R25 is halogen ; l-4C-alkyl; or l-4C-alkoxy; R3 is hydrogen; halogen ; 14C-alkyl ; or l-4C-alkoxy ; the salts; the N-oxides; and the salts of the N-oxides of these compounds. 2. Compounds of formula I according to claim 1 in which Rl is l-4C-alkoxy ; A is l-4C-alkylene ; R2 is hydrogen; halogen ; l-7C-alkyl; trifluoromethyl; l-4C-alkoxy; completely or predominantiy fluo- rine-substituted l-2C-alkoxy ; phenyl ; R21 -and/or R22-substituted phenyl ; or Het; wherein R21 is l-4alkyl ; l-4C-alkoxy ; hydroxy-l-4C-aikyl ; l-2C-alkoxy-l-2C-alkyl ; completely or predomi- nantly fluorine-substituted l-2C-alkoxy ; R22 is l-4C-alkoxy ; Het represents a bicydic fused 9-or 10-membered heteroaryl radical containing one to three het- eroatoms, each of which is selected from a group consisting of nitrogen, oxygen and sulfur ; R3 is hydrogen; the salts ; the N-oxides; and the salts of the N-oxides of these compounds. 3. Compounds of formula) according to claim 1 in which Rl is methoxy ; A is ethylene ; R2 is hydrogen; halogen; l-4C-alkyl ; l-4C-alkoxy ; R21-and/or R22-substituted phenyl ; or Het ; wherein R21 is 14C-alkoxy ; R22 is 14C-alkoxy ; Het is benzofuranyl ; or benzothiophenyl; R3 is hydrogen; or Rl is methoxy; A is ethylene ; R2 is hydrogen ; halogen ; l-4C-alkyl; l-4C-alkoxy ; R21 -substituted phenyl ; or Het ; wherein R21 is hydroxy-l-4C-alkyl; Het is banzofuranyl ; or berEotMophenyi; R3 is hydrogen ; the salts ; the N-oxides ; and the salts of the N-oxides of these compounds. 20 4. Compounds of formula I according to daim 1 which are selected from the group consisting of 2-[2-(4-methoxypyridin-2-yl)ethyl]-3H-imidazo [4, 5-b] quinoline, 2- [2- (4-methoxypyridin-2-yl) ethyl]-7-methyl-3H-imidazo [4, 5-b] quinoline, 2-[2-(4-methoxypyridin-2-yl)ethyl]-5-methyl-3H-imidazo [4, 5-b] quinoline, 7-methoxy-2- [2-(4-methoxypyridin-2-yl)ethyl]-3H-imidazo[4,5-b]quinoline, 7-bromo-2-[2-(4-methoxypyridin-2-yl)ethyl]-3H-imidazo [4, 5-b] quinoline, 7-(4-hydroxymethylphenyl)-2-[2-(4-methoxypyridin-2-yl)ethyl]-3H-imidazo [4,5-b] quinone, 7-benzofuran-2-yl-2-[2-(4-memoxypyridin-2-yl)ethyl]-3H-imidazo [4, 5-b]quinoline and 7- (3,4-dimemoxyphenyl)-2-[2-(4-memoxypyridin-2-yl)ethyl]-3H-imidazo[4,5-b]quinoline, or the salts, the N-oxides and the salts of the N-oxides of these compounds. 5. Compounds of formula I according to claim 1 in which Rl is methoxy and A is ethylene. 6. Compounds of formula) according to claim 1 for the treatment of diseases. 7. Pharmaceutical compositions comprising one or more compounds of formula I according to claim 1 together with the usual pharmaceutical auxiliaries and/or excipients. 8. Use of compounds of formula I according to daim 1 for the manufacture of pharmaceutical compositions for the treatment of acute inflammatory diseases. 9. Use of compounds of formula I according to daim 1 for the manufacture of pharmaceutical compositions for the treatment of chronic inflammatory diseases of peripheral organs and the CNS. 10. A method for therapy of illnesses or disorders in a mammal comprising administering to said mammal a therapeutically active and pharmaceutically effective and tolerable amount of a compound of formula) according to claim 1. 21 Abstract The compounds of formula I In which Rl, R2, R3 and A have the meanings as given In the description are novel effective INOS Inhibitors. To The Controller of Patent The Patent Office Mumbai 22

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