WO2001081324A1 - Benzoxazine derivatives and benzothiazine derivatives having nos-inhibitory and antioxidant properties - Google Patents

Abstract

The invention relates to compounds of formula (I) and to the tautomeric and isomeric forms and salts thereof, wherein: X represents O or S; R<1> represents -(CHR<9>)n-NR<7>-A-NR<8>-B, -(CHR<9>)n-NR<8>-B or -(CHR<9>)n-B; R<2> represents hydrogen or R<1> and R<2>, together with two adjacent carbon atoms, form a 5-, 6-, 7- or 8-member ring, which is monocyclic or bicyclic, saturated or unsaturated, and in which 1 or 2 CH2 groups can be replaced by oxygen or carbonyl, and which is substituted by -(CHR<9>)r-NR<7>-A-NR<8>-B, -(CHR<9>)n-B or -(CHR<9>)r-NR<8>-B; R<3> represents hydrogen or NR<15>R<16>; R<4> represents hydrogen or acyl; R<5> and R<6>, independent of one another, represent hydrogen, C3-7 cycloalkyl, phenyl, C1-6 alkyl, C2-6 alkenyl radicals or C2-6 alkynyl radicals, which can each be substituted by halogen, OH, O-C1-6 alkyl, SH, S-C1-6 alkyl, NR<15>R<16>, 5- or 6-member heteroaryl with 1-3 N, O or S atoms, phenyl or C3-7 cycloalkyl; A represents a straight-chain or branched C1-6 alkylene or -(CH2)p-Q-(CH2)q-, and; B represents (II) or (III). The invention also relates to the method for preparing said compounds and to their use in medicaments.

Description

BENZOXAZINE AND BENZOTHIAZINE DERIVATIVES WITH MOS INHIBITORIC AND AMTIOXIDATIVE PROPERTIES

The invention relates to benzoxazine and benzothiazine derivatives, the process for their preparation and their use in pharmaceuticals.

There are at least 3 forms of nitric oxide synthases in human cells that convert arginine to nitric oxide (NO) and citrulline. Two constitutive NO synthases (NOS) were identified, which are present as calcium / calmodulin 10 dependent enzymes in the brain (ncNOS or NOS 1) or in the endothelium (ecNOS or NOS 3). Another isoform is the inducible NOS (iNOS or NOS 2), which is a practically Ca ⁺⁺ independent enzyme and is induced by endotoxin or other substances after activation of different cells.

15 NOS inhibitors and in particular selective inhibitors of NOS 1, NOS 2 or NOS 3 are therefore suitable for the therapy of various diseases which are caused or exacerbated by pathological concentrations of NO in cells. A number of reviews provide information on the effects and inhibitors of NO synthases. Examples include: Drugs 1, 321 (1998) or Current Pharmac. Design 3,

20 447 (1997).

It is also known that reactive oxygen species (ROS) such as superoxide radical anions (O ₂ '^" ) or hydroxyl radicals (OH ^' ) play an important role in the development of diverse cell damage and are also involved in neuronal dysfunction and neuronal cell death ,

It has now been found that the heterocycles substituted according to the invention have both NOS-inhibitory and also radical-scavenging / antioxidative properties and can therefore be used particularly advantageously as medicaments.

30

The invention relates to the compounds of formula I, their tautomeric and isomeric forms and salts

worin

wherein

X O or S,

R ¹ - (CHR ⁹ ) _n -NR ⁷ -A-NR ⁸ -B, - (CHR ⁹ ) _n -NR ⁸ -B or - (CHR ⁹ ) _n -B,

R ^{2 is} hydrogen or

R1 and R2 together with two adjacent carbon atoms form a 5-, 6-, 7- or δ-membered ring which is monocyclic or bicyclic, saturated or unsaturated and in which 1 or 2 CH ₂ groups can be replaced by oxygen or carbonyl and the is substituted with - (CHR ⁹ ) _r -NR ⁷ -A-NR ⁸ -B, - (CHR ⁹ ) _n -B or - (CHR ⁹ ) _r -NR ⁸ -B,

R3 is hydrogen or NR ¹⁵ R ¹⁶ ,

R ^{4 is} hydrogen or acyl,

R ⁵ and R ⁶ independently of one another are hydrogen, C _3-7 cycloalkyl, phenyl, C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl radicals, which can each be substituted by halogen, OH, Ode-alkyl, SH, SC _1-6- alkyl, NR ¹⁵ R ¹⁶ , 5- or θ-membered heteroaryl with 1-3 N, O or S atoms, phenyl or C _3-7 cycloalkyl,

R ⁷ and R ⁸ independently of one another are hydrogen, C _1-6 -alkyl, which may be substituted by phenyl, COOC _1-6 -alkyl or CO-C _1-6 -alkyl,

or

R ⁸ together with the adjacent nitrogen atom forms a 5-7-membered saturated heterocycle which can contain a further oxygen, nitrogen or sulfur atom or forms an unsaturated δ-membered heterocycle which can contain 1-3 N atoms,

or R ⁷ together with the neighboring nitrogen atom forms a 5-7-membered saturated heterocycle which can contain a further oxygen, nitrogen or sulfur atom,

A straight-chain or branched C _1-6 -AlkyIen or - (CH ₂ ) _p -Q- (CH ₂ ) _q -,

B

means

QC _3- cycloalkyI, indanyl, 5-, 6- or 7-membered saturated heterocycloalkyl with 1 - 2 N, O or S atoms, C _6- ιo-aryl or 5- or θ-membered heteroaryl with 1 - 3 N-, O or S atoms,

m, n and r 0, 1 to 6,

p and q represent 0 to 6,

R ⁹ and R ^{1ü are} hydrogen or C _1-6 alkyl,

R ¹¹ and R are hydrogen, hydroxy, C _1-6 alkyl or C _1-6 alkoxy,

R ^1b and R ^1b are hydrogen, _-6 alkyl, phenyl or benzyl, or

R ¹⁵ , R ¹⁶ together with the nitrogen atom form a saturated 5-, 6- or 7-membered ring which may contain a further nitrogen, oxygen or sulfur atom and which may be substituted by C 1-4 alkyl, phenyl, benzyl or benzoyl.

The compounds of the formula can exist as tautomers, stereoisomers or geometric isomers. The invention also encompasses all possible isomers, such as E and Z isomers, S and R enantiomers, diastereomers, racemates and mixtures thereof, including the tautomeric compounds of the formulas Ia and Ib.

la Ib

The physiologically acceptable salts can be formed with inorganic and organic acids such as oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, HCl, HBr, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and others.

The inorganic or organic bases which are known for the formation of physiologically compatible salts, such as, for example, alkali metal hydroxides, such as sodium and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, Tris, are also suitable for salt formation of acid groups - (hydroxymethyl) methylamine etc.

Alkyl means in each case a straight-chain or branched alkyl group such as e.g. Methyl, ethyl, propyl, isopropyl, n-butyl, sec. Butyl, tert. Butyl, n-pentyl, sec. Pentyl, tert. Pentyl, neopentyl, n-hexyl, sec. Hexyl, heptyl, octyl.

Alkenyl and alkynyl substituents preferably contain a double bond and are each straight-chain or branched. For example, the following radicals may be mentioned: vinyl, 2-propenyl, 1-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 4-hexenyl, ethynyl, 1-propynyl , 2-propynyl, 1-butynyl, 2-butynyl.

Cycloalkyl is understood to mean cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Halogen means fluorine, chlorine, bromine or iodine.

Aryl is to be understood in each case as naphthyl or phenyl, which can be substituted one to three times in the same or different ways. The following 5- and 6-ring heteroaromatics may be mentioned as examples of heteroaryl radicals which can be bonded via the hetero atom or a carbon atom:

Imidazole, indole, isooxazole, isothiazole, furan, oxadiazole, oxazole, pyrazine, pyridazine, pyrimidine, pyridine, pyrazole, pyrrole, tetrazole, thiazole, triazole, thiophene, thiadiazole, benzimidazole, benzofuran, benzoxazole, isoquinoline, quinoline.

Piperidine, pyrrolidine, morpholine, thiomorpholine, hexahydroazepine and piperazine may be mentioned as a saturated heterocycle. The heterocycle can be substituted 1-3 times with C 1-4 alkyl or an optionally substituted with halogen phenyl, benzyl or benzoyl. Examples include: N-methylpiperazine, 2,6-dimethylmorpholine, phenylpiperazine or 4- (4-fluorobenzoyl) piperidine.

If -NR ⁸ or -NR ^{7 form} a saturated heterocycle together with the nitrogen atom, the heterocycles mentioned above are suitable.

Simple substitution is preferred for the substituents R ⁵ and R ⁶ in position 2 of the oxazine or thiazine, where the substituent R ^{6 is} in particular C _1-6 alkyl and the substituent R ^{5 is} in particular hydrogen.

The substituent Q can be linked at any point via a carbon atom or, if appropriate, via an nitrogen atom.

If R ¹ and R ^{2 form} a ring together with two adjacent carbon atoms, this ring can be in position 5, 6 or 7, 8 or in particular 6, 7 of the benzoxazine or benzothiazine and has the formula

wherein

E represents a 3 - membered ring, the 1 - 2fold with

- (CHR ⁹ ) _r -NR ⁷ -A-NR ⁸ B, (CHR ⁹ ) _r -NR-B or - (CHR ⁹ ) _n -B is substituted and in which 1 or 2 CH ₂ groups can be replaced by oxygen or carbonyl, and which can be fused with benzene, for example indane, or can be present as a bicyclus, for example bicycloheptane.

Examples of structures of E are:

Preferably, two adjacent carbon atoms of the aromatic compound with C-ι _-6 alkylene to give a 3 - δgliedrigen, especially C _3-4 alkylene to a 5 - linked θgliedrigen ring in any position, but especially in the 6-position of the molecule, is substituted with - (CHR ⁹ ) _r -NR ⁷ -A-NR ⁸ B, (CHR ⁹ ) _r -NR-B or - (CHR ⁹ ) _n -B.

4

The acyl radical R is derived from straight-chain or branched aliphatic C * _-6 -carboxylic acids such as, for example, formic acid, acetic acid, propionic acid, butyric acid, trimethyl acetic acid or caproic acid or from known benzenesulfonic acids, which can be substituted by halogen or C 1-4 alkyl, and C _1- alkanesulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid.

R ⁴ , R ⁷ and R ⁸ each preferably represent hydrogen.

The following are mentioned as preferred embodiments:

For R ³ : hydrogen and NH ₂ ,

for A: d-e-alkylene,

for X: oxygen, for r: null,

for m and n: C _1-6 alkylene, especially methylene or ethylene,

for R ¹¹ and R ¹² : hydroxy, C-ι. ₆ -A! Koxy or in particular C _1-6 alkyl,

for B: 4-hydroxy-3,5-di-tert-butyl-benzyl or 6-hydroxy-2,5,7, δ-tetramethylchroman-2-carbonyl,

for R ¹ : - (CHR ⁹ ) _n -NR ⁷ -A-NR ⁸ -B or - (CHR ⁹ ) _n -NR ⁸ -B.

The invention also relates to the use of the compounds according to the invention for the manufacture of a medicament for the treatment of diseases which are caused by the action of nitrogen monoxide in pathological concentrations and by reactive oxygen species. These include neurodegenerative

Diseases, inflammatory diseases, autoimmune diseases, cardiovascular diseases.

Examples include: cerebral ischemia, hypoxia and other neurodegenerative diseases that are associated with inflammation, such as multiple sclerosis, amyotrophic lateral sclerosis and comparable skierotic diseases, Parkinson's disease, Huntington's disease, Korksakoff's disease, epilepsy, vomiting, sleep disorders, schizophrenia, depression, Stress, pain, migraines, hypoglycemia, dementia such as Alzheimer's disease, HIV dementia and presenile dementia.

They are also suitable for the treatment of diseases of the cardiovascular system and for the treatment of autoimmune and / or inflammatory diseases such as hypotension, ARDS (adult respiratory distress syndrome), sepsis or septic shock, rheumatoid arthritis, osteoarthritis, and insulin-dependent diabetes mellitus (IDDM) , pelvic / bowel inflammatory disease, meningitis, glomerulonephritis, acute and chronic liver diseases, rejection diseases (e.g. allogeneic heart, kidney or liver transplants) or inflammatory skin diseases such as psoriasis and others.

For the use of the compounds according to the invention as medicaments, they are brought into the form of a pharmaceutical preparation which, in addition to the active substance, is suitable for vehicles, enteral or parenteral administration, with carriers, auxiliaries and / or additives. contains substances. The application can be administered orally or sublingually as a solid in the form of capsules or tablets or as a liquid in the form of solutions, suspensions, elixirs, aerosols or emulsions or rectally in the form of suppositories or in the form of injection solutions which can optionally be used subcutaneously or intravenously or topically in Form of aerosols or transdermal systems or intrathecally. Suitable auxiliaries for the desired pharmaceutical formulation are the inert organic and inorganic carrier materials known to the person skilled in the art, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. If necessary, preservatives and stabilizers can also be used -, wetting agents, emulsifiers or salts for changing the osmotic pressure or buffers may be included.

Injection solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.

Surfactant auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.

Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. It can also be used in liquid form, for example as juice, to which a sweetener may be added.

In combination with an NMDA or AMPA receptor antagonist, the compounds according to the invention have a synergistic neuroprotective effect and can be administered as combination preparations, where the active compounds can be present in a formulation or in separate formulations, and the dose, depending on the route of administration, and the weight of the patient and the type and severity of the disease varies (CA Hicks et al. Eur. J. of Pharm. 381, 113-119 (1999)).

The dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors. The daily dose is 1 - 2000 mg, preferably 20 - 500 mg, whereby the dose can be given as a single dose to be administered once or divided into two or more daily doses. The NOS inhibitory activity of the compounds of the formula I and their physiologically tolerable salts can be determined by the methods of Bredt and Snyder in Proc. Natl. Acad. Be. USA 86: 9030-9033 (1989).

The compounds of the invention are prepared by adding a compound of the formula II or its salt

lla or mb

wherein

R ¹ , R ² , R ³ , R ⁵ , R ⁶ and X are as defined above, Z is oxygen or sulfur and R is C- | _g-alkyl, reacted with ammonia or primary amines, amino groups present being optionally protected as intermediates , and, if desired, then acylated, the isomers separated or the salts formed.

The reaction with ammonia is carried out under pressure in autoclaves with excess ammonia at low temperatures (-76 ° C.) or by stirring in methanol saturated with ammonia at room temperature. Thiolactams are preferably reacted. When reacting with amines, the imine ether or iminothioether is first prepared as an intermediate compound (e.g. with methyl iodide or methyl sulfate) from the lactam or thiolactam and is reacted with or without isolation of the intermediate compound with the corresponding amines or their salts.

Examples of amino protecting groups are carbamates such as tert. Butoxycarbonyl, benzyloxycarbonyl or acetyl suitable.

If desired, esters are saponified at the precursors, acids are esterified, hydroxyl groups are etherified or acylated, amines are acylated, alkylated, diazotized, halogenated, NO2 introduced or reduced, reacted with isocyanates or isothiocyanates, the isomers are separated or the salts are formed. The saponification of an ester group can be carried out in a basic or acidic manner by hydrolyzing at room temperature or elevated temperature to the boiling point of the reaction mixture in the presence of alkali metal hydroxides in ethanol or other alcohols or by means of acids such as hydrochloric acid and, if appropriate, further processing salts of the aminobenzoxazines or thiazines.

The carboxylic acid is esterified in a manner known per se with diazomethane or the corresponding alcohol in acid or in the presence of an activated acid derivative. Examples of suitable acid derivatives are acid chloride, imidazolide or anhydride.

The reduction of an ester group to alcohol is carried out in a manner known per se using DiBAH in a suitable solvent at low temperatures. The reductive amination of a ketone or a benzaldehyde with amine with the addition of a borohydride gives benzylic amines. With appropriately chosen diamines, symmetrical or asymmetrical amino compounds are obtained after addition of the same or different aldehydes.

In addition, a nitro group or halogen, especially bromine, can be introduced by electrophilic aromatic substitution. The resulting mixtures can be separated in the usual way, also by means of HPLC. If a nitrile is present, it can be saponified by known methods or converted into the corresponding amine, tetrazole or amidoxime, or it becomes a substituted amidine by attacking substituted anilines or amines.

Friedel-Crafts acylation is successfully used for type Ila lactams, and then the lactam can be selectively converted to the thiolactam or the acylation product can be reductively aminated.

The reduction of the nitro group or possibly the cyano group to the amino group takes place catalytically in polar solvents at room temperature or elevated temperature under hydrogen pressure. Suitable catalysts are metals such as Raney nickel or noble metal catalysts such as palladium or platinum, optionally in the presence of barium sulfate or on supports. Instead of hydrogen, ammonium formate or formic acid can also be used in a known manner. Reducing agents such as tin-Il chloride can be used as well as complex metal hydrides possibly in the presence of heavy metal salts. It may be advantageous to reduce the Introduce ester group as in formula V. The reduction with zinc or iron in acetic acid has proven effective for nitro groups.

If a single or multiple alkylation of an amino group or a CH-acidic carbon position is desired, alkylation can be carried out using alkyl halides, for example, using conventional methods. The lactam group may need to be protected as an anion by a second equivalent base or by a suitable protective group.

The amino group is acylated in a customary manner, for example using an acid halide or acid anhydride, if appropriate in the presence of a base.

The introduction of the halogens chlorine, bromine or iodine via the amino group can also be carried out, for example, according to Sandmeyer by reacting the diazonium salts formed intermediately with nitrites with Cu (l) chloride or Cu (l) bromide in the presence of the corresponding acid such as hydrochloric acid or hydrobromic acid reacted with potassium iodide.

As usual, benzyl alcohols can be converted into the corresponding benzyl halides using methanesulfonyl chloride.

The introduction of a Nθ2 group succeeds through a number of known nitration methods. For example, nitrates or with nitrronium tetrafluoroborate can be nitrated in inert solvents such as halogenated hydrocarbons or in sulfolane or glacial acetic acid. It is also possible to introduce e.g. by nitrating acid in water or conc. Sulfuric acid as a solvent at temperatures between -10 ° C and 30 ° C.

The isomer mixtures can be converted into the enantiomers or E / Z by conventional methods such as, for example, crystallization, chromatography or salt formation.

Isomers are separated. The enantiomers can also be obtained by chromatography on chiral phases and by stereoselective synthesis.

The salts are prepared in a customary manner by adding a solution of the compound of the formula I - optionally also with protected amino groups - with the equivalent amount or an excess of an acid, which is optionally in solution, and removing the precipitate or in a conventional manner worked up the solution. The corresponding benzylamines provide nucleophilic substitution of benzyl halides with secondary amines.

Thiolactams of the formula IIIa (Z = S) are obtained, for example, from lactams with phosphorus pentasulfide (P4S-10) or Lawesson's reagent (2,4-bis (4-methoxphenyl) -1,3,2,4-dithiaphosphetane-2,4- disulfide) in suitable solvents and compounds of the formula IIb can be obtained, for example, by reaction with Meerwein reagent (trimethyioxonium tetrafluoroborate).

The invention also relates to the intermediate compounds of the formulas IIa and IIb and their salts

lla llb

wherein

R ^1, R ^2, R ^3, R ^5, R ⁶ and X have the above meaning, Z is oxygen or sulfur and R Cι _-6 alkyl.

The compounds of the formula IIIa can be prepared, for example, by adding a compound of the formula III

wherein R ^ to R ^{3 have} the above meaning with a compound of formula IV

wherein R ^ and R have the meaning given above and Y is a reactive carboxyl group such as acid halide, nitrile, carboxylic acid ester and optionally reductively cyclized or by reacting a compound of formula V.

reductively cyclized.

Aromatic thiols of type III are obtained, among other things, as described in Chem. Pharm. Bull. 39, 2888 (1991) and the literature mentioned there, by rearrangement of the corresponding dimethylaminothiocarbamates.

The substituents R ¹ -R ³ can be introduced at the stage of the compounds of the formula III or II.

To prepare compounds of the formula II, the aldehyde or the ketone of the corresponding 1,4-benzoxazin-3-one or 1,4-benzothiazin-3-one can be reductively aminated. This is also possible twice with diamonds chosen appropriately. Diamines can also be reacted with the aldehyde of 1,4-benzoxazin-3-one and, at the same time, with other aldehydes chosen appropriately.

Diamines are obtained, as described in the literature (Synthesis 11; 917-918 (1988)), also by reacting benzamides with diamine with the release of ammonia, or by forming amides via the carboxylic acid after customary activation, for example using carbonyldiimidazole ( CDI).

If the introduction of a heteroaryl radical Q is desired, the corresponding halogen derivative can be substituted nucleophilically. Is a primary or secondary

Amino group present, it may be advantageous to protect it as an intermediate, for example by introducing a tert. Butoxycarbonylgruppe, which is split off after the amidine formation in the usual way.

The production of pharmacologically active compounds from the intermediates is carried out as described above.

Insofar as the preparation of the starting compounds is not described, these are known and can be prepared commercially or analogously to known compounds or by the processes described here.

New compounds were characterized by one or more of the following methods: melting point, mass spectroscopy, NMR. NMR spectra were measured with a Bruker 300 MHz device, the (deuterated) solvents are abbreviated as follows: CDCI3 (chloroform), DMSO (dimethyl sulfoxide). Shifts are given in delta and ppm. They mean: m (multiplet, multiple signals), s (singlet), d (doublet), dd (double doublet, etc.), tr (triplet), q (quartet), H (hydrogen protons), J (coupling constant). Also mean: THF (tetrahydrofuran), DMF (N, N-dimethylformamide), MeOH (methanol), EE (ethyl acetate) ml (milliliter), RT (room temperature). All solvents are p.A. quality, unless otherwise noted. All reactions are carried out under protective gas, unless they are aqueous solutions.

The presentation of some preliminary stages, intermediate products and products is described as an example.

Ausgangsverbindυngen

A

6-Hvdroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid: Aldrich

6-Hvdroxy-2.5.7.δ-tetramethylchroman-2-carboxylic acid-f3- (tert-butyloxycarbonyl) aminoprop-1-yl-amide 6-hydroxy-2,5,7, δ-tetramethylchroman-2-carboxylic acid (500 mg) 356 mg carbonyldiimidazole are added in THF, 340 mg mono-N-Boc-1, 3-diaminopropane in dichloromethane are added dropwise. Dichloromethane is added, it is washed with sodium hydrogen carbonate and then with brine. You dry the org. Phase and constricts. After column chromatography with hexane and ethyl acetate, 694 mg of product result.

6-Hvdroxy-2,5,7.δ-tetramethylchroman-2-carboxylic acid- (3-aminoprop-1-vO-amide hydrochloride

680 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid- [3- (tert-butyloxycarbonyl) aminoprop-1-yl] -amide are stirred in THF with 6 ml of HCl (4n in dioxane) and the precipitate is suctioned off. Yield 77%.

The synthesis of 6-formyl-2-methyl-2H-1.4-benzoxazin-3 (4H) -one is described in DE-

19δ 26 232.9.

e-fNS-ie-Hvdroxy ^ .δJ.δ-tetramethylchroman ^ -carbonyl-VS-aminoprop-l-yl-aminomethvn-2-methyl-2H-1.4-benzoxazin-3 (4H) -one

126 mg of 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid (3-aminoprop-1-yl) amide hydrochloride are dissolved in 8 ml of methanol / THF 2: 1. Triethylamine (0.11 ml) is added and the mixture is stirred briefly, then 73 mg of 6-formyl-2-methyl-2H-1,4-benzoxazin-3 (4H) -one are added. The mixture is stirred at RT for 60 minutes and then 22 mg are added

Potassium borohydride added. After 2 hours at RT, the mixture is poured onto water, extracted 3 times with ethyl acetate and the organic phase is washed with brine. It is dried with magnesium sulfate and concentrated, 175 mg of crude product. B

6-fN- (4-Hvdroxy-3.5-di-tert-butylbenzyl) aminomethyl] -2-methyl-2H-1,4-benzoxazin-3 (4H) -one 200 mg of 6-aminomethyl are added to 20 ml of methanol -2-methyl-2H-1,4-benzoxazine-

3 (4H) -one and 438 mg of 3,5-di-tert-butyl-4-hydroxy-benzaldehyde (purchased goods) were added. The mixture is stirred at RT for 60 minutes and then 81 mg of potassium borohydride are added. After 2 hours at RT, the mixture is poured onto water, extracted with ethyl acetate and the organic phase is washed with brine. It is dried with magnesium sulfate and concentrated. 600 mg of crude product are produced.

6-r (N4- (4-Hvdroxy-3.5-di-tert-butylbenzyl} -aminobut-1-yl) -aminomethvn-2-methyl-2H-1,4-benzoxazin-3 (4H) -one

382 mg mg of 6-formyl-2-methyl-2H-1,4-benzoxazin-3 (4H) -one and 487 mg of 3,5-di-tert-butyl-4-hydroxy-benzaldehyde ( Kaulware) with 185 mg of 1,4-diaminobutane. The mixture is stirred at RT for a few hours and 193 mg of potassium borohydride are then added. After 2 hours at RT, the mixture is poured onto water, extracted with ethyl acetate and the organic phase is washed with brine. It is dried with magnesium sulfate and concentrated. 860 mg of crude product are produced.

6- [N- (4-Hydroxy-3,5-di-tert-butylbenzyl) - (tert-butyloxycarbonyl) -aminomethvπ-2-methyl-2H-1,4-benzoxazin-3 (4H) -one 590 mg 6 - ([4-Hydroxy-3,5-di-tert-butylbenzyl] aminomethyl) -2-methyl-2H-1,4-benzoxazin-3 (4H) -one in 30 ml dichloromethane with addition of 0, Stir 4 ml triethylamine and 393 mg di-tert-butyl dicarbonate. After 40 hours at RT, the mixture is diluted with dichloromethane, washed with sodium hydrogen carbonate and then with brine. You dry the org. Phase and constricts. After column chromatography with hexane and ethyl acetate 3: 1, 370 mg of product result.

In the same way are made:

6- [N3- {6-Hvdroxy-2.5.7.8-tetramethylchroman-2-carbonyl -> - 3-aminoprop-1-yl- (tert.-butyloxycarbonvπ-aminomethvπ-2-methyl-2H-1.4-benzoxazin-3 ( 4H) -one

6- N4- {4-Hvdroxy-3.5-di-tert-butylbenzyl} - (tert-butyloxycarbonyl) aminobut-1-yl) - (tert.-butyloxycarbonylVaminomethyl] -2-methyl-2H-1, 4- benzoxazin-3 (4H) -one as a mixture with various mono-protected amines

6-rN- (4-Hvdroxy-3.5-di-tert-butylbenzvπ- (tert-butyloxycarbonvπaminomethvn-2-methyl-2H-1, 4-benzoxazin-3 (4H) -thione

To 100 mg of 6- [4-hydroxy-3,5-di-tert-butylbenzyl] - (tert-butyloxycarbonyl) amino-methyl] -2-methyl-2H-1, 4-benzoxazin-3 (4H) -one in 7 ml of dimethoxyethane is added at RT to Lawesson's reagent 93 mg and stirred for 12 hours; After concentration and column chromatography with hexane / ethyl acetate 4: 1, 91 mg of product result.

In the same way are made:

6- [N3- {6-Hvdroxy-2.5.7.δ-tetramethylchroman-2-carbonyl -) - 3-aminoprop-1-yl- (tert-butyloxycarbonyl) -aminomethvπ-2-methyl-2H-1.4-benzoxazine -3 (4H) -thione

6-ffN4- (4-Hvdroxy-3,5-di-tert-butylbenzylMtert.-butyloxycarbonyl) -aminobut-1-yl) - (tert-butyloxycarbonvπ-aminomethvn-2-methyl-2H-1.4-benzoxazin-3 (4H) -thione

Yield 53%

e

2R-6 - [(N4- {4-Hydroxy-3,5-di-tert-butylbenzylV (tert-butyloxycarbonyl) -aminobut-1-yl) -

(tert-Butyloxycarbonyl) -aminomethvn-2-methyl-2H-1.4-benzoxazin-3 (4HVthion and 2S-6-f (N4- {4-Hydroxy-3.5-di-tert-butylbenzyl) - (tert.- butyloxycarbonyl) -aminobut-1-yl) -

(tert-Butyloxycarbonvπ-aminomethyl ^' | -2-methyl-2H-1.4-benzoxazin-3 (4HVthion is obtained from

6 - [(N4- (4-Hvdroxy-3.5-di-tert-butylbenzyl> - (tert-butyloxycarbonyl) -aminobut-1-vπ- (tert-butyloxycarbonvO-aminomethyl1-2-methyl-2H-1, 4-benzoxazin-3 (4H) -thione by chiral HPLC.

example 1

6- [ ^" N- (4-Hydroxy-3,5-di-tert-butylbenzyl) - (tert-butyloxycarbonyl) aminomethyl-3-amino-2-methyl-2H-1,4-benzoxazine

66 mg of 6- [N- (4-hydroxy-3,5-di-tert-butylbenzyl) - (tert-butyloxycarbonyl) aminomethyl] -2-methyl-2H-1,4-benzoxazin-3 are stirred (4H) -thione in 40 ml sat. Ammonia solution in methanol (commercially available). After 1 day at room temperature the crude product is obtained after concentration. Column chromatography with ethyl acetate purifies the product. The result is 80 mg.

In the same way are made:

6-rN- {6-Hvdroxy-2.5.7,8-tetramethylchroman-2-carbonyl -} - 3-aminoprop-1-yl- (tert.-butyloxycarbonyl) -aminomethvπ-3-amino-2-methyl-2H- 1.4-benzoxazin

6-f (N4- {4-Hvdroxy-3.5-di-tert-butylbenzyl> - (tert-butyloxycarbonyl) -aminobut-1-yl) - (tert-butyloxycarbonyl) -aminomethvn-3-amino-2- methyl-2H-1.4-benzoxazine yield 51 mg = 96% of theory

2R-6-f (N4- {4-Hvdroxy-3.5-di-tert-butylbenzyl | - (tert-butyloxycarbonyl) -aminobut-1-yl) - (tert-butyloxycarbonvπ-aminomethvn-3-amino-2 -methyl-2H-1.4-benzoxazin 2S-6-r (N4- (4-Hvdroxy-3.5-di-tert.-butylbenzyl) - (tert.-butyloxycarbonyl) -aminobut-1-vπ- (tert.-butyloxycarbonyl) -aminomethvn-3-amino-2-methyl-2H-1.4-benzoxazine

Example 2

6-fN- (4-Hvdroxy-3.5-di-tert-butylbenzyl) aminomethyll-3-amino-2-methyl-2H-1.4-benzoxazine dihydrochloride

75 mg of 6- [N- (4-hydroxy-3,5-di-tert-butylbenzyl) - (tert-butyloxycarbonyl) amino-methyl] -3-amino-2-methyl-2H-1,4- benzoxazin are in 2.5 ml of THF with 1.1 ml of 4 n

Hydrochloric acid (solution in dioxane) stirred. After 12 hours, the mixture is evaporated to dryness.

49 mg of product (69% yield) are obtained. [1HJ-NMR (MeOH): 7.33 d J = 1 Hz 1H, 7.22 dd 1H, 7.20 s 2H, 7.05 d 1H, 5.18 q 1H,

4.14 s 2H, 4.05 s 2H, 1.50 d 3H, 1.34 s 18H.

In the same way are made:

6-fN- (6-Hvdroxy-2.5.7, δ-tetramethylchroman-2-carbonyl -) - 3-aminoprop-1-yl-aminomethyll-3-amino-2-methyl-2H-1.4-benzoxazine-dihydrochloride [1HJ -NMR (MeOH): 7.42 d 1H, 7.31 dd 1H, 7.15 d 1H, 5.29 dq (J = 3Hz, 1Hz) 1H, 4.01 s 2H, 3.3 m 2H, 2 , 8 to 2.5 m 4H, 2.35 m 1H, 2.2 s 3H, 2.15 s 3H, 2.09 s 3H, 1.8 m 2 + 1H, 1.54 d 3H, 1.50 d (J = 1Hz) 3H.

6 - [(N4- (4-Hvdroxy-3.5-di-tert-butylbenzyl) aminobut-1-yl) aminomethyll-3-amino-2-methyl-2H-1, 4-benzoxazine trihydrochloride yield 16 mg = 38%. [1H] -NMR (DMSO): 9.4, 9.1 each s broad, 7.47 d J = 1 Hz 1H, 7.36 dd 1H, 7.31 s 2H, 7.11 d 1H, 7.10 s OH, 5.31 q 1H, 4.11 s wide 2H, 4.0 s wide 2H, 2.95 m wide 4H, 1.75 m wide 4H, 1.52 d 3H, 1.40 s 18H.

2R-6-l (N4- {4-Hvdroxy-3.5-di-tert-butylbenzyl) aminobut-1-yl) aminomethyl1-3-amino-2-methyl-2H-1,4-benzoxazine trihvdrochloride

2S-6 - [(N4- (4-Hvdroxy-3.5-di-tert-butylbenzyl) aminobut-1-yl) aminomethvπ-3-amino-2-methyl-2H-1,4-benzoxazine trihydrochloride

Claims

claims 1.) Compounds of formula I, their tautomeric and isomeric forms and salts

wherein X O or S, R ¹ - (CHR ⁹ ) _n -NR ⁷ -A-NR ⁸ -B, - (CHR ⁹ ) _n -NR ⁸ -B or - (CHR ⁹ ) _n -B, R ^{2 is} hydrogen or R1 and R ² together with two adjacent carbon atoms form a 5-, 6-, 7- or δ-membered ring which is monocyclic or bicyclic, saturated or unsaturated and in which 1 or 2 CH ₂ groups can be replaced by oxygen or carbonyl and which is substituted with - (CHR ⁹ ) _r -NR ⁷ -A-NR ⁸ -B, - (CHR ⁹ ) _n -B or - (CHR ⁹ ) _r -NR ⁸ -B, R ^{3 is} hydrogen or NR ¹⁵ R ¹⁶ , R ^{4 is} hydrogen or acyl, R ⁵ and R ⁶ independently of one another are hydrogen, C _3-7 cycloalkyl, phenyl, C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl radicals, which can each be substituted by Halogen, OH, OC _1-6 -alkyl, SH, SC-, _-6 -alkyl, NR ¹⁵ R ¹⁶ , 5- or 6-membered heteroaryl with 1-3 N, O or S atoms, phenyl or C _3-7 cycloalkyl, R ⁷ and R ⁸ independently of one another are hydrogen, C _1-6 -alkyl, which may be substituted with phenyl, COOC _1-6 -alkyl or CO-Cι _-6- alkyl, or R ⁸ together with the adjacent nitrogen atom forms a 5-7-membered saturated heterocycle which can contain a further oxygen, nitrogen or sulfur atom or forms an unsaturated δ-membered heterocycle which can contain 1-3 N atoms, or R ⁷ together with the neighboring nitrogen atom forms a 5-7-membered saturated heterocycle which can contain a further oxygen, nitrogen or sulfur atom, A straight-chain or branched C _-6 alkylene or - (CH ₂ ) pQ- (CH ₂ ) q B

means QC _3-7 -cycloalkyl, indanyl, 5-, 6- or 7-membered saturated heterocycloalkyl with 1 - 2 N, O or S atoms, C ₆ -ιo-aryl or 5- or ₆ -membered heteroaryl with 1 - 3 N- , O or S atoms, m, n and r 0, 1 to 6, p and q represent 0 to 6, R} 9 ^a , u, * n-.d D R1 ¹ 0 ^U hydrogen or C _1-6 alkyl, R "and R ¹ ^ are hydrogen, hydroxy, C _1-6 alkyl or C _1-6 alkoxy, R ¹⁰ and R ^{1b are} hydrogen, C _1-6 alkyl, phenyl or benzyl or R ¹⁵ , R ¹⁶ together with the nitrogen atom form a saturated 5-, 6- or 7-membered ring which can contain a further nitrogen, oxygen or sulfur atom and can be substituted by C- | _4-alkyl, phenyl, benzyl or benzoyl , 2.) Compounds according to claim 1, wherein R ^{5 is} hydrogen. 3.) Compounds according to claim 1 or 2, wherein R ^{6 is} C _1-6 alkyl. 4.) Compounds according to claim 1 to 3, wherein R ^{4 is} hydrogen. 5.) Compounds according to claim 1 to 4, wherein R ^{8 is} hydrogen. 6.) Compounds according to claim 1, wherein A is -C _-6 alkylene. 7.) 6-fN- (4-hydroxy-3,5-di-tert-butylbenzyl) aminomethane-3-amino-2-methyl-2H-1,4-benzoxazine dihydrochloride 6-rN- (6-Hvdroxy-2,5.7.8-tetramethylchroman-2-carbonyl -) - 3-aminoprop-1-yl-aminomethvπ-3-amino-2-methyl-2H-1.4-benzoxazine-dihydrochloride 6-r (N4- (4-Hvdroxy-3.5-di-tert-butylbenzyl} -aminobut-1-vπ-aminomethvπ-3-amino-2-methyl-2H-1,4-benzoxazine trihvdrochloride 8.) Medicament containing a compound according to any one of claims 1 to 7 and one or more pharmaceutically customary excipients or auxiliaries. 9.) Use of a compound according to one of claims 1 to 7 for the manufacture of a medicament for the treatment of a disease which is triggered by NOS. 10.) Process for the preparation of a compound of formula I according to claim 1, characterized in that a compound of formula II or its salt

lla or

llb where R1, R ² , R ³ , p, R6 and X have the above meaning, Z is oxygen or sulfur and R is C- | _ß-alkyl, reacted with ammonia or primary amines, amino groups present being optionally protected, and if desired then acylated, the isomers separated or the salts formed. 11.) Compounds of the formula II a and II b and their salts

lla llb wherein R \ R ² , R ³ , R ⁵ , R ⁶ and X have the meaning given above, Z is oxygen or sulfur and means RC _1-6 -alkyl.