DE3701737A1 - 1H-Pyrido[2,3-b][1,4]thiazines for therapeutic treatment - Google Patents

Abstract

1H-Pyrido[2,3-b][1,4]thiazines are employed for therapeutic treatment. In particular, they can be used as lipoxygenase inhibitors.

Description

The invention relates to 1H-pyrido (2,3-b) (1,4) thiazines for therapeutic treatment and its use in Medicines.

From CA 75, 35906a (1971) it is known that the 2- and 3- Chlorine derivatives of 6-phenyl-1H-pyrido- (2,3-b) (1,4) - thiazine has an anti-tumor effect.

Hydrazine derivatives of 1,4-thiazines show an antineoplastic Activity (CA 87, 5909j [1977]).

There were 1H-pyrido- (2,3-b) (1,4) -thiazines

in the

R¹ is hydrogen, halogen or alkoxy, R² means hydrogen or halogen, R³hydrogen or optionally substituted Pyridyl means R⁴hydrogen, optionally substituted alkyl, optionally substituted aryl, amino or Alkoxycarbonyl means R⁵hydrogen, optionally substituted aryl, Alkylcarbonyl, arylcarbonyl or, in the event that R⁴ is not hydrogen, including alkoxycarbonyl means, and the radicals R⁴ and R⁵ to a 5- or 6-membered optionally substituted carbocycle or heterocycle can be connected,

found for therapeutic treatment.

The 1H-pyrido- (2,3-b) (1,4) -thiazines according to the invention are known per se (CA 50, 13032e [1956], CA 50, 10101 [1956], CA 70, 106503b [1969], CA 71, 124479y [1969], CA 76, 99692f [1972], CA 83, 193384y [1975], CA 95, 97844a [1981], CA 98, 126139u [1983], CA 98, 126133n [1963], CA 51, 14738a [1957], CA 88, 89602k [1978], CA 72, 121468d [1970], CA 99, 139876c [1963], CA 74, 141668p [1971], CA 74, 99959g [1971], CA 75, 35637p [1971], CA 77, 126570u [1972], CA 79, 146475m [1973] and J. Heterocycl. Chem. 70, 199 to 203 [1983]); a possible use however, was not found.  

The use of the 1H-pyrido (2,3-b) according to the invention (1,4) -thiazines for therapeutic treatment, in particular their high lipoxygenase inhibitory effect is therefore surprised.

In the context of the present invention, the substituents can generally have the following meanings:
Halogen can mean fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

Alkyl generally represents a straight-chain or branched hydrocarbon radical with 1 to 8 carbon atoms. Lower alkyl with 1 to approximately is preferred 6 carbon atoms. For example, methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, Called hexyl and isohexyl.

As a substituent of an alkyl group, for example (C₁- to C₈) called alkoxycarbonyl.

Alkoxy generally represents one via an oxygen atom bound, straight chain or branched Hydrocarbon residue with 1 to 8 carbon atoms. Prefers is lower alkoxy with 1 to 6 carbon atoms. For example, methoxy, ethoxy, propoxy, Isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, Called hexoxy and isohexoxy.

Alkylcarbonyl represents the group

where alkyl is a straight-chain or branched hydrocarbon radical having 1 to 8 carbon atoms. A lower alkyl radical having 1 to about 6 carbon atoms is preferred. The following alkylcarbonyl radicals may be mentioned, for example:
Methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, pentylcarbonyl, hexylcarbonyl.

Arylcarbonyl generally represents the group

wherein aryl represents an aromatic radical having 6 to about 12 carbon atoms. The following arylcarbonyl radicals may be mentioned, for example:
Benzoyl, naphthoyl and diphenoyl.

Alkoxycarbonyl generally represents the group

wherein the alkoxy radical is a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms which is bonded via an oxygen. A lower alkoxy radical having 1 to about 6 carbon atoms is preferred. The following alkoxycarbonyl radicals may be mentioned, for example:
Methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, isohexyloxycarbonyl.

Aryl generally represents phenyl which is 1 to 3, preferably 1 or 2, can carry substituents. Preferred Substituents are halogen, nitro, (C₁- to C₄) Alkoxy and / or hydroxy.  

Pyridyl is preferably 2-, 3- and 4-pyridyl.

The substituents on the pyridyl radical are nitro and Called lower alkyl.

The radicals R⁴ and R⁵ can be 5- or 6-membered Carbocycle or heterocycle may be connected. Prefers are 6-membered carbocycles and heterocycles.

Cyclohexene may be mentioned as the carbocycle, which can still carry 1 to 2 substituents.

The radicals R⁴ and R⁵ can form a nitrogen, oxygen and / or sulfur atom-containing heterocycle be connected.

6-membered one or two are particularly preferred Heterocycles containing nitrogen and / or oxygen atoms.

Oxazinones are preferred as a 6-membered heterocycle and called pyridazinones, which still have 1 or 2 substituents, preferably 1 substituent.

As substituents on carbocycles or heterocycles carbonyl, lower alkyl and / or phenyl are preferred called.

Preferred are 1H-pyrido- (2,3-b) (1,4) -thiazines, in which

R¹ means hydrogen, halogen or C₁- to C₈-alkoxy, R² means hydrogen or halogen, R³ means hydrogen or pyridyl optionally substituted by lower alkyl or nitro, R⁴hydrogen optionally alkyl substituted by alkoxy (C₁ to C₈) carbonyl, optionally by lower alkyl, halogen, nitro , Alkoxy (C₁ to C₄) and / or hydroxy substituted aryl (C₆ to C₁₂), amino or alkoxy (C₁- to C₈) carbonyl, R⁵hydrogen, optionally by lower alkyl, halogen, nitro, alkoxy (C₁ to C₈) and / or Hydroxy substituted aryl (C₆ to C₁₂), alkyl (C₁- to C₈) carbonyl, aryl (C₆- to C₁₂) carbonyl or, if R⁴ is not hydrogen, also alkoxy (C₁- to C₈) carbonyl, and
wherein the radicals R⁴ and R⁵ can be linked to a 5- or 6-membered carbocycle optionally substituted by carbonyl, lower alkyl and / or phenyl or a nitrogen, oxygen and / or sulfur atom-containing heterocycle.

1H-Pyrido- (2,3-b) (1,4) - are particularly preferred thiazine, wherein

R¹ means hydrogen, fluorine, chlorine, bromine or lower alkoxy, R² means hydrogen, fluorine, chlorine or bromine, R³ means hydrogen or 2-, 3- or 4-pyridyl optionally substituted by lower alkyl or nitro, R⁴hydrogen, optionally substituted by lower alkoxycarbonyl lower alkyl, optionally by lower alkyl , Fluorine, chlorine, bromine, nitro, lower alkoxy and / or hydroxy-substituted phenyl, amino or lower alkoxycarbonyl means R⁵hydrogen, optionally substituted by lower alkyl, fluorine, chlorine, bromine, nitro, lower alkoxy and / or hydroxy-substituted phenyl, lower alkylcarbonyl, phenylcarbonyl or, for the case that R⁴ is not hydrogen, also means lower alkoxycarbonyl, and
where the radicals R⁴ and R⁵ can be linked to form a 6-membered carbocycle optionally substituted by carbonyl, lower alkyl and / or phenyl or one or two nitrogen and / or oxygen atoms.

The 1H-pyrido- (2,3-b) (1,4) -thiazines according to the invention can be made by using pyridine compounds of the formula (III)  

in the
R¹, R² and R³ have the meaning given above, with carbonyl compounds of the formula (IV)

in the
R⁴ and R⁵ have the meaning given above and X represents halogen, preferably chlorine and bromine, or with cyano compounds of the formula (V)

in the
R⁵ and X have the meaning given above,
in the presence of base, if appropriate in the presence of solvents.

The method can be, for example, by the following Reaction schemes are shown:  

The pyridine compounds, carbonyl derivatives and cyano compounds are known.

Since the reaction releases hydrogen halide it is convenient to work in the presence of bases. Therefore come inorganic bases, such as alkali or alkaline earth metal hydroxides or carbonates or the corresponding Ammonium compounds and organic bases such as triethylamine or pyridine in question.

All inert organic diluents can be used Solvents are used. These include preferably ethers such as dioxane and tetrahydrofuran, Alcohols such as methanol, ethanol or isopropanol, dipolar aprotic solvents such as dimethylformamide, Dimethyl sulfoxide or N-methylpyrrolidone and water.  The method according to the invention can be carried out in the presence of only one or more organic Solvents or water and one or several water-immiscible solvents.

The reaction temperatures can be in a wide range can be varied. Generally one works between about 0 ° C and about + 200 ° C, preferably between 20 ° C and 150 ° C. The implementation can be done at normal pressure, however also carried out under reduced or increased pressure will. Generally one works at normal pressure.

When carrying out the method according to the invention it can be useful to work in an inert gas atmosphere, preferably under nitrogen. To represent the Compounds according to the invention are preferably used Pyridine compounds, carbonyl compounds or cyano compounds and bases in a molar ratio of 1: 1: 1 µm, it can but be useful to use an excess of base.

If the azahalbacetals or -ketals as intermediates, so it is appropriate that Dehydration in the presence of an acid in one to carry out inert solvent at elevated temperature.

As the acid, p-toluenesulfonic acid is preferred, suitable Solvents are hydrocarbons such as benzene and toluene and xylene and chlorinated hydrocarbons such as Chloroform, carbon tetrachloride or chlorobenzene. The The reaction can be carried out between 50 ° and 200 ° C.  Working up the reaction batches to isolate the Compounds according to the invention take place in known per se Wise.

The compounds of formula (I) according to the invention in which Case that R⁴ and R⁵ a 6-membered heterocycle close, can be obtained by implementing 1H-pyrido- (2,3-b) (1,4) -thiazines of the formula (VI) or (Via)

in the
R¹, R² and R³ have the meaning given above and R⁶ is (C _1-4 ) alkyl and R⁷ is H, (C _1-4 ) alkyl or optionally substituted phenyl,
with compounds of formula (VII)

in which

R⁸ is hydrogen, (C _1-4 ) alkyl or optionally substituted phenyl and R⁹ is -NH₂ or -OH,

optionally in the presence of inert solvents.

The method can be, for example, by the following Formula scheme are shown:

The 1H-pyrido- (2,3-b) (1,4) - which can be used as starting material As stated above, thiazines can be reacted with Pyridine compounds of formula (III) with carbonyl compounds of the formula (IV) are prepared.

The compounds of formula (VII) are known (S. R. Sandler and W. Karo, Organic Functional Group Preparations, Vol. I, pages 363-379 and Vol. II, pp. 321-364,  Academic Press, 1968-1972). It may be appropriate that Compounds of formula (VII) in the form of their salts with use inorganic acids, then you carry out the Reaction in the presence of equimolar amounts of an acid scavenger by. Alkali metal hydroxides, Alkali carbonates, alkaline earth hydroxides, alkaline earth carbonates, Alkali acetates, alkali alcoholates and tert. Amines or Serve pyridine.

All inert organic come as diluents Solvent in question.

These preferably include chlorinated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,2,2-trichloroethane and Chlorobenzene, alcohols, preferably methanol, ethanol and isopropanol, ethers such as dioxane or tetrahydrofuran and dipolar aprotic solvents such as dimethylformamide, Dimethyl sulfoxide or N-methyl pyrrolidone.

The method according to the invention can be carried out in the presence of only one or more organic solvents.

The reaction temperatures can be in a wide range can be varied. Generally one works between about 0 ° C and about + 200 ° C, preferably between + 20 ° C and + 150 ° C. The implementation can be carried out at normal pressure, but also carried out under reduced or increased pressure will. Generally one works at normal pressure.  

When carrying out the method according to the invention you can get the starting materials in equimolar amounts use, the use of an excess can be advantageous compound (VII).

Working up the reaction batches to isolate the Connections according to the invention are generally made in general known way.

The 1H-pyrido- (2,3-b) (1,4) -thiazines according to the invention are active ingredients for medicinal and therapeutic Suitable for the treatment of humans and animals. you are Lipoxygenase inhibitors and especially for the treatment of inflammatory, allergic and asthmatic diseases suitable.

The new active ingredients can in a known manner conventional formulations, such as tablets, Capsules, coated tablets, pills, granules, aerosols, Syrups, emulsions, suspensions and solutions, under Use of inert, non-toxic pharmaceutically suitable Carriers or solvents. Here should the therapeutically active compound in one Concentration of about 0.5 to 90% by weight of the total mixture be present, d. H. in amounts that are sufficient are in order to achieve the specified dosage range.

The formulations are produced, for example by stretching the active ingredients with solvents and / or carriers, optionally using  of emulsifiers and / or dispersants, where e.g. B. in the use of water as a diluent optionally organic solvents as Auxiliary solvents can be used.

Examples of auxiliary substances are:
Water, non-toxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut / sesame oil), alcohols (e.g. ethyl alcohol, glycerin), glycols (e.g. propylene glycol, polyethylene glycol) , solid carriers, such as. B. natural rock flours (e.g. kaolins, clays, talc, chalk), synthetic rock flours (e.g. highly disperse silica, silicates), sugar (e.g. raw, milk and glucose), emulsifiers, such as non-ionogens anionic emulsifiers (e.g. polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulfonates and aryl sulfonates), dispersants (e.g. lignin, leachate, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, Talc, stearic acid and sodium lauryl sulfate).

The application is carried out in the usual way, preferably orally or parenterally, especially perlingually or intravenously. In the case of oral use Tablets, of course, apart from the carriers mentioned also additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, like starch, preferably potato starch,  Contain gelatin and the like. Can continue Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. in the In the case of aqueous suspensions and / or elixirs for Oral applications are intended, the active ingredients except with the above-mentioned auxiliaries with various Flavor enhancers or colorants added will.

In the case of parenteral use, solutions can be found of the active ingredients using suitable liquid Carrier materials are used.

In general, it has been found to be beneficial in intravenous administration amounts from about 0.01 to 10 mg / kg, preferably about 0.05 to 5 mg / kg body weight to be administered per day for effective results and with oral application the dosage is about 0.05 to 100 mg / kg, preferably 0.1 to 10 mg / kg body weight per day.

Nevertheless, it may be necessary from deviate from the amounts mentioned, depending on the body weight of the test animal or the type the route of application, but also due to the animal species and their individual behavior towards the Drug or the type of its formulation and the Time or interval at which the administration he follows. So in some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above mentioned  Limit must be exceeded. In the case of the application larger quantities it may be advisable to distribute them in several single doses throughout the day. The same is true for application in human medicine Dosing scope provided. The same applies here also the above statements.

Example 1

A solution of 1.61 g (0.01 mol) of 3-amino-6-chloro-2-mercaptopyridine in 30 ml of ethanol containing 0.56 g (0.01 mol) of potassium hydroxide is added at 25 ° C a solution of 1.65 g (0.01 mol) of α- chloroacetoacetic ester. The mixture is heated at 50 ° C. for 1 hour, then the solvent is stripped off and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / 2% methanol). Yield: 2 g (= 74% of theory), mp: 202-205 ° C.

In an analogous way one can get:

Example 36

2.48 g (0.01 mol) of 2-mercapto-3 - ((5′-nitro-2′- pyridyl) amino) pyridine in a hot solution of 0.56 g (0.01 mol) potassium hydroxide in 50 ml of methanol and sets then 0.93 g (0.01 mol) of chloroacetone was added. To It is filtered for 1 hour and the mother liquor is concentrated. The residue is dissolved in a solution of 0.2 g p-toluenesulfonic acid added to 200 ml of toluene and 12 hours on Reflux cooked. After cooling down, wash with Bicarbonate solution, separates the organic phase and the solvent is distilled off. The backlog is out Petroleum ether / toluene recrystallized. Yield: 1.54 g (= 44% of theory), Mp: 154-155 ° C; in an analogous way one obtains

Example 37

(5′-nitro-pyridyl-2 ′) -pyrido- (2,3-b) (1,4) -thiazine, Mp .: 143-145 ° C / yield 30%.  

Example 38

1- (5′-nitro-pyridyl-2 ′) - 2-phenyl-pyrido- (2,3-b) (1,4) - thiazine, m.p .: 155-156 ° C / yield 43%.

Example 39

It is added to a solution of 2 ml of hydrazine hydrate 20 ml ethanol 1 g (0.0033 mol) 6-chloro-2-ethoxycar bonyl-3-methylcarbonyl-1H-pyrido (2,3-b) (1,4) thiazine and heated to reflux for 15 hours. Then the The precipitate is suction filtered, washed with water and dried. Yield: 0.8 g (= 90% of theory), Mp: <300 ° C; in an analogous way you can get:

Example 40

2H, 1OH-1-oxo-2,4-diphenyl-7-chloropyrido- (2,3-b) (1,4) - thiazino- (2,3-d) (1,2) -pyridazine, mp: <300 ° C / yield: 70%.  

Example 41

2H, 1OH-1-oxo-2-phenyl-4-methyl-7-chloropyrido- (2,3-b) (1,4) -thiazino- (2,3-d) (1,2) -pyridazine, mp: 300 ° C / Yield: 50%.

Example 42

2H, 1OH-1-oxo-4-n-propyl-7-chloropyrido- (2,3-b) (1,4) - thiazino- (2,3-d) (1,2) -pyridazine, mp: 250 ° C / yield: 33%.

Example 43

7-methoxy-2,3,6-triazaphenothiazin-1 (2H) -one, Mp .: <300 ° C / yield: 82%.

Example 44

7-methoxy-2,3,6-triazaphenothiazin-4 (3H) -one, Mp .: <300 ° C / yield: 89%.

Example 45

A solution of 0.5 g (0.0016 mol) of 6-chloro-2-carbethoxy 3-phenylcarbonyl-1H-pyrido (2,3-b) (1,4) thiazine, 0.12 g (0.0017 mol) hydroxylammonium chloride and 0.15 g (0.0018 mol) sodium acetate in 10 ml ethanol and 2 ml Water is refluxed for 15 hours. After that suction filtered, the filter residue washed with water and then dried. Yield: 0.12 g (= 26% of theory), Mp: 223-225 ° C; in an analogous way one can obtain:

Example 46

3-methyl-6-chloropyrido- (2,3-b) (1,4) -thiazino (2,3-d) (1,2) - oxazin, m.p .: 238-240 ° C / yield: 25%.  

Application example Example 45

The detection of the lipoxygenase inhibitory properties of the 1H-pyrido- (2,3-b) (1,4) -thiazines is carried out analogously to the methods of
Borgeat, P., Samuelsson, B. (1979), Proc. Nat. Acad. Sci., 76, 2148-2152 and
Hamilton, JG, Karol, RJ (1982) Prog. Lipid Res., 21, 155-170.

Rat polymorphonuclear leukocytes (PMNL) were isolated from the Peritoneal space of Wistar rats, 18 hours after i.p. Application of 6 ml of a 12% sodium caseinate suspension won.

The release was used as a measure of lipoxygenase inhibition of LTB₄ on polymorphonuclear granulocytes Addition of substance and calcium ionophore using HPLC certainly.

After centrifugation and washing the PMNL with incubation buffer (137 mM NaCl; 2.7 mM KCl; 5.0 mM Na₂HPO₂; 5.5 mM glucose; 2.0 mM CaCl₂; pH = 7.2) was the cell density set to 2 × 10⁷ ml (Coulter Counter) and 1 ml of this cell suspension with 2.5 µl DMSO or 2.5 σl of different test substance concentrations in DMSO Pre-incubated for 5 min at 37 ° C. After stimulating the cells  with 2.5 ul calcium ionophore A 23187 (1 mg / ml DMSO) the 6-minute main incubation by adding 1.5 ml PGB₂-containing methanol stopped (1 µl / ml), 2 ml cell-free Supernatant by centrifugation (1000 g, 3 min, RT) and after acidification with 1 N-HCl to pH 3.0 extracted twice with 4 ml ether. The United Ether phases were washed with 4 ml of water (Bidest), dried under nitrogen and in 80 µl Methanol added.

20 µl of each of the samples prepared in this way were used a finished column (Nucleosil, type 7.5 C 18M 4 × 25 mm) applied and at a flow rate of 1 ml / min (Kontron pump system 600), where as mobile phase methanol, H₂O and acetic acid (75: 25: 0: 0.01) served. The detection was carried out at 280 nm (Uvicon 720 LC). The formation of the metabolite was determined using the internal standards PGB₂ as the quotient of the area integrals (Shimadzu C-R1B) quantified from LTB₄ to PGB₂ and inhibition determined as a percentage of controls.

The effect of a 1H-pyrido- (2,3-b) (1,4) -thiazine may be mentioned as an example:
Inhibition of leukotriene B₄ biosynthesis in rat granulocytes: Example 3: 42% inhibition at 1 · 10 ^-5 (M / l).

Claims (9)

1. 1H-pyrido (2,3-b) (1,4) thiazines in which R¹ is hydrogen, halogen or alkoxy, R² is hydrogen or halogen, R³ is hydrogen or optionally substituted pyridyl, R⁴ is hydrogen, optionally substituted alkyl, optionally substituted aryl, amino or alkoxycarbonyl, R⁵ is hydrogen, optionally substituted aryl, alkylcarbonyl, arylcarbonyl or, in the case that R⁴ is not hydrogen, also means alkoxycarbonyl, and the radicals R⁴ and R⁵ can be linked to form a 5- or 6-membered, optionally substituted carbocycle or heterocycle, for therapeutic treatment. 2. 1H-pyrido- (2,3-b) (1,4) -thiazines according to claim 1, wherein R¹ is hydrogen, halogen or C₁- to C₈-alkoxy, R² is hydrogen or halogen, R³ is hydrogen or optionally substituted by lower alkyl or nitro Pyridyl means R⁴hydrogen, optionally substituted by alkoxy (C₁- to C₈) carbonyl alkyl, optionally substituted by lower alkyl, halogen, nitro, alkoxy (C₁ to C₄) and / or hydroxy substituted aryl (C₆ to C₁₂), amino or alkoxy (C₁- to C₈) carbonyl, R⁵hydrogen, optionally substituted by lower alkyl, halogen, nitro, alkoxy (C₁ to C₈) and / or hydroxy-substituted aryl (C₆ to C₁₂), alkyl (C₁- to C₈) carbonyl, aryl (C₆- to C₁₂) carbonyl or, in the event that R⁴ is not hydrogen, also alkoxy (C₁- to C₈) carbonyl, and
wherein the radicals R⁴ and R⁵ to a 5- or 6-membered carbocycle optionally substituted by carbonyl, lower alkyl and / or phenyl or nitrogen, oxygen and / or sulfur atoms containing heterocycle can be connected for therapeutic treatment. 3. 1H-pyrido- (2,3-b) (1,4) -thiazines according to claims 1 and 2, wherein R¹ is hydrogen, fluorine, chlorine, bromine or lower alkoxy, R² is hydrogen, fluorine, chlorine or bromine, R³hydrogen or means 2-, 3- or 4-pyridyl optionally substituted by lower alkyl or nitro, R, means hydrogen, optionally lower alkyl substituted by lower alkoxycarbonyl, optionally substituted by phenyl, amino or lower alkoxycarbonyl substituted by lower alkyl, fluorine, chlorine, bromine, nitro, lower alkoxy and / or hydroxy, R⁵hydrogen, optionally substituted by lower alkyl, fluorine, chlorine, bromine, nitro, lower alkoxy and / or hydroxy-substituted phenyl, lower alkylcarbonyl, phenylcarbonyl or, in the event that R⁴ is not hydrogen, also means lower alkoxycarbonyl, and
wherein the radicals R⁴ and R⁵ can be linked to a 6-membered carbocycle optionally substituted by carbonyl, lower alkyl and / or phenyl or one or two nitrogen and / or oxygen atoms containing heterocycle for therapeutic treatment. 4. 1H-pyrido- (2,3-b) (1,4) -thiazines according to the claims 1 to 3 as a lipoxygenase inhibitor. 5. Medicament containing 1H-pyrido- (2,3-b) (1,4) - thiazines of the formula in which R¹ is hydrogen, halogen or alkoxy, R² is hydrogen or halogen, R³ is hydrogen or optionally substituted pyridyl, R⁴ is hydrogen, optionally substituted alkyl, optionally substituted aryl, amino or alkoxycarbonyl, R⁵ is hydrogen, optionally substituted aryl, alkylcarbonyl, arylcarbonyl or, in the case that R⁴ is not hydrogen, also means alkoxycarbonyl, and the radicals R⁴ and R⁵ can be linked to form a 5- or 6-membered, optionally substituted carbocycle or heterocycle. 6. Medicament according to claim 5, containing 0.5 to 90% by weight of 1H-pyrido- (2,3-b) (1,4) -thiazines on the overall mix. 7. Use of 1H-pyrido- (2,3-b) (1,4) -thiazines of the formula in which R¹ is hydrogen, halogen or alkoxy, R² is hydrogen or halogen, R³ is hydrogen or optionally substituted pyridyl, R⁴ is hydrogen, optionally substituted alkyl, optionally substituted aryl, amino or alkoxycarbonyl, R⁵ is hydrogen, optionally substituted aryl, alkylcarbonyl, arylcarbonyl or, in the case that R⁴ is not hydrogen, also means alkoxycarbonyl, and the radicals R⁴ and R⁵ can be linked to form a 5- or 6-membered, optionally substituted carbocycle or heterocycle, for the preparation of medicaments. 8. Use of 1H-pyrido- (2,3-b) (1,4) -thiazines according to claim 7 for the production of lipoxygenase inhibitors. 9. Use of 1H-pyrido- (2,3-b) (1,4) -thiazines according to claims 7 and 8 for the production of Anti-inflammatory, anti-allergic and anti-asthmatic.