FI93362C - Process for the preparation of therapeutically effective pyrido- / 2,3-b // 1,5 / benzoxazepine and thiazepine-5- (6H) ones - Google Patents

Description

93362

The process for the preparation of therapeutically effective pyrido [2,3-b] - [1.5] benzoxazepine and thiazepine-5- (6H) ones - For the preparation of therapeutically effective pyrido [2,3-b] - [1.5] benzoxazepine and thiazepine-5- (6H) one

The invention relates to a process for the preparation of therapeutically effective pyrido [2,3-b] [1,5] benzooxazepine and thiazepine-5- (6H) ones of formula (I) in which X is oxygen or sulfur; R 1 is alkyl of 1 to 3 carbons or an allyl group; R 3 is a hydrogen atom or an amino or hydroxy group; R5 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or an amino group; R7 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

The human disease, Acquired Immune Deficiency 'Syndrome (AIDS), is caused by the immunodeficiency virus (HIV), especially a strain known as HIV-1.

Like other viruses, HIV-1 cannot replicate without taking over the biosynthetic device of the host cell it infects. . . hardware. It causes this equipment to produce structural proteins that form the offspring of the virus. These proteins are encoded by the genetic material contained in the infecting virus particle, or virion. However, because HIV is a retrovirus, its genetic material is RNA and not DNA, like the host cell genome. Thus, viral RNA must first be converted to DNA and then inserted into the genome of the host cell in order for host cell 2 93362 to produce the necessary viral proteins. Conversion of RNA to DNA is accomplished using the reverse transcriptase (RT) enzyme contained in the infecting virion in addition to the RNA. Reverse transcriptase has 3 enzymatic functions; it acts as an RNA-dependent DNA polymerase, a ribonuclease, and a DNA-dependent DNA polymerase. Acting first as an RNA-dependent DNA polymerase, RT first makes a 1-stranded DNA copy of viral RNA. RT, acting as a ribonuclease, releases the freshly produced DNA from the original viral RNA, and then destroys the original RNA. Finally, RT makes a second, complementary strand of DNA acting as a DNA-dependent DNA polymerase, using the first strand of DNA as a template. These 2 strands form a 2-stranded DNA that is attached to the genome of the host cell by another enzyme called integrase.

Compounds that inhibit the enzymatic functions of HIV-1 reverse transcriptase inhibit HIV-1 replication in infected cells. Such compounds are useful in the prevention or treatment of HIV-1 infection in human subjects.

The compounds of formula I may be prepared by known methods or obvious modifications thereof. Methods A and B described below are illustrative of methods for preparing compounds of formula I.

Method A

Compounds of formula I in which Z is oxygen and X and R 1 to R 8 are as defined above may be obtained, for example, by converting a compound of formula II in which R 3 to R 7 are as defined above to the corresponding compounds of formula III. alkali or alkaline earth metal compounds XR7 wherein R3 to R7 are as defined above, and subsequently reacting this alkali metal compound under well known alkylation or acylation conditions with a reactive alkylation or acylation reagent of formula IV RXY (IV) wherein Y1 is as defined above, a leaving group such as chloride, bromide, iodide, alkyl or aryl sulfonate, or an alkylcarbonyloxy or arylcarbonyloxy group.

It will be appreciated by those skilled in the art that the presence of nucleophilic substituents in the compounds of formula II requires the use of an intermediate ... in which the substituents are not nucleophilic, other than the 5-position nitrogen, but can be derivatized to give the required group. For example, amino or monoalkylamino substituents are preferably obtained by alkylation or acylation of an intermediate of formula II having a nitro group or groups at the desired positions and alkylation, if appropriate, to give the final product.

•. ·

Method B

Compounds of formula I wherein X and R 1 to R 7 are as defined above can be obtained by cyclization of formula V. . compounds 4 93362 / h / wherein X and R3 to R7 are as defined above and Hal is fluorine, chlorine, bromine or iodine, preferably in the presence of an inorganic base such as sodium or potassium hydride, lithium alkyls such as n-butyllithium, sodium or in the presence of potassium hydroxide, or an organic base such as quinoline or 4- (N, N-dimethylamino) pyridine at ambient or elevated temperature, preferably 80 to 175 ° C, even at the boiling point of the reaction mixture. Suitable solvents include e.g. inert aprotic solvents such as toluene, sulfolane or dimethylformamide. t

The pyridophenylamides of the formula V can be obtained, for example, by condensing, under well-known reaction conditions, appropriately substituted 2-halonicotinic acid chlorides of the formula VI • · * t C 9 0 R 3

/ \ ji — Cl VI

N- / halo wherein Hal is fluorine, chlorine, bromine or iodine and R 3 is as defined above, with ortho-aminophenols of formula VII wherein X, R 5 and R7 are as defined above Depending on the reaction conditions used and the nature of X and R3 to R7, condensation of compounds of formulas VI and VII can in one step form tricyclic compounds of formula I wherein X, R3 and R7 are as defined above. 1-step formation is most readily accomplished when X is sulfur and at elevated temperatures, especially in the range of 80 to 175 ° C.

The compounds of formula I may, if desired, be converted into their pharmaceutically acceptable acid addition salts by conventional methods. The invention also relates to such salts.

Examples of inorganic and organic acids which can form non-toxic, pharmaceutically acceptable acid addition salts with a compound of formula I include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, tartaric acid, citric acid, citric acid, citric acid.

Examples of bases which may form pharmaceutically acceptable salts with compounds of formula I containing acidic substituents include sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, tromethamine and the like.

The compounds of formula I may be administered in single or divided doses orally, parenterally or topically. A suitable oral dose for a compound of formula I would be in the range of about 0.5 mg to 1 g / day. For parenteral formulations, a suitable dosage unit may contain from 1 to 250 mg of said compounds, while formulations containing from 0.01 to 1% of active ingredient are preferred for topical administration. It should be understood, however, that the dose to be administered will vary from patient to patient, and that the dose to a particular patient will depend on the clinician's assessment of the patient's size and condition as well as the patient's response to the drug.

As mentioned above, the compounds of the invention inhibit the enzyme activity of HIV-1-RT. Based on the tests described below, these compounds are known to inhibit the RNA-dependent DNA polymerase activity of HIV-1 RT. Based on tests other than those described herein, it is believed that they also inhibit the DNA-dependent DNA polymerase activity of HIV-1-RT.

The ability of the compounds to inhibit the RNA-dependent DNA polymerase activity of HIV-1 RT can be tested using the reverse transcriptase (RT) assay described below. Thus, certain specific compounds described in the Examples below were also tested. The results of these tests are shown in Table I below.

... REVERSE TRANSCRIPTASE (RT) DETERMINATION

• c · Theory of determination:

Enzymes encoded by the human immunodeficiency virus (HIV-1) include reverse transcriptase (1), called by this name because it translates a copy of DNA from an RNA template. This activity can be quantified in the cell-free enzyme assay described previously (2), based on the observation that reverse transcriptase can use a synthetic template [Poly r (C) primed with oligo d (G)] radiolabeled. , in the transcription of an acid-precipitated DNA strand using the substrate 3H-dGTP.

7 93362

Materials: a) Enzyme preparation The reverse transcriptase enzyme from the immunodeficiency virus (HIV-1) LAV strain (1) was isolated from the bacterial strain JM109 (3) expressing the DNA clone pBRTprt1 + (2), which is under the control of the Lac promoter in the 412 expression vector. Overnight culture in 2XYT medium (37 ° C, 225 g / min) (5) supplemented with 100 μ9 / π \ 1: 1ΐ3 thiamine, 0.5% casamino acids and 50 μ9 / πι1: 1ΐ3 ampicillin (5). The culture is incubated (37 ° C, 225 rpm) until it reaches an OD540 of 0.3-0.4. The repressor inhibitor IPTG (isopropyl / S-D-thiogalactopyranoside) is then added to 0.5 mM and incubated for a further 2 hours. The bacteria are pelleted, resuspended in 50 mM Tris, 0.6 mM EDTA, 0.375 M NaCl buffer and thawed by the addition of lysozyme (1 mg / ml) for 30 min on ice.

The cells are lysed by adding 0.2% NP-40, and adjusted to 1 M NaCl.

. After insoluble cellular debris is removed by centrifugation, the protein is precipitated by adding 3 volumes of saturated aqueous ammonium sulfate solution. The enzyme is pelleted, resuspended in RT buffer (50 mM Tris, pH 7.5, 1 mM EDTA, 5 mM DTT, 0.1% NP-40, 0.2M NaCl and 50% glycerol), and further stored for use. for -70 ° C.

b) 2X concentration formation of the base reaction mixture base reagent 2X concentration mixture

1 M Tris pH 7.4 100 mM

1 M dithiothrietol 40 mM

1 M NaCl 120 mM

1% Nonidet P-40 0.1%

1 M MgCl 4 mM

[Poly r (C) / oligo d (G)] (5: 1) 2 μg / ml 3H-dGTP (81 μΜ) 0.6 μΜ \ 8 93362 Method of determination: The reaction stock mixture at 2X concentration is aliquoted and stored at -20 ° C :in. The mixture is stable and thawed for use in each assay. This enzyme assay is adapted for a 96-well microtiter plate system and has been described previously (6). Tris buffer (50 mM, pH 7.4), medium (solvent diluted to suit compound dilution), or compounds in medium are added to 96-well microtiter plates (10 μΐ / well; 4 wells / compound). The HIV-1 RT enzyme is thawed, diluted to 50 mM Tris pH 7.4, so that 15 μΐ of diluted enzyme contains 0.001 units (1 unit is the amount of enzyme which changes 1 μπιοοίΐη substrate / min at 25 ° C). , and add 15 μΐ / well. Add 20 μΐ 0.12 to 0.5 M EDTA to the first 3 wells of the microtiter plate. EDTA chelates the Mg ++ present, and prevents reverse transcription.

This group acts as a background polymerization that is subtracted from all other groups. 25 μΐ 2X of the reaction mixture is added to all wells and the assay is allowed to incubate at room temperature for 60 min. The assay is terminated by precipitating the DNA in each well with 50 μl: 1 ^ 10% trichloroacetic acid (TCA) (10% w / v) in sodium pyrophosphate (1% w / v). The microtiter plate is incubated for 15 min at 4 ° C, and the pellet is attached to # 30 glass fiber paper (Schleicher & Schuell) using a Skatron semi-automatic collector.

The filters are then further washed with TCA (5%) containing sodium pyrophosphate (1%), rinsed with aqueous ethanol (70%), dried, and transferred to scintillation vials (6). Add 2 ml of scintillation cocktail to each flask, and count on a Beckman beta counter.

• «* * Calculations for percentage inhibition are as follows: Inhibition% = CPM Avg. test value -CPM avg. control value x 100 CPM Avg. control value 9 93362

References: 1. Benn, S., et al., Science 230 (1985) 949 2. Farmerie, W.G. you do not. ai., Science 236 (1987) 305 3. Yanisch-Perron, C., Viera, J., and Messing, J., Gene 33.

(1985) 103 4. International Biotechnologies, Inc. New Haven, CT 06535 5. Maniatis, T. Fritsch, EF, and J. Sambrook, editors, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, 1982 6. Spira, T., et. al. J. Clinical Microbiology 25. (1987) 97

In order to roughly determine the cytotoxicity of the compounds of the invention, several such compounds were tested in the MTT cell cytotoxicity assay described below. The results of these tests are shown in Table I below. Compounds with a relatively high EC50 are preferred.

MTT DETERMINATION OF CELL CYTOTOXICITY

. Assay theory: The MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) assay is based on cleavage of tetrazolium bromide in metabolically active cells, resulting in a very quantitative blue color. This assay has been described previously (1), but has been optimized for the tests presented here.

Assay Method: The H9 cell line (2), a reliable human lymph node tumor, a pension cell line grown in RPMI 1640 supplemented with 10% fetal bovine serum, is used as a target cell line in the assay. Cells (100 μΐ) are added to the wells of the microtest plate at a concentration of 105 cells / ml in the presence of varying concentrations of inhibitor. The cells are incubated at 37 ° C in a humidified CO 2 incubator. 5 days later, 10 μM of MTT (5 mg / ml in RPMI 1640, sonicated, filtered as 0.2 μτα filter, and stored at 4 ° C) is added to each well. After a further 4 hours of incubation at 37 ° C, 60 μΐ Triton-X is added to each well, and mixed thoroughly to help dissolve the crystals. Absolute ethanol (5 μΐ) is added to each well, and the resulting mixture is incubated for 30 min at 60 ° C, and read immediately on a plate reader (Dynatech) at 570 nm. Data from this assay were used to generate a non-linear regression analysis to obtain an EC50.

References: 1. Mosmann, Tim, J. Immunol. Methods 65, (1983) 55.

2. Jacobs, J.P., J. Natl. Cancer Inst. 34. (1965) 231.

TABLE I

Compound e.g. RT inhibition from cytotoxicity marker no. % @ 10 μ $ / πι1 assay (EC50)

1 80 NT

2 89 NT

3 57 * 315 μΜ

4 92 * NT

5 93 * NT

6 82 * NT

7 71 NT

• ·

8 77 NT

9 89 NT

10 28 NT

11 43 * NT

12 67 * NT

13 41+ NT

14 33 * NT

15 85 NT

Note: NT = not tested *% Inh. @ 1 μΜ. .. +% Inh. @ 2.5 μΜ il 11 93362

The following examples further illustrate this invention and will enable one skilled in the art to more fully understand the invention. It should be understood, however, that the invention is not limited to the specific examples set forth below.

Example 1 6- (n-Propyl) pyrido [2,3-b] benzoxazepin-5 (6H) -one

Sodium hydride (0.96 g of a 50% suspension in mineral oil) was added to a solution of 2.12 g of pyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one (synthesized according to published methods). in 1 ml of dimethylformamide, and the resulting mixture was stirred for 1 hour. 1-Bromopropanol (2.46 g) was added slowly, and the reaction mixture was stirred overnight at room temperature. Crushed ice was added to decompose the unreacted sodium hydride. Water was then added and the product was extracted with ether, dried (anhydrous sodium sulfate), and concentrated in vacuo. Purification on a silica gel column (ethyl acetate / hexane, 1: 4) gave 1.25 g of a viscous, colorless oil.

Example 2 6-ethyl chloride rid2.3-1 Γΐ. 51 benzothiazepin-5 (6H) -one a) Pyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one (t · t ·

A mixture of 2-chloronicotinic acid (31.5 g, 0.2 mol) and thionyl chloride (100 ml) was refluxed for 3 hours. The solvent was removed in vacuo and then the acid chloride was added to a mixture of 2-aminothiophenol (25 g), toluene (400 ml) and pyridine (34 g). The resulting mixture was refluxed for 4 hours, and allowed to stand overnight at room temperature.

- <. v *

The yellow precipitate was collected and stirred with water for 3 hours, filtered and air dried. The product was recrystallized from ethyl acetate to give 20.8 g (45% of theory) of an almost pure yellow product suitable for use in the next reaction. A small amount of e 9 12 93362 of this product was recrystallized from acetonitrile to give the pure product as a pale yellow solid, m.p. 260-261 ° C.

b) 6-Ethylpyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one

Sodium hydride (1.05 g of a 50% suspension in mineral oil) was added to a suspension of pyrido [2,3-b] [1,5] benzothiazepin-5 (6) -one (4.0 g, 0.0175 mol) in 100 ml of dimethylformamide. , and the resulting mixture was stirred until gas evolution ceased, at which time the mixture was heated at 50 ° C for 30 min. After cooling to room temperature, ethyl iodide (5.46 g, 0.035 mol) was added slowly, and the reaction mixture was stirred for 2 hours. Crushed ice was added to decompose unreacted sodium hydride. Water was then added and the product was extracted with ether, dried (anhydrous sodium sulfate) and concentrated in vacuo. After washing the solid residue with hexane, it was recrystallized from ethyl acetate / hexane to give 0.66 g (14% of theory) of the product as yellow crystals, m.p. 148-149 ° C.

Example 3 3-Amino-6,9-dimethylpyrrido f2.3-bT Γ1.51 benzoxazepin-5 (6H) -one • ♦ '* * J a) 2-Hydroxy-5-nitronicotinic acid

Fuming nitric acid (d 1.5, 10 mL, 0.24 mL) was added to a solution of 2-hydroxynicotinic acid (14 g, 0.1 mol) and concentrated sulfuric acid (40 mL). The resulting mixture was heated at 50 ° C for 4 hours, and then carefully poured. ; ·. ti in water. The pale orange precipitate was collected, washed with cold water and then recrystallized from water to give 13.3 g (72% of theory) of almost pure product as pale yellow crystals, m.p. 240 ° C, which were suitable for use in the next reaction.

13 93362 b) 2-Chloro-5-nitronicotinic acid

A solution of 2-hydroxy-5-nitronicotinic acid (9.2 g, 0.05 mol) in phosphorus oxychloride (25 mL) was refluxed for 5 hours. The solvent was removed in vacuo and the residue was dissolved in a mixture of tetrahydrofuran and ether. After cooling in an ice bath, water was carefully added dropwise with stirring until the layers separated clearly. The organic layer was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and concentrated. Recrystallized from ether to give 6.94 g (69% of theory) of pure product, m.p. 135 ° C (decomposes).

c) 2-Chloro-5-nitro-N- (3-hydroxytol-4-yl) -3-pyridinecarboxamide

A mixture of 2-chloro-5-nitronicotinic acid (6.1 g, 0.03 mol) and thionyl chloride (15 mL) was refluxed for 3 hours, the solvent was removed in vacuo, and the acid chloride was dissolved in tetrahydrofuran (150 mL). The resulting solution was added slowly at 0 ° C under argon to a solution of 6-amino-m-cresol (4 g, 0.03 mol), N, N-diisopropylethylamine (7 mL, 0.04 mol) and tetrahydrofuran (150 ml), and the resulting solution was stirred for 2 hours. The mixture was then diluted with water, and the product was extracted with ether, washed with saturated sodium chloride solution, dried (anhydrous magnesium sulfate), and concentrated to half volume. The gummy orange crude product was collected and stirred with methylene chloride (50 mL) for 30 min. The precipitate was washed with methylene chloride and air-dried to give 6.3 g (68% of theory) of pure product as a pale orange powder.

d) 3-Nitro-9-methylpyrido [2,3-b] [1,5] benzoxazepinS (6H) -one

A mixture of 2-chloro-5-nitro-N- (3-hydroxytol-4-yl) -3-pyridinecarboxamide (6.3 g, 0.02 mol) and pyridine. .. (100 ml) was stirred for 2.5 hours at 90 ° C. The cooled solution 14 93362 was diluted with water, and the light orange precipitate was collected and washed with water. The solid was then stirred for 45 min in hot water (100 mL), filtered and washed with ethanol and ether to give 4.3 g of a tan solid. Recrystallization from dimethylformamide / water gave 3.76 g (69% of theory) of the product.

e) 3-Nitro-6,9-dimethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one

To a suspension of sodium hydride (0.73 g, 0.015 mol of a 50% dispersion in mineral oil) in dimethylformamide (875 ml) under argon was added in one portion 3-nitro-9-methylpyrido [2,3-b] [1,5] benzoxazepine. 5 (6H) -one (3.75 g, 0.014 mol). Methyl iodide (1.3 mL, 0.021 mol) was added and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with ice water, and the precipitated product was collected and washed with water and petroleum ether. The crude product was recrystallized from ethyl acetate to give 3.14 g (79% of theory) of the product as a pale yellow solid, m.p. 197-198 ° C.

f) 3-Amino-6,9-dimethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one

To a suspension of 3-nitro-6,9-dimethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one (1.6 g, 5.6 mmol) in acetic acid (30 ml), a solution of stannous chloride hydrate (10 g, 55 mmol) in concentrated hydrochloric acid (13 ml) was added. After stirring for 3 hours, the precipitate formed was filtered and washed with ether. The product was then dissolved in water, adjusted to basic pH with 2N sodium hydroxide, extracted with ether and ethyl acetate, dried (anhydrous magnesium sulfate), and concentrated. Crystallization from ethanol / hexane gave 0.82 g (57% of theory) of pure product as tan needles, m.p. 191-193 ° C.

il.

15 93362

Examples 4-15

The compounds of the following examples were prepared by methods analogous to those described above:

Example no.

4. 3-Amino-6,7,9-trimethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one, m.p. 234-236 ° C.

5. 3-Amino-7,9-dimethyl-6-ethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one, m.p. 232-234 ° C.

6. 3-Amino-7,9-dimethyl-6- (n-propyl) pyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one, m.p. 195-197 ° C.

7. 6-methylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one, m.p. 107-109 ° C.

8. 6-ethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one, m.p. 81-83 ° C.

9. 6-allylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one, m.p. 58-60 ° C.

10. 6-propionylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one, <0 m.p. 111-113 ° C.

11. 6,9-dimethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one, m.p. 165-168 ° C.

12. 6-ethyl-9-methylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one, m.p. 114-116 ° C.

13. 3-hydroxy-6,9-dimethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one, m.p. 257-258.5 ° C.

16 93362 14. 7-Amino-6-ethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one, m.p. 114-116 ° C.

15. 6-methylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one, m.p. 172-174 ° C.

Example 16 3-Amino-6,9-dimethylpyrido β2,3-bβ1.51 benzothiazepin-5 (6H) -one

The title compound was obtained using a method analogous to the method of Example 3, but starting from 2-mercapto-5-nitronicotinic acid.

Examples 17 to 21

The following compounds could be prepared in ways analogous to the methods described above.

Example no.

17. 3-Amino-6,7,9-trimethylpyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one 18. 3-Amino-7,9-dimethyl-6-ethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one 19. 3-amino-7,9-dimethyl-6- (n-propyl) pyrido [2,3-b] [1, 5] -benzothiazepin-5 (6H) -one 20. 3-Amino-7,9-dimethyl-6- (i-propyl) pyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one -one 21. 3-Amino-7,9-dimethyl-6-allylpyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one

Claims (11)

17 93362 A process for the preparation of therapeutically effective pyrido [2,3-b] - [1,5] benzooxazepine and thiazepine-5- (6H) ones of formula (I) O R 1 V_ / f * past V wherein X is oxygen or sulfur; R 1 is alkyl of 1 to 3 carbons or an allyl group; R 3 is a hydrogen atom or an amino or hydroxy group; R5 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or an amino group; R7 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, characterized in that a) compounds of formula I in which X and R1 to R7 are as defined above are prepared by converting compounds of formula II in which R3- R 7 are as defined above to give the corresponding alkali or alkaline earth metal compounds of formula III 18 93362 O M + χ £ ά XR 7 wherein R 2 to R 8 are as defined above, and these alkali or alkaline earth metal compounds are subsequently reacted under well known alkylation or acylation conditions of formula IV with reactive alkylation or acylation reagents according to R1Y IV wherein t R1 is as defined above and Y is a suitable leaving group such as chloride, bromide, iodide, alkyl or arylsulfonate, or alkylcarbonyloxy or arylcarbonyloxy group, or b) condensing a 2- halogenotinic acid chloride itc R3 \ ° / —Cl VI \\ // NY -r nai where Hai is fluorine , chlorine, bromine or iodine and R 2 to R 4 are as defined above, with an ortho-aminophenol or thio-phenol of formula VII ti 19 93362 γ, .. hx ^ \ ^ \ r7 wherein X and R 3 to R 7 are as defined above, cyclized the compound of formula V thus obtained, R 3 R 5 in HX and X is oxygen and R 3 to R 7 are as defined above and Hal is fluorine, chlorine, bromine or iodine, preferably an inorganic base such as sodium or potassium hydride, lithium alkyl, sodium or potassium hydroxide, or in the presence of an organic base at temperatures even at the boiling point of the reaction mixture in the presence of a solvent, ... and if desired, the compound of formula I is converted into its pharmaceutically acceptable acid addition salts. A process according to claim 1 for the preparation of 3-amino-6,9-dimethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one and a pharmaceutically acceptable acid addition salt thereof. characterized in that corresponding starting materials are used. 20 93362 A process according to claim 1 for the preparation of 3-amino-6,7,9-trimethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one and a pharmaceutically acceptable acid addition salt thereof, characterized in that similar starting materials are used. A process according to claim 1 for the preparation of 3-amino-7,9-dimethyl-6-ethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one and a pharmaceutically acceptable acid addition salt thereof, characterized in that corresponding starting materials are used. A process according to claim 1 for the preparation of 3-amino-7,9-dimethyl-6- (n-propyl) pyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one and a pharmaceutically acceptable acid addition salt thereof. , characterized in that corresponding starting materials are used. Process for the preparation of 3-amino-6,9-dimethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one and a pharmaceutically acceptable acid addition salt thereof according to Claim 1, characterized in that the corresponding starting materials are used. A process according to claim 1 for the preparation of 3-amino. 6,7,9-Trimethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one and its pharmaceutically acceptable acid addition salt, characterized in that the corresponding starting materials are used. A process according to claim 1 for the preparation of 3-amino-7,9-dimethyl-6-ethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one and a pharmaceutically acceptable acid addition salt thereof, characterized in that similar starting materials are used. A process according to claim 1 for the preparation of 3-amino-7,9-dimethyl-6- (n-propyl) pyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one and its pharmaceutically acceptable acid addition. 21 93362 salts, characterized in that corresponding starting materials are used. A process according to claim 1 for the preparation of 3-amino-7,9-dimethyl-6- (i-propyl) pyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one and its pharmaceutically acceptable substances. acceptable acid addition salt, characterized in that the corresponding starting materials are used. A process according to claim 1 for the preparation of 3-amino-7,9-dimethyl-6-allylpyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one and a pharmaceutically acceptable acid addition salt thereof, characterized in that that similar starting materials are used. • c • «« · • I 22 93362