HU206723B - Process for producing pyrido/2,3-b//1,5/benzoxazepin- and thiazepin/-5/6h/-ones and pharmaceutical compositions containing them - Google Patents

Abstract

"Disclosed is the use of dipenz"

Description

The present invention relates to novel pyrido [2,3-b] [1,5] benzoxazepine (and -thiazepine) -5 (6H) -ones and their pharmaceutically acceptable acid addition salts and to pharmaceutical compositions containing these compounds as active ingredients. Pharmaceutical compositions containing the compounds of the invention as active ingredients are useful in the prevention and treatment of infections caused by human immunodeficiency virus (HIV).

The human disease known as AIDS (Acquired Immune Deficiency Syndrome) is caused by HIV (Human Immunodeficiency Virus), especially a strain known as HIV-1.

Like viruses, HIV-1 is unable to replicate without controlling the biosynthetic apparatus of the host cell it infects. Its presence in the cell causes this apparatus to produce the structural proteins that make up the virus's progeny. These proteins are encoded by genetic material contained in the infectious virus particle or virion. However, being a retrovirus, the genetic material for HIV is RNA, not DNA, as the host cell genome. Accordingly, the viral RNA must first be transcribed into DNA and then incorporated into the host cell genome to produce the desired viral proteins. Transcription of RNA into DNA is accomplished by the reverse transcriptase (RT) enzyme, which is contained in the infectious virion along with RNA. Reverse transcriptase has three types of enzymatic functions: RNA-dependent DNA polymerase, ribonuclease and DNA-dependent DNA polymerase. The first function, acting as an RNA-dependent polymerase, RT generates a single-stranded copy of viral RNA. Then, acting as a ribonuclease, RT frees the finished DNA from the original viral RNA, then breaks down the original RNA. Finally, acting as a DNA-dependent DNA polymerase, the RT, using the first strand of DNA as a template, produces a second complementary strand of DNA. The two strands form double-stranded DNA, which is inserted into the host cell's genome by another enzyme called integrase.

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

GB-A-1 156781 discloses pyrido [2,3-b] [1,5] benzothiazepin-5-ones having antihistamine and antispasmodic activity and pyrido [2,3-b] [1,5] benzoxazepin-5-ones. AGB-A 1 587 128 discloses pyrido [2,3-b] [1,5] benzothiazepines substituted at the 5-position by a piperazinyl group which possess antihistamine and anti-anaphylactic activity.

The present invention relates to a process for the preparation of pyrido [2,3-b] [1,5] benzoxazepine (and -thiazepine) 5- (6H) -one of formula (I):

X is oxygen or sulfur,

R ¹ is C 1 -C 5 alkyl, C 3 -C 5 alkenylmethyl, or C 2 -C 3 alkanoyl,

R ^{3 is} hydrogen, hydroxy or amino,

One of R ⁵ and R ⁷ is hydrogen, C 1-4 alkyl or amino, and the other is hydrogen, methyl or ethyl.

Compounds of formula (I) may be prepared by converting a compound of formula (II) wherein R ³ , R ⁵ and R ⁷ are as defined above into the corresponding alkali metal or alkaline earth metal salt of formula (III). - where R ³ , R ⁵ and R ⁷ are as defined above and then this alkali metal compound is isolated without reaction with a reactive alkylating or acylating reagent of formula IV - wherein R ¹ is as defined above and Y a suitable leaving group such as a chlorine, bromine, iodine, alkyl or arylsulfonyl group or an alkylcarbonyloxy or arylcarbonyloxy group - is well reacted by alkylation or acylation reactions known circumstances.

It will be apparent to those skilled in the art that the presence of nucleophilic substituents in the compounds of formula (II) requires, for example, the use of an intermediate which does not have a nucleophilic substituent at the 3, 7 or 9 position. For example, compounds of formula (I) containing an amino substituent can advantageously be prepared by alkylating or acylating an intermediate of formula (II) having a nitro group at the desired position and subsequently reducing the nitro group and optionally alkylating the final product. .

The compounds of formula (I) may, if desired, be converted into their pharmaceutically acceptable salts by conventional means. The preparation of salts is also within the scope of the present invention.

Examples of inorganic and organic acids which can form non-toxic pharmaceutically acceptable acid addition salts of the compounds of formula (I) include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, tartaric, citric, methanesulfonic and the like.

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

The compounds of formula (I) described above have inhibitory activity against HIV-1 reverse transcriptase. When administered in suitable dosage forms, they can be used to prevent and treat diseases associated with AIDS, ARC and HIV-1 infection. The compounds thus provide an opportunity to prevent or treat HIV-1 infection by administering to a subject exposed to or infected with HIV-1 a prophylactically or therapeutically effective amount of a novel compound of formula (I) as hereinbefore described.

The compounds of formula (I) may be administered in single or divided doses, orally, parenterally or topically. A compound of formula (I)

The appropriate oral dose is in the range of about 0.51 g / day. For parenteral administration, a suitable dosage unit may contain from 0.1250 mg of the compound of formula (I), whereas for topical administration, compositions containing from 0.01 to 1% by weight of the active ingredient will be preferred. It will be understood, however, that the dose to be administered may vary from patient to patient and the dosage to be used in a particular patient will depend on the judgment of the clinician, who will consider the patient's body weight and condition and patient response to the drug.

When the compounds of the invention are administered orally, they can be administered in the form of a pharmaceutical composition containing the active ingredient in combination with a pharmaceutically acceptable carrier. Such a carrier may be an inorganic organic or inorganic carrier suitable for oral administration. Examples of the carrier include water, gelatin, talc, starch, acacia, vegetable oils, polyalkylene glycols, petrolatum gel and the like.

The pharmaceutical compositions may be formulated in conventional manner, and may include, for example, solid dosage forms such as tablets, dragees, capsules, and the like, or liquid forms such as solutions, suspensions, emulsions, and the like. The pharmaceutical compositions may be subjected to conventional pharmaceutical procedures such as sterilization. The pharmaceutical compositions may also contain conventional adjuvants such as preservatives, stabilizers, emulsifiers, flavor enhancers, wetting agents, buffers, salts for varying the osmotic pressure, and the like. Solid carriers for pharmaceutical compositions include starch, lactose, mannitol, methylcellulose, microcrystalline cellulose, talc, silica gel, calcium hydrogen phosphate, and a high molecular weight polymer (such as polyethylene glycol).

For parenteral administration, a compound of formula (I) may be administered, for example, in the form of an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable oil or liquid mixture, which may contain bacteriostatic agents, antioxidants, preservatives, buffers or other isotonic agents, thickeners, suspending agents, or pharmaceutically acceptable additives. Examples of such additives are tartrate, citrate and acetate buffers, ethanol, propylene glycol, polyethylene glycol, complexing agents (such as EDTA), antacid agents (such as sodium bisulfite, sodium pyrosulfite, liquid polyethylene oxides) and polyethylene derivatives of anhydrosorbite. Preservatives such as benzoic acid, methyl or propyl paraben, benzalkonium chlorides or other quaternary ammonium compounds may be added as needed.

The compounds of the invention may also be administered in the form of nasal solutions. These compositions may contain, in addition to the compounds of the present invention, suitable buffers, tonicity adjusters, microbial preservatives, antioxidants and viscosity enhancers in an aqueous carrier. Examples of materials which may be used as viscosity enhancing agents are polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone, polysorbates or glycerol. Microbial preservatives may include benzalkonium chloride, thimerosal, chlorobutanol or phenylethyl alcohol.

The compounds of the invention may also be administered in the form of suppositories.

As stated above, the compounds of the present invention inhibit HIV-1 reverse transcriptase (RT) activity. Based on the assays of these compounds described below, they are known to inhibit the activity of HIV-1 RT RNA-dependent DNA polymerase. The compounds are also believed to inhibit HIV-1 RT DNA-dependent DNA polymerase activity.

Using the reverse transcriptase (RT) assay described below, the compounds of the invention can be tested for their ability to inhibit HIV-1 RT RNA-dependent DNA polymerase activity. Some of the specific compounds described in the examples below were tested by this method. The results of this study are shown in Table 1.

Reverse transcriptase (RT) assay:

Principle of definition:

Among the enzymes encoded by HIV-1 (human immunodeficiency virus) is a reverse transcriptase (1), which is called because it transmits a DNA copy of an RNA template. This activity can be quantitatively measured by a cell-free enzyme assay method already described (2) and based on the observation that reverse transcriptase is capable of radiolabeling a synthetic template [oligo d (G) primer made with primer] into acid-precipitated DNA strands using ³ H-dGTP as substrate.

Materials:

a) Preparation of the enzyme:

The reverse transcriptase enzyme (1) from the LAV strain of HIV-1 (human immunodeficiency virus) was isolated from the JM109 bacterial strain (3) expressing the pBRTprtR DNA clone (2), which is controlled by the lac promoter in the pIBI21 expression vector (4). For positive selection, overnight culture (5) in 2XYT medium supplemented with 100 µg / ml ampicillin (37 ° C, 225 rpm) was inoculated at 1:40 with 10 µg / ml thiamine, 0.5% w / v casaminic acid and 50 µg / ml. ml of M9 medium supplemented with ampicillin (5). The culture was incubated at 37 ° C at 225 rpm until the OD ₅₄₀ reached 0.3-0.4. 0.5 mM IPTG (isopropyl PD-thiogalactopyranoside) was added and the mixture was incubated for an additional 2 hours. Bacteria were pelleted by centrifugation, resuspended in 50 mM Tris, 0.6 mM EDTA, and 0.375 M NaCl, and digested with ice-lysozyme (1 mg / ml) for 30 min. The cells were 0.2

It was lysed by adding NP-40% and adjusted to 1M sodium chloride.

After removing the insoluble debris by centrifugation, the protein is precipitated with 3 volumes of saturated aqueous ammonium sulfate solution. The enzyme was pelleted by centrifugation and resuspended in RT buffer (50 mM Tris, pH 7.5 + 1 mM EDTA + 5 mM DTT + 0.1% w / w NP-40 + 0.1 M sodium chloride and 50% w / w glycerol). and stored at -70 ° C until further use.

b) 2x Concentration of reaction mixture stock solution:

Reagent stock solution 1M Tris pH 7.4

M dithiothreitol (DTT)

M sodium chloride 1% by weight Nonidet P-40 1 M magnesium chloride [poly (C) Zoligo d (G)] (5: 1) ³ H-dGTP (81 μΜ)

2x concentration 100 mM 40 mM 120 mM

0.1 wt% 4 mM 2 µg / ml 0.6 μΜ

Determination procedure:

The 2x stock solution was homogenized and stored at -20 ° C. The mixture is stable and heated prior to use in each assay. The enzyme assay method is adapted to a 96-well microtiter plate and has been described previously (6). Tris buffer (50 mM, pH 7.4), vehicle (solvent diluted according to compound dilution) or compounds dissolved in vehicle solution were added to 96-well microtiter plates (10 μϊ / well, 3 well / compound). The HIV-1-RT enzyme is thawed, diluted with 50 mM Tris pH 7.4 so that 15 μΐ of the diluted enzyme solution is 0.001 units (1 unit of enzyme at 25 ° C per minute). micron to substrate) and add 15 μΐ per well. Add 20 μϊ 0.12-0.5 m EDTA to the first three wells of the microtiter plate. EDTA chelates the magnesium (II) ions present10 and prevents reverse transcription. This group serves as a blank for polymerization, which is subtracted from all other groups. 25 μΐ of 2x reaction mixture was added to each well and incubated for 60 minutes at room temperature. The assay is terminated by precipitation of DNA in the wells with 1% w / v sodium pyrophosphate containing 10% trichloroacetic acid (TCA). The microtiter plate is kept at 4 'C for 15 minutes and the precipitate is fixed on a No.30 glass fiber filter (Schleicher & Schuell) using a Skatron semi-automatic harvester. The filters are then washed with an additional 5% TCA in 1% sodium pyrophosphate solution, rinsed with 70% aqueous ethanol, dried and transferred to scintillation vials (6). 2 ml of scintillation mixture was added to each vial and measured on a Beckmann beta counter.

The percentage inhibition is calculated as follows:

test CPM average - control CPM average% inhibition --------------------------------------- -------------------- x 100 controls average CPM

References:

(1) Benn, S, et al., Science 230, 949 (1985).

(2) Farmerie, W.G. et al., Science 236, 305 (1987).

(3) Yanisch-Perron, C., Viera, J. and Messing, J. Gene

33, 103 (1985).

(4) International Biotechnologies, Inc., New Haven,

CT 06535 (5) Maniatis, T., Fritsch, Ε. E and Sambrook, J., eds.

Molecular Cloning; A Laboratory Manual, Cold

Spring Harbor Laboratory, 1982.

(6) Spira, T. et al., J. Clinical Microbiology 25, 91 (1987).

To approximate the cytotoxicity of the compounds of the present invention, some of these compounds were assayed using the MTT cellular cytotoxicity assay described below. The results of the assay are listed in Table 1. Compounds with relatively high EC ₅₀ values are preferred.

MTT assay for cellular cytotoxicity:

Principle of definition:

The MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) assay is based on the cleavage of tetrazolium bromide by metabolically active cells, which produces an almost blue color. This assay has already been described (1) but has been optimized for the assay described herein.

Method of determination:

The H9 cell line (2), a defined human lymphoma suspension cell line cultured in RPMI 1640 medium supplemented with 10% fetal calf serum, was used as a target cell line in the assay. 100 μΐ of the suspension at 10 ⁵ cells / ml was added to the wells of the microtiter plate in the presence of varying concentrations of inhibitor. Cells were incubated at 37 ° C in a humidified atmosphere of carbon dioxide. Five days later, 20 μΐ MTT solution (5 mg / ml in RPMI 1640, sonicated, filtered through a 0.2 micron filter and stored at 4 ° C) was added to each well and mixed thoroughly to facilitate crystal dissolution. Subsequently, 5 μϊ absolute ethanol was added to each well and the resulting mixture was incubated for 30 minutes at 60 ° C and read immediately at 570 nm on a Dynatech plate reader. The data from the assay are used to construct a non-linear regression analysis curve resulting in EC ₅₀ .

Literature sources:

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

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

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Table 1

Compound Example number RT inhibition% @ 11 μg / ml Cytotoxicity is affected. (ECjo) 1 80 NT 2 89 NT 3 * 57 315μΜ 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 4! ⁺ NT 14 * 33 NT 15 85 NT

Notes to the spreadsheet:

*% inhibition @ 1 μΜ ⁺ % inhibition @ 2.5 μΜ.

The following examples are intended to illustrate the process of the invention in more detail and to assist those skilled in the art to understand it more fully. However, it is to be understood that the scope of the invention is not limited to the specific examples given below.

Example 7

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

To a solution of 2.12 g of pyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one (prepared according to known procedures) in 50 ml of dimethylformamide is 0.96 g of 50% mineral oil. sodium hydride dispersion was added and the reaction mixture was stirred for 1 hour. Then, 2.46 g of 1-bromopropanol are slowly added and the resulting reaction mixture is stirred overnight at room temperature. Crushed ice is added to decompose unreacted sodium hydride. Water was added and the product was extracted with diethyl ether, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the product by silica gel column chromatography with ethyl acetate: hexane (1: 4) gave 1.52 g of a colorless viscous oil.

Example 2

6-Ethyl-pyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one a) Pyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one 31, A mixture of 5 g (0.2 mol) of 2-chloronicotinic acid and 100 ml of sulfinyl chloride was heated under reflux for 3 hours. The solvent was distilled off in vacuo and the acid chloride was then added with 25 g of 2-aminothiophenol.

400 ml of toluene and 34 g of pyridine. The resulting reaction mixture was refluxed for 4 hours and then allowed to stand overnight at room temperature. The precipitated precipitate was filtered off and stirred with water for 3 hours, then filtered again and air dried. The product was recrystallized from ethyl acetate to give 20.8 g of an almost pure yellow solid, which was used in the next reaction.

Yield: 45%.

A small sample of the product was recrystallized from acetonitrile to give a pale yellow solid, m.p. 260-261 ° C.

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

To a solution of 4.0 g (0.0175 mol) of pyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one in 100 ml of dimethylformamide was added 1.05 g of 50% w / w sodium hydride. dispersion was added and the resulting reaction mixture was stirred until gas evolution had ceased and then heated to 50 ° C for 30 minutes. After cooling to room temperature, 5.46 g (0.035 mol) of ethyl iodide are slowly added and the reaction mixture is stirred for 2 hours. The unreacted sodium hydride is then decomposed by addition of crushed ice. Water was added and the product was extracted with diethyl ether, dried over anhydrous sodium sulfate and concentrated in vacuo. The solid residue was washed with hexane and recrystallized from ethyl acetate by precipitation with hexane. 0.66 g of a yellow crystalline product is obtained, m.p. 148-149 ° C.

Yield: 14%.

Example 3

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

a) 2-Hydroxy-5-nitro-nicotinic acid Add 1.5 ml of fuming nitric acid 1.5 ml (0.24 mol) to a mixture of 14 g (0.1 mol) of 2-hydroxy nicotinic acid and 40 ml concentrated sulfuric acid. The resulting reaction mixture was heated at 50 ° C for 4 hours and then carefully poured into ice water. The light orange precipitate was filtered off, washed with cold water and then recrystallized from water. This gives 13.3 g of an almost pure product as a pale yellow crystalline solid, m.p. 240 DEG C., which can be used directly for the next reaction.

Yield: 72%.

b) 2-Chloro-5-nitro-nicotinic acid

A solution of 9.2 g (0.05 mol) of 2-hydroxy-5-nitro-nicotinic acid in 25 ml of phosphoryl chloride was heated at reflux for 5 hours. The solvent was then evaporated in vacuo and the residue was dissolved in a mixture of tetrahydrofuran and diethyl ether. The solution was cooled in an ice bath and water was added dropwise with stirring until the phases were clearly separated. After separation, the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated. Recrystallization from diethyl ether gave 6.94 g of pure product, m.p. 135 ° C (dec).

Yield: 69%.

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c) N- (3-Hydroxy-4-tolyl) -2-chloro-5-nitropyridine-3-carboxamide

A mixture of 6.1 g (0.03 mol) of 2-chloro-5-nitro-nicotinic acid and 15 ml of sulfinyl chloride was heated under reflux for 3 hours. The solvent was then evaporated in vacuo and the acid chloride was dissolved in 150 ml of tetrahydrofuran. The resulting solution was added slowly to a mixture of 4-g (0.03 mol) of 6-amino-m-cresol, 7 ml (0.04 mol) of N-ethyl, Ν-diisopropylamine and 150 ml of tetrahydrofuran at 0 ° C under argon. and the resulting solution was stirred for 2 hours. The mixture was then diluted with water and the product was extracted with diethyl ether, and the extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated to half volume. The gummy orange residue was separated and stirred with dichloromethane (50 mL) for 30 min. The precipitate was washed with dichloromethane and air dried. The resultant 6.3 g of a bright orange powder is a pure product.

mining; 68%.

d) 9-Methyl-3-nitropyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one

A mixture of 6.3 g (0.02 mol) of N- (3-hydroxy-4-tolyl) -2-chloro-5-nitropyridine-3-carboxamide and 100 ml of pyridine was heated at 90 ° C under argon for 2.5 hours. on. The cooled solution was diluted with water and the yellow-orange precipitate was filtered off and washed with water. The solid residue was stirred with 100 ml of hot water for 45 minutes, then filtered and washed with ethanol and diethyl ether. The resulting 4.3 g light brown solid was recrystallized from dimethylformamide by precipitation with water. 3.76 g of product are obtained.

Yield: 69%.

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

To a suspension of 0.73 g (0.015 mol) of a 50% w / w mineral oil hydride dispersion in 75 ml of dimethylformamide was added 3.75 g (0.014 mol) of 9-methyl-3-nitropyrido [2.3] in one portion. -b] [1,5] benzoxazepin-5 (6H) -one. After

Methyl iodide (1.3 mL, 0.021 mol) was added and the resulting solution was stirred overnight at room temperature. The mixture was diluted with ice water and the precipitate was filtered off and washed with water and petroleum ether. The crude product was recrystallized from ethyl acetate to give 3.14 g of a pale yellow solid, m.p. 197-198 ° C.

Yield: 79%.

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

To a suspension of 1.6 g (5.6 mmol) of 6,9-dimethyl-3-nitropyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one in 30 ml of acetic acid was added 10 g ( 44 mmol) of tin (II) chloride dihydrate in 13 ml of concentrated hydrochloric acid. After stirring for 3 hours, the precipitated product is filtered off and washed with diethyl ether. The product was then dissolved in water, basified with 2N sodium hydroxide solution, extracted with diethyl ether and ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. Recrystallization of the residue from a mixture of ethanol and hexane gave 0.82 g of pure product as a pale yellow-brown needle crystalline solid, m.p. 191-193 ° C.

Yield: 57%.

4-15. examples

The compounds listed by the following exemplary numbers are prepared by analogy to those described above:

Example Code:

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

5. 3-Amino-6-ethyl-7,9-dimethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one; mp 232-234 ° C.

6. 3-Amino-7,9-dimethyl-6-propylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one; m.p. 195—

197 ° C.

7. 6-Methyl-pyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one; mp 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;

mp 58-60 ° C.

10. 6-Propionylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one; mp 111-113 ° C.

11.6,9-Dimethyl-pyrido [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; 114-116 ° C.

13. 3-Hydroxy-6,9-dimethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one; mp 257-258.5 ° C.

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

15. 6-Methyl-pyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one; mp 172-174 ° C.

Example 16

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

The title compound was prepared as described in Example 3, but using 2-mercapto-5-nitricotinic acid as starting material.

17-21. examples

By analogy to the procedures described above, the following compounds are prepared with the following exemplary numbers:

Example Code:

17. 3-Amino-6,7,9-trimethylpyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one.

18. 3-Amino-6-ethyl-7,9-dimethylpyrido [2,3-b] - [1,5] benzothiazepin-5 (6H) -one.

19. 3-Amino-7,9-dimethyl-6-propyl-pyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one.

20. 3-Amino-6-isopropyl-7,9-dimethylpyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one.

6.21-Allyl-3-amino-7,9-dimethyl-pyrido [2,3-b] - [l, 5] benzothiazepin-5 (6H) -one.

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Example 22 Pharmaceutical products: Example 22a) Capsules or tablets: a-l) Ingredients: Quantity: Example 1 Compound 50 mg Starch 160 mg Microcrystalline cellulose 90 mg Sodium starch gluktát 10 mg Magnesium stearate 2 mg Colloidal silica gel 1 mg a-2) Ingredients: Quantity: Example 1 Compound 50 mg Dicalcium phosphate 160 mg Microcrystalline cellulose 90 mg stearic 5 mg Sodium starch glycolate 10 mg Colloidal silica gel 1 mg Example 1 was prepared as described above.

except for a lubricant and pre-mixed with excipients. The lubricant is then mixed and the resulting powder mixture is compressed into tablets or filled into hard gelatine capsules. 25

Example 22b

Parenteral solutions:

Ingredients: Quantity:

Example 1 500 mg

Tartaric acid 1,5 g

Benzyl alcohol diluted to 100 ml with 0.1% w / v water for injection.

The excipients are mixed with water and the compound of Example 1 is then added. Stirring is continued until a clear solution is obtained. The solution was adjusted to pH 3.0 and then filtered into suitable vials or ampoules and sterilized by autoclaving.

Example 22c Nasal Solutions: Ingredients:

EXAMPLE 1 Compound Citric acid

Benzalkonium chloride

EDTA

Poly (vinyl alcohol)

Filled with water

Quantity:

100 mg

1.92 g

0.025% by weight 0.1% by weight

To 100 ml.

The excipients are mixed with water and the compound of Example 1 is then added and stirring is continued until the solution is clear. The pH of the solution is then adjusted to 4.0 and filtered into suitable vials or ampoules.

Claims (5)

PATENT CLAIMS A process for the preparation of a compound of formula I wherein: 60 X is oxygen or sulfur, R ¹ is C 1 -C 5 alkyl, C 3 -C 5 alkenylmethyl, or C 2 -C 3 alkanoyl, R ^{3 is} hydrogen, hydroxy or amino, ^R5 and ^R7 are hydrogen, C1-4 alkyl or amino and the other is hydrogen, methyl or ethyl, and pharmaceutically acceptable salts thereof, wherein (II) is a compound of formula - where R ³ , R ⁵ and R ⁷ are as defined in the scope except for the amino group, but may also represent a nitro group - to the corresponding metal compound of formula (ΠΙ) - where R ³ , R ⁵ and R ⁷ are as defined above, an alkali metal or alkaline earth metal ion M® is then formed and then the alkali metal or alkaline earth metal compound is reacted with a reactive alkylating or acylating agent of formula IV R ¹ has the same meaning as defined herein; and Y is a leaving group, preferably chlorine, bromine or iodine, an alkyl or arylsulfonyl group, an alkylcarbonyl group or an arylcarbonyl oxy group is reacted under the known alkylation or acylation reaction conditions, if necessary, R ³ R ⁵ and R ⁷ site reducing the nitro group to an amino group; optionally converting the resulting compound of formula (I) into a pharmaceutically acceptable salt thereof. 2. A process according to claim 1 for the preparation of a compound of formula I wherein: X is O or S; R ¹ is C 1-4 alkyl or allyl; R ³ is hydrogen or amino; and R ⁵ and R ⁷ is hydrogen or methyl, characterized by reacting an appropriately substituted starting materials. The method of claim 1 3-amino-6,9-dimethylpyrido [2,3-b] [1,5] benzoxazepin5 (6H) -one, 3-amino-6,7,9-trimethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one, 3-amino-6-ethyl-7,9-dimethylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one, 3-amino-7,9-dimethyl-6-propylpyrido [2,3-b] [1,5] benzoxazepin-5 (6H) -one, 3-amino-6,9-dimethylpyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one, 3-amino-6,7,9-trimethylpyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one, 3-amino-6-ethyl-7,9-dimethylpyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one, 3-amino-7,9-dimethyl-6-propylpyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one, 3-amino-6-isopropyl-7,9-dimethylpyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one, 3-amino-6-allyl-7,9-dimethyl- pyrido [2,3-b] [1,5] benzothiazepin-5 (6H) -one, A process for preparing their pharmaceutically acceptable acid addition salts comprising reacting appropriately substituted starting materials. 4. A process for the preparation of a compound of formula (I) as an active ingredient X, R ', R ³ , R ⁵ and R ^{7 for} the manufacture of a medicament containing the same as claimed in claim 1, characterized in that the active ingredient of formula (I) or a pharmaceutically acceptable salt thereof prepared according to any one of the preceding claims is used in conventional pharmaceutical technology. , diluents and / or other excipients, and the mixture is processed into a pharmaceutical composition. 5. A process for the manufacture of a medicament for treating or preventing HIV-1 infection according to any one of claims 1 to 3, wherein A compound of formula (I) according to any one of claims 1 to 6, which is processed into an anti-HIV-1 effective pharmaceutical composition.