HK1086261A - Novel tricyclic azepine derivatives, method for production thereof and pharmaceutical compositions comprising the same - Google Patents

Description

Novel tricyclic aza * derivatives, process for their preparation and pharmaceutical compositions containing them

The present invention relates to novel tricyclic aza * compounds, processes for their preparation, pharmaceutical compositions containing them and their use as anti-cancer agents.

The need for anticancer treatments requires the continuous development of new antitumor agents with the aim of obtaining drugs with both higher activity and better tolerability.

In addition to the compounds of the invention being novel, they also have valuable antitumor properties.

Compounds having closely related structures, in particular amino-dihydro-dibenzothiazepine * compounds in the field of psychoneuropathy (patent specification FR 2104728), dihydro-pyridobenzodiazepine * compounds as psychoactive agents (patent specification US 3274058) and antiviral agents (patent specification WO 9417075), dihydro-pyridobenzodiazepine * and dihydro-bipyridodiazepine * compounds as antiviral agents (patent specifications EP 0393530, US 5620974 and EP 0393604) and amino-dihydro-dibenzoazepine * compounds as anticonvulsants (eur.j.med.chem.1988,23(5)，473-6；J.Pharm.Pharmcol.1969， 21(8)，520-530). Finally, other aryl-pyridodiazepine * and thiodiazepine * compounds with closely related structures have been described as selective HIV inhibitors (Antiviral Research 1996,30(2，3)，109-124；Bioorg.Med.Chem.Lett.1995， 5(14)，1461-6；J.Med.Chem.1991， 34(7) 2231-41; and Farmaco, Ed. scientific 1985,40(6)，391-403)。

however, cytotoxic activity has not been described for these compounds.

More particularly, the present invention relates to compounds of formula (I), their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base:

wherein:

● represents a benzo or pyrido group, optionally fused in the 2-3, 3-4 or 4-5 positions, it being understood that the nitrogen atom of the pyrido group occupies any of the 2 to 5 positions of the ring, which is unsubstituted or substituted by one or more identical or different atoms or groups selected from halogen atoms and hydroxyl groups, linear or branched (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Trihaloalkyl, amino (optionally substituted at the nitrogen by one or two straight or branched chains (C)₁-C₆) Alkyl substituted), nitro, straight or branched chain (C)₁-C₆) Acyl and (C)₁-C₂) (ii) an alkylenedioxy group,

● W represents a group X-Y or Y-X wherein:

x represents a group > SO₂Or > C ═ CO，

Y represents an oxygen atom or a group N-R₃Wherein R is₃Represents a hydrogen atom, a straight chain or a branched chain (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Arylalkyl, -Alk-Z-R or-Alk-Z-Alk ' -Z ' -R, where Alk and Alk ' independently of one another represent a linear or branched chain (C)₁-C₆) Alkylene or straight or branched chain (C)₂-C₆) Alkenylene, Z and Z ' independently of one another represent an oxygen, sulphur atom or a group-N (R ') -, R and R ' being identical or different and representing a linear or branched (C)₁-C₆) An alkyl group, a carboxyl group,

● n represents zero or an integer wherein 1. ltoreq. n.ltoreq.6,

● G represents a hydrogen atom, an aryl group or a heteroaryl group,

●R₁and R₂Are identical or different and represent a hydrogen or halogen atom or a hydroxyl, linear or branched (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Trihaloalkyl, amino (optionally substituted at the nitrogen by one or two straight or branched chains (C)₁-C₆) Alkyl substituted), nitro or straight or branched chain (C)₁-C₆) Acyl or (C)₁-C₂) (ii) an alkylenedioxy group,

the conditions are as follows:

-if G represents a hydrogen atom, n is not zero,

-if G represents a hydrogen atom and Y represents a group N-R₃Then R is₃Represents a hydrogen atom, a straight chain or a branched chain (C)₂-C₆) Alkyl or aryl- (C)₁-C₆) An alkyl group, wherein the alkyl group is linear or branched,

if G represents a hydrogen atom and W represents two NR' s₃One of the groups C (O), wherein R₃Represents ethyl or benzyl, n is not 1, 2 or 3,

-the compound of formula (I) is not 1-benzyl-5, 10-dimethyl-1, 5-dihydro-6H-pyrido [2, 3-b ] [1, 4] benzodiazepine * -6-one, 1, 2-dimethyl-5-oxo-5, 6-dihydro-1H-pyrido [2, 3-b ] [1, 5] benzodiazepine * 3-carboxylic acid ethyl ester, 3-acetyl-1-ethyl-2-methyl-1, 6-dihydro-5H-pyrido [2, 3-b ] [1, 5] benzodiazepine * -5-one, 2-amino-1-methyl-5-oxo-5, 6-dihydro-1H-pyrido [2, 3-b ] [1, 5] benzodiazepine * -3-carbonitrile and ethyl 2-amino-1-methyl-5-oxo-5, 6-dihydro-1H-pyrido [2, 3-b ] [1, 5] benzodiazepine * 3-carboxylate, it being understood that:

aryl represents phenyl, biphenyl, naphthyl or tetrahydronaphthyl, each of these radicals being unsubstituted or substituted by one, two or three identical or different atoms or groups selected from halogen atoms and linear or branched (C)₁-C₆) Alkyl, hydroxy, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Trihaloalkyl, amino (optionally substituted at the nitrogen by one or two straight or branched chains (C)₁-C₆) Alkyl substituted), nitro, straight or branched chain (C)₁-C₆) Acyl, straight or branched (C)₁-C₆) Alkylcarbonylamino group, (C)₁-C₂) Alkylenedioxy, phenoxy, benzyloxy, straight or branched amino- (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Alkylamino radical- (C)₁-C₆) Alkoxy and straight or branched chain di (C)₁-C₆) Alkylamino radical- (C)₁-C₆) An alkoxy group,

heteroaryl represents a mono-or bicyclic aromatic 5-to 12-membered radical containing one, two or three heteroatoms selected from oxygen, nitrogen and sulphur, it being understood that heteroaryl is unsubstituted or substituted by one or more identical or different atoms or groups selected from halogen atoms and linear or branched (C)₁-C₆) Alkyl, hydroxy, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Trihaloalkyl, amino (optionally substituted by one or more straight or branched chains)(C₁-C₆) Alkyl substituted), nitro, straight or branched chain (C)₁-C₆) Acyl, straight or branched (C)₁-C₆) Alkylcarbonylamino group, (C)₁-C₂) Alkylenedioxy, phenoxy, benzyloxy, straight or branched amino- (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Alkylamino radical- (C)₁-C₆) Alkoxy and straight or branched chain di (C)₁-C₆) Alkylamino radical- (C)₁-C₆) An alkoxy group,

-groupOptionally condensed in the 2-3, 3-4 or 4-5 position, meaning that benzo or pyrido groups are optionally presentOrPosition with phenyl, (C)₄-C₈) Cycloalkyl or heterocyclyl condensed with the proviso that ifRepresents a pyrido group, then a nitrogen atom

The atoms are not points of attachment to fused rings,

alkylene represents a divalent radical of a saturated hydrocarbon chain,

-alkenylene represents a divalent radical of a hydrocarbon chain containing from 1 to 3 double bonds,

-(C₄-C₈) Cycloalkyl denotes cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,

-heterocyclyl represents a saturated or unsaturated 5-to 7-membered monocyclic group containing one to three heteroatoms selected from nitrogen, oxygen and sulphur.

Among the heteroaryl groups, the groups thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl and pyrimidinyl may be mentioned without any restriction.

Among the heterocyclic groups there may be mentioned without any restriction the groups thienyl, pyridyl, pyranyl, furyl, pyrrolyl, imidazolyl, thiazolyl, pyrimidinyl, piperidinyl, piperazinyl and morpholinyl.

Among the pharmaceutically acceptable acids there may be mentioned, without any limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid and camphoric acid.

Among the pharmaceutically acceptable bases there may be mentioned, without any restriction, sodium hydroxide, potassium hydroxide, triethylamine and tert-butylamine.

The term "aryl" in relation to the group G as defined for formula (I) is preferably substituted phenyl.

An advantageous embodiment of the present invention relates to compounds of formula (I) as defined below: wherein G represents an aryl or heteroaryl group, more advantageously an aryl group.

A particularly advantageous aspect relates to compounds of formula (I) as defined below: wherein G represents a phenyl group substituted by one, two or three groups selected from linear or branched (C)₁-C₆) Alkoxy, benzyloxy, and hydroxy. More advantageously, the group substituted for phenyl G is linear or branched (C)₁-C₆) Alkoxy or hydroxy.

Preferred compounds of formula (I) are those wherein X represents > SO₂And Y represents N-R₃Or O.

Other preferred compounds of the invention relate to compounds of formula (I) as defined below: wherein X represents > C ═ O, Y represents N-R₃Or O.

Other preferred compounds of formula (I) are those wherein R is₃Represents a hydrogen atom or a linear chainOr branched (C)₁-C₆) Arylalkyl groups and more advantageously those of a hydrogen atom.

In which Y represents N-R₃In the compound of formula (I), R₃Preferably represents straight-chain or branched (C)₁-C₆) Alkyl, more particularly methyl.

Advantageously, the present invention relates to compounds of formula (I) as defined below: whereinRepresents a group which is unsubstituted or substituted by 1, 2 or 3 identical or different atoms or groupsThe atoms or groups being selected from halogen atoms and hydroxyl groups, linear or branched (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Trihaloalkyl, amino (optionally substituted at the nitrogen by one or two straight or branched chains (C)₁-C₆) Alkyl substituted), nitro, straight or branched chain (C)₁-C₆) Acyl and (C)₁-C₂) An alkylenedioxy group.

Preferably the substituents are located in groupsIs selected from a halogen atom and a linear or branched (C)₁-C₆) Alkyl and more particularly methyl, straight or branched (C)₁-C₆) Alkoxy and more particularly methoxy, and straight-chain or branched (C)₁-C₆) Trihaloalkyl and more particularly trifluoromethyl.

Another advantageous aspect relates to compounds of formula (1) as defined below: wherein R is_lAnd R₂Are identical or different and represent a hydrogen or halogen atom or a linear or branched (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy or straight or branched chain (C)₁-C₆) A trihaloalkyl group.

Among the preferred compounds that may be mentioned are:

1- [2- (4-methoxyphenyl) ethyl ] -6-methyl-1, 6-dihydropyrido [3, 2-c ] [2, 1, 5] benzothiepin * 5, 5-dioxide,

1- [2- (4-methoxyphenyl) ethyl ] -5-methyl-1, 5-dihydropyrido [3, 2-c ] [1, 2, 5] benzothiepin * 6, 6-dioxide,

1- [2- (4-methoxyphenyl) ethyl ] -1H-pyrido [3, 2-c ] [1, 2, 5] benzoxathiane * 5, 5-dioxide,

6- [ (2-methoxyethoxy) methyl ] -1- [2- (4-methoxyphenyl) ethyl ] -1, 6-dihydropyrido [3, 2-c ] [2, 1, 5] benzothiepin * 5, 5-dioxide,

1- [2- (4-methoxyphenyl) ethyl ] -1, 6-dihydropyrido [3, 2-c ] [2, 1, 5] benzothiepin * 5, 5-dioxide,

4- [2- (5, 5-dioxide-1H-pyrido [3, 2-c ] [1, 2, 5] benzoxathiazepin * -1-yl) ethyl ] phenol,

1- [2- (2-methoxyphenyl) ethyl ] -1H-pyrido [3, 2-c ] [1, 2, 5] benzoxathiazepine * 5, 5-dioxide,

1- {2- [3- (benzyloxy) -4-methoxyphenyl ] ethyl } -1H-pyrido [3, 2-c ] [1, 2, 5] benzoxathiazepine * 5, 5-dioxide,

5- [2- (5, 5-dioxide-1H-pyrido [3, 2-c ] [1, 2, 5] benzoxathiazepin * -1-yl) ethyl ] -2-methoxyphenol.

The invention also relates to a process for the preparation of a compound of formula (I), characterized in that in a basic medium:

-reacting a compound of formula (II):

w, A, R therein₁And R₂As defined in formula (I),

reacting with a compound of formula (III):

Z₂-(CH₂)_n-G (III)

wherein n and G are as defined for formula (I) and Z₂Represents a nucleofugic group, to give a compound of formula (I), if necessary purified according to conventional purification techniques, if necessary separated into its stereoisomers according to conventional separation techniques, and if necessary converted into their addition salts with a pharmaceutically acceptable acid or base.

The compound of formula (II) is obtained as follows:

or from reagent (IV):

wherein A is as defined for formula (I) and T represents a group X-Cl or Y₁-H, wherein X is as defined for formula (I), Y₁Represents an oxygen atom or a group N-R₄Wherein R is₄Represents a hydrogen atom, a straight chain or a branched chain (C)₁-C₆) A protecting group for an alkyl or amino function,

-initiation of condensation with a compound of formula (V):

wherein R is₁And R₂As defined in formula (I), Z₁Represents a halogen atom, when T represents a group X-Cl, then V represents a group Y₁-H, or when T represents a group Y₁when-H, then V represents a group X-Cl,

-obtaining a compound of formula (VIa):

a, R therein₁、R₂And Z₁As defined above, W₁Represents a group X-Y₁Or Y₁-X, wherein X and Y₁As defined above, the above-mentioned,

● when Y is₁When representing the group NH, the compounds of formula (VIa) may be reacted in basic medium with the halogenated compounds R₃Hal coupling, wherein R₃As defined in formula (I) to give a compound of formula (VIb) or (VIc):

a, R therein₁、R₂、R₃X and Z₁As defined above, the above-mentioned,

● it is possible to represent the compounds of formulae (VIa), (VIb) and (VIc) by the general formula (VI):

a, R therein₁And R₂As defined in formula (I), Z₁W 'as defined above'₁Represents a group X-Y'₁

Or Y'_1-X, wherein X is as defined for formula (I), Y'₁Represents an oxygen atom or a group N-R'₄，

Wherein R'₄A protecting group representing an amino function,

-then converting NO of the compound of formula (VI) by means of a conventional organic chemical reaction₂A functional group to give a compound of formula (VII):

wherein A, W'₁、R₁、R₂And Z₁As defined above, P₁A protecting group representing a hydrogen atom or an amino function,

-then converting into the compound of formula (II) in an acidic or basic medium by a cyclisation reaction, optionally followed by a deprotection reaction in one or two steps and followed by an alkylation reaction,

or from a compound of formula (VIII):

wherein A and T are as defined above, P₂A protecting group representing a hydrogen atom or an amino function,

-initiation of condensation with a compound of formula (V) as defined above to give a compound of formula (IX):

a, T, V, P therein₂、R₁And R₂As defined above, the above-mentioned,

-then converting into the compound of formula (II) in an acidic or basic medium, optionally followed by a one-or two-step deprotection reaction, and then optionally followed by an alkylation reaction.

In addition to the compounds of the invention being novel, they also have valuable pharmacological properties. They are cytotoxic, which makes them useful in the treatment of cancer.

The invention also relates to pharmaceutical compositions comprising at least one compound of formula (I) as active ingredient, together with one or more suitable inert non-toxic excipients. Among the pharmaceutical compositions of the invention, mention may be made more particularly of those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous) or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, emulsions, ointments, dermal gels, injectable preparations, drinkable suspensions and the like.

The dosage used may vary depending on the nature and severity of the condition, the route of administration, the age and weight of the patient and any relevant treatment, and may vary from 1 to 500 mg/day in one or more divided administrations.

The following examples illustrate the invention without limiting it in any way.

The starting compounds used are known compounds or are prepared according to known preparation methods.

The structures of the compounds described in the examples were determined according to conventional spectroscopic and spectroscopic techniques.

Preparation example A: 6-methyl-6, 11-dihydropyrido [3, 2-c ]][2，1，5]Benzothiadiazepine * 5, 5-dioxide

Step A: 2-chloro-N- (2-nitrophenyl) -3-pyridinesulfonamide

Starting from 2-chloro-3-pyridinesulfonyl chloride and 2-nitroaniline, the product was obtained according to the procedure described in publication J.Med.chem.1991, 34(4), 1356-one 1362.

Step B: 6-methyl-6, 11-dihydropyrido [3, 2-c ]][2，1，5]Benzothiadiazepine * 5, 5-dioxide

Synthesis of 2-chloro-N-methyl-N- (2-nitrophenyl) -3-pyridinesulfonamide by N-alkylation of the compound prepared in the preceding step using methyl iodide in a basic medium (process described in publication J.Med.chem.1991, 34(4), 1356-propan 1362). 2-chloro-N-methyl-N- (2-nitrophenyl) -3-pyridinesulfonamide (0.005mol) was then dissolved in concentrated acetic acid (20ml) and iron (0.025mol) was added. Evaporated under reduced pressure, dissolved in water and extracted with ethyl acetate. Dried over sodium sulfate and then evaporated under reduced pressure. The resulting precipitate was recrystallized from ethanol.

Melting point 180 deg.C

Preparation example B: 5-methyl-5, 11-dihydropyrido [3, 2-c ]][1，2，5]Benzothiadiazepine * 6, 6-dioxide

Step A: n- (2-chloro-3-pyridinyl) -2-nitrobenzenesulfonamide

To a solution of 2-nitrobenzenesulfonyl chloride (0.001mol) in pyridine (3ml) was added 3-amino-2-chloropyridine (0.001mol) in portions. Heating was carried out at 70 ℃ for 2 hours. After cooling, the solution was dissolved in water. Extraction with ethyl acetate was carried out, and then the organic phase was washed with 1N hydrochloric acid. Dried over sodium sulfate, filtered and the organic phase evaporated under reduced pressure. The sulfonamide is then recrystallized from ethanol.

Melting point 145-147 deg.C

Step B: n- (2- { [ (2-chloro-3-pyridinyl) (methyl) amino]Sulfonyl } phenyl) acetamide N- (2-chloro-3-pyridyl) -N-methyl-2-nitrobenzenesulfonamide was synthesized by N-alkylating the compound prepared in the previous step in basic medium using methyl iodide (process described in publication j. med. chem.1991, 34(4), 1356-. N- (2-chloro-3-pyridyl) -N-methyl-2-nitrobenzenesulfonamide (0.001mol) was then hydrogenated over Raney nickel (0.003mol) in dry ethanol (150ml) at atmospheric pressure and ambient temperature. The nickel was removed, the solvent was evaporated under reduced pressure and acetic anhydride (20ml) was added to the crude product. The solution was stirred for 12 hours. The mixture was then diluted with water, extracted with dichloromethane, dried and recrystallized.

Melting point 116-

Step C: 5-methyl-5, 11-dihydropyrido [3, 2-c ]][1，2，5]Benzothiadiazepine * 6, 6-dioxide

A solution of the compound prepared in the preceding step (0.04mol), potassium carbonate (0.008mol) and copper (0.10g) in dimethylformamide (20ml) was refluxed for 8 hours. Filtering, and evaporating under reduced pressure. Dissolved in water, the solution is extracted with dichloromethane, the organic phase is dried over sodium sulfate, evaporated under reduced pressure and recrystallized from ethanol.

Melting point 203 vs. 204 deg.C

Preparation example C: 11H-pyrido [3, 2-c][1，2，5]Benzoxathiazepine * 5, 5-dioxide

Step A: 2-chloro-3-pyridinesulfonic acid 2-aminophenyl ester

A solution of 2-chloro-3-pyridinesulfonyl chloride (0.019mol) in methylene chloride (30ml) was added dropwise to a mixture of 2-aminophenol (0.019mol) and triethylamine (0.022 mol). Stir at ambient temperature for 24 hours. The solution was washed with 1N hydrochloric acid and then with water. Drying, filtering and evaporating the organic phase under reduced pressure. 2-chloro-3-pyridinesulfonic acid 2-aminophenyl ester was used as such in the subsequent cyclization step.

Step B: 11H-pyrido [3, 2-c][1，2，5]Benzoxathiazepine * 5, 5-dioxide

Refluxing the compound prepared in the previous step in anhydrous ethanol to give 11H-pyrido [3, 2-c ] [1, 2, 5] benzoxathiazepine * 5, 5-dioxide. The solvent was then evaporated, dissolved in dichloromethane, washed with 7% ammonium hydroxide solution and then with water. Dried over sodium sulfate. Evaporated under reduced pressure and recrystallized from ethanol.

Melting point 208-

Preparation example D: pyrido [3, 2-c][1，5]Benzoxazepine * -5(11H) -ones

Step A: 2- (2-hydroxyphenylamino) nicotinic acid

A mixture of 2-chloronicotinic acid (0.032mol) and 2-aminophenol (0.038mol) in xylene (25ml) was refluxed for 3 hours. After the reaction, the resulting precipitate was filtered off with suction. The resulting black precipitate was recrystallized from water in the presence of carbon black.

Melting point 225-H₂O)

Step B: pyrido [3, 2-c][1，5]Benzoxazepine * -5(11H) -ones

A solution of 2- (2-hydroxyphenylamino) nicotinic acid (0.009mol) in 250ml of dichloromethane is cooled to 0 ℃. A solution of 1- [3- (dimethylamino) propyl ] -3-ethylcarbodiimide hydrochloride (0.010mol) in 50ml of methylene chloride was added dropwise. Stir at 0 ℃ for 1 hour, then return to ambient temperature and stir overnight. Filtered, washed with water, evaporated under reduced pressure and recrystallized from propanol.

Melting point 189-

Preparation example E: 6- [ (2-methoxyethoxy) methyl group]-6, 11-dihydropyrido [3, 2-c ]][2，1，5]Benzothiadiazepine * 5, 5-dioxide

Following the procedure described in preparation B, methyl iodide was replaced with methoxyethoxymethyl chloride in step B to give the expected compound.

Melting point of 119-

Preparation example F: 6-methyl-6, 11-dihydro-5H-pyrido [2, 3-b][1，5]Benzodiazepine * -5-ones

The expected compound is obtained by following the procedure described in preparation D, substituting 2-aminophenol with 2-aminoaniline in step A. The intermediate derivative 6, 11-dihydro-5H-pyrido [2, 3-b ] [1, 5] benzodiazepine * -5-one is N-alkylated with methyl iodide in a basic medium (process described in the publication J.Med.chem.1991, 34(4), 1356-1362).

Example 1: 1- (4-methoxybenzyl) -6-methyl-1, 6-dihydropyrido [3, 2-c)][2，1，5]Benzothiadiazepine * 5, 5-dioxide

To a suspension of sodium hydride (60%) (0.012mol) in dimethylformamide (20ml) was added dropwise a solution of aza * (0.004mol) prepared in preparation A in dimethylformamide. Stirring was carried out at 60 ℃ for 2 hours. A solution of 4-methoxybenzyl chloride (0.012mol) was added dropwise. Stirring was carried out overnight at 60 ℃. The solution was evaporated to dryness and the residue was dissolved in water and extracted with dichloromethane. Drying, filtering and evaporating the organic phase under reduced pressure. The resulting oil was purified by preparative HPLC (50mm diameter column packed with 250g of standard Lichoprep Si 60MERCK silica (15/25 μm)), and recrystallized from ethanol.

Melting point 127-

Example 2: 1- [2- (4-methoxyphenyl) ethyl]-6-methyl-1, 6-dihydropyrido [3, 2-c][2，1，5]Benzothiadiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described in example 1, substituting 4-methoxybenzyl chloride with 4-methoxyphenylethyl methanesulfonate.

Melting point 105-

Example 3: 1- [3- (4-methoxyphenyl) propyl group]-6-methyl-1, 6-dihydropyrido [3, 2-c][2，1，5]Benzothiadiazepine * 5, 5-dioxide

The expected compound was obtained by following the procedure described in example 1, substituting 3- (4-methoxyphenyl) propyl methanesulfonate for 4-methoxybenzyl chloride.

Melting point 50-55 deg.C (isopropanol)

Example 4: 9-chloro-1- (4-methoxybenzyl) -6-methyl-1, 6-dihydropyrido [3, 2-c][2，1，5]Benzothiadiazepine * 5, 5-dioxide

The expected compound was obtained by following the procedure described in example 1, substituting 4-chloro-2-nitroaniline for the 2-nitroaniline in step A of preparation A.

Melting point 149 deg.C (ethanol)

Example 5: 9-chloro-1- [2- (4-methoxyphenyl) ethyl]-6-methyl-1, 6-dihydropyrido [3, 2-c][2，1，5]Benzothiadiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described in example 1, substituting 4-chloro-2-nitroaniline for the 2-nitroaniline in step A of preparation A and 4-methoxyphenylethyl methanesulfonate for 4-methoxybenzyl chloride.

Melting point 163 ℃ (ethanol)

Example 6: 8-chloro-1- (4-methoxybenzyl) -6-methyl-1, 6-dihydropyrido [3, 2-c][2，1，5]Benzothiadiazepine * 5, 5-dioxide

The expected compound was obtained by following the procedure described in example 1, substituting 5-chloro-2-nitroaniline for the 2-nitroaniline in step A of preparation A.

Melting point 109 deg.C (ethanol)

Example 7: 8-chloro-1- [2- (4-methoxyphenyl) ethyl]-6-methyl-1, 6-dihydropyrido [3, 2-c][2，1，5]Benzothiadiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described in example 1, substituting 5-chloro-2-nitroaniline for the 2-nitroaniline in step A of preparation A and 4-methoxyphenylethyl methanesulfonate for 4-methoxybenzyl chloride.

Melting point 100-

Example 8: 1- (4-methoxybenzyl) -6, 9-dimethyl-1, 6-dihydropyrido [3, 2-c ]][2，1，5]Benzothiadiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described in example 1, replacing the 2-nitroaniline of step A of preparation A with 4-methyl-2-nitroaniline.

Melting point 90-92 deg.C (ethanol)

Example 9: 1- [2- (4-methoxyphenyl) ethyl]-6, 9-dimethyl-1, 6-dihydropyrido [3, 2-c ]][2，1，5]Benzothiadiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described in example 1, replacing the 2-nitroaniline from preparation A, step A with 4-methyl-2-nitroaniline and the 4-methoxybenzyl chloride with 4-methoxyphenylethyl methanesulfonate.

Melting point 156-

Example 10: 9-methoxy-1- (4-methoxybenzyl) -6-methyl-1, 6-dioxopyrido [3, 2-c][2，1，5]Benzothiadiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described in example 1, replacing the 2-nitroaniline in step A of preparation A with 4-methoxy-2-nitroaniline.

Melting point 95-96 deg.C (ethanol)

Example 11: 9-methoxy-1- [2- (4-methoxyphenyl) ethyl]-6-methyl-1, 6-dihydropyrido [3, 2-c][2，1，5]Benzothiadiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described in example 1, substituting 4-methoxy-2-nitroaniline for 2-nitroaniline in step A of preparation A and 4-methoxyphenylethyl methanesulfonate for 4-methoxybenzyl chloride.

Melting point 146 deg.C (ethanol)

Example 12: 1- [2- (4-methoxyphenyl) ethyl]-6- [2- (N, N-diethylamino) ethyl]-1, 6-dihydropyrido [3, 2-c ]][2，1，5]Benzothiadiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described in example 1, substituting 1-chloro-2- (N, N-diethylamino) ethane hydrochloride for methyl iodide used for N-alkylation in step B of preparation A and 4-methoxyphenylethyl methanesulfonate for 4-methoxybenzyl chloride.

Melting Point 92 ℃ decomposition (ethanol)

Example 13: 1, 6-bis (4-methoxybenzyl) -1, 6-dihydropyrido [3, 2-c ] s][2，1，5]Benzothiadiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described in example 1, substituting 4-methoxybenzyl chloride for the N-substituted methyl iodide used in step B of preparation A.

Melting point 95-98 deg.C (ethanol)

Example 14: 6- (4-methoxybenzyl) -1- [2- (4-methoxyphenyl) ethyl]-1, 6-dihydropyrido [3, 2-c ]][2，1，5]Benzothiadiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described in example 1, substituting 4-methoxybenzyl chloride for the N-substituted methyl iodide used in step B of preparation A and 4-methoxyphenylethyl methanesulfonate for 4-methoxybenzyl chloride.

Melting point 67 deg.C (ethanol)

Example 15: 1- (4-methoxybenzyl) -5-methyl-1, 5-dihydropyrido [3, 2-c)][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The procedure described in example 1 was followed, starting from the compound prepared in step C of preparation B, to give the expected compound.

Melting point 174 + 177 deg.C (ethanol)

Example 16: 1- [2- (4-methoxyphenyl) ethyl]-5-methyl-1, 5-dihydropyrido [3, 2-c ]][1，2，5]BenzothiaDiaza * 6, 6-dioxide

The expected compound is obtained by following the procedure described in example 15, except that 4-methoxyphenylethyl methanesulfonate is used instead of 4-methoxybenzyl chloride.

Melting point 181 plus 183 deg.C (ethanol)

Example 17: 1- [3- (4-methoxyphenyl) propyl group]-5-methyl-1, 5-dihydropyrido [3, 2-c ]][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The expected compound is obtained by following the procedure described in example 15, except that 3- (4-methoxyphenyl) propyl methanesulfonate is used instead of 4-methoxybenzyl chloride.

Melting point 94-96 deg.C (ethanol)

Example 18: 5-methyl-1- (3, 4, 5-trimethoxybenzyl) -1, 5-dihydropyrido [3, 2-c][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The expected compound is obtained by following the procedure described in example 15, except that 3, 4, 5-trimethoxybenzyl methanesulfonate is used instead of 4-methoxybenzyl chloride.

Melting point 178-

Example 19: 9-chloro-1- (4-methoxybenzyl) -5-methyl-1, 5-dihydropyrido [3, 2-c][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The expected compound was obtained by following the procedure described for example 15, substituting 4-chloro-2-nitrobenzenesulfonyl chloride for 2-nitrobenzenesulfonyl chloride in step A of preparation B.

Mass Spectrometry [ M ⁺ ]＝415

Example 20: 9-chloro-1- [2- (4-methoxyphenyl) ethyl]-5-methyl-1, 5-dihydropyrido [3, 2-c ]][1，2，5]BenzothiadiazidesHetero * 6, 6-dioxide

Following the procedure described for example 15, substituting 4-chloro-2-nitrobenzenesulfonyl chloride for 2-nitrobenzenesulfonyl chloride in step A of preparation B and 4-methoxyphenylethyl methanesulfonate for 4-methoxybenzyl chloride gave the expected compound.

Mass Spectrometry [ M ⁺ ]＝429

Example 21: 9-chloro-1- [3- (4-methoxyphenyl) propyl]-5-methyl-1, 5-dihydropyrido [3, 2-c ]][1，2，5]Benzothiadiazepine * 6, 6-dioxide

Following the procedure described for example 15, substituting 4-chloro-2-nitrobenzenesulfonyl chloride for 2-nitrobenzenesulfonyl chloride in step A of preparation B and 4-methoxyphenylpropyl methanesulfonate for 4-methoxybenzyl chloride gave the expected compound.

Melting point 112-

Example 22: 9-chloro-5-methyl-1- [2- (3, 4, 5-trimethoxyphenyl) ethyl]-1, 5-dihydropyrido [3, 2-c ]][1，2，5]Benzothiadiazepine * 6, 6-dioxide

Following the procedure described for example 15, substituting 4-chloro-2-nitrobenzenesulfonyl chloride for 2-nitrobenzenesulfonyl chloride in step A of preparation B and 2- (3, 4, 5-trimethoxyphenyl) ethyl methanesulfonate for 4-methoxybenzyl chloride gave the expected compound.

Melting point 203-

Example 23: 1- [4- (benzyloxy) benzyl]-9-chloro-5-methyl-1, 5-dihydropyrido [3, 2-c][1，2，5]Benzothiadiazepine * 6, 6-dioxide

Following the procedure described for example 15, substituting 4-chloro-2-nitrobenzenesulfonyl chloride for 2-nitrobenzenesulfonyl chloride in preparation B, step A, and 4-benzyloxybenzyl chloride for 4-methoxybenzylfluoride, the expected compound was obtained.

Melting point 86 deg.C (ethanol)

Example 24: 1- {2- [4- (benzyloxy) phenyl]Ethyl } -9-chloro-5-methyl-1, 5-dihydropyrido [3, 2-c)][1，2，5]Benzothiadiazepine * 6, 6-dioxide

Following the procedure described for example 15, substituting 4-chloro-2-nitrobenzenesulfonyl chloride for 2-nitrobenzenesulfonyl chloride in step A of preparation B and 2- (4-benzyloxyphenyl) ethyl chloride for 4-methoxybenzyl methanesulfonate gave the expected compound.

Melting point 121-

Example 25: 9-chloro-1, 5-bis (4-methoxybenzyl) -1, 5-dihydropyrido [3, 2-c ] s][1，2，5]Benzothiadiazepine * 6, 6-dioxide

Following the procedure described for example 15, substituting 4-chloro-2-nitrobenzenesulfonyl chloride for 2-nitrobenzenesulfonyl chloride in step A of preparation B and 4-methoxybenzyl chloride for methyl iodide used in the N-substitution of the compound, the expected compound was obtained.

Melting point 70-71 deg.C (ethanol)

Example 26: 9-chloro-5- (4-methoxybenzyl) -1- [2- (4-methoxyphenyl) ethyl]-1, 5-dihydropyrido [3, 2-c ]][1，2，5]Benzothiadiazepine * 6, 6-dioxide

Following the procedure described for example 15, substituting 4-chloro-2-nitrobenzenesulfonyl chloride for 2-nitrobenzenesulfonyl chloride in step A of preparation B, and 4-methoxybenzyl methanesulfonate for the N-substituted methyl iodide used for compound and 2- (4-benzyloxyphenyl) ethyl chloride for 4-methoxybenzyl chloride, the expected compound was obtained.

Melting point 168 + 169 deg.C (ethanol)

Example 27: 8-chloro-1- (4-methoxybenzyl) -5-methyl-1, 5-dihydropyrido [3, 2-c][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The procedure described in example 19 was followed starting from 5-chloro-2-nitrobenzenesulfonyl chloride instead of 4-chloro-2-nitrobenzenesulfonyl chloride in preparation B to give the expected compound.

Melting point 162-

Example 28: 8-chloro-1- [2- (4-methoxyphenyl) ethyl]-5-methyl-1, 5-dihydropyrido [3, 2-c ]][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The procedure described in example 19 was followed starting from 5-chloro-2-nitrobenzenesulfonyl chloride instead of 4-chloro-2-nitrobenzenesulfonyl chloride in preparation B and starting from 2- (4-methoxyphenyl) ethyl methanesulfonate instead of 4-methoxybenzyl chloride to give the expected compound.

Melting point 186-

Example 29: 8-chloro-1- [3- (4-methoxyphenyl) propyl]-5-methyl-1, 5-dihydropyrido [3, 2-c ]][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The procedure described in example 21 was followed starting from 5-chloro-2-nitrobenzenesulfonyl chloride instead of 4-chloro-2-nitrobenzenesulfonyl chloride in preparation B to give the expected compound.

Melting point 62-65 deg.C (isopropanol)

Example 30: 1- (4-methoxybenzyl) -5, 9-dimethyl-1, 5-dihydropyrido [3, 2-c)][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The procedure described in example 19 was followed starting from 4-methyl-2-nitrobenzenesulfonyl chloride instead of 4-chloro-2-nitrobenzenesulfonyl chloride in preparation B to give the expected compound.

Melting point 135-

Example 31: 1- [2- (4-methoxyphenyl) ethyl]-5, 9-dimethyl-1, 5-dihydropyrido [3, 2-c ]][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The procedure described in example 20 was followed starting from 4-methyl-2-nitrobenzenesulfonyl chloride instead of 4-chloro-2-nitrobenzenesulfonyl chloride in preparation B to give the expected compound.

Melting point 128 deg.C (ethanol)

Example 32: 1- [3- (4-methoxyphenyl) propyl group]-5, 9-dimethyl-1, 5-dihydropyrido [3, 2-c ]][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The procedure described in example 21 was followed starting from 4-methyl-2-nitrobenzenesulfonyl chloride instead of 4-chloro-2-nitrobenzenesulfonyl chloride in preparation B to give the expected compound.

Melting point 130-

Example 33: 9-methoxy-1- (4-methoxybenzyl) -5-methyl-1, 5-dihydropyrido [3, 2-c][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The procedure described for example 19 was followed starting from 4-methoxy-2-nitrobenzenesulfonyl chloride instead of 4-chloro-2-nitrobenzenesulfonyl chloride in preparation B to give the expected compound.

Melting point 179 + 180 deg.C (ethanol)

Example 34: 9-methoxy-1- [2- (4-methoxyphenyl) ethyl]-5-methyl-1, 5-dihydropyrido [3, 2-c ]][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The expected compound was obtained following the procedure described for example 20 starting from 4-methoxy-2-nitrobenzenesulfonyl chloride instead of 4-chloro-2-nitrobenzenesulfonyl chloride in preparation B.

Melting point 65-68 deg.C (ethanol)

Example 35: 9-methoxy-1- [2- (4-methoxyphenyl) propyl]-5-methyl-1, 5-dihydropyrido [3, 2-c ]][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The expected compound was obtained following the procedure described for example 21 starting from 4-methoxy-2-nitrobenzenesulfonyl chloride instead of 4-chloro-2-nitrobenzenesulfonyl chloride in preparation B.

Melting point 128-

Example 36: 1- (4-methoxybenzyl) -5-methyl-9- (trifluoromethyl) -1, 5-dihydropyrido [3, 2-c][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The procedure described for example 19 was followed starting from 4-trifluoromethyl-2-nitrobenzenesulfonyl chloride instead of 4-chloro-2-nitrobenzenesulfonyl chloride in preparation B to give the expected compound.

Melting point 142-

Example 37: 1- [2- (4-trifluoromethylphenyl) ethyl]-5-methyl-9- (trifluoromethyl) -1, 5-dihydropyrido [3, 2-c][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The expected compound was obtained following the procedure described for example 20 starting from 4-trifluoromethyl-2-nitrobenzenesulfonyl chloride instead of 4-chloro-2-nitrobenzenesulfonyl chloride in preparation B.

Melting point 43-44 deg.C (methanol)

Example 38: 1- [3- (4-methoxyphenyl) propyl group]-5-methyl-9- (trifluoromethyl) -1, 5-dihydropyrido [3, 2-c][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The expected compound was obtained following the procedure described for example 21 starting from 4-trifluoromethyl-2-nitrobenzenesulfonyl chloride instead of 4-chloro-2-nitrobenzenesulfonyl chloride in preparation B.

Melting point 144-

Example 39: 1- {2- [4- (benzyloxy) phenyl]Ethyl } -5-methyl-1, 5-dihydropyrido [3, 2-c)][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The procedure described in example 24 was followed starting from 2-nitrobenzenesulfonyl chloride instead of 4-chloro-2-nitrobenzenesulfonyl chloride in preparation B to give the expected compound.

Melting point 133-

Example 40: 1- [2- (4-Phenolethyl) ethyl]-5-methyl-1, 5-dihydropyrido [3, 2-c ]][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The compound prepared in example 39 was catalytically hydrogenated overnight at hydrogen atmospheric pressure at ambient temperature in the presence of 10% palladium on carbon. The palladium was removed and the filtrate was evaporated under reduced pressure. The resulting precipitate was recrystallized from a methanol/water 90/10 mixture.

Melting point 170-

EXAMPLE 41: 1- (4-methoxybenzyl) -1H-pyrido [3, 2-c][1，2，5]Benzoxathiazepine * 5, 5-dioxide

The procedure described in example 1 was followed, starting from the compound prepared in step B of preparation C, to give the expected compound.

Melting point 162-

Example 42: 1- [2- (4-methoxyphenyl) ethyl]-1H-pyrido [3, 2-c][1，2，5]Benzoxathiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described in example 41, except that 4-methoxyphenylethyl methanesulfonate is used instead of 4-methoxybenzyl chloride.

Melting point 115-

Example 43: 1- [3- (4-methoxyphenyl) propyl group]-1H-pyrido [3, 2-c][1，2，5]Benzoxathiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described in example 41, except that 3- (4-methoxyphenyl) propyl methanesulfonate is used instead of 4-methoxybenzyl chloride.

Melting point 99-100 deg.C (ethanol)

Example 44: 1- [2- (3, 4, 5-trimethoxyphenyl) ethyl]-1H-pyrido [3, 2-c][1，2，5]Benzoxathiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described in example 41, except that 2- (3, 4, 5-trimethoxyphenyl) ethyl methanesulfonate is used instead of 4-methoxybenzyl chloride.

Melting point 165-

Example 45: 1- [2- (1-naphthyl) ethyl]-1H-pyrido [3, 2-c][1，2，5]Benzoxathiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described in example 41, except that [2- (1-naphthyl) ethyl ] methanesulfonate is used instead of 4-methoxybenzyl chloride.

Melting point 201-

Example 46: 1- (2- [1, 1' -biphenyl)]-4-ylethyl) -1H-pyrido [3, 2-c][1，2，5]Benzoxathiazepine * 5, 5-dioxide

The expected compound was obtained by following the procedure described in example 41, except that [2- (4-biphenylyl) ethyl ] methanesulfonate was used instead of 4-methoxybenzyl chloride.

Melting point 163-

Example 47: 1- {2- [4- (benzyloxy) phenyl]Ethyl } -1H-pyrido [3, 2-c)][1，2，5]Benzoxathiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described in example 41, except that 2- (4-benzyloxyphenyl) ethyl methanesulfonate is used instead of 4-methoxybenzyl chloride.

Melting Point 142 deg.C (ethanol)

Example 48: 9-chloro-1- [2- (4-methoxyphenyl) ethyl]-1H-pyrido [3, 2-c][1，2，5]Benzoxathiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described for example 41, substituting 2-amino-4-chlorophenol for 2-aminophenol in step A of preparation C and 4-methoxybenzyl chloride with 4-methoxyphenylethyl methanesulfonate.

Melting point 126-

Example 49: 9-methyl-1- [2- (4-methoxyphenyl) ethyl]-1H-pyrido [3, 2-c][1，2，5]Benzoxathiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described for example 41, substituting 2-amino-4-methylphenol for the 2-aminophenol in step A of preparation C and 4-methoxyphenylethyl methanesulfonate for 4-methoxybenzyl chloride.

Melting point 114-

Example 50: 9-methoxy-1- [2- (4-methoxyphenyl) ethyl]-1H-pyrido [3, 2-c][1，2，5]Benzoxathiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described for example 41, substituting 2-amino-4-methoxyphenol for 2-aminophenol in step A of preparation C and 4-methoxyphenylethyl methanesulfonate for 4-methoxybenzyl chloride.

Melting point 115-

Example 51: 2-chloro-1- [2- (4-methoxyphenyl) ethyl]-1H-pyrido [3, 2-c][1，2，5]Benzoxathiazepine * 5, 5-dioxide

Following the procedure described for example 41, substituting 2, 4-dichloro-3-pyridinesulfonyl chloride for 2-chloro-3-pyridinesulfonyl chloride in step A of preparation C and 4-methoxyphenylethyl methanesulfonate for 4-methoxybenzyl chloride, the expected compound was obtained.

Mass Spectrometry [ M ⁺ ]＝416

Example 52: 5-methyl-1- [2- (3, 4, 5-trimethoxyphenyl) ethyl]-1, 5-dihydropyrido [3, 2-c ]][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The procedure described in example 15 was followed to give the expected compound except that 2- (3, 4, 5-trimethoxyphenyl) ethyl methanesulfonate was used instead of 4-methoxybenzyl chloride.

Melting point 165-

Example 53: 5-methyl-1- [2- (4-N, N-dimethylaminoethoxyphenyl) ethyl]-1, 5-dihydropyrido [3, 2-c ]][1，2，5]Benzothiadiazepine * 6, 6-dioxide

The procedure described in example 15 was followed to give the expected compound except that 2- (4-N, N-dimethylaminoethoxyphenyl) ethyl methanesulfonate was used instead of 4-methoxybenzyl chloride.

Mass Spectrometry [ M⁺]＝452

Example 54: 6- [ (2-methoxyethoxy) methyl group]-1- [2- (4-methoxyphenyl) ethyl]-1, 6-dihydropyrido[3，2-c][2，1，5]Benzothiadiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described for example 2, substituting aza * from preparation E for aza * from preparation A.

RMN ¹H (solvent CDCl)₃) ：δ(ppm)：3,10(m，2H)；3,34(s，3H)；3,52(t，2H)；3,81(s，3H)；

3,95(m，2H)；4,30(m，2H)；4,90(m，2H)；5,81(dd，1H)；

6,86(d，2H)；7-7,15(m，4H)；7,20-7,35(m，3H)；7,85(dd，1H)

Example 55: 1- [2- (4-methoxyphenyl) ethyl]-1, 6-dihydropyrido [3, 2-c ]][2，1，5]Benzothiadiazepine * 5, 5-dioxide

A mixture of the compound from example 54 (0.001mol), 95 ℃ ethanol (10ml) and 6N hydrochloric acid (10ml) was refluxed for 1 hour 30 minutes. After the reaction, as much ethanol as possible was removed by evaporation, diluted with water and ethyl acetate was added. Neutralized with saturated sodium bicarbonate solution. Then re-acidified with acetic acid to pH 4-5. Extracted with ethyl acetate and washed with brine. Dried over sodium sulfate. Evaporated under reduced pressure and recrystallized from a suitable solvent.

Melting point 174-

Example 56: 4- [2- (5, 5-dioxide-1H-pyrido [3, 2-c)][1，2，5]Benzoxathiazepine * -1-yl) ethyl]Phenol and its preparation

A mixture of the compound from example 47 (0.0004mol), hydrobromic acid (4ml) and acetic acid (6ml) was heated at 35 ℃ for 5 days. The mixture was dissolved in ice water. Ethyl acetate was added and neutralized with sodium bicarbonate. Extracted with ethyl acetate and washed with brine. The organic phase was dried over sodium sulfate. Filtering, and evaporating under reduced pressure. The precipitate is recrystallized from a suitable solvent.

Melting Point 58-61 deg.C (ethanol/water)

Example 57: 1- [2- (2-methoxyphenyl) ethyl]-1H-pyrido [3, 2-c][1，2，5]Benzoxathiazepine * 5, 5-dioxide

The expected compound is obtained by following the procedure described in example 41, except that 2-methoxyphenylethyl methanesulfonate is used instead of 4-methoxybenzyl chloride.

Melting point 138-

Example 58: 1- {2- [3- (benzyloxy) -4-methoxyphenyl ] ethyl } -1H-pyrido [3, 2-c ] [1, 2, 5] benzoxathiazepine * 5, 5-dioxide

The expected compound is obtained by the procedure described in example 41, except that 2- [3- (benzyloxy) -4-methoxyphenyl ] ethyl methanesulfonate is used instead of 4-methoxybenzyl chloride.

RMN ¹H (solvent CDCl)₃) ：δ(ppm)：3,05(t，2H)；3,89(s，3H)；4,24(t，2H)；5,14(s，2H)；

5,71(dd，1H)；6,70-7,45(m，13H)；7,83(dd，1H)。

Example 59: 5- [2- (5, 5-dioxido-1H-pyrido [3, 2-c ] [1, 2, 5] benzoxathiazepin * -1-yl) ethyl ] -2-methoxyphenol

The expected compound was obtained by following the procedure described in example 56, using the compound of example 58 instead of the compound of example 47 as starting material.

Melting point 158-

Example 60: 1- [2- (4-methoxyphenyl) ethyl ] pyrido [3, 2-c ] [1, 5] benzoxaza * -5(1H) -one

Starting from the compound prepared as in preparation D, step B, the expected compound was obtained following the procedure described for example 42.

Example 61: 1- [2- (3-hydroxy-4-methoxyphenyl) ethyl ] pyrido [3, 2-c ] [1, 5] benzoxaza * -5(1H) -one

Starting from the compound prepared as in preparation D, step B, the expected compound was obtained according to the procedure described for example 59.

Example 62: 1- [2- (4-methoxyphenyl) ethyl ] -6-methyl-1, 6-dihydro-5H-pyrido [2, 3-b ] [1, 5] benzodiazepine * -5-one

Starting from the compound prepared as in preparation F, step B, the expected compound was obtained following the procedure described for example 42.

Example 63: 1- [2- (3-hydroxy-4-methoxyphenyl) ethyl ] -6-methyl-1, 6-dihydro-5H-pyrido [2, 3-b ] [1, 5] benzodiazepine * -5-one

Starting from the compound prepared as in preparation F, step B, the expected compound was obtained according to the procedure described for example 59.

Pharmacological study of the Compounds of the invention

Example A: in vitro cytotoxicity

Five cell lines were used:

-murine leukemia L1210,

-non-small cell human lung carcinoma A549,

human epidermoid carcinoma KB-3-1 and the corresponding resistant cell line KB-A1, which is multidrug-resistant induced by doxorubicin (ADR),

human colon cancer HT 29.

In RPMI 1640 complete medium containing 10% fetal bovine serum, 2mM glutamine, 50 units/ml penicillin, 50. mu.g/ml streptomycin and 10mM Hepes(pH7.4) in a culture medium. Cells are distributed on a microplate and contacted with a cytotoxic compound. The cells were then incubated for 2 days (L1210) or 4 days (A549, KB-A1, KB-3-1, HT 29). The sample was then analyzed by means of a colorimetric Assay, namely a Microculture Tetrazolium Assay (Cancer res.1987,47936-942) to quantify the number of surviving cells.

Result in IC₅₀-the concentration at which the cytotoxic agent inhibits the proliferation of the treated cells by 50%. For example, the compound of example 42 has the IC given in the table below₅₀The value:

	IC50nM
						test compounds	HT29	L1210	A549	KB-3-1	KB-A1
Example 42	9.8	8.2	11.3	15.6	13.3

The compound of example 42 was therefore strongly cytotoxic to these tumor cell lines. The drug-resistant cell line KB-A1 is as sensitive as the sensitive cell line KB-3-1, demonstrating that the compound of example 42 is not recognized by the P-glycoprotein, which is responsible for multiple resistance to cytotoxic drugs.

Thus, the compounds of the present invention are additionally useful for the treatment of human tumors that are resistant to chemotherapy.

Example B: effect on cell cycle

L1210 cells were cultured at 37 ℃ for 21 hours in the presence of different concentrations of test compound. The cells were then fixed with 70% ethanol (v/v), washed twice in PBS, and incubated in PBS containing 100. mu.g/ml RNase and 50. mu.g/ml propidium iodide at 20 ℃ for 30 minutes. Results are expressed as the percentage of cells aggregated at G2+ M phase after 21 hours compared to controls.

The compounds of the invention are potent cytotoxic agents with selective effects on the cell cycle. For example, a concentration of 25nM of the compound of example 42 caused aggregation of 80-90% of cells in the G2+ M phase after 21 hours (untreated cells-20% in the G2+ M phase).

Example C: pharmaceutical composition

A formulation for 1000 tablets each containing 10mg of active ingredient

EXAMPLE 42 Compound … … … … … … … … … … … … … … … … … … 10g

Hydroxypropyl cellulose … … … … … … … … … … … … … … … … … … … 2g

… … … … … … … … … … … … … … … … … … … … … 10g of wheat starch

Lactose … … … … … … … … … … … … … … … … … … … … … … … 100g

… … … … … … … … … … … … … … … … … … … … … 3g of magnesium stearate

Talcum powder … … … … … … … … … … … … … … … … … … … … … … 3g

Claims (20)

1. Compounds of formula (I), their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base,

wherein: ●Represents a benzo or pyrido group, optionally fused in the 2-3, 3-4 or 4-5 positions, it being understood that the nitrogen of the pyrido groupThe atom(s) occupying any of the 2 to 5 positions of a ring, which ring is unsubstituted or substituted by one or more identical or different atoms or groups selected from halogen atoms and hydroxyl groups, straight or branched (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Trihaloalkyl, amino (optionally substituted at the nitrogen by one or two straight or branched chains (C)₁-C₆) Alkyl substituted), nitro, straight or branched chain (C)₁-C₆) Acyl and (C)₁-C₂) (ii) an alkylenedioxy group,

● W represents a group X-Y or Y-X wherein:

x represents a group > SO₂Or > C ═ O,

y represents an oxygen atom or a group N-R₃Wherein R is₃Represents a hydrogen atom, a straight chain or a branched chain (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Arylalkyl, -Alk-Z-R or-Alk-Z-Alk ' -Z ' -R, where Alk and Alk ' independently of one another represent a linear or branched chain (C)₁-C₆) Alkylene or straight or branched chain (C)₂-C₆) Alkenylene, Z and Z ' independently of one another represent an oxygen, sulphur atom or a group-N (R ') -, R and R ' being identical or different and representing a linear or branched (C)₁-C₆) An alkyl group, a carboxyl group,

● n represents zero or an integer wherein 1. ltoreq. n.ltoreq.6,

● G represents a hydrogen atom, an aryl group or a heteroaryl group,

●R₁and R₂Are identical or different and represent a hydrogen or halogen atom or a hydroxyl, linear or branched (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Trihaloalkyl, amino (optionally substituted at the nitrogen by one or two straight or branched chains (C)₁-C₆) Alkyl substituted), nitro or straight or branched chain (C)₁-C₆) Acyl or (C)₁-C₂) An alkylenedioxy group, provided that:

-if G represents a hydrogen atom, n is not zero,

-if G represents a hydrogen atom and Y represents a group N-R₃Then R is₃Represents a hydrogen atom, a straight chain or a branched chain (C)₂-C₆) Alkyl or aryl- (C)₁-C₆) An alkyl group, wherein the alkyl group is linear or branched,

if G represents a hydrogen atom and W represents two NR' s₃One of the groups C (O), wherein R₃Represents ethyl or benzyl, n is not 1, 2 or 3,

-the compound of formula (I) is not 1-benzyl-5, 10-dimethyl-1, 5-dihydro-6H-pyrido [2, 3-b ] [1, 4] benzodiazepine * -6-one, 1, 2-dimethyl-5-oxo-5, 6-dihydro-1H-pyrido [2, 3-b ] [1, 5] benzodiazepine * 3-carboxylic acid ethyl ester, 3-acetyl-1-ethyl-2-methyl-1, 6-dihydro-5H-pyrido [2, 3-b ] [1, 5] benzodiazepine * -5-one, 2-amino-1-methyl-5-oxo-5, 6-dihydro-1H-pyrido [2, 3-b ] [1, 5] benzodiazepine * -3-carbonitrile and ethyl 2-amino-1-methyl-5-oxo-5, 6-dihydro-1H-pyrido [2, 3-b ] [1, 5] benzodiazepine * 3-carboxylate, it being understood that:

aryl represents phenyl, biphenyl, naphthyl, tetrahydronaphthyl, each of these radicals being unsubstituted or substituted by one, two or three identical or different atoms or groups chosen from halogen atoms and linear or branched (C)₁-C₆) Alkyl, hydroxy, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Trihaloalkyl, amino (optionally substituted at the nitrogen by one or two straight or branched chains (C)₁-C₆) Alkyl substituted), nitro, straight or branched chain (C)₁-C₆) Acyl, straight or branched (C)₁-C₆) Alkylcarbonylamino group, (C)₁-C₂) Alkylenedioxy, phenoxy, benzyloxy, straight or branched amino- (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Alkylamino radical- (C)₁-C₆) Alkoxy and straight or branched chain di (C)₁-C₆) Alkylamino radical- (C)₁-C₆) An alkoxy group,

heteroaryl represents a mono-or bicyclic aromatic 5-to 12-membered radical containing oneTwo or three heteroatoms selected from oxygen, nitrogen and sulphur, it being understood that the heteroaryl radical is unsubstituted or substituted by one or more atoms or groups, which may be the same or different, selected from halogen atoms and linear or branched (C)₁-C₆) Alkyl, hydroxy, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Trihaloalkyl, amino (optionally substituted by one or more straight or branched chain (C)₁-C₆) Alkyl substituted), nitro, straight or branched chain (C)₁-C₆) Acyl, straight or branched (C)₁-C₆) Alkylcarbonylamino group, (C)₁-C₂) Alkylenedioxy, phenoxy, benzyloxy, straight or branched amino- (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Alkylamino radical- (C)₁-C₆) Alkoxy and straight or branched chain di (C)₁-C₆) Alkylamino radical- (C)₁-C₆) An alkoxy group,

-groupOptionally condensed in the 2-3, 3-4 or 4-5 position, meaning that benzo or pyrido groups are optionally presentOrPosition with phenyl, (C)₄-C₈) Cycloalkyl or heterocyclyl condensed with the proviso that ifRepresents a pyrido group, the nitrogen atom is not the point of attachment to a fused ring,

alkylene represents a divalent radical of a saturated hydrocarbon chain,

-alkenylene represents a divalent radical of a hydrocarbon chain containing from 1 to 3 double bonds,

-(C₄-C₈) Cycloalkyl denotes cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,

-heterocyclyl represents a saturated or unsaturated 5-to 7-membered monocyclic group containing one to three heteroatoms selected from nitrogen, oxygen and sulphur.

2. Compounds of formula (I) according to claim 1, their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base, wherein X represents > SO₂Y represents N-R₃。

3. Compounds of formula (I) according to claim 1, their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base, wherein X represents > SO₂And Y represents O.

4. Compounds of formula (I) according to claim 1, wherein X represents > C ═ O and Y represents N-R, their enantiomers and diastereomers, and their addition salts with a pharmaceutically acceptable acid or base₃。

5. Compounds of formula (I), their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base according to claim 1, wherein X represents > C ═ O and Y represents O.

6. Compounds of formula (I), their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base according to any one of claims 1 to 5, wherein G represents aryl or heteroaryl.

7. The compounds of formula (I), their enantiomers and diastereomers and the addition salts thereof with a pharmaceutically acceptable acid or base according to claim 6, wherein G represents phenyl substituted by one, two or three groups selected from linear or branched (C)₁-C₆) Alkoxy, benzyloxy, and hydroxy.

8. Compounds of formula (I) according to any one of claims 1, 2, 4, 6 and 7, their useEnantiomers and diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base, wherein R₃Represents a straight chain or branched chain (C)₁-C₆) An alkyl group.

9. The compounds of formula (I), their enantiomers and diastereomers and the addition salts thereof with a pharmaceutically acceptable acid or base according to any one of claims 1, 2, 4, 6 and 7, wherein R is₃Represents a hydrogen atom or a linear or branched chain (C)₁-C₆) An arylalkyl group.

10. Compounds of formula (I), their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base according to any one of claims 1 to 9, whereinRepresents a group which is unsubstituted or substituted by 1, 2 or 3 identical or different atoms or groupsThe atoms or groups being selected from halogen atoms and hydroxyl groups, linear or branched (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Trihaloalkyl, amino (optionally substituted at the nitrogen by one or two straight or branched chains (C)₁-C₆) Alkyl substituted), nitro, straight or branched chain (C)₁-C₆) Acyl and (C)₁-C₂) An alkylenedioxy group.

11. Compounds of formula (I) according to claim 10, their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base, wherein the substituents are located in the groupsIs selected from halogen atoms and groups straight or branched (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy and straight or branched chain (C)₁-C₆) A trihaloalkyl group.

12. Compounds of formula (I) according to any one of claims 1 to 11, their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base, wherein R₁And R₂Are identical or different and represent a hydrogen or halogen atom or a linear or branched (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy or straight or branched chain (C)₁-C₆) A trihaloalkyl group.

13. A compound of formula (I) according to any one of claims 1, 2, 6, 7 and 10 to 12 which is 6- [ (2-methoxyethoxy) methyl ] -1- [2- (4-methoxyphenyl) ethyl ] -1, 6-dihydropyrido [3, 2-c ] [2, 1, 5] benzothiepin * 5, 5-dioxide and addition salts thereof with a pharmaceutically acceptable acid.

14. A compound of formula (I) according to any one of claims 1, 2, 6, 7, 9 and 10 to 12 which is 1- [2- (4-methoxyphenyl) ethyl ] -1, 6-dihydropyrido [3, 2-c ] [2, 1, 5] benzothiadiazine * 5, 5-dioxide and addition salts thereof with a pharmaceutically acceptable acid.

15. A compound of formula (I) according to any one of claims 1, 2, 6 to 8 and 10 to 12, and addition salts thereof with a pharmaceutically acceptable acid, which compound is:

1- [2- (4-methoxyphenyl) ethyl ] -6-methyl-1, 6-dihydropyrido [3, 2-c ] [2, 1, 5] benzothiepin * 5, 5-dioxide,

1- [2- (4-methoxyphenyl) ethyl ] -5-methyl-1, 5-dihydropyrido [3, 2-c ] [1, 2, 5] benzothiepin * 6, 6-dioxide.

16. A compound of formula (I) according to any one of claims 1, 3, 6, 7 and 10 to 12, and addition salts thereof with a pharmaceutically acceptable acid, which compound is:

1- [2- (4-methoxyphenyl) ethyl ] -1H-pyrido [3, 2-c ] [1, 2, 5] benzoxathiazepine * 5, 5-dioxide,

4- [2- (5, 5-dioxide-IH-pyrido [3, 2-c ] [1, 2, 5] benzoxathiazepin * -1-yl) ethyl ] phenol,

1- [2- (2-methoxyphenyl) ethyl ] -1H-pyrido [3, 2-c ] [1, 2, 5] benzoxathiazepine * 5, 5-dioxide,

1- {2- [3- (benzyloxy) -4-methoxyphenyl ] ethyl } -1H-pyrido [3, 2-c ] [1, 2, 5] benzoxathiazepine * 5, 5-dioxide,

5- [2- (5, 5-dioxide-1H-pyrido [3, 2-c ] [1, 2, 5] benzoxathiazepin * -1-yl) ethyl ] -2-methoxyphenol.

17. Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that in a basic medium:

-reacting a compound of formula (II):

w, A, R therein₁And R₂As defined in formula (I),

^*with a compound of formula (III):

Z₂-(CH₂)_n-G (III)

wherein n and Ar are as defined for formula (I) and Z₂Represents a nucleofugic group, to give a compound of formula (I), if necessary purified according to conventional purification techniques, if necessary separated into its stereoisomers according to conventional separation techniques, and if necessary converted into their addition salts with a pharmaceutically acceptable acid or base.

18. A pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 16 alone or in combination with one or more pharmaceutically acceptable inert non-toxic carriers.

19. The pharmaceutical composition of claim 18 for use as an anticancer agent.

20. Use of the pharmaceutical composition of claim 18 in the preparation of an anti-cancer agent.