HK1071749B - Novel benzothiazine and benzothiadiazine derivatives, method for preparing same and pharmaceutical compositions containing same - Google Patents

Description

Benzothiazine and benzothiadiazine derivatives, method for preparing same and pharmaceutical compositions containing same

Technical Field

The present invention relates to novel benzothiazine and benzothiadiazine compounds, a process for their preparation and pharmaceutical compositions comprising them.

Background

It has been recognized that excitatory amino acids, particularly glutamate, play important roles in the physiological processes of neuronal plasticity and in the mechanisms of learning and memory. Pathophysiological studies have clearly shown that defects in glutamatergic neurotransmission are closely related to the development of Alzheimer's disease (Neuroscience and Biobehavioral reviews, 1992, 16, 13-24; Progress in neurobiology, 1992, 39, 517-545).

Furthermore, a great deal of work in recent years has shown the existence of subtypes of excitatory amino acid receptors and their functional interactions (Molecular Neuropharmacology, 1992, 2, 15-31).

Among these receptors, the AMPA (α -amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptor appears to be associated to a large extent with physiological neuronal excitability phenomena, in particular those during memory. For example, learning has been shown to be associated with increased binding of AMPA to its receptors in the hippocampus, a region of the brain essential for memory and cognitive processes. Similarly, nootropic agents such as semicarbazones have recently been recognized to modulate the AMPA receptors of neuronal cells in a positive manner (Journal of Neurochemistry, 1992,58，1199-1204)。

compounds with a benzamide structure have been reported in the literature to have this same mechanism of action and to improve memory behavior (Synapse, 1993,15,326-329). In particular compound BA 74 is the most active compound of these new pharmacological agents.

Finally, european patent application EP 692484 describes a benzothiadiazine compound having a promoting effect on AMPA flow, and patent application WO 99/42456 describes in particular a number of benzothiadiazine compounds as AMPA receptor modulators.

Description

Surprisingly, the benzothiazine and benzothiadiazine compounds to which the present invention relates are not only novel, but also exhibit pharmacological activity towards AMPA streams that is significantly superior to that of compounds having similar structures described in the prior art. They are useful as AMPA modulators for the treatment or prevention of memory and cognitive disorders associated with: age, anxiety or depressive syndromes, progressive neurodegenerative diseases, Alzheimer's disease, pick's disease, Huntington's chorea, schizophrenia, sequelae of acute neurodegenerative diseases, sequelae of ischemia and sequelae of epilepsy.

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

wherein:

R₁represents an aryl group or a heteroaryl group,

R₂represents a hydrogen atom, a halogen atom or a hydroxyl group,

a represents CR₄R₅Or NR₄，

R₃Represents a hydrogen atom, a straight chain or a branched chain (C)₁-C₆) Alkyl or (C)₃-C₇) A cycloalkyl group,

R₄represents a hydrogen atom or a linear or branched chain (C)₁-C₆) Alkyl, or

A represents a nitrogen atom and is adjacent to-CHR₃The radicals forming the ringWherein m represents 1, 2 or 3,

R₅represents a hydrogen atomA carbon atom or a halogen atom,

it should be understood that:

● "aryl" means an aromatic monocyclic group, or a bicyclic group in which at least one ring is aromatic, optionally substituted by one or more identical or different groups selected from halogen, straight or branched (C)₁-C₆) Alkyl (optionally substituted with one or more hydroxyl groups), straight or branched (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Perhaloalkyl, straight or branched chain (C)₁-C₆) Alkoxycarbonyl, straight or branched (C)₁-C₆) Alkylthio, carboxyl, straight or branched chain (C)₁-C₆) Acyl, straight or branched (C)₁-C₆) Perhaloalkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or more straight or branched chains (C)₁-C₆) Alkyl or straight or branched chain (C)₁-C₆) Acyl substituted), aminocarbonyl (optionally substituted with one or more straight or branched chain (C)₁-C₆) Alkyl substituted), aminosulfonyl (optionally substituted with one or more linear or branched (C)₁-C₆) Alkyl substituted), mono-or di- ((C)₁-C₆) Alkylsulfonyl) amino, mono-OR di- (trifluoromethylsulfonyl) amino, PO (OR)_a)(OR_b) (wherein, R_aAnd R_bMay be the same or different and represents a hydrogen atom or a linear or branched chain (C)₁-C₆) Alkyl), benzyloxy or phenyl (optionally substituted by one or more of the same or different groups selected from: halogen, straight or branched chain (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Perhaloalkyl, hydroxy or straight or branched chain (C)₁-C₆) An alkoxy group),

● "heteroaryl" refers to an aromatic monocyclic group or bicyclic group in which at least one ring is aromatic, containing 1, 2 or 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by one or more identical or different groups selected from: halogen, straight or branched chain(C₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Perhaloalkyl, straight or branched chain (C)₁-C₆) Alkoxycarbonyl, carboxyl, straight or branched chain (C)₁-C₆) Acyl, straight or branched (C)₁-C₆) Perhaloalkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or more straight or branched chains (C)₁-C₆) Alkyl substituted), aminosulfonyl (optionally substituted with one or more linear or branched (C)₁-C₆) Alkyl substituted) or (C)₁-C₆) An alkylsulfonylamino group.

Among the pharmaceutically acceptable acids, mention may be made, without being limited thereto: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric 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, methanesulfonic acid, camphoric acid, and the like.

Among the pharmaceutically acceptable bases there may be mentioned, but are not limited to: sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, and the like.

R₁The O-group is preferably in the b-position of the phenyl radical carrying it.

Preferably R₁Is aryl, in particular substituted or unsubstituted phenyl.

When aryl is substituted phenyl, the substituent is preferably in the meta position.

Preferably R₂The radical is a hydrogen atom.

Preferred compounds of the present invention are those wherein A represents a nitrogen atom and is adjacent to-CHR₃The radicals forming the ringWherein m represents 1, 2 or 3, preferably 1.

Preferred compounds of the invention are:

7- (3-methylphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazine 5, 5-dioxide,

3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazin-7-yl) oxy ] benzoic acid,

3- (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazin-7-yl) oxy ] aniline,

n- [3- (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazin-7-yl) oxy ] phenyl ] methanesulfonamide,

3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazin-7-yl) oxy ] phenyl-phosphonic acid ethylester,

and isomers thereof.

The invention also relates to a process for the preparation of the compounds of formula (I).

A process for the preparation of a compound of formula (I) wherein A represents NR₄Or A represents a nitrogen atom and adjacent CHR₃Form a ringWherein m represents 1 or2,

characterized in that a compound of formula (II) is used as a starting material:

wherein:

R′₁represents a straight chain or branched chain (C)₁-C₆) An alkoxy group,

R′₂represents a hydrogen atom, and is represented by,

the compound is prepared by

(a) Reacting with an acid chloride of formula (III) in a tetrahydrofuran or acetonitrile medium in the presence of a base:

Cl-CH₂-(CH₂)_m-CH₂-COCl (III)，

wherein m is as defined for formula (I) to obtain a compound of formula (IV):

wherein R'₁And R'₂As defined above, the above-mentioned materials,

this compound is then cyclized in basic medium to give the compound of formula (V):

wherein R'₁、R′₂And m is as defined above, and m is,

reducing the compound, optionally in an alcoholic or dimethylformamide medium, in the presence of sodium borohydride to obtain a compound of formula (VI):

wherein R'₁、R′₂And m is as defined above, and m is,

treating it with boron tribromide to give a compound of formula (VII):

wherein R is₂And m is as defined above, and m is,

(b) or cyclizing as follows:

cyclisation in the presence of an amidine of formula (VIII):

wherein R is₃As defined in formula (I), to obtain a compound of formula (IX):

wherein R'₁、R′₂And R₃As defined above, the above-mentioned materials,

the compound is prepared by reacting:

● to produce a compound of formula (X) by reduction with a metal hydride:

wherein R'₁、R′₂And R₃As defined above, the above-mentioned materials,

● or in alkylating agent R'₄Alkylation with a strong base in the presence of-X,

wherein R'₄Represents a straight chain or branched chain (C)₁-C₆) Alkyl and X represents a halogen atom, and then reduced to produce a compound of formula (XI):

wherein R'₁、R′₂、R₃And R'₄As defined above, or

Cyclizing in the presence of an aldehyde of formula (XII):

wherein R is₃As defined for formula (I), to obtain a compound of formula (X) as defined previously,

wherein, in the compound of formula (X) or (XI),

a radical R'₁And a group R'₂When it denotes a straight or branched chain (C)₁-C₆) When alkoxy, conversion to hydroxy affords compounds of formula (XIII):

wherein R is₂、R₃And R₄As defined in formula (I),

reacting a compound of formula (VII) or (XIII) with a boronic acid compound of formula (XIV):

R₁B(OH)₂ (XIV)

wherein R is₁As defined in formula (I), to obtain formula (I/a)₁) Or (I/a)₂) Are particular forms of compounds of formula (I):

wherein R is₁、R₂、R₃And R₄As defined in formula (I),

wherein R is₁、R₂And m is as defined for formula (I),

if desired for the radical R₁By substitution ofA group represented by the formula (I/a)₁) Or (I/a)₂) The compound (a) is subjected to a conventional transformation,

if desired, the formula (I/a) is purified by conventional purification techniques₁) Or (I/a)₂) The compound of (a) is purified, if necessary, by separating it into its isomers using conventional separation techniques, and if necessary, converting it into an addition salt using a pharmaceutically acceptable acid or base.

A represents CR₄R₅A process for the preparation of a compound of formula (I) characterised in that a compound of formula (XV):

wherein:

R′₁represents a straight chain or branched chain (C)₁-C₆) An alkoxy group,

R′₂represents a hydrogen atom, a halogen atom or a linear or branched chain (C)₁-C₆) An alkoxy group,

which is treated with chloroacetone in the presence of dimethylformamide to give the compound of formula (XVI):

wherein R'₁And R'₂As defined above, the above-mentioned materials,

which is rearranged in a basic medium to give a compound of formula (XVII):

wherein R'₁And R'₂As defined above, the above-mentioned materials,

it is deacetylated by heating under reflux in a benzene medium in the presence of an excess of ethylene glycol and a catalytic amount of p-toluenesulfonic acid to give a compound of formula (XVIII):

wherein R'₁And R'₂As defined above, the above-mentioned materials,

which is hydrolyzed in an acidic medium to produce a compound of formula (XIXa):

wherein R'₁And R'₂As defined above, the above-mentioned materials,

optionally, depending on the desired radical R₃Optionally protected with a protecting group and then, after treatment with a strong base, with a compound of formula R'₃-treatment of the compound of P,

wherein R'₃Represents a straight chain or branched chain (C)₁-C₆) Alkyl or (C)₃-C₇) Cycloalkyl and P represents a leaving group, which upon deprotection of the nitrogen atom yields a compound of formula (XIX' a):

wherein R'₁、R′₂And R'₃As defined above, the above-mentioned materials,

reacting a compound of formula (XIXa) or (XIX' a) represented by formula (XIX):

wherein the content of the first and second substances,R′₁and R'₂As defined hereinbefore and R₃As defined by formula (I):

-carrying out a catalytic reduction to produce a compound of formula (XX):

wherein R'₁、R′₂And R₃As defined above, the above-mentioned materials,

-or by conversion into an alcohol by treatment with a hydride, the hydroxyl group of the resulting compound being converted into a halogen atom by treatment with a suitable reagent, to obtain a compound of formula (XXI):

wherein R'₁、R′₂And R₃R 'as hereinbefore defined'₅Represents a halogen atom, and is a halogen atom,

or with an organomagnesium compound R'₄-MgBr treatment, wherein R'₄Represents a straight chain or branched chain (C)₁-C₆) Alkyl to yield a compound of formula (XIXb):

wherein R'₁，R′₂，R₃And R'₄As defined above, the above-mentioned materials,

reacting a compound of formula (XIXb)

-carrying out a catalytic reduction to obtain a compound of formula (XXII):

wherein R'₁、R′₂、R₃And R'₄As defined above, the above-mentioned materials,

-or its hydroxyl group is converted into a halogen atom by treatment with a suitable reagent, to obtain a compound of formula (XXIII):

wherein R'₁、R′₂、R₃And R'₄R 'as hereinbefore defined'₅Represents a halogen atom, and is a halogen atom,

wherein, in the compounds of the formulae (XX) to (XXIII),

a radical R'₁And a group R'₂When it denotes a straight or branched chain (C)₁-C₆) When alkoxy is present, conversion to hydroxy affords a compound of formula (XXIV):

wherein R is₂、R₃、R₄And R₅As defined in formula (I),

reacting a compound of formula (XXIV) with a boronic acid compound of formula (XIV):

R₁B(OH)₂ (XIV)

wherein R is₁Obtaining a compound of formula (I/b), as defined for formula (I), which is a particular form of the compound of formula (I):

wherein R is₁、R₂、R₃、R₄、R₅As defined in formula (I),

if desired for the radical R₁The compounds of formula (I/b) are subjected to conventional transformations which, if desired, are purified using conventional purification techniques, are, if desired, separated into their isomers using conventional separation techniques, and, if desired, are converted into addition salts using pharmaceutically acceptable acids or bases.

The invention also relates to pharmaceutical compositions comprising a compound of formula (I) as active ingredient, together with one or more suitable inert, non-toxic excipients. Among the pharmaceutical compositions of the present invention, those suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions, etc. can be specifically mentioned.

The useful dosage may vary depending on the nature and severity of the disease, the route of administration, and the age and weight of the patient. The dosage range is 1-500 mg/day, and the dosage is single or divided into multiple times.

The following examples are intended to illustrate the invention, but not to limit the scope of the invention in any way.

The raw materials used are all known products or can be prepared according to known preparation methods.

The structural formulae of the compounds described in the examples are determined according to conventional spectroscopic techniques (infrared, NMR, mass spectrometry, etc.).

Examples

Example 1: 7-phenoxy-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine 5, 5-dioxide

Step A: n- [2- (aminosulfonyl) -4-methoxyphenyl ] -4-chlorobutanamide

144mmol of triethylamine and 30ml of a Tetrahydrofuran (THF) solution containing 135mmol of 4-chlorobutyryl chloride are successively added dropwise to a solution of 96.4mmol of 2-amino-5-methoxybenzenesulphonamide in 200ml of THF. After stirring at room temperature overnight, THF was distilled off and the residue was added to water. After extraction with ethyl acetate, the organic phase is washed and dried. After evaporation, the desired product is obtained as an oil.

And B: 5, 5-dioxide-7-methoxy-2, 3-dihydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine

The product obtained in the above step was stirred in 320ml of 1N aqueous sodium hydroxide solution at room temperature overnight. After addition of 50ml of ethyl acetate, vigorous stirring is carried out and the precipitated desired product is filtered off, washed and dried.

And C: 5, 5-dioxide-7-methoxy-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine

106.5mmol of sodium borohydride were added to a suspension of 40ml of Dimethylformamide (DMF) containing 35.5mmol of the product obtained in the above step. After stirring at room temperature overnight, the reaction mixture was cooled, and then 150ml of ice-cold 1N hydrochloric acid was added to the above mixture. The desired product is precipitated and filtered off.

Melting point: 193, 198 deg.C

Step D: 5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-ol

79.3mmol of boron tribromide are added dropwise, under a nitrogen atmosphere, to a suspension of 350ml of dichloromethane containing 26.7mmol of the product obtained in the preceding step, which is maintained at-60 ℃. The temperature was maintained for 1 hour, then the mixture was warmed to room temperature and stirred overnight. After cooling the reaction mixture in an ice bath, 100ml of water were added and the resulting biphasic system was stirred vigorously. The resulting suspension was filtered, and the obtained white solid was washed with water, ether and dried to obtain the objective product.

Melting point 237-

Step E: 7-phenoxy-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine 5, 5-dioxide

A suspension comprising 0.832mmol of the compound obtained in the preceding step, 1.66mmol of phenylboronic acid, 1.25mmol of copper acetate, 2.5mmol of pyridine and 100mg of molecular sieve in 20ml of dichloromethane (CH)₂Cl₂) And stirred for 5 hours. After addition of 20ml of CH₂Cl₂After that, the suspension was filtered. After evaporation of the filtrate, the residue was purified by column on silica eluting with a dichloromethane/ethyl acetate (95/5) mixture to give the desired product.

Melting point: 239-

Elemental microanalysis:

C％ H％ N％ S％

calculated value 60.745.108.8510.13

Found value 60.675.068.6510.22

Example 2: 7-phenoxy-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine 5, 5-dioxide, alpha-isomer

Example 3: 7-phenoxy-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine 5, 5-dioxide, beta-isomer

The compounds of examples 2 and 3 were prepared by chromatography on a chiral column, Chiralcel OC^®The isomer from example 1 was isolated as above using a 1000/0.5 isopropanol/diethylamine mixture as the eluting solvent. After separation, each isomer was chromatographed on a column of silica gel, eluting with a dichloromethane/ethyl acetate (20/10) mixture.

Example 4: 8-phenoxy-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazine 5, 5-dioxide

The compound of this example was prepared according to the procedure described in example 1, using the appropriate starting materials.

Melting point: 184-187 ℃ C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 60.745.108.8510.14

Found value 60.245.048.6910.09

The compounds of the following examples were prepared according to the procedure described in example 1, using the appropriate boronic acid in step E.

Example 5: 4- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazin-7-yl) oxy ] benzonitrile

Melting point: 245 ℃ of 242-

Elemental microanalysis:

C％ H％ N％ S％

calculated value 59.814.4312.319.39

Found value 59.724.5311.959.61

Example 6: 3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazin-7-yl) oxy ] benzonitrile

Melting point: 227 ℃ 230 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 59.814.4312.319.39

Found value 59.874.5011.799.12

Example 7: 7- (4-Methylphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine 5, 5-dioxide

Melting point: 222- & 226 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 61.805.498.489.70

Found value 61.775.548.299.38

Example 8: 7- (3-methylphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine 5, 5-dioxide

Melting point: 190 ℃ plus 195 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 61.805.498.489.70

Found value 62.165.558.229.56

Example 9: 7- (4-methoxyphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazine 5, 5-dioxide

Melting point: 188 ℃ C191

Elemental microanalysis:

C％ H％ N％ S％

calculated value 58.945.248.099.26

Found value 59.115.357.909.43

Example 10: 7- (3-methoxyphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazine 5, 5-dioxide

Melting point: 152 ℃ and 155 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 58.945.248.099.26

Found value 59.065.377.759.12

Example 11: 7- (3-methoxyphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazine 5, 5-dioxide, alpha isomer

Example 12: 7- (3-methoxyphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazine 5, 5-dioxide, beta isomer

The compound of example 10 was separated on a chiral column under the same conditions as described in examples 2 and 3 to obtain the compounds of examples 11 and 12.

Example 13: 7- (2-methoxyphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine 5, 5-dioxide

Melting point: 175 ℃ C. (176 ℃ C.)

Elemental microanalysis:

C％ H％ N％ S％

calculated value 58.945.248.099.26

Found value 58.915.347.939.26

Example 14: 7- (3-trifluoromethylphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazine 5, 5-dioxide

Melting point: 195 + 197 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 53.123.937.298.34

Found value 53.314.057.208.22

The compound of example 14 was separated on a chiral column under the same conditions as described in examples 2 and 3 to obtain the compounds of examples 14a and 14 b.

Example 14 a: 7- (3-Trifluoromethylphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazine 5, 5-dioxide, alpha isomer

Elemental microanalysis:

C％ H％ N％ S％

calculated value 53.123.937.298.34

Found value 53.054.297.218.08

Example 14 b: 7- (3-Trifluoromethylphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazine 5, 5-dioxide, beta isomer

Elemental microanalysis:

C％ H％ N％ S％

calculated value 53.123.937.298.34

Found value 53.244.197.288.12

Example 15: 7- (3-Nitrophenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine 5, 5-dioxide

Melting point: 201 ℃ to 204 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 53.184.1811.638.87

Found value 53.534.2311.368.80

Example 16: 7- [3, 5-bis (trifluoromethyl) phenoxy ] -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazine 5, 5-dioxide

Melting point: 201 ℃ 203-

Elemental microanalysis:

C％ H％ N％ S％

calculated value 47.793.126.197.09

Found value 47.903.246.107.07

Example 17: 7- (3-chlorophenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine 5, 5-dioxide

Melting point: 194 deg.C 198 deg.C

Elemental microanalysis:

C％ H％ N％ S％ Cl％

calculated value 54.784.317.999.1410.11

Found value 54.924.367.919.1510.95

Example 18: 7- (3-ethoxyphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine 5, 5-dioxide

Melting point: 150 ℃ C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 59.985.597.778.90

Found value 60.115.647.568.61

Example 19: 7- (3-Trifluoromethoxyphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazine 5, 5-dioxide

Melting point: 175 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 51.003.787.008.01

Found value 51.103.826.938.10

Example 20: 7- (1-Naphthyloxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine 5, 5-dioxide

Melting point: 227 ℃ 229 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 65.564.957.648.75

Found value 65.295.117.378.42

Example 21: 7- (2-Naphthyloxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine 5, 5-dioxide

Melting point: 234 ℃ and 236 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 65.564.957.648.75

Found value 65.314.957.448.66

Example 22: 7- (3-Benzyloxyphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazine 5, 5-dioxide

Melting point: 179 plus 182 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 65.385.256.637.59

Found value 65.555.246.527.25

Example 23: 4- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] phenol

The expected product is obtained starting from the compound described in example 9. I.e. it is dissolved in dichloromethane and cooled in an ice bath and added to the CH of boron tribromide₂Cl₂In solution (1M). After warming to room temperature and stirring overnight, the mixture was cooled in an ice bath. After addition of water, with CH₂Cl₂Extraction, drying and evaporation, filtration of the residue, addition of ether and filtration gave the desired product.

Melting point: 175 ℃ 178-

Elemental microanalysis:

C％ H％ N％ S％

calculated value 57.824.858.439.65

Found value 57.664.838.189.63

Example 24: 3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] phenol

100mg of the product from example 22 are hydrogenated in 20ml of ethanol and 10. mu.l of concentrated hydrochloric acid at room temperature under atmospheric pressure in the presence of 20mg of palladium on carbon for 5 hours. Filtered and evaporated, the residue is taken up in diethyl ether and the desired product is obtained after filtration.

Melting point: 205 deg.C and 208 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 57.824.858.439.65

Found value 57.804.898.279.31

Example 25: {3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] phenyl } ethanone

Melting point: 170 ℃ and 172 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 60.325.067.828.95

Found value 60.525.247.718.91

Example 26: 3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] benzoic acid methyl ester

Melting point: 223 ℃ 227 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 57.744.857.488.56

Found value 57.495.027.318.37

Example 27: 3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazin-7-yl) oxy ] benzoic acid

300mg of the product of example 26 are suspended in 5ml of 1N NaOH. After stirring at reflux for 1 hour, the reaction mixture was acidified with 1N hydrochloric acid and filtered to obtain the desired product.

Melting point: 271 plus 274 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 56.664.477.778.90

Found value 56.584.687.708.84

Example 28: 4-methyl-7-phenoxy-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine 1, 1-dioxide step a: 7-methoxy-4H-1, 2, 4-benzothiadiazine 1, 1-dioxide

3.0g of 2-amino-5-methoxybenzenesulphonamide are stirred in 50ml of toluene overnight at 80 ℃ in the presence of 1.31g of formamidine hydrochloride and 2.27ml of triethylamine. Toluene was distilled off in vacuo. The residue was added to water and the precipitate was filtered off.

Melting point: 253 temperature 257 deg.C

And B: 7-methoxy-4-methyl-4H-1, 2, 4-benzothiadiazine 1, 1-dioxide

2.88g of the product obtained in the above step are added portionwise to 9ml of DMF suspension containing 570mg of a 60% NaH dispersion in mineral oil. The mixture was stirred for 30 minutes until a black solution was obtained. Then 929. mu.l of methyl iodide was added dropwise thereto. After stirring for another 1 hour, the reaction mixture was precipitated by adding water. The precipitate is filtered off and washed with water and then with diethyl ether to give the desired product.

Melting point: 205 ℃ C

And C: 7-methoxy-4-methyl-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine 1, 1-dioxide

1.19g of sodium borohydride were added to a suspension of 2.37g of the product of the above step in 40ml of ethanol. The mixture gradually became homogeneous. After 1 hour of reaction at room temperature, the mixture was cooled in an ice bath and neutralized by addition of 1N HCl. The white precipitate was stirred for 15 minutes and the title compound was filtered off.

Melting point: 126-

Step D: 4-methoxy-3, 4-dihydro-2H-1, 2, 4-benzothiadiazin-7-ol 1, 1-dioxide

79.3mmol of boron tribromide were added dropwise, under a nitrogen atmosphere, to a suspension of 200ml of dichloromethane containing 2g of the product obtained in the above step, which was maintained at-60 ℃. The temperature was maintained for 1 hour, then warmed to room temperature and stirred overnight. After cooling the reaction mixture in an ice bath, 100ml of water were added and the two-phase system was stirred vigorously. The resulting suspension was filtered. The obtained solid is washed by water, then washed by ether and dried to obtain the target product.

Melting point: 168-

Step E: 4-methyl-7-phenoxy-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine 1, 1-dioxide

The desired product was prepared according to the procedure described in step E of example 1, using the compound described in the previous step as starting material.

Melting point: 141 ℃ 145 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 57.924.869.6511.04

Found value 57.974.959.4511.36

The compounds of examples 29-32 were obtained according to the procedure described for example 28, using the appropriate starting materials.

Example 29: 4-Ethyl-7-phenoxy-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine 1, 1-dioxide

Melting point: 179 plus 181 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 59.195.309.2010.53

Found value 59.005.319.0710.53

Example 30: 4-propyl-7-phenoxy-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine 1, 1-dioxide

Melting point: 143 ℃ C. (145 ℃ C.)

Elemental microanalysis:

C％ H％ N％ S％

calculated value 60.365.708.8010.07

Found value 60.755.748.6210.15

Example 31: 3- [ (4-Ethyl-1, 1-dioxide-3, 4-dihydro-2H-1, 2, 4-benzothiadiazin-7-yl) oxy ] benzonitrile

Melting point: 143 ℃ C. and 146 ℃ C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 58.344.5912.769.74

Found value 58.714.6812.449.49

Example 32: 4-Ethyl-7- (3-methoxyphenoxy) -3, 4-dihydro-2H-1, 2, 4-benzothiadiazine 1, 1-dioxide

Melting point: 91-93 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 57.475.438.389.59

Found value 57.175.408.019.41

Example 33: 7-phenoxy-3, 4-dihydro-2H-1, 2-benzothiazine 1, 1-dioxides

Step A: 6-methoxy-2- (2-oxopropyl) -1, 2-benzisothiazol-3 (2H) -one 1, 1-dioxide

360mg of 6-methoxy-1, 1-dioxide-1, 2-dihydro-benzo [ d ] isothiazol-3-one are added in portions to a suspension of 72mg of a 60% NaH dispersion in mineral oil in 1.6ml of anhydrous dimethylformamide. After stirring at room temperature for 30 minutes, the reaction mixture became homogeneous, to which 162. mu.l of chloroacetone was added. The reaction mixture was heated at 110 ℃ for 30 minutes. It was allowed to cool to room temperature and then water was added to precipitate the mixture. The precipitate is filtered off, washed several times with water, filtered off with suction and dried in vacuo.

Melting point: 185 deg.C and 191 deg.C

And B: 2-acetyl-7-methoxy-2H-1, 2-benzothiazin-4-ol 1, 1-dioxide

An ethanol solution of sodium ethoxide was prepared by dissolving 1.08g of sodium in 23ml of ethanol under reflux. The temperature of the solution was lowered to 40 ℃ and 6.30g of the product of step A were added with stirring. The reaction mixture thickened. 5ml of ethanol was added with stirring, and the mixture was heated at 50 to 55 ℃ for 10 minutes. The reaction mixture was cooled in an ice bath, acidified with 3N HCl and the yellow precipitate formed filtered off.

Melting point: 162- & ltSUB & gt 166- & lt/SUB & gt

And C: 7-methoxy-2, 3-dihydro-4H-1, 2-benzothiazine-4, 4-ethylenedioxy-1, 1-dioxide

5.35g of the product obtained in the preceding step, 200mg of p-toluenesulfonic acid and 5.6ml of ethylene glycol are stirred under reflux in 200ml of benzene in a round-bottom flask fitted with a Dean-Stark apparatus. After refluxing for 72 hours, the benzene was distilled off in vacuo. The residue was dissolved in ethyl acetate and the organic phase was washed with water and then with saturated NaCl. Drying, filtration and evaporation gave an oil which was crystallized from diethyl ether/isopropyl ether.

Melting point: 100-110 DEG C

Step D: 7-methoxy-2, 3-dihydro-4H-1, 2-benzothiazin-4-one 1, 1-dioxide

A solution of 2.63g of the product of the above step in a mixture of 50ml of methanol and 50ml of 3N HCl is stirred for 15 minutes at reflux. The methanol was distilled off in vacuo and the aqueous phase was extracted with diethyl ether. The organic phase was dried and treated with bone char. Filtered and evaporated, the residue was taken up in isopropyl ether and the solid was filtered.

Melting point: 124 ℃ to 127 DEG C

Step E: 7-methoxy-3, 4-dihydro-2H-1, 2-benzothiazine 1, 1-dioxide

1.77g of the product of the above step in 40ml of acetic acid were hydrogenated at 5 bar and 70 ℃ in the presence of 1.75g of 10% Pd/C. The mixture was allowed to return to room temperature and the catalyst was filtered off. The filtrate was evaporated to dryness and the residue was chromatographed on silica gel using 95/5 dichloromethane/ethyl acetate system as eluent to give the desired product.

Melting point: 144 ℃ C. (145 ℃ C.)

Step F: 3, 4-dihydro-2H-1, 2-benzothiazin-7-ol 1, 1-dioxide

14.1ml of 1M BBr₃To a solution of 1g of the product of the above step in 45ml of dichloromethane cooled to-35 ℃. The mixture was warmed to room temperature. After stirring at room temperature for 3 hours, the reaction mixture was poured into water at 5 ℃ and extracted with ethyl acetate. The organic phases were combined, washed with saturated NaCl, dried, filtered and evaporated. A solid was obtained, which was added to a small amount of isopropyl ether. The title compound was filtered off.

Melting point: 173 ℃ 177-

Step G: 7-phenoxy-3, 4-dihydro-2H-1, 2-benzothiazine 1, 1-dioxides

The compound described in the above step was used as a starting material, and the desired product was obtained by the method described in example 1, step E.

Melting point: 129 ℃ C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 61.074.765.0911.65

Found value 61.404.855.1111.40

The compounds of examples 34-38 were obtained in step E by the method described in example 1 using the appropriate aryl boronic acid.

Example 34: 7- (3-methylthiophenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazine 5, 5-dioxide

Melting point: 160 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 56.335.017.7317.69

Found value 56.334.937.7717.83

Example 35: 7- (3-ethylphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazine 5, 5-dioxide

Melting point: 143 ℃ C. -

Elemental microanalysis:

C％ H％ N％ S％

calculated value 62.775.858.139.31

Found value 62.695.888.19.26

Example 36: 7- (3-isopropylphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine 5, 5-dioxide

Melting point: 171 ℃ 172 ℃

Elemental microanalysis:

C％ H％ N％ S％

calculated value 63.666.197.818.95

Found value 63.636.187.778.69

Example 37: 7- (3-fluorophenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine 5, 5-dioxide

Melting point: 201 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 57.474.528.389.59

Found value 57.064.518.159.63

Example 38: 7- (3-bromophenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazine 5, 5-dioxide

Melting point: 193- & ltSUB & gt 195 & deg.C-

Elemental microanalysis:

C％ H％ N％ S％ Br％

calculated value 48.623.827.098.1120.21

Found value 48.953.827.038.1320.02

Example 39: 3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] benzamide

Will use 1ml of CH₂Cl₂Diluted 0.71mmol of oxalyl chloride are added dropwise to 5ml of CH containing 0.46mmol of the acid obtained in example 27₂Cl₂And 10. mu.l DMF. The mixture was stirred at room temperature for 1 hour 30 minutes and evaporated to dryness. In parallel, 5ml of CH₂Cl₂Saturated with ammonia and then dissolved in 3ml of CH dropwise₂Cl₂The acid chloride obtained as described above. After stirring at room temperature for 2 hours, the reaction mixture was quenched with CH₂Cl₂Dilute and wash the organic phase sequentially with 1N HCl, water and saturated NaCl. Drying (MgSO)₄) After this time, the solvent was removed by evaporation and the residue was triturated in a mixture of isopropyl ether and diethyl ether. The white solid was filtered off to give the desired product.

Melting point: 139-142 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 56.814.7711.698.92

Found value 56.394.8811.228.65

Example 40: 3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] -N, N-dimethylbenzamide

This compound was prepared according to the procedure for example 39, substituting dimethylamine for ammonia in the presence of pyridine.

Melting point: 199 + 202 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 58.95.4610.858.28

Found value 58.975.5410.667.86

Example 41: 3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] -N-methylbenzamide

This compound is prepared by the method of example 39 substituting methylamine for ammonia in the presence of pyridine.

Melting point: 130 ℃ and 135 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 57.885.1311.258.59

Found value 58.085.4510.568.26

Example 42: 3- (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] aniline

The product from example 15 (2.19mmol) was dissolved in a mixture of 100ml ethyl acetate and 50ml ethanol; 100mg of 10% palladium on carbon was added and the mixture was hydrogenated at atmospheric pressure for 1 hour. The catalyst is filtered off, the filtrate is evaporated to dryness and the residue is precipitated in diethyl ether to obtain the desired product after filtration.

Melting point: 221-226 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 57.995.1712.689.68

Found value 57.905.2812.449.59

Example 43: n- {3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] phenyl } -N- (methylsulfonyl) methanesulfonamide

0.90mmol of triethylamine, one spatula tip of DMAP were added to 0.45mmol of the amine from example 42 in 30ml of CH₂Cl₂To the solution, 0.90mmol of CH 8ml are added dropwise₂Cl₂Diluted methanesulfonic anhydride. After stirring overnight at room temperature, the reaction mixture was washed (1N HCl, saturated NaCl) and dried (MgSO)₄). The two products formed were purified by chromatography on silica gel using CH₂Cl₂ 100％→CH₂Cl₂A gradient of/MeOH 95/5. The first eluted product corresponds to the di-sulfonylated title compound. The second product was a mono-mesylated compound corresponding to the product described in the examples below.

Melting point: 214 ℃ and 215 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 44.344.348.6219.73

Found value 44.724.558.5519.84

Example 44: n- [3- (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] phenyl ] methanesulfonamide

As shown in the above examples, the title compound corresponds to the second product isolated by chromatography under the conditions mentioned.

Melting point: 117 ℃ C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 49.864.6810.2615.66

Found value 50.134.7710.0615.34

Example 45: n- {3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] phenyl } ethanesulfonamide

This compound was prepared according to the procedure described for example 43, using the appropriate sulfonyl chloride.

Melting point: 169 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 51.055.009.9215.14

Found value 50.94.979.8715.00

Example 46: n- {3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] phenyl } propane-2-sulfonamide

This compound was prepared according to the procedure described for example 43, using the appropriate sulfonyl chloride.

Melting point: 179 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 52.165.309.6014.66

Found value 51.885.339.8714.71

Example 47: n- {3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] phenyl } benzenesulfonamide

This compound was prepared according to the procedure described for example 43, using the appropriate sulfonyl chloride.

Melting point: 142 ℃ C. and 145 ℃ C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 56.044.498.9113.60

Found value 56.334.628.6013.67

Example 48: n- {3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] phenyl } acetamide

This compound was prepared as described in example 43, using acetic anhydride.

Melting point: 251, 253 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 57.895.1311.258.59

Found value 58.165.1811.098.48

Example 49: 3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] benzenesulfonamide

Step A3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazin-7-yl) oxy ] benzenesulfonyl chloride

A solution of 2ml glacial acetic acid and 340. mu.l water was bubbled with SO₂The gas was saturated for 15 minutes. At the same time, a solution of 1.51mmol of the amine from example 42 in a mixture of 1.3ml of glacial acetic acid and 2.4ml of concentrated HCl is prepared at 5 ℃. To this solution, 1.7mmol of sodium nitrite dissolved in 1ml of water in advance was added dropwise, and the reaction mixture was stirred at 5 ℃ for 30 minutes. To the SO₂0.6mmol of CuCl was added to the saturated solution₂.2H₂O, cooling the obtained suspension to 5 ℃. The diazonium salt solution prepared above was added dropwise to the latter. The mixture was stirred at 5 ℃ for 1 hour, then for another 1 hour and 30 minutes while warming to room temperature. The reaction mixture was poured into ice and the precipitate was filtered off and washed with water. Drying to obtain the target product, namely beige powder.

Step B3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] benzenesulfonamide

0.48mmol of the product of step A above is stirred in a mixture of 10ml of 28% ammonium hydroxide, 2ml of water and 1ml of acetone at room temperature overnight. A slow transition was observedThe solution gave a cloudy orange solution after overnight. The solution was poured into 1N HCl, which was cooled in an ice bath beforehand. The resulting suspension was stirred for 10 minutes and the crude product was collected by filtration. Purifying by silica gel chromatography with 90/10CH₂Cl₂Acetone mixture as eluent.

Melting point: 197 ℃ at 200 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 48.64.3310.6316.22

Found value 48.814.4910.2316.27

Example 50: 3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] -N-propylbenzenesulfonamide

This compound was obtained by reacting the product of step a, example 49 with a suitable amine.

Melting point: 86-91 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 52.165.309.6014.66

Found value 52.965.309.3314.41

Example 51: 3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] -N-isopropylbenzenesulfonamide

This compound was obtained by reacting the product of step a, example 49 with a suitable amine.

Melting point: 151 ℃ and 155 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 52.165.309.6014.66

Found value 52.415.509.6814.66

Example 52: 3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] phenylphosphonic acid diethyl ester

Under a nitrogen atmosphere, 5.40mmol of the bromine compound of example 38, 16.2mmol of diethyl phosphite, 16.2mmol of triethylamine, 1.62mmol of Pd [ P (Ph) ]₃]₄The mixture was stirred in 4ml DMF at 110 ℃ overnight. The DMF is distilled off, the residue is taken up in ethyl acetate and the organic phase is washed with 1N NaOH, water and saturated NaCl. After drying and evaporation in vacuo, a mixture is obtained which is crystallized from diethyl ether to give the desired product.

Melting point: 148- & lt152- & gt

Elemental microanalysis:

C％ H％ N％ S％

calculated value 53.095.576.197.09

Found value 53.085.646.106.95

Example 53: 3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazin-7-yl) oxy ] phenylphosphonic acid ethyl ester

0.66mmol of the product from example 52 are stirred in 3ml of 1N NaOH for 8 hours at 70 ℃. The reaction solution was acidified with 1N HCl and the white precipitate was filtered off to obtain the desired product.

Melting point: 177-

Elemental microanalysis:

C％ H％ N％ S％

calculated value 50.944.996.607.56

Found value 50.855.026.597.65

Example 54: 3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] -benzothiadiazin-7-yl) oxy ] phenylphosphonic acid

Acetonitrile (20ml), 0.66mmol of the product from example 52 and 1.98mmol of bromotrimethylsilane were stirred at reflux for 1 hour. The solvent and excess reagent were distilled off in vacuo and the residue was taken up in 10ml of methanol. After stirring for 30 minutes, the solution was evaporated to dryness and the residue was added to 1N HCl. Obtaining a gum by adding small amount of CH₂Cl₂Allowing it to crystallize. The target product is recovered by filtration.

Melting point: 166 ℃ and 169 ℃ of-

Elemental microanalysis:

C％ H％ N％ S％

calculated value 48.494.327.078.09

Found value 48.344.297.008.06

Example 55: 7- (3-methylphenoxy) -3, 4-dihydro-2H-1, 2-benzothiazine 1, 1-dioxide

The title compound was prepared by coupling the product obtained in step F, example 33, with 3-methylphenyl-boronic acid according to the procedure described in step E, example 1.

Melting point: 116 ℃ C. and 118 ℃ C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 62.265.234.8411.08

Found value 62.695.174.9410.90

The compounds of examples 56-61 were prepared according to the procedure described for example 28, using ethyl iodide in step B and the appropriate aryl boronic acid in step E.

Example 56: 4-Ethyl-7- [ (3-methylthio) phenoxy ] -3, 4-dihydro-2H- [1, 2, 4] -benzothiadiazine 1, 1-dioxide

Melting point: 127 ℃ C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 54.835.187.9918.30

Found value 54.805.167.9718.22

Example 57: 4-Ethyl-7- (3-methylphenoxy) -3, 4-dihydro-2H- [1, 2, 4] benzothiadiazine 1, 1-dioxide

Melting point: 72-75 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 60.365.708.8010.07

Found value 60.65.648.829.97

Example 58: n- {3- [ (4-Ethyl-1, 1-dioxide-3, 4-dihydro-2H-1, 2, 4-benzothiadiazin-7-yl) oxy ] phenyl } methanesulfonamide

Melting point: 165-

Elemental microanalysis:

C％ H％ N％ S％

calculated value 48.354.8210.5716.13

Found value 48.745.0210.3916.22

Example 59: 1- {3- [ (4-Ethyl-1, 1-dioxide-3, 4-dihydro-2H-1, 2, 4-benzothiadiazin-7-yl) -oxy ] phenyl } ethanone

Melting point: 164 ℃ and 166 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 58.945.248.099.26

Found value 59.065.247.818.88

Example 60: ethyl-7- (3-thienyloxy) -3, 4-dihydro-2H-benzo [1, 2, 4] thiadiazine 1, 1-dioxide

Melting point: 152 ℃ and 154 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 50.304.559.0320.66

Found value 50.264.428.9220.97

Example 61: 7- (3, 4-dimethylphenoxy) -4-ethyl-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine 1, 1-dioxide

Melting point: 109 ℃ and 111 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 61.426.068.439.65

Found value 61.376.098.259.36

Example 62: 3- [ (4-Ethyl-1, 1-dioxide-3, 4-dihydro-2H-1, 2, 4-benzothiadiazin-7-yl) oxy ] aniline

This compound was obtained by reducing the nitro product of example 15 according to the procedure described for example 42.

Melting point: 128-132 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 56.415.3713.1610.04

Found value 56.845.5312.8910.17

Example 63: n- {3- [ (4-Ethyl-1, 1-dioxide-3, 4-dihydro-2H-1, 2, 4-benzothiadiazin-7-yl) oxy ] phenyl } -1, 1, 1-trifluoromethane-sulphonamide

This compound was obtained by reacting the amine of example 62 with trifluoromethanesulfonic anhydride under the conditions described in example 43.

Melting point: 136 ℃ and 138 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 42.573.579.3114.21

Found value 43.243.769.1014.33

Example 64: 1- {3- [ (4-Ethyl-1, 1-dioxide-3, 4-dihydro-2H-1, 2, 4-benzothiadiazin-7-yl) oxy ] phenyl } ethanol

0.42mmol of NaBH was added to 0.8ml of absolute ethanol in portions₄Then 0.21mmol of the product from example 59 are added. The solution was stirred at room temperature for 20 minutes. The reaction mixture was cooled in an ice bath and acidified by dropwise addition of 1N HCl. The reaction mixture was extracted with ethyl acetate, the organic phase was washed (water, saturated NaCl) and dried (MgSO)₄) And evaporating to obtain the target product.

Melting point: 60 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 58.605.798.049.20

Found value 58.575.717.758.97

Example 65: 3- [ (4-Ethyl-1, 1-dioxide-3, 4-dihydro-2H-1, 2, 4-benzothiadiazin-7-yl) oxy ] boronic acid

The compound was obtained according to the procedure described in example 27.

Melting point: 228 ℃ and 230 DEG C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 55.164.638.049.20

Found value 54.894.697.899.32

Example 66: 3- [ (4-Ethyl-1, 1-dioxide-3, 4-dihydro-2H-1, 2, 4-benzothiadiazin-7-yl) oxy ] benzamide

This compound was prepared by aminating the product of example 65 according to the procedure described for example 39.

Melting point: 85-90 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 55.324.9312.109.23

Found value 55.215.1311.528.85

Example 67: 3- [ (4-Ethyl-1, 1-dioxide-3, 4-dihydro-2H-1, 2, 4-benzothiadiazin-7-yl) oxy ] -N, N-dimethylbenzamide

This compound was prepared by aminating the product of example 65 according to the procedure described in example 40.

Melting point: 65-70 deg.C

Elemental microanalysis:

C％ H％ N％ S％

calculated value 57.585.6411.198.54

Found value 57.545.7810.558.20

Example 68: 3-phenoxy-6, 6a, 7, 8, 9, 10-hexahydropyrido [2, 1-c ] [1, 2, 4] benzothiadiazine 5, 5-dioxide

This compound was prepared according to the procedure described in example 1, using 5-chloropropionyl chloride in step A.

Melting point: 211 ℃ C. (213 ℃ C.)

Elemental microanalysis:

C％ H％ N％ S％

calculated value 61.805.498.489.70

Found value 61.615.458.359.79

Pharmacological investigation of the products of the invention

AMPA-induced excitatory Current Studies in Xenopus oocytes

a-method:

mRNA was prepared from the cerebral cortex of male Wistar rats using guanidinium thiocyanate/phenol/chloroform method. Separation of poly (A) by chromatography on low-dT cellulose⁺) mRNA and was injected at a level of 50 ng/oocyte. The oocytes were cultured at 18 ℃ for 2-3 days to allow receptor expression, and then stored at 8-10 ℃.

Electrophysiology was recorded in plexiglas ® chamber by the two-electrode "voltage-clamp" method at 20-24 ℃ in OR2 medium (j.exp.zoom., 1973,184321- & 334) placed in a bath used as a reference.

All compounds were applied via the culture medium and the current was measured at the end of the application. AMPA is used at a concentration of 10. mu.M. For each compound studied, the concentration that produces a current intensity (5-50nA) two-fold (EC2X) or five-fold (EC5X) greater than that induced by AMPA alone was determined.

b-results:

the compounds of the invention potentiate the excitatory effects of AMPA to a large extent and their activity is clearly superior to that of the comparative compounds. Specifically, the compound of example 3 had an EC2X of 0.8. mu.M, an EC5X of 3.6. mu.M, an EC2X of 1.4. mu.M, and an EC5X of 4.5. mu.M.

Pharmaceutical composition

A formulation for preparing 1000 tablets each containing 100mg of the compound of example 1

100g of the Compound of example 1

Hydroxypropyl cellulose 2g

Wheat starch 10g

Lactose 100g

Magnesium stearate 3g

3g of talc.

Claims (14)

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

wherein:

R₁represents an aryl group or a heteroaryl group,

R₂represents a hydrogen atom, and is represented by,

a represents CR₄R₅Or NR₄，

R₃Represents a hydrogen atom, a straight chain or a branched chain (C)₁-C₆) Alkyl or (C)₃-C₇) A cycloalkyl group,

R₄represents a hydrogen atom or a linear or branched chain (C)₁-C₆) Alkyl, or

A represents a nitrogen atom and is adjacent to-CHR₃The radicals forming the ringWherein m represents 1 or2,

R₅represents a hydrogen atom, and is represented by,

it should be understood that:

● "aryl" means a phenyl or naphthyl group, optionally substituted by one or more identical or different groups selected from halogen, straight or branched (C) optionally substituted by one or more hydroxyl groups₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Perhaloalkyl, straight or branched chain (C)₁-C₆) Alkoxycarbonyl, straight or branched (C)₁-C₆) Alkylthio, carboxyl, straight or branched chain (C)₁-C₆) Acyl, straight or branched (C)₁-C₆) Perhaloalkoxy, hydroxy, cyano, nitro, optionally substituted by one or more straight or branched chains (C)₁-C₆) Alkyl or straight or branched chain (C)₁-C₆) Amino substituted by acyl, optionally substituted by one or more straight or branched chains (C)₁-C₆) Aminocarbonyl substituted by alkyl, optionally substituted by one or more linear or branched chains (C)₁-C₆) Alkyl-substituted aminosulfonyl, mono-or di- ((C)₁-C₆) Alkylsulfonyl) amino, mono-OR di- (trifluoromethylsulfonyl) amino, PO (OR)_a)(OR_b) Or benzyloxy, wherein, R_aAnd R_bMay be the same or different and represents a hydrogen atom or a linear or branched chain (C)₁-C₆) Alkyl radical

● "heteroaryl" refers to thienyl.

2. The method ofA compound of the formula (I) as claimed in claim 1, wherein OR₁The radical is in the b position of the phenyl radical carrying it.

3. A compound of formula (I) according to claim 1, wherein R₁Represents phenyl, optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C) optionally substituted by one or more hydroxyl groups₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Perhaloalkyl, straight or branched chain (C)₁-C₆) Alkoxycarbonyl, straight or branched (C)₁-C₆) Alkylthio, carboxyl, straight or branched chain (C)₁-C₆) Acyl, straight or branched (C)₁-C₆) Perhaloalkoxy, hydroxy, cyano, nitro, optionally substituted by one or more straight or branched chains (C)₁-C₆) Alkyl or straight or branched chain (C)₁-C₆) Amino substituted by acyl, optionally substituted by one or more straight or branched chains (C)₁-C₆) Aminocarbonyl substituted by alkyl, optionally substituted by one or more linear or branched chains (C)₁-C₆) Alkyl-substituted aminosulfonyl, mono-or di- ((C)₁-C₆) Alkylsulfonyl) amino, mono-OR di- (trifluoromethylsulfonyl) amino, PO (OR)_a)(OR_b) Or benzyloxy, wherein, R_aAnd R_bMay be the same or different and represents a hydrogen atom or a linear or branched chain (C)₁-C₆) An alkyl group.

4. A compound of formula (I) according to claim 1, wherein A represents a nitrogen atom and is adjacent to-CHR₃The radicals forming the ringWherein m represents 1 or 2.

5. A compound according to claim 4, wherein m represents 1.

6. A compound of formula (I) according to claim 1 which is 7- (3-methylphenoxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazine 5, 5-dioxide.

7. A compound of formula (I) according to claim 1 which is 3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazin-7-yl) oxy ] benzoic acid.

8. A compound of formula (I) according to claim 1 which is 3- (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazin-7-yl) oxy ] aniline.

9. A compound of formula (I) according to claim 1 which is N- [3- (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazin-7-yl) oxy ] phenyl ] methanesulfonamide.

10. A compound of formula (I) according to claim 1 which is 3- [ (5, 5-dioxide-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 1-c ] [1, 2, 4] benzothiadiazin-7-yl) oxy ] phenyl-phosphonic acid hydrogen ethyl ester.

11. A process for the preparation of a compound of formula (I) as claimed in claim 1 wherein a represents NR₄Or A represents a nitrogen atom and adjacent CHR₃Form a ringWherein m and R₄As defined in claim 1, the first and second,

characterized in that a compound of formula (II) is used as a starting material:

wherein:

R′₁represents a straight chain or branched chain (C)₁-C₆) An alkoxy group,

R′₂represents a hydrogen atom, and is represented by,

the compound is prepared by

(a) Reacting with an acid chloride of formula (III) in a tetrahydrofuran or acetonitrile medium in the presence of a base:

Cl-CH₂-(CH₂)_m-CH₂-COCl (III)，

wherein m is as defined in claim 1, to obtain a compound of formula (IV):

wherein R'₁And R'₂As defined in the present claims,

this compound is then cyclized in basic medium to give the compound of formula (V):

wherein R'₁And R'₂As defined in the claims, m is as defined in claim 1,

reducing the compound, optionally in an alcoholic or dimethylformamide medium, in the presence of sodium borohydride to obtain a compound of formula (VI):

wherein R'₁And R'₂As defined in the claims, m is as defined in claim 1,

treating it with boron tribromide to give a compound of formula (VII):

wherein R is₂And m is as defined in claim 1,

(b) or cyclizing as follows:

^*in the presence of amidines of the formula (VIII)And (2) carrying out cyclization:

wherein R is₃As defined in claim 1, to obtain a compound of formula (IX):

wherein R'₁And R'₂As defined in the claims, R₃As defined in claim 1, the compound:

● to produce a compound of formula (X) by reduction with a metal hydride:

wherein R'₁And R'₂As defined in the claims, R₃As defined in claim 1, the first and second,

● or in alkylating agent R'₄Alkylation with a strong base in the presence of-X,

wherein R'₄Represents a straight chain or branched chain (C)₁-C₆) Alkyl and X represents a halogen atom, and then reduced to produce a compound of formula (XI):

wherein R'₁、R′₂And R'₄As defined in the claims, R₃As defined in claim 1, the first and second,

or

^*Cyclizing in the presence of an aldehyde of formula (XII):

wherein R is₃Obtaining a compound of formula (X) as defined in claim 1, as defined in claim，

Wherein, in the compound of formula (X) or (XI),

a radical R'₁And a group R'₂When it denotes a straight or branched chain (C)₁-C₆) When alkoxy, conversion to hydroxy affords compounds of formula (XIII):

wherein R is₂、R₃And R₄As defined in claim 1, the first and second,

reacting a compound of formula (VII) or (XIII) with a boronic acid compound of formula (XIV):

R₁B(OH)₂ (XIV)

wherein R is₁As defined in claim 1, to obtain the formula (I/a)₁) Or (I/a)₂) Are particular forms of compounds of formula (I):

wherein R is₁、R₂、R₃And R₄As defined in claim 1, the first and second,

wherein R is₁、R₂And m is as defined in claim 1,

optionally for the group R₁A substituent of the formula (I/a)₁) Or (I/a)₂) Optionally subjecting the compound of formula (I/a) to conventional transformation, optionally using conventional purification techniques₁) Or (I/a)₂) Optionally separating into its isomers by conventional separation techniques, and optionally converting into addition salts with pharmaceutically acceptable acids or bases.

A represents CR₄R₅Of radicalsA process for the preparation of a compound of formula (I) as claimed in claim 1 wherein R₄And R₅As defined in claim 1, characterized in that a compound of formula (XV):

wherein:

R′₁represents a straight chain or branched chain (C)₁-C₆) An alkoxy group,

R′₂represents a hydrogen atom, and is represented by,

which is treated with chloroacetone in the presence of dimethylformamide to give the compound of formula (XVI):

wherein R'₁And R'₂As defined in the present claims,

which is rearranged in a basic medium to give a compound of formula (XVII):

wherein R'₁And R'₂As defined in the present claims,

it is deacetylated by heating under reflux in a benzene medium in the presence of an excess of ethylene glycol and a catalytic amount of p-toluenesulfonic acid to give a compound of formula (XVIII):

wherein R'₁And R'₂As defined in the present claims,

which is hydrolyzed in an acidic medium to produce a compound of formula (XIXa):

wherein R is′₁And R'₂As defined in the present claims,

optionally, the nitrogen atom of this compound is optionally protected with a protecting group and then, after treatment with a strong base, with a compound of formula R'₃-treatment of the compound of P,

wherein R'₃Represents a straight chain or branched chain (C)₁-C₆) Alkyl or (C)₃-C₇) Cycloalkyl and P represents a leaving group,

(ii) upon deprotection of the nitrogen atom to produce a compound of formula (XIX' a):

wherein R'₁、R′₂And R'₃As defined in the present claims,

reacting a compound of formula (XIXa) or (XIX' a) represented by formula (XIX):

wherein R'₁And R'₂As defined in the claims and R₃As defined in claim 1:

-carrying out a catalytic reduction to produce a compound of formula (XX):

wherein R'₁And R'₂As defined in the claims and R₃As defined in claim 1, the first and second,

-or by conversion into an alcohol by treatment with a hydride, the hydroxyl group of the resulting compound being converted into a halogen atom by treatment with a suitable reagent, to obtain a compound of formula (XXI):

wherein R'₁And R'₂As defined in the claimsMeaning, R₃And R 'as defined in claim 1'₅Represents a halogen atom, and is a halogen atom,

or with an organomagnesium compound R'₄-MgBr treatment, wherein R'₄Represents a straight chain or branched chain (C)₁-C₆) Alkyl to yield a compound of formula (XIXb):

wherein R'₁、R′₂And R'₄As defined in the claims, R₃A compound of the formula (XIXb), as defined in claim 1

-carrying out a catalytic reduction to obtain a compound of formula (XXII):

wherein R'₁、R′₂And R'₄As defined in the claims, R₃As defined in claim 1, the first and second,

-or its hydroxyl group is converted into a halogen atom by treatment with a suitable reagent, to obtain a compound of formula (XXIII):

wherein R'₁、R′₂And R'₄As defined in the claims, R₃And R 'as defined in claim 1, and'₅Represents a halogen atom, and is a halogen atom,

wherein, in the compounds of the formulae (XX) to (XXIII),

a radical R'₁And a group R'₂When it denotes a straight or branched chain (C)₁-C₆) When alkoxy is present, conversion to hydroxy affords a compound of formula (XXIV):

wherein R is₂、R₃、R₄And R₅As defined in claim 1, the first and second,

reacting a compound of formula (XXIV) with a boronic acid compound of formula (XIV):

R₁B(OH)₂ (XIV)

wherein R is₁Obtaining a compound of formula (I/b), as defined in claim 1, which is a particular form of the compound of formula (I):

wherein R is₁、R₂、R₃、R₄、R₅As defined in claim 1, the first and second,

optionally for the group R₁The compound of formula (I/b) is subjected to a conventional transformation,

optionally purified using conventional purification techniques, optionally separated into its isomers using conventional separation techniques, and optionally converted into addition salts using pharmaceutically acceptable acids or bases.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 as active ingredient together with one or more pharmaceutically acceptable inert, non-toxic excipients or carriers.

14. A pharmaceutical composition according to claim 13 for use as an AMPA modulator comprising a compound according to any one of claims 1 to 10 as active ingredient.