EP1343774A1

EP1343774A1 - 1,1-dioxo-2h-1, 2-benzothiazine-3-carboxamide derivatives, method for preparing same and pharmaceutical compositions comprising same

Info

Publication number: EP1343774A1
Application number: EP01989655A
Authority: EP
Inventors: Jean-Claude Madelmont; Isabelle Giraud; Aurélien VIDAL; Emmanuelle Mounetou; Maryse Rapp; Jean-Claude Maurizis; Pierre Renard; Daniel-Henri Caignard; Jean-Guy Bizot-Espiard
Original assignee: Institut National de la Sante et de la Recherche Medicale INSERM; Laboratoires Servier SAS
Current assignee: Institut National de la Sante et de la Recherche Medicale INSERM; Laboratoires Servier SAS
Priority date: 2000-12-21
Filing date: 2001-12-21
Publication date: 2003-09-17
Also published as: PL361664A1; WO2002050049A1; BR0116424A; US20040063696A1; AU2002228120A1; FR2818641A1; EA200300672A1; CA2432807A1; KR20030086247A; NO20032497D0; NO20032497L; JP2004519442A; CN1481372A; CZ20031972A3; HUP0600065A2; SK9092003A3; FR2818641B1; AR032380A1; MXPA03005556A

Abstract

The invention concerns a compound of formula (I) wherein: (a) represents a single or double bond; R1 represents a hydrogen atom or a hydroxy, alkoxy, acyloxy, alkylsulphonyloxy, arylsulphonyloxy or arylalkoxy group; R2 represents a hydrogen atom or an alkyl group; R3 and R4, identical or different, represent each a hydrogen, a halogen atom or an alkyl, hydroxy or alkoxy group; Ak represents an alkylene chain; R5, R6 and R7, identical or different, represent each an alkyl group, or R5, R6 and R7 together with the nitrogen which bears them, form a saturated or unsaturated nitrogenous heterocycle; X represents a halogen atom; and its optical isomers when they exist.

Description

DERIVATIVES OF 1, 1-DIOXO-2H-1, 2 -BENZOTHIAZINE-3-CARBOXAMIDES, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to new derivatives of 1,1-dioxo-2H-1,2-benzothiazine-3-carboxamides, their preparation process and the pharmaceutical compositions containing them, as well as their use for the treatment of cartilage pathologies.

The anti-inflammatory drugs currently marketed for the treatment of joint pathologies such as arthritis or osteoarthritis generally have a low affinity for the target tissues and require administrations at high doses to obtain the desired therapeutic effect.

These administrations with high doses of active ingredients result in an increase in the frequency of side effects. It is notably known that taking nonsteroidal anti-inflammatory drugs causes significant gastrointestinal toxicity.

It was therefore particularly advantageous to obtain new compounds capable of targeting cartilage tissue in a targeted manner and thus of limiting, or even eliminating, the undesirable effects observed with existing anti-inflammatory drugs.

Derivatives of 1,1-dioxo-2H-1,2-benzothiazine-3-carboxamides as well as their potential use for the treatment of cartilage pathologies have already been described in J. Med. Chem. 1999, 42, 5235-40.

However, these derivatives exhibit only a modest activity on the expression of proteoglycans which protect cartilage.

The new compounds, objects of the present invention, retain the very strong affinity for the cartilaginous tissues already described for the derivatives of the prior art but, moreover, they have protective properties of cartilage very clearly superior to those of the compounds already described, which, given the proximity of their structures, was completely unpredictable. These properties therefore make the compounds of the invention extremely advantageous for the treatment of pathologies such as arthritis or osteoarthritis.

More specifically, the present invention relates to the compounds of formula (I):

in which:!> rrr- represents a single or double bond,

* P represents a hydrogen atom or a hydroxy group, linear or branched (Ci-C ₆ ) alkoxy, linear or branched acyloxy (CrC ₆ ), linear or branched alkylsulfonyloxy (Ci-C ₆ ), arylsulfonyloxy or arylalkoxy (-C _Ô ) linear or branched,

^> R ₂ represents a hydrogen atom or a linear or branched (-C _Ô ) alkyl group,

^ R ₃ and R, identical or different, each represent a hydrogen atom, a halogen atom or a linear or branched (-C _Ô ) alkyl group, hydroxy or alkoxy

(CrC ₆ ) linear or branched,

^ Ak represents a linear or branched alkylene chain (Cι-C ₆ ),

**> R ₅ , R ₆ and R ₇ , identical or different, each represent a linear or branched (-C _Ô ) alkyl group, or else R ₅ , R ₆ and R ₇ , taken together with the nitrogen atom who wear them, form a saturated or unsaturated nitrogen heterocycle, ^ X represents a halogen atom,

as well as its optical isomers when they exist,

with the exclusion of the compounds for which, simultaneously, ^ _- represents a double bond, Ri represents a hydroxy group, R, R ₅ and R _Ô , each represent a methyl group, R ₃ and R each represent a hydrogen atom , and Ak represents a group - (CH ₂ ) -.

By saturated or unsaturated nitrogen heterocycle is understood to mean a 5- to 7-membered, saturated or unsaturated, aromatic or non-aromatic monocyclic group containing one, two or three heteroatoms, one of these heteroatoms being the nitrogen atom, and the additional heteroatom (s) possibly present being chosen from oxygen, nitrogen or sulfur atoms, it being understood that the nitrogen heterocycle can be optionally substituted by one or more groups, identical or different, alkyl (Cι-C ₆ ) linear or branched. The preferred nitrogen heterocycles are the pyridyl and piperidyl groups N-substituted by a linear or branched (C Cβ) alkyl group.

The preferred compounds of formula (I) are those for which R ₂ represents a linear or branched alkyl group (Cι-C ₆ ).

The preferred compounds of formula (I) are those for which X represents an iodine atom.

According to an advantageous variant, the preferred compounds of the invention are those for which R ₆ and R ₇ , identical or different, each represent a linear or branched (C ₂ - C ₆ ) alkyl group.

Among the preferred compounds of the invention, mention may be made of iodide of {3 - [(4-hydroxy-2-methyl-l, l-dioxo-2H-l, 2-benzothiazin-3-yl) -carbonylamino] -propyl} - diethylmethylammonium. The invention also extends to a process for preparing the compounds of formula (I) characterized in that a compound of formula (H) is reacted:

in which R ₃ and Ri have the same meaning as in formula (I), in the presence of a base, to lead to the compound of formula (lu):

in which R ₃ and R ^ are as defined above,

which is reacted, when desired, with a compound of formula (IN): R ' ₂ -Y _! (IV) in which R ' ₂ represents a linear or branched (Cι-C ₆ ) alkyl group, and Y _! represents a classic leaving group of organic chemistry,

to lead to the compound of formula (N):

in which R ' ₂ , R ₃ and R ₄ are as defined above,

compounds of formula (HI) or (N) which are reacted, when desired, either with a compound of formula (NI):

R'ι - Y ₂ (NI) in which R'i represents a linear or branched (Ci-C ₆ ) alkyl group, linear or branched acyl (Cι-C ₆ ), linear or branched alkylsulfonyl (Ci-C ₆ ), linear or branched arylsulfonyl or arylalkyl (Ci-C ₆ ), and Y ₂ represents a leaving group customary in organic chemistry,

to lead to the compound of formula (VIT):

in which R '_1; R, R ₃ and R ₄ are as defined above,

either with an appropriate reduction agent, to yield the compound of formula (NUI):

in which R, R ₃ and R ₄ are as defined above,

which we possibly transform:

* or, by elimination, as a compound of formula (IX), under conventional conditions of organic chemistry:

in which R ₂ , R ₃ and Rj are as defined above, which, if desired, is reduced to a compound of formula (X):

in which R ₂ , R ₃ and i are as defined above,

* either by reaction with a compound of formula (NI), to yield the compound of formula (XI):

in which R'i, R ₂ , R and i are as defined above,

the compounds of formulas (IH), (N), (NU), (Nm), (IX), (X) and (XI) forming the set of compounds of formula (XH):

in which rrr, Ri, R ₂ , R ₃ and i have the same meaning as in formula (I),

which we transform into a compound of formula (XIII)

in which R ₁₃ R ₂ , R ₃ , R ₄ are as defined above, Ak has the same meaning as in formula (I), and Z represents either a group X as defined in formula (I), or an NR'sR'e group in which R ' ₅ and R' ₆ , identical or different, each represent a linear or branched (Ci-C ₆ ) alkyl group, or together form a saturated or unsaturated, non-aromatic nitrogen heterocycle,

that we put in reaction,

0 or, when Z represents a group NR ' ₅ R' ₆ as defined above, with a compound of formula (XIV):

R ' ₇ -X (XIV) in which R' ₇ represents a linear or branched (Cι-C ₆ ) alkyl group, and X has the same meaning as in formula (I),

to lead to the compound of formula (la), special case of the compounds of formula (I):

in which Ri, R ₂ , R ₃ , R ₄ , Ak, R ' ₅ , R' ₆ , R ' ₇ and X are as defined above,

0 or, when Z represents a group X as defined above, with a compound of formula (XV):

NR " ₅ R" ₆ R " ₇ (XV) in which R" ₅ , R " ₆ and R" form together with the nitrogen atom which carries them an aromatic nitrogen heterocycle,

to lead to the compound of formula (Ib), special case of the compounds of formula (I): in which Ri, R ₂ , R, i, Ak, R " ₅ , R" ₆ , R " ₇ and X are as defined above,

compounds of formula (la) and (Ib) which constitute the set of compounds of formula (I), which are purified, if necessary, according to a conventional purification technique, and from which the optical isomers are separated, where appropriate where appropriate, using a conventional separation technique.

The compound of formula (H) is obtained from the compound of formula (XVI):

in which R ₃ and R ₄ have the same meaning as in formula (I),

according to the method described in J. Med. Chem. 1999, 42, 5235-40.

The derivatives of the present invention have demonstrated in biological studies an enhanced tropism for the cartilage tissues. These molecules have, on the other hand, properties on the cartilage which makes them particularly useful for the treatment of pathologies such as osteoarthritis and arthritis.

The invention also extends to pharmaceutical compositions containing as active principle at least one compound of formula (I) with one or more inert, non-toxic and pharmaceutically acceptable vehicles. Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those which are suitable for oral, parenteral (intravenous or subcutaneous), nasal administration, simple or coated tablets, sublingual tablets, capsules, tablets, the suppositories, creams, ointments, dermal gels, injections, oral suspensions, etc.

The useful dosage is adaptable according to the nature and severity of the disease, the route of administration as well as according to the age and weight of the patient. This dosage varies from 0.5 mg to 2 g per 24 hours in one or more doses.

The following examples illustrate the invention but do not limit it in any way.

The starting materials used are known products or prepared according to known procedures.

The structures of the compounds described in the examples were determined according to the usual spectroscopic techniques (infrared, NMR, mass spectrometry (MS)).

EXAMPLE 1 Iodide of {3-iï4 ~ vdroxy-2-méthvMα-dioxo-2H-1.2-benzQthiaziιι-3- vDcarbonylaminQlpro yπdiéthvIméthvIammonimn

Stage A: N- [3- (diethylamino) -propyl] -4-hydroxy-2-methyl-l, l-dioxo-2Α-l, 2-benzothiazine-3-carboxamide

A suspension of 10 mmol of methyl 4-hydroxy-2-methyl-1,1-dioxo-2H-1,2-benzothiazine-3-carboxylate (the preparation of which is described in J. Med. Chem. 1999, 42, 5235-40) and 11 mmol of 3- (diethylamino) -propylamine in xylene is brought to reflux under an inert atmosphere for 18 hours. After cooling and evaporation, the residue obtained is purified by chromatography on silica (eluent: ethanol gradient in dichloromethane ranging from 0 to 50%, then dichloromethane / ethanol / ammonia 50/48/2), then recrystallized to yield the product expected as a beige solid. Melting point: 107-110 ° C

Stage B: β-iodide - [(4-hydroxy-2-methyl-l, l-dioxo-2H-l, 2-benzothiazin-3-yl) carbonylamino] propyl} diethylmethylammonium To 10 mmol of the compound described in stage A above, suspended in acetone, 2.5 ml of methyl iodide are added, then the reaction mixture is brought to reflux under an inert atmosphere for 6 hours. After returning to ambient temperature and evaporation of the mixture, the residue obtained is filtered, washed, dried and then recrystallized, to yield the expected product in the form of a beige solid.

Melting point: 169-171 ° C

EXAMPLE 2 Iodide of 3-f (4-hvdroxy-2-methyl-l, l-dîoxo-2H-l., 2-benzothiaziιι-3- yl> cajbonvIaminQlpropylHriethylammonmm

The expected product is obtained according to the process described in Stage B of Example 1, starting from the compound described in Stage A of Example 1 and ethyl iodide.

Melting point: 204-206 ° c

EXAMPLE 3 {4-K4-hvdrQxγ-2-methyl-1,1-dioxo-2H-1,2,2-benzothiazm-3-yl arbonylammolbiitylltrimethylaromoiimn iodide

Stage A: 4- (Dimethylamino) -butyronitrile

To a suspension of 10 mmol of dimethylamine hydrochloride, 15 mmol of potassium carbonate and 1 mmol of potassium iodide in acetonitrile is added, at 50 ° C., a solution of 10 mmol of 4-bromobutyronitrile in same solvent. The mixture is then kept at this temperature for 16 hours. After evaporation, the residue obtained is taken up in 1N hydrochloric acid. The aqueous phase is washed with ether, neutralized with a 1N sodium hydroxide solution and reextracted several times with ether. The various organic phases are then combined, dried, filtered and evaporated to yield the expected product in the form of a dark oil.

Stage B: 4- (Dimethylamino) -butylamine To a suspension of lithium aluminum hydride (26.7 mmol) in ether is added, under an inert atmosphere, at 0 ° C, a solution of the compound obtained in the preceding stage A (17.8 mmol) in ether. The mixture is then brought to room temperature and left stirring at this temperature for 1 hour. After hydrolysis according to the Mihaïlovic method (1 g of water, 1 g of 15% sodium hydroxide and 3 g of water), the reaction medium is filtered through celite. Evaporation of the filtrate under reduced pressure makes it possible to isolate the expected product, in the form of a clear oil.

Stage C: N- [4- (dimethylamino) -butyl] -4-hydroxy-2-methyl-1,1-dioxo-2H-1,2,2-benzothiazine-3-carboxamide

The expected product is obtained according to the process described in stage A of Example 1, from methyl 4-hydroxy-2-methyl-1,1-dioxo-2H-1,2,2-benzothiazine-3-carboxylate ( whose preparation is described in J. Med. Chem. 1999, 42, 5235-40) and of the compound obtained in stage B above. SM (electrosprav) m / z: 354, 13 [M + f]

Stage D: {4 - [(4-hydroxy-2-methyl-l, l-dioxo-2Η.-l, 2-benzothiazin-3-yl) carbonylamino] butyl} trimethylammonium iodide

The expected product is obtained according to the process described in stage B of Example 1 from the compound described in preceding stage C and methyl iodide. Melting point: 240-242 ° C

EXAMPLE 4 {3 ~ iodide [(4-hvdrQxy-2-methyl-l, l-diQXQ-2H-l, 2-benzothiazin-3- yI) carbonyIamino1) ro | j> yl} pyridinium

Stage A: N- [3-hydroxy-propyl] -4-hydroxy-2-methyl-l, l-dioxo-2Η.-l, 2-benzothiazine-3-carboxamide

The expected product is obtained according to the process described in stage A of Example 1, from methyl 4-hydroxy-2-methyl-1,1-dioxo-2H-1,2,2-benzothiazine-3-carboxylate (whose preparation is described in J. Med. Chem. 1999, 42, 5235-40) and 3-amino-1-propanol.

Stage B: N- [3-iodo-propyl] -4-hydroxy-2-methyl-l, l-dioxo-2Α-l, 2-benzothiazine-3-carboxamide

To 15 mmol of triphenylphosphine and 15 mmol of imidazole in solution in an ether / acetonitrile mixture 75/25 are added, in portions and at 0 ° C., 15 mmol of iodine, then 10 mmol of the compound described in the preceding stage in ether solution. The reaction mixture is then stirred at room temperature for 2 hours, then hydrolyzed and extracted with ethyl acetate. The combined organic phases are washed, dried, filtered and then concentrated. The residue obtained is purified by chromatography on silica (eluent: dichloromethane) to yield the expected product.

Stage C: {3 - [(4-hydroxy-2-methyl-1,1-dioxo-2H-1,2,2-benzothiazin-3-yl) carbonylamino] propyl} pyridinium iodide

The expected product is obtained from the compound described in the previous stage, according to the process described in stage B of Example 1, replacing the methyl iodide with pyridine.

EXAMPLE 5 I-iodide of B-ff4-methoxy-2-methvMJ-dioxo-2H-1,2-benzothiazm-3-vI) carbonylam olpropyI> trimethylam oaium

Stage A: methyl 4-Methoxy-2-methyl-l, l-dioxo-2Α-l, 2-benzothiazine-3-carboxylate

A suspension of 10 mmol of methyl 4-hydroxy-2-methyl-1,1-dioxo-2H-1,2-benzothiazine-3-carboxylate (the preparation of which is described in J. Med. Chem. 1999, 42, 5235-40), 20 mmol of potassium carbonate and 15 mmol of dimethyl sulfate in acetone is stirred at room temperature under an inert atmosphere for 24 hours. After filtration, the reaction mixture is treated with 1 ml of concentrated ammonia, then evaporated. The residue obtained is taken up in ethyl acetate and washed with water. The sentence organic is then dried, filtered and evaporated. The oily residue obtained is then purified by chromatography on silica (eluent: dichloromethane) to yield the expected product in the form of a clear oil which crystallizes. Melting point: 79-80 ° C

Stage B: N- [3- (dimethylamino) -propyl] -4-methoxy-2-methyl-l, l-dioxo-2Α-l, 2-benzothiazine-3-carboxamide

The expected product is obtained according to the method described in stage A of Example 1 from the compound described in preceding stage A and from 3- (dimethylamino) -propylamine. SM (electrospray) m / z: 354, 15 [M + f j

Stage C: {3 - [(4-methoxy-2-methyl-l, l-dioxo-2Α-l, 2-benzothiazin-3-yl) carbonylamino] propyl} trimethylammonium iodide

The expected product is obtained according to the process described in stage B of Example 1 starting from the compound described in preceding stage B and methyl iodide. SM (electrospray) m / z: 368.15 [M]

EXAMPLE 6 {3 - [(4-aetoxy-2-methvI-U-dioxo-2H-1,2,2-benzothiazm-3-yl) iodide) carbonvIamιnolpropyI} trimethvIammonium

Stage A: Methyl 4-acetoxy-2-methyl-l, l ~ dioxo-2Yl-l, 2-benzothiazine-3-carboxylate

A 10 mmol of methyl 4-hydroxy-2-methyl-1,1-dioxo-2H-1,2-benzothiazine-3-carboxylate (the preparation of which is described in J. Med. Chem. 1999, 42, 5235- 40) in solution in ether are added 11.5 mmol of pyridine, then, at 0 ° C, 11.5 mmol of acetyl chloride. The reaction mixture is then stirred at room temperature for 5 hours, then hydrolyzed and extracted with ethyl acetate. The combined organic phases are washed, dried, filtered and then concentrated. The residue obtained is purified by chromatography on silica (eluent: dichloromethane) to yield the expected product. Stage B: (3 - [(4-acetoxy-2-methyl-l, l-dioxo-2Α-l, 2-benzothiazin-3-yl) carbonylamino] propyl} trimethylammonium iodide

The expected product is obtained according to the process described in stages B and C of Example 5, starting from the compound described in the preceding stage.

EXAMPLE 7; Io ure ei --- ^ -} - ^ benzQthiazin-3-yI) carbonylaTO

Stage A: methyl 4-Hydroxy-2-methyl-l, l-dioxo-3,4-dihydro-2Η.-l, 2-benzothiazine-3-carboxylate

A 10 mmol of methyl 4-hydroxy-2-methyl-1,1-dioxo-2H-1,2-benzothiazine-3-carboxylate (the preparation of which is described in J. Med. Chem. 1999, 42, 5235- 40) in methanol are added 10 mmol of sodium borohydride, then the reaction mixture is stirred for 2 hours. After evaporation of the solvent, the residue obtained is hydrolyzed and then extracted with ethyl acetate. The combined organic phases are washed, dried, filtered and then concentrated. The residue obtained is purified by chromatography on silica (eluent: dichloromethane) to yield the expected product.

Stage B: {3 - [(4-hydroxy-2-methyl-l, l-dioxo-3,4-dihydro-2Α-l, 2-benzothiazin-3-yl) carbonylamino] propyl} iodide trimethylammonium

EXAMPLE 8: iodide of f3-14-aetoxy-2-methvI-ia-dioxo-3,4-dihvdro-2H-l, 2-benzothiazin-3-yl) carbonyIamino1propyIΗrimêthvIammonium

Stage A: methyl 4-Acetoxy ~ 2-methyl-l, l-dioxo-3,4-dihydro-2Η.-l, 2-benzothiazine-3-carboxylate The expected product is obtained according to the process described in stage A of example 6, starting from the compound described in stage A of example 7.

Stage B: {3 - [(4-acetoxy-2-methyl-1,1-dioxo-3,4-dihydro-2,1-l, 2-benzothiazin-3-yl) carbonylamino] propyl} trimethylammonium iodide

EXAMPLE 9 Iodide of (3-ff2-methyl-l., L-diQxo-2g-l, 2-benzothiazin-3-yl) carbonylammolpropylltrimethylammonium

Stage A: methyl 2-Methyl-l, l-dioxo-2Α-l, 2-benzothiazine-3-carboxylate

To 10 mmol of the compound described in stage A of Example 8 in solution in tetrahydrofiirane are added 10 mmol of 1,8-diazabicyclo [5.4.0] undec-7-ene, then the reaction mixture is stirred at room temperature for 4 hours. After hydrolysis and extraction with ethyl acetate, the combined organic phases are washed, dried, filtered and then concentrated. The residue obtained is purified by chromatography on silica (eluent: dichloromethane) to yield the expected product.

Stage B: {3 - [(2-methyl-l, l-dioxo-2Η.-l, 2-benzothiazin-3-yl) carbonylamino] propyljtrimethylammonium iodide

EXAMPLE 10 Iodide of (3-rf2 _" methyl-l, l-dioxo-3,4-dihvdro-2H-l, 2-benzothiazîn-

3-γI) carbonvIammo1propyIUriméthv.ammonium

Stage A: methyl 2-Methyl-l, l-dioxo-3,4-dihydro-2Εi.-l, 2-benzothiazine-3-carboxylate A solution of the compound described in stage A of Example 9 (10 mmol) in methanol is placed under hydrogen overnight in the presence of Pd / C at 10%. After filtration of the catalyst, the solvent is evaporated to yield the expected product.

Stage B: {3 - [(2-methyl-l, l-dioxo ~ 3,4-dihydro-2ΕL-l, 2-benzothiazin-3-yl) carbonylamino] propyl} trimethylammonium iodide

EXAMPLE 11; 3- [f4- (para-toIuènesuIfonvIoxy ~ 2-methvI-l, l-dioxo-2H- l, 2-benzQthiazιn-3-yI) iodide carbonvIam o1propyIltriméthyIam onium

Stage A; Methyl 2-Methyl-4-toluenesulfonyloxy) -l, l-dioxo-2Εi-l, 2-benzothiazine-3-carboxylate

The expected product is obtained according to the process described in stage A of Example 6, replacing acetyl chloride with para-toluenesulfonyl chloride.

Stage B: {3 - [(4- (para-toluenesulfonyloxy) -2-methyl-l, l-dioxo-2H-l, 2-benzothiazin-3-yl) carbonylamino] propyl} trimethylammonium iodide

The expected product is obtained according to the process described in stages B and C of Example 5, starting from the compound described in preceding stage A.

EXAMPLE 12 {3-f (4- (methanesulfonvIoxy) -2-methyl-1,1-dioxo-2H-1,2-benzothiazm-3-vI) carbonvIammo1propyI} trimethylammonium iodide

Stage A: methyl 2-methyl-4-methanesulfonyloxy) -l, l-dioxo-2ΕL-l, 2-benzothiazine-3-carboxylate

The expected product is obtained according to the process described in stage A of Example 6 in replacing acetyl chloride with methanesulfonyl chloride.

Stage B: {3 - [(4- (methanesulfonyloxy) -2-methyl-1,1-dioxo-2ΕL-1,2-benzothiazin-3-yl) carbonylamino] propyl} trimethylammonium iodide

EXAMPLE 13 Iodide of {3-f (4-benzyloxy-2-methvI-l, l-dioxo-2H-l., 2-benzothiazm-3-vI) earbonγIaminolpropyI} trimethvIammoninm

Stage A: methyl 4-Benzyloxy-2-methyl-l, l-dioxo-2ΕL-1,2,2-benzothiazine-3-carboxylate

The expected product is obtained according to the process described in stage A of Example 6, replacing acetyl chloride with benzyl chloride.

Stage B: {3 - [(4-Benzyloxy-2-methyl-1,1-dioxo-2H-1,2-benzothiazin-3-yl) carbonylamino] propyl} trimethylammonium iodide

EXAMPLE 14 Bromide of {3-r (4-hvdroxy-2-methyl-l, l-dιoxo-2H-l., 2-benzQthiazin- 3-yl carbonγIamino1propyIldiéthylméthvIammonmm

The expected product is obtained according to the process described in stage B of example 1, starting from the compound obtained in stage A of example 1 and bromomethane.

EXAMPLE 15 Chloride of (3-ff4-hvdroxy-2-methvI-Ll-dioxo-2H-1.2-benzothiazin-

3-yl) carbonylamino | propyl} diéthyIméthvIammonium The expected product is obtained according to the process described in stage B of example 1, starting from the compound obtained in stage A of example 1 and chloromethane.

PHARMACOLQGIOUE STUDY OF THE DERIVATIVES OF THE INVENTION

EXAMPLE 16 Pharmacokinetic study; tissue distribution study

This study was carried out with molecules labeled with ¹⁴ C. The study of tissue distribution was carried out by direct measurement of radioactivity on whole body sections according to the following method: male rats of the Sprague-Dawley strain received intravenously or orally a dose of labeled molecule. The animals were then sacrificed at times ranging from 5 min to 24 h by inhalation of ether and frozen in liquid nitrogen.

Slices were then prepared with a cryomicrotome and after drying, the distribution of radioactivity was measured using an image analyzer.

The results obtained with the derivatives of the invention show that these compounds have a reinforced tropism for the cartilaginous tissues.

EXAMPLE 17 Expression of Pagrecanne in Joint Chondrocvtes Treated with

FIL-1.

The expression of the agrecanne was analyzed by "northern-blot". Total RNAs from cultures of calf articular chondrocytes (CAV) cultivated in DMEM + 10% S VF and treated with different concentrations of the studied compounds, in the presence of IL-1 (10 ng / ml), were extracted. 10 μg of total RNA were fractionated by electrophoresis on a 1% agarose gel in the presence of a MOPS-formaldehyde buffer, transferred to a nylon membrane and hybridized with a cDNA probe specific for agrecanne.

By way of example, the compound of Example 1, at 10-6 and 10-8 M, stimulates the expression of 150% and 200% agrecan, respectively, compared to the cultures treated with 10 ng / ml of IL-1.

By way of comparison, the "propoxicam N +" described in the publication J. Med. Chem. 1999, 42, 5235-5240, at 10-6 and 10-8 M, only stimulates the expression of agrecanne by 28% and 30% respectively, under the same conditions.

These results demonstrate that the compounds of the invention have very advantageous properties for protecting cartilage.

EXAMPLE 18 Pharmaceutical composition

Preparation formula for 1000 tablets dosed at 10 mg Compound of Example 1 10 g

Hydroxypropylcellulose 2 g

Wheat starch 10 g

Lactose 100 g

Magnesium stearate 3 g Talc 3 g

Claims

1. Compound of formula (I):

in which :

> r - ^ r represents a single or double bond,

^ Ri represents a hydrogen atom or a hydroxyl group, linear or branched (Ci-C ₆ ) alkoxy, linear or branched (Ci-C) acyloxy, linear or branched alkylsulfonyloxy (Ci-C ₆ ), arylsulfonyloxy or arylalkoxy (- Ce) linear or branched,

^ R represents a hydrogen atom or a linear or branched (-C ₆ ) alkyl group,

Q> R ₃ and R ₄ , identical or different, each represent a hydrogen atom, a halogen atom or a linear or branched (C _! -C ₆ ) alkyl, hydroxy or alkoxy (Cι-C ₆ ) linear or branched group ,

^ Ak represents a linear or branched alkylene chain (Cι-C ₆ ),

^ R ₅ , R ₆ and R ₇ , identical or different, each represent a linear or branched alkyl group (Cι-C ₆ ), or else R ₅ , R ₆ and R ₇ , taken together with the nitrogen atom which the carriers, form a saturated or unsaturated nitrogen heterocycle, ^ X represents a halogen atom,

as well as its optical isomers when they exist,

excluding the compounds for which, simultaneously, r- - represents a double bond, Ri represents a hydroxy group, R ₂ , R ₅ and Re, each represent a methyl group, R ₃ and R ₄ each represent an atom d 'hydrogen, and Ak represents a group - (CH) ₃ -,

it being understood that by saturated or unsaturated nitrogen heterocycle is understood to mean a 5- to 7-membered monocyclic group, saturated or unsaturated, aromatic or non-aromatic, containing one, two or three heteroatoms, one of these heteroatoms being the atom d nitrogen, and the additional heteroatom (s) possibly present being chosen from oxygen, nitrogen or sulfur atoms, it being understood that the nitrogen heterocycle can be optionally substituted by one or more groups, identical or different, alkyl ( Cι-C ₆ ) linear or branched. The preferred nitrogen heterocycles are the pyridyl and piperidyl groups N-substituted by a linear or branched (-Ce) alkyl group.

2, Compound of formula (I) according to claim 1 such that R represents a linear or branched (C ₁ -C ₆ ) alkyl group.

3, Compound foπnule (I) according to any one of claims 1 or 2 such that R ₅ , Re and R ₇ , identical or different, each represent an alkyl group (Cι-C ₆ ) linear or branched.

4, Compound of formula (I) according to claim 3 such that R ₆ and R ₇ , identical or different, each represent a linear or branched (C ₂ -C ₆ ) alkyl group.

5, Compound of formula (I) according to any one of claims 1 or 2 such that R ₅ , Re and R ₇ , taken together with the nitrogen atom which carries them, form a saturated or unsaturated nitrogen heterocycle.

6. Compound of formula (I) according to claim 5 such that R ₅ , Rβ and R ₇ , taken together with the nitrogen atom which carries them, form a pyridyl group.

7, Compound of formula (I) according to any one of claims 1 to 6 such that X represents an iodine atom.

8, Compound of formula (I) according to claim 1 which is the iodide of {3 - [(4-hydroxy-2-methyl-l, l-dioxo-2H-l, 2-benzothiazin-3-yl) - carbonylamino] - propyl} -diethylmethylammonium.

9. Process for preparing the compounds of formula (I) according to claim 1 characterized in that a compound of formula (H) is reacted:

in which R and R} have the same meaning as in formula (I),

in the presence of a base, to lead to the compound of formula (IH):

in which R ₃ and i are as defined above,

which is reacted, when desired, with a compound of formula (IN):

R ' ₂ - Yι (IV) in which R' ₂ represents a linear or branched (Cι-C ₆ ) alkyl group, and Yi represents a conventional leaving group in organic chemistry, to lead to the compound of formula (V):

in which R ', R ₃ and ₄ are as defined above,

compounds of formula (DOT) or (V) which are reacted, when desired,

either with a compound of formula (VI):

R'i - Y ₂ (VI) in which R'i represents a linear or branched (Ci-C ₆ ) alkyl, linear or branched (Ci-C ₆ ) acyl, linear or branched (C Ce) alkylsulfonyl, arylsulfonyl or arylalkyl (Cι-C ₆ ) linear or branched, and Y ₂ represents a usual leaving group of organic chemistry,

to lead to the compound of formula (VU)

in which R'i, R ₂ , R and j are as defined above,

either with an appropriate reduction agent, to yield the compound of formula (VIE):

in which R ₂ , R and i are as defined above, which we possibly transform:

in which R ₂ , R ₃ and Ri are as defined above,

which, if desired, is reduced to a compound of formula (X)

in which R ₂ , R ₃ and i are as defined above,

in which R'i, R ₂ , R ₃ and j are as defined above,

the compounds of formulas (m), (N), (VU), (VET), (IX), (X) and (XI) forming the set of compounds of formula (XH): in which rrrr-, Ri, R ₂ , R ₃ and R ₄ have the same meaning as in formula (I),

which we transform into a compound of formula (XUI)

in which Ri, R ₂ , R ₃ , R ^ are as defined above, Ak has the same meaning as in formula (I), and Z represents either a group X as defined in formula (I), or an NR'sR'e group in which R ' ₅ and R' ₆ , identical or different, each represent a linear or branched alkyl group (Cι-C ₆ ), or together form a non-aromatic saturated or unsaturated nitrogen heterocycle,

that we put in reaction,

NR " ₅ R" ₆ R "7 (XV) in which R" ₅ , R " ₆ and R" ₇ form together with the nitrogen atom which carries them an aromatic nitrogen heterocycle,

to lead to the compound of formula (Ib), special case of the compounds of formula (I):

in which Ri, R ₂ , R ₃ , _t , Ak, R " ₅ , R" ₆ , R " ₇ and X are as defined above,

10. Pharmaceutical composition containing as active ingredient a compound according to any one of claims 1 to 8, in combination with one or more inert, non-toxic and pharmaceutically acceptable vehicles.

11. A pharmaceutical composition according to claim 10 useful as a medicament for the treatment of osteoarthritis or arthritis.