EP1343774A1 - Derives de 1, 1-dioxo-2h-1, 2-benzothiazine-3-carboxamides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent - Google Patents

Derives de 1, 1-dioxo-2h-1, 2-benzothiazine-3-carboxamides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

Info

Publication number
EP1343774A1
EP1343774A1 EP01989655A EP01989655A EP1343774A1 EP 1343774 A1 EP1343774 A1 EP 1343774A1 EP 01989655 A EP01989655 A EP 01989655A EP 01989655 A EP01989655 A EP 01989655A EP 1343774 A1 EP1343774 A1 EP 1343774A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
branched
linear
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01989655A
Other languages
German (de)
English (en)
French (fr)
Inventor
Jean-Claude Madelmont
Isabelle Giraud
Aurélien VIDAL
Emmanuelle Mounetou
Maryse Rapp
Jean-Claude Maurizis
Pierre Renard
Daniel-Henri Caignard
Jean-Guy Bizot-Espiard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institut National de la Sante et de la Recherche Medicale INSERM
Laboratoires Servier SAS
Original Assignee
Institut National de la Sante et de la Recherche Medicale INSERM
Laboratoires Servier SAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institut National de la Sante et de la Recherche Medicale INSERM, Laboratoires Servier SAS filed Critical Institut National de la Sante et de la Recherche Medicale INSERM
Publication of EP1343774A1 publication Critical patent/EP1343774A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines

Definitions

  • 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.
  • 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.
  • 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 ⁇ ) linear or branched,
  • R 2 represents a hydrogen atom or a linear or branched (-C ⁇ ) alkyl group
  • ⁇ R 3 and R identical or different, each represent a hydrogen atom, a halogen atom or a linear or branched (-C ⁇ ) alkyl group, hydroxy or alkoxy
  • ⁇ Ak represents a linear or branched alkylene chain (C ⁇ -C 6 ),
  • R 5 , R 6 and R 7 identical or different, each represent a linear or branched (-C ⁇ ) 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,
  • Ri represents a hydroxy group
  • R, R 5 and R ⁇ each represent a methyl group
  • R 3 and R each represent a hydrogen atom
  • Ak represents a group - (CH 2 ) -.
  • 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 (C ⁇ -C 6 ) linear or branched.
  • the preferred nitrogen heterocycles are the pyridyl and piperidyl groups N-substituted by a linear or branched (C C ⁇ ) alkyl group.
  • the preferred compounds of formula (I) are those for which R 2 represents a linear or branched alkyl group (C ⁇ -C 6 ).
  • the preferred compounds of formula (I) are those for which X represents an iodine atom.
  • 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.
  • the invention also extends to a process for preparing the compounds of formula (I) characterized in that a compound of formula (H) is reacted:
  • R ' 2 -Y ! (IV) in which R ' 2 represents a linear or branched (C ⁇ -C 6 ) alkyl group, and Y ! represents a classic leaving group of organic chemistry,
  • R 13 R 2 , R 3 , R 4 are as defined above
  • Ak has the same meaning as in formula (I)
  • 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,
  • 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.
  • 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 starting materials used are known products or prepared according to known procedures.
  • Stage B ⁇ -iodide - [(4-hydroxy-2-methyl-l, l-dioxo-2H-l, 2-benzothiazin-3-yl) carbonylamino] propyl ⁇ diethylmethylammonium
  • 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.
  • Stage B 4- (Dimethylamino) -butylamine
  • a solution of the compound obtained in the preceding stage A (17.8 mmol) in ether is then brought to room temperature and left stirring at this temperature for 1 hour.
  • 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.
  • 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 electrorosprav
  • Stage D ⁇ 4 - [(4-hydroxy-2-methyl-l, l-dioxo-2 ⁇ .-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
  • 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.
  • 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.
  • Stage B N- [3- (dimethylamino) -propyl] -4-methoxy-2-methyl-l, l-dioxo-2 ⁇ -l, 2-benzothiazine-3-carboxamide
  • Stage C ⁇ 3 - [(4-methoxy-2-methyl-l, l-dioxo-2 ⁇ -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.
  • Stage A methyl 4-Hydroxy-2-methyl-l, l-dioxo-3,4-dihydro-2 ⁇ .-l, 2-benzothiazine-3-carboxylate
  • Stage B ⁇ 3 - [(4-hydroxy-2-methyl-l, l-dioxo-3,4-dihydro-2 ⁇ -l, 2-benzothiazin-3-yl) carbonylamino] propyl ⁇ iodide trimethylammonium
  • 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 8 iodide of f3-14-aetoxy-2-methvI-ia-dioxo-3,4-dihvdro-2H-l, 2-benzothiazin-3-yl) carbonyIamino1propyI ⁇ rimêthvIammonium
  • Stage A methyl 4-Acetoxy ⁇ 2-methyl-l, l-dioxo-3,4-dihydro-2 ⁇ .-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
  • 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.
  • Stage B ⁇ 3 - [(2-methyl-l, l-dioxo-2 ⁇ .-l, 2-benzothiazin-3-yl) carbonylamino] propyljtrimethylammonium 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.
  • Stage A methyl 2-Methyl-l, l-dioxo-3,4-dihydro-2 ⁇ i.-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-2 ⁇ L-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.
  • 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.
  • Stage A methyl 2-methyl-4-methanesulfonyloxy) -l, l-dioxo-2 ⁇ L-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-2 ⁇ L-1,2-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.
  • 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
  • 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.
  • 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.
  • CAV calf articular chondrocytes
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP01989655A 2000-12-21 2001-12-21 Derives de 1, 1-dioxo-2h-1, 2-benzothiazine-3-carboxamides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent Withdrawn EP1343774A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0016739A FR2818641B1 (fr) 2000-12-21 2000-12-21 Nouveaux derives de 1,1-dioxo-2h-1,2-benzothiazine 3-carboxamides, leur procede de preparation et les compositions pharmaceutiques que les contiennent
FR0016739 2000-12-21
PCT/FR2001/004135 WO2002050049A1 (fr) 2000-12-21 2001-12-21 Derives de 1, 1-dioxo-2h-1, 2-benzothiazine-3-carboxamides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

Publications (1)

Publication Number Publication Date
EP1343774A1 true EP1343774A1 (fr) 2003-09-17

Family

ID=8857980

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01989655A Withdrawn EP1343774A1 (fr) 2000-12-21 2001-12-21 Derives de 1, 1-dioxo-2h-1, 2-benzothiazine-3-carboxamides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

Country Status (18)

Country Link
US (1) US20040063696A1 (cs)
EP (1) EP1343774A1 (cs)
JP (1) JP2004519442A (cs)
KR (1) KR20030086247A (cs)
CN (1) CN1481372A (cs)
AR (1) AR032380A1 (cs)
AU (1) AU2002228120A1 (cs)
BR (1) BR0116424A (cs)
CA (1) CA2432807A1 (cs)
CZ (1) CZ20031972A3 (cs)
EA (1) EA200300672A1 (cs)
FR (1) FR2818641B1 (cs)
HU (1) HUP0600065A2 (cs)
MX (1) MXPA03005556A (cs)
NO (1) NO20032497D0 (cs)
PL (1) PL361664A1 (cs)
SK (1) SK9092003A3 (cs)
WO (1) WO2002050049A1 (cs)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4434164A (en) * 1981-06-01 1984-02-28 Pfizer Inc. Crystalline benzothiazine dioxide salts
IT1206525B (it) * 1982-12-10 1989-04-27 Zionale S R L A Roma Preparato anti-infiammatorio nonsteroideo, per il trattamento delle affezioni artroreumatiche e metodo per la sua preparazione
DE3431588A1 (de) * 1983-09-12 1985-04-04 Pfizer, Inc., New York, N.Y. Kristalline benzothiazindioxid-salze und diese enthaltende pharmazeutische zusammensetzungen
US4623486A (en) * 1985-05-29 1986-11-18 Pfizer Inc. [4-substituted benzoyloxy]-N-substituted-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides having anti-arthritic activity
JP2002514192A (ja) * 1996-11-13 2002-05-14 セフアロン・インコーポレーテツド ベンゾチアゾおよび関連の複素環基を含有するシステインおよびセリンプロテアーゼ阻害剤
FR2795412B1 (fr) * 1999-06-23 2001-07-13 Adir Nouveaux derives d'ammonium quaternaire, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0250049A1 *

Also Published As

Publication number Publication date
CA2432807A1 (fr) 2002-06-27
AR032380A1 (es) 2003-11-05
FR2818641A1 (fr) 2002-06-28
JP2004519442A (ja) 2004-07-02
WO2002050049A1 (fr) 2002-06-27
FR2818641B1 (fr) 2004-03-05
EA200300672A1 (ru) 2003-12-25
PL361664A1 (en) 2004-10-04
CZ20031972A3 (cs) 2003-11-12
BR0116424A (pt) 2006-02-21
MXPA03005556A (es) 2004-05-31
US20040063696A1 (en) 2004-04-01
KR20030086247A (ko) 2003-11-07
AU2002228120A1 (en) 2002-07-01
CN1481372A (zh) 2004-03-10
SK9092003A3 (en) 2004-01-08
NO20032497L (no) 2003-06-03
NO20032497D0 (no) 2003-06-03
HUP0600065A2 (en) 2006-04-28

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