EP0971900A1 - Benzolsulfonamidderivate, ihre verstellung und ihre verwendung in arzneimitteln - Google Patents

Benzolsulfonamidderivate, ihre verstellung und ihre verwendung in arzneimitteln

Info

Publication number
EP0971900A1
EP0971900A1 EP98914930A EP98914930A EP0971900A1 EP 0971900 A1 EP0971900 A1 EP 0971900A1 EP 98914930 A EP98914930 A EP 98914930A EP 98914930 A EP98914930 A EP 98914930A EP 0971900 A1 EP0971900 A1 EP 0971900A1
Authority
EP
European Patent Office
Prior art keywords
group
formula
compounds
methoxy
sulfonamidophenyl
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.)
Ceased
Application number
EP98914930A
Other languages
English (en)
French (fr)
Inventor
Christophe Philippo
Patrick Mougenot
Philippe Bovy
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.)
Sanofi Aventis France
Original Assignee
Sanofi Synthelabo SA
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 Sanofi Synthelabo SA filed Critical Sanofi Synthelabo SA
Publication of EP0971900A1 publication Critical patent/EP0971900A1/de
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/47—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
    • C07D239/14—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to said nitrogen atoms

Definitions

  • the present invention relates to benzenesulfonamide derivatives, their preparation and their therapeutic application.
  • A represents either a hydrogen atom, a halogen such as fluorine, chlorine or bromine, a cyano group, a C- L group. 4 alkyl or a group C 1 . 4 alkoxy,
  • R and R 2 / identical or different, each represent a hydrogen atom, a C- ⁇ g alkyl group, a C 2 group. 6 alkenyl or R x and R 2 together form a chain C 2 _ 6 alkylene or C 2 . 6 alkenylene, and
  • R 3 represents a hydrogen atom or a group C 1 . 4 alkyl, excluding 3-benzenesulfonamidoguanidine hydrochloride.
  • the preferred compounds according to the invention are those for which R and R 2 together form a chain C 2 . 6 alkylene or C 2 . 6 alkenylene, and preferably those for which R x and R 2 together form a C 2 - 3 alkylene or C 2 chain. 3 alkenylene, A and R 3 having the meaning according to formula I.
  • Particularly preferred compounds are those for which R and R 2 together form a C 2 chain. 6 alkylene or C 2 . 6 alkenylene, preferably a C 2 chain. 3 alkylene or C 2 . 3 alkenylene, and A represents a group C 1 . 4 alkyl, preferably a methyl group, or a ⁇ _ alkoxy group, preferably a methoxy group, R 3 having the meaning according to formula I.
  • C 1 is understood. alkyl, a saturated, linear or branched aliphatic group, comprising from 1 to 4 carbon atoms.
  • C 2 _ 6 alkenyl designates a linear or branched mono or poly-unsaturated aliphatic group comprising from 2 to 6 carbon atoms.
  • An alkenyl group according to the invention preferably comprises 1 or 2 ethylenic unsaturations.
  • the cycle formed consists of a nitrogen heterocycle, saturated, unsaturated or aromatic, comprising 2 to 6 (or 2 to 3) atoms of carbon, and, as a heteroatom, the nitrogen atoms carrying R ⁇ and R 2 .
  • a cycle can for example consist of a pyrimidine, an imidazoline or an imidazole.
  • the compounds of general formula I can have one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures including racemic mixtures are part of the invention.
  • the compounds of general formula I can be in the form of a free base or of an addition salt with pharmaceutically acceptable acids, which also form part of the invention.
  • the compounds derived from benzenesulfonamide of formula I according to the invention can be prepared according to various methods. These processes are described below.
  • the compounds of formula I can be prepared according to scheme (1).
  • the compounds of formula I can be obtained by an aminolysis reaction of a sulfonyl chloride of formula II which comes from a chlorosulfonation reaction between chlorosulfonic acid and a phenylguanidine derivative of formula III.
  • the meanings of A, R 1 # R 2 and R 3 , of the compounds of formula II and III, are those indicated in formula I.
  • the compounds of formula III can be obtained from the anilines of formula IV by a coupling reaction (or guanydila ion), for example, with imidazoline derivatives, such as 2-methylthio-2-imidazoline iodhydrate (commercial), 2-chloro-2-imidazoline bisulfate (prepared according to the procedure of J. Het. Chem. 1974, 11, 257), or by taking advantage of a recently described N-methylguanydilation reagent (Tetrahedron letters 1996 , 37, 6815).
  • the compounds of formula III can also be prepared according to the reaction scheme (2).
  • an aniline of formula IV is reacted in the presence of benzoyl thioisocyanate or in the presence of potassium thiocyanate and benzoyl chloride in an organic solvent such as acetone, to give a benzoyl thiourea which is then hydrolyzed by the action of a base such as sodium hydroxide in a solvent such as ethanol.
  • the thioureas of formula V are then activated by an electrophilic agent such as methyl iodide in methanol and then treated with an amine to yield the compounds of formula III.
  • a nitro compound of formula VII is made to act with chlorosulfonic acid, followed by treatment with a primary amine (NH 2 R 3 ), so as to form a para-nitro benzenesulfonamide of formula VIII.
  • the nitro group can then be reduced in a manner known to those skilled in the art, for example by catalytic hydrogenation or the action of tin chloride, to give a compound of formula IX.
  • the meanings of A and R 3 of the compounds of formula VII, VIII and IX are those indicated in formula I.
  • the compounds of formula I are then prepared by guanydilation of the compounds of formula IX by the methods described above for the preparation of the compounds of formula III.
  • the meanings of R ⁇ , R 2 , R 3 , of the compounds of formula II and III, are those indicated in formula I.
  • the in vitro activity of the compounds of the invention has been studied on the urethral and arterial smooth muscles. These tests were carried out on female New Zealand rabbits weighing 3 to 3.5 kg. The animals were killed by vertebral dislocation, and then rings of tissue from the mesenteric arteries and urethra were removed. These tissue rings were immersed in a modified Krebs solution, oxygenated by a mixture of 95% of 0 2 and 5% of CO 2 . Each tissue sample was subjected to a tension of 1 g and then phenylephrine was introduced at cumulative doses and the dose / response curve was established. After rinsing the samples, the compound to be studied was introduced at cumulative doses and the dose / response curve established.
  • the contractile effect of each compound is evaluated by calculating pD 2 (negative logarithm of the agonist concentration which induces 50% of the maximum contraction) as well as by the maximum effect representing the percentage of the maximum contraction obtained with the phenylephrine (% E max ).
  • the experiments are carried out on female New Zealand rabbits weighing between 3 and 4 kg, anesthetized with pentobarbital.
  • the catheters are inserted for the descending aorta into the femoral artery, into a jugular vein and into the urethra (1.5 cm below the neck of the bladder).
  • test compounds are administered 5 to 15 days after the operation, by oral administration (orally) at (10 mg / kg).
  • PU urethral pressure
  • PA blood pressure
  • the results obtained are expressed as a percentage of premedication values at 5 minutes after dosing.
  • the compounds of the invention thus tested, allowed an increase in the PU greater than 80%, usually between 90 and 25%.
  • the increase in BP was always less than 10%, usually it was 0%.
  • the compounds of the invention are ligands for the adrenergic receptors.
  • the compounds according to the invention can be used as a medicament, in particular as a contracting agent for smooth muscles, and more particularly still, in the treatment of stress urinary incontinence.
  • the compounds according to the invention exhibit good efficacy and, usually, less side effects than the drugs conventionally used for such treatment, in particular as regards the side effects affecting the cardiovascular system.
  • the compounds of the invention were subjected to biological tests intended to demonstrate their contractile activity on the smooth trigone muscles.
  • the in vitro activity of the compounds of the invention was studied on the smooth trigone muscles of New Zealand male rabbits weighing from 3 to 3.5 kg. The animals were killed by cervical dislocation, and then rings of mesenteric artery tissue and bands of trigone were prepared. These rings or strips of tissue were immersed in a solution of
  • Each tissue sample was subjected to a tension of 1 g and then phenylephrine was added in cumulative doses and the concentration / response curve was established.
  • the compound to be studied was introduced at cumulative doses and the concentration / response curve established.
  • the contractile effect of each compound is evaluated by calculating pD 2 (negative logarithm of the agonist concentration which induces 50% of the maximum contraction) as well as by the maximum effect expressed as a percentage of the contraction obtained with phenylephrine (% E max ).
  • the compounds according to the invention can be used as a medicament, in particular as a contracting agent for the smooth muscles of the trigone, and more particularly still, in the treatment of ejaculation disorders such as retrograde ejaculation or aspermia.
  • the compounds according to the invention exhibit good efficacy and, usually, less side effects than the drugs conventionally used for such treatment, in particular as regards the side effects affecting the cardiovascular system.
  • the compounds according to the invention can be presented in different pharmaceutical forms suitable for oral or parenteral administration, if necessary by combining with at least one pharmaceutical excipient.
  • suitable pharmaceutical forms are for example tablets, capsules, dragees, capsules, oral or injectable solutions, syrups, suppositories.
  • These pharmaceutical forms can be dosed to allow a daily dose of 1 ⁇ g / kg to 30 mg / kg.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP98914930A 1997-03-20 1998-03-17 Benzolsulfonamidderivate, ihre verstellung und ihre verwendung in arzneimitteln Ceased EP0971900A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9703394 1997-03-20
FR9703394A FR2761061B1 (fr) 1997-03-20 1997-03-20 Derives de benzenesulfonamide, leur preparation et leur application en therapeutique
PCT/FR1998/000530 WO1998042679A1 (fr) 1997-03-20 1998-03-17 Derives de benzenesulfonamide, leur preparation et leur application en therapeutique

Publications (1)

Publication Number Publication Date
EP0971900A1 true EP0971900A1 (de) 2000-01-19

Family

ID=9505005

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98914930A Ceased EP0971900A1 (de) 1997-03-20 1998-03-17 Benzolsulfonamidderivate, ihre verstellung und ihre verwendung in arzneimitteln

Country Status (6)

Country Link
EP (1) EP0971900A1 (de)
AR (1) AR012109A1 (de)
AU (1) AU6924198A (de)
FR (1) FR2761061B1 (de)
WO (1) WO1998042679A1 (de)
ZA (1) ZA982358B (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ331480A (en) * 1997-09-04 2000-02-28 F 2-(Arylphenyl)amino-imidazoline derivatives and pharmaceutical compositions
US6323231B1 (en) 2000-02-17 2001-11-27 Abbott Laboratories Use of α1A adrenoceptor agonists with α1B and α1D antagonism for the treatment of stress urinary incontinence
DE10106214A1 (de) * 2001-02-10 2002-08-14 Boehringer Ingelheim Pharma Neue Alkyl-phenylimino-imidazolidin-Derivate zur Behandlung der Harninkontinenz

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2456731A1 (fr) * 1979-05-16 1980-12-12 Choay Sa Nouveaux derives substitues d'ary
FR2549049B1 (fr) * 1983-07-13 1986-06-20 Chauvin Blache Lab Nouvelles amidines, leur procede de preparation et leur application therapeutique
US4788195A (en) * 1986-01-13 1988-11-29 American Cyanamid Company 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines
FR2737494B1 (fr) * 1995-08-04 1997-08-29 Synthelabo Derives de benzenesulfonamide, leur preparation et leur application en therapeutique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LAMMIN S.G., PEDGRIFT B.L., RATCLIFFE A.J.: "Conversion of Anilines to Bis-Boc Protected N-methylguanidines", TETRAHEDRON LETTERS, vol. 37, 1996, pages 6815 - 6819 *
MARCH J.: "Advanced Organic Chemistry, Reactions, Mechanisms and Structure, Third Edition", JOHN WILEY & SONS *
See also references of WO9842679A1 *

Also Published As

Publication number Publication date
WO1998042679A1 (fr) 1998-10-01
FR2761061A1 (fr) 1998-09-25
AU6924198A (en) 1998-10-20
AR012109A1 (es) 2000-09-27
ZA982358B (en) 1998-09-22
FR2761061B1 (fr) 1999-04-23

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