Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

• the present invention relates to new pyridobenzoindole derivatives of general formula:
• R 1 and R 5 are inter alia hydrogen atoms
• R 2 can represent a hydrogen atom, a hydroxy or aleoyloxy radical
• R 3 and 3 14 are in particular alkyl radicals and n equal 2 to 4, which have anti-tumor activity.
• R represents a hydrogen atom or an alkyl radical containing 1 or 2 carbon atoms
• alk represents a straight or branched alkylene radical containing 2 to 4 carbon atoms
• R 1 represents a hydrogen atom or an alkyl radical containing 1 or 2 carbon atoms
• R 2 represents a hydroxy or methoxy radical
• R 1 is defined as above by the action of an amine of general formula:
• R, R 1 and alk are defined as above, to a 9-hydroxy pyrido [4,3-b] benzo [e] indole derivative.
• reaction of the amine of general formula (III) with the chlorinated derivative of general formula (II) is carried out in the presence of an excess of the amine, preferably under nitrogen, optionally in an inert organic solvent, or without solvent, at a temperature between the reflux temperature of the reaction mixture and 250 ° C (autoclave).
• a chlorinating agent chosen from phosphorus oxychloride or halogenated derivatives of phosphorus in the presence of a tertiary base (diethylaniline, dimethylaniline for example) in an organic solvent such as a nitrile (acetonitrile for example), at a temperature between 75 and 90 ° C. (reflux temperature of the reaction mixture).
• a tertiary base diethylaniline, dimethylaniline for example
• organic solvent such as a nitrile (acetonitrile for example
• the reaction is carried out under nitrogen.
• the product of general formula (II) for which R 1 is an alkyl radical may be obtained by alkylation of the product for which R 1 is a hydrogen atom, for example by the action of the suitable halogen derivative, in the presence of potassium carbonate.
• the product of formula (IV) can be prepared from the hydrazone of formula:
• the hydrazone of formula (V) is prepared by condensation of hydrazino-4-1H-pyridone-2 with 6-methoxy-2-tetralone.
• the reaction is generally carried out in an organic solvent such as an alcohol (ethanol for example), at the reflux temperature of the reaction mixture.
• 6-methoxy tetralone can be obtained according to the method described in J. Am. Chenu Soc, 82, 2573 (1960).
• Hydrazino-4-1H-pyridone-2 can be prepared according to the method described by C.H. NGUYEN and E. BISAGNI, Tetrahedron, 42 (8), 2203 (1986).
• the pyridobenzoindole derivatives of general formula (I) can be purified by crystallization or by chromatography.
• the new pyridobenzoindole derivatives according to the invention can be converted into addition salts with acids, by the action of an acid in an organic solvent.
• the salt precipitates, possibly after concentration of its solution, it is separated by filtration or decantation.
• salts As pharmaceutically acceptable salts, mention may be made of addition salts with mineral acids such as hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, or organic salts such as acetate, propionates, succinates, naleates, fumarates, methanesulfonates, p.toluenesulfonates, isethionates or derivatives of substitution of these compounds.
• mineral acids such as hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, or organic salts such as acetate, propionates, succinates, naleates, fumarates, methanesulfonates, p.toluenesulfonates, isethionates or derivatives of substitution of these compounds.
• pyridobenzoindole derivatives according to the invention and their salts can exist in the form of hydrates, it is understood that these hydrated forms also come within the scope of the present invention.
• the derivatives of general formula (I) are particularly advantageous as anti-tumor agents.
• mice expressed by their maximum tolerated dose is greater than 20 and 40 mg / kg intraperitoneally.
• R is a methyl radical
• alk is a straight or branched alkyl radical containing 2 to 4 carbon atoms
• R 1 is a hydrogen atom or a methyl radical
• R 2 is a hydroxy radical, as well as their salts and the case where appropriate their hydrates.
• the excess diamine is evaporated in a water bath under reduced pressure and the residue is taken up in water and then made alkaline with ammonia.
• the solid formed is filtered, washed with water, taken up in methylene chloride and washed with 150 cm 3 of water and 10 cm 3 of ammonia.
• Chloro-1 methoxy-9 5H-pyrido [4,3-b] benzo [e] indole can be obtained in the following way:
• N- (1H-pyridone-2 yl) -4 N '- (6-methoxy-1,2,3,4 tetrahydro naphthalenylidene) -2 hydrazine can be obtained in the following way:
• the precipitate formed is filtered, taken up in ethanol in which the hydrazone is poorly soluble and then filtered cold to give (19.3 g (83%)) of yellow microcrystals of N- (1H-pyridone-2 yl) - 4 N '- (6-methoxy-1,2,3,4-naphthalenylidene tetrahydro) -2 hydrazine, mp 220-225 ° C, with decomposition.
• Hydrazino-4-1H-pyridone-2 can be obtained according to the method described by E. Bisagni and CH Nguyen, Tetrahedron, 42, 2303 (1986).
• the present invention also relates to pharmaceutical compositions which contain as active product at least one product of general formula (I) in the pure state (in free form or in salt form) or in combination with one or more pharmaceutically acceptable adjuvants. These compositions can be used parenterally.
• compositions for parenteral administration can be sterile aqueous or non-aqueous solutions, suspensions or emulsions.
• solvent or vehicle propyleneglycol, a polyethylene glycol, vegetable oils, in particular olive oil and injectable organic esters, for example ethyl oleate.
• These compositions can also contain adjuvants, in particular wetting agents, emulsifiers or dispersants. Sterilization can be done in several ways, for example using a bacteriological filter, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which will be dissolved at the time of use in sterile water or any other sterile injectable medium.
• the medicaments according to the present invention are particularly useful in the treatment of digestive cancers, of lung cancers, of cancers of the testes or of the ovaries as well as in the treatments of cancers of the head and of the neck.
• the doctor will determine the dosage he considers most appropriate based on age, weight and all other factors specific to the subject to be treated.
• the preferred mode of administration is the intravenous route.
• the medicaments according to the invention can be administered to humans at a rate of 30 to 200 mg / m 2 per treatment, by intravenous route.
• the following example given without limitation, illustrates a composition according to the present invention:
• the solution obtained is aseptically distributed in ampoules, at the rate of 2 cm 3 per ampoule.
• the ampoules are sealed and each contain 100 mg of [(dimethylamino-3) propyl] amino-1 hydroxy-9 5H-pyrido [4,3-b] benzo [e] indole.

Landscapes

• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Pharmacology & Pharmacy (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (3)

Applications Claiming Priority (2)

Publications (1)

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Family Applications (1)

Country Status (14)

Cited By (2)

• 1990
  • 1990-11-23 FR FR9014636A patent/FR2669637A1/fr not_active Withdrawn
• 1991
  • 1991-11-21 ZA ZA919208A patent/ZA919208B/xx unknown
  • 1991-11-21 IL IL100118A patent/IL100118A0/xx unknown
  • 1991-11-22 CA CA002096719A patent/CA2096719A1/fr not_active Abandoned
  • 1991-11-22 WO PCT/FR1991/000926 patent/WO1992009602A1/fr not_active Application Discontinuation
  • 1991-11-22 PT PT99579A patent/PT99579A/pt not_active Application Discontinuation
  • 1991-11-22 KR KR1019930701548A patent/KR930702344A/ko not_active Application Discontinuation
  • 1991-11-22 MX MX9102179A patent/MX9102179A/es unknown
  • 1991-11-22 EP EP92900717A patent/EP0558613A1/fr not_active Ceased
  • 1991-11-22 JP JP4501700A patent/JPH06502861A/ja active Pending
  • 1991-11-22 HU HU9301501A patent/HUT64344A/hu unknown
  • 1991-11-22 AU AU90650/91A patent/AU9065091A/en not_active Abandoned
  • 1991-11-22 IE IE407291A patent/IE914072A1/en not_active Application Discontinuation
• 1993
  • 1993-05-21 FI FI932332A patent/FI932332A0/fi not_active Application Discontinuation

Non-Patent Citations (2)

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