EP0538436A1 - Nouveaux sels d'ammonium quaternaire, leurs procedes d'obtention et les compositions pharmaceutiques en renfermant - Google Patents
Nouveaux sels d'ammonium quaternaire, leurs procedes d'obtention et les compositions pharmaceutiques en renfermantInfo
- Publication number
- EP0538436A1 EP0538436A1 EP92910049A EP92910049A EP0538436A1 EP 0538436 A1 EP0538436 A1 EP 0538436A1 EP 92910049 A EP92910049 A EP 92910049A EP 92910049 A EP92910049 A EP 92910049A EP 0538436 A1 EP0538436 A1 EP 0538436A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hal
- formula
- radical
- group
- hydrogen
- 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- Withdrawn
Links
Classifications
-
- 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
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/62—Quaternary ammonium compounds
- C07C211/63—Quaternary ammonium compounds having quaternised nitrogen atoms bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/40—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
Definitions
- the present invention relates to the field of organic chemistry and more particularly to that of therapeutic chemistry.
- It relates more particularly to new compounds of the quaternary ammonium type carrying at least one haloalkyl radical with nitrogen.
- Hal is a halogen atom other than fluorine
- R and R 1 are lower alkyl radicals in straight or branched chain
- n is an integer varying from 2 to 16
- Z is an alkenyl radical having up to 3 carbon atoms, a carboxyl
- R 2 is hydrogen, an optionally substituted lower alkyl radical, an acyl residue derived from a saturated carboxylic or carbonic inorganic or organic acid having from 1 to 20 carbon atoms, a tocol radical, a sterolic radical, or a carboxamide chain of the form
- n 1 is an integer varying from 0 to 4
- R 3 and R are either one of hydrogen and in this case the other substituent represents the alkylene chain of a heterocycle, optionally interrupted by one or more hetero atoms chosen from the group consisting of an oxygen or sulfur atom or the group -NH-,
- alkylene chain of a nitrogen heterocycle which may comprise another heteroatom as well as one or more functional groups chosen from the group consisting of a halogen, an oxo group, a hydroxy group, an amino group or a glucoside radical
- A is a hydroxyl or the anion of a mineral or organic acid with the restriction that the acyl residue can only include a residue of 1-hydroxy 1,1-diphenyl acetic acid, when Hal is iodine, R 2 is not an acetyl residue and when Hal is bromine and R- an acetyl residue, n is different from 2.
- n is an integer varying from 2 to 4
- A is a hydroxyl, or an anion of mineral or organic acid
- R 5 is hydrogen, an acyl residue derived from a mineral or organic acid having from 1 to 18 carbon atoms or a lower alkyl optionally substituted by hydroxy, lower alkoxy, an amino group or an alkyl- or dialkoylamino radical
- R 6 is hydrogen, halogen or lower alkyl and R 7 is hydrogen or a molecule of a sugar
- R 8 is hydrogen or a molecule of a sugar, the hydroxyls of which are free, blocked or phosphorylated, i.e. derived from guanine (2.9) or adenine (6.9 ).
- B, C and D are hydrogen, hydroxyl or a methyl radical
- E is a farnesyl or phytyl chain
- n is an integer between 6 and 16
- n ' is equal to O or 1
- n 1, 2 or 3
- R, R 1 , Hal and A are defined as above.
- the invention also relates to pharmaceutical compositions containing as active ingredient at least one compound of general formula I '
- Z ' is hydrogen, the group OR 2 defined as above, an alkenyl radical or a carboxyl group n 2 is an integer varying from 1 to 16
- A is a hydroxyl or: the anion of a therapeutically-compatible mineral or organic acid
- halides such as chlorides or bromides, sulfates, phosphates, nitrates, methane sulfonates, benzene sulfonates, naphthalene sulfonates, methyl sulfates, acetates, benzoates or trimethoxybenzoates.
- compositions according to the invention are in one of the forms suitable for use by the parenteral, digestive, rectal or percutaneous route. They contain, in addition to the active principle, a vehicle such as an aqueous medium, a glucose serum or a saline solution, or a solid excipient such as, for example, lactose, tricalcium phosphate, calcium sulfate, carboxymethyl cellulose, microcrystalline cellulose. or colloidal silica. Binding agents such as polyvinyl pyrrolidone or methylcellulose, agents which facilitate the wetting of the powder such as formalin casein, dispersing agents, surface-active agents, sweetening agents, flavoring agents and / or also can be added thereto.
- a vehicle such as an aqueous medium, a glucose serum or a saline solution, or a solid excipient such as, for example, lactose, tricalcium phosphate, calcium sulfate, carboxymethyl cellulose, microcrystalline cellulose. or colloidal
- the average unit dose ranges from 0.1 to 50 mg depending on the route of administration.
- the amounts administered parenterally range from 0.1 to 10 mg per unit dose.
- Quantities administered by the digestive or rectal route range from 5 to 25 mg.
- the amounts of active ingredient administered percutaneously range from 10 to 50 mg per unit dose.
- compositions according to the invention find use in human or animal therapy, in particular as anti-tumor agents. They are particularly suitable for the treatment of skin tumors alone or in combination with conventional chemotherapy. They also exhibit immunosuppressive properties which make them useful in the treatment of rheumatic diseases and rheumatoid arthritis.
- the invention further extends to a process for obtaining the compounds of general formula I which consists in subjecting a dialkylamino alkanol of general formula II
- A- is a halide
- R, R 1 , n, Hal and A are defined as above
- R ' is a lower alkyl radical, optionally substituted by a hydroxyl or an amino radical
- R, R 1 , Hal, n, R 7 and A are defined as above.
- the quaternary ammonium salts of general formula I are easily converted into hydroxide by the action of a basic agent such as a hydroxide or a carbonate of an alkali, alkaline earth metal or silver or else by passage over an ion exchange resin in alkaline form.
- a basic agent such as a hydroxide or a carbonate of an alkali, alkaline earth metal or silver or else by passage over an ion exchange resin in alkaline form.
- the hydroxides thus obtained can again be converted to another salt, if desired.
- the invention also relates to a process for obtaining NN-dimethyl N-chloromethyl N- (carboxymethyl) ammonium chloride which consists in reacting monochloroacetic acid and dimethylamine in the presence of a proton acceptor to form NN-dimethylglycine which is subjected to the action of dichloromethane in polar solvent, to form the desired quaternary ammonium salt.
- a subject of the invention is also a process for obtaining NN-dimethyl N-chloromethyl N-undecen-8-yl ammonium chloride in which an undecen-8-yl halide is reacted with dimethylamine and then condenses the tertiary amine thus formed with dichloromethane to form the desired quaternary ammonium salt.
- the addition also relates to a process for obtaining NN-dimethyl chloride N-chloromethyl N-ketyl ammonium which consists in reacting NN-dimethyl hexadecylamine with dichloromethane in polar solvent to obtain the salt of desired quaternary ammonium.
- the invention also relates to an improved process for the synthesis of NN-dimethyl chloride N-chloromethyl (2-hydroxy ethyl) ammonium, which consists in subjecting NN-dimethyl ethanolamine to the action of dihydropyran in the presence of an organic acid to obtain the corresponding tetrahydropyranyl derivative which, by reaction with dicMoromethane, provides NN-dimethyl N-chloromethyl N- (2-tetrahydropyranyl 2-oxy ethanol) ammonium chloride, the tetrahydropyran ether of which is hydrolyzed 'a mineral acid and obtains the desired quaternary ammonium salt.
- the invention also relates to a variant of the process for obtaining the compounds of formula I C
- A is an anion derived from a mineral or organic acid
- the subject of the invention is also a variant of the process in which a pyrimidine dione of formula VI is subjected
- R 6 and R 7 have the meanings provided previously which are not purified and condensed as such with a salt of NN-dialkoyl N- (halomethyl) N- (hydroxyalkyl) ammonium of formula III
- A is an anion derived from a mineral or organic acid
- the invention also relates to a variant of the process for obtaining the compounds of formula I c in which the compounds of formula I C are prepared according to a process which consists in reacting an euninopyrimidine of formula (VIII)
- A is an anion derived from a mineral or organic acid
- the product obtained is dissolved in 70 ml of isopropyl alcohol, 70 ml of acetonitrile, 56 ml of water and 300 ml of methylene chloride. It is treated at reflux for 16 hours.
- the pH is brought to 2 with a hydrochloric acid solution (10%).
- the amine is extracted with methylene chloride.
- the organic phase is evaporated in vacuo.
- the pH is adjusted to
- step I The amine obtained in step I is treated at reflux for 48 hours in 5 volumes of methylene chloride. The reaction is checked by. TLC in the ethyl acetate / taethanol / acetic acid system (50/25/25) and development by the DRAGENDORFF reagent.
- the preceding crude product is dissolved in 0.5 vol. of a 0.6% hydrochloric acid solution and 0.5 volume of ethanol. The mixture is brought 45 minutes to 50 ° C. Neutralized with sodium carbonate. Filtered on celite. After concentration under vacuum, the product is crystallized from isopropyl alcohol. The purity of the product obtained is greater than that of the product described in Example III.
- the Erlenmeyer flask is closed with a ground glass stopper and left stirring at room temperature for five days. After concentrating to dryness, under vacuum, the residue is taken up 3 times with 250 ml of absolute ethanol, concentrating under vacuum each time.
- the silver chloride is removed by filtration; the filtrate, concentrated under vacuum, is kept as it is until use.
- the reaction is quantitative.
- reaction product is cooled to -15 ° C (pH around 14). We filter on Buchner. The crystals are washed with essence B. Finally, the product is purified by percolation on a column of neutral alumina (MERCK, 1077) with methylene chloride as the initial eluent. The product is eluted with acetone.
- MERCK neutral alumina
- the temperature is then lowered to -15 ° C.
- the crystals formed are filtered on B ⁇ chner, washed with toluene, then with gasoline B.
- the mixture is stirred for one hour at 20 ° C.
- the end of the reaction is monitored by thin layer chromatography on silica gel.
- the chromatogram being developed in the CHCl 3 / MeOH / NH 4 OH system (85/15 / 1.5); revelation by the DRAGENDORFF reagent.
- the product is purified by passage over a column of silica gel.
- the elutions are carried out with gasoline B progressively enriched in ethyl acetate.
- These compounds can be used as antineoplastic agents and also as depressants.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Transplantation (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9105693A FR2676224B1 (fr) | 1991-05-10 | 1991-05-10 | Nouveaux sels d'ammonium quaternaire, leurs procedes d'obtention et les compositions pharmaceutiques en renfermant. |
FR9105693 | 1991-05-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0538436A1 true EP0538436A1 (fr) | 1993-04-28 |
Family
ID=9412674
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP92910049A Withdrawn EP0538436A1 (fr) | 1991-05-10 | 1992-04-10 | Nouveaux sels d'ammonium quaternaire, leurs procedes d'obtention et les compositions pharmaceutiques en renfermant |
Country Status (5)
Country | Link |
---|---|
US (1) | US5399590A (fr) |
EP (1) | EP0538436A1 (fr) |
JP (1) | JPH06500340A (fr) |
FR (1) | FR2676224B1 (fr) |
WO (1) | WO1992020646A1 (fr) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5853375A (en) * | 1995-11-29 | 1998-12-29 | Medtronic, Inc. | Guide wire extension peg and hole with 90 degree latch |
RU2013112156A (ru) * | 2010-09-21 | 2014-10-27 | ДжиИ ХЕЛТКЕР ЛИМИТЕД | Аналоги холина в качестве радиоактивного индикатора |
US9145352B2 (en) * | 2012-05-30 | 2015-09-29 | Universidad De Caldas | Quaternary N-(halomethyl) ammonium salts as therapeutic agents |
US9694020B2 (en) | 2014-09-26 | 2017-07-04 | The Cleveland Clinic Foundation | Treating and preventing disease with TMA and TMAO lowering agents |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE519324C (de) * | 1927-09-29 | 1931-03-07 | Egon Gluecksmann | Verfahren zur Herstellung von Salzen halogensubstituierter, quartaerer, aliphatischer Ammoniumbasen |
US3420822A (en) * | 1964-11-02 | 1969-01-07 | Angeli Inst Spa | Quaternary salts of basic esters of beta-(1-naphthyl)-acrylic acid |
US3932664A (en) * | 1971-07-19 | 1976-01-13 | The Dow Chemical Company | Substituted phenoxyalkyl quaternary ammonium compounds as antiarrhythemic agents |
US4444971A (en) * | 1983-07-25 | 1984-04-24 | Texaco Inc. | Acrylic and methacrylic quaternary chloromethyl ammonium chloride cationic monomers and polymers thereof |
US4710304A (en) * | 1984-11-26 | 1987-12-01 | Joseph J. Campbell | Method for improving the utilization of polyelectrolytes in dewatering aqueous suspensions |
US4824867A (en) * | 1986-08-08 | 1989-04-25 | Smith Kim R | Quaternary ammonium compounds |
US5030756A (en) * | 1990-08-03 | 1991-07-09 | Clairol Incorporated | Halide containing quaternary ammonium salts as hair conditioning agents |
-
1991
- 1991-05-10 FR FR9105693A patent/FR2676224B1/fr not_active Expired - Fee Related
-
1992
- 1992-04-10 EP EP92910049A patent/EP0538436A1/fr not_active Withdrawn
- 1992-04-10 WO PCT/FR1992/000317 patent/WO1992020646A1/fr not_active Application Discontinuation
- 1992-04-10 US US07/969,832 patent/US5399590A/en not_active Expired - Fee Related
- 1992-04-10 JP JP4509512A patent/JPH06500340A/ja active Pending
Non-Patent Citations (1)
Title |
---|
See references of WO9220646A1 * |
Also Published As
Publication number | Publication date |
---|---|
JPH06500340A (ja) | 1994-01-13 |
FR2676224B1 (fr) | 1996-08-02 |
WO1992020646A1 (fr) | 1992-11-26 |
US5399590A (en) | 1995-03-21 |
FR2676224A1 (fr) | 1992-11-13 |
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