Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
  • C07D213/72—Nitrogen atoms
  • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• • 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
  • C07D239/50—Three nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the subject of the invention is new compounds for the associative synthesis of sulfur or unsulfurized amino acids with aminopyrimidinic and aminopyridinic derivatives, as well as their addition salts with mineral or organic acids in the presence of the amino group, their methods of preparation. , their pharmacological activities and the pharmaceutical compositions containing them.
• minoxidil for our study is known for the following properties:
• Minoxidil applied topically stimulates the growth of keralinocytes in vitro and in vivo, and hair growth, in some subjects with androgenic alopecia. The onset of this phenomenon occurs after approximately 4 months (or more) of use of the product and varies depending on the subject.
• Minoxidil when applied topically is only weakly absorbed: an average amount of 1.4% (for values ranging from 0.3 to 4.5%) of the applied dose reaches the general circulation. .
• the mechanism for hair regrowth is based on its vasodilatory properties in the peripheral arterioles of the scalp.
• regrowth of hair requires prolonged treatment; the hair formed is fragile and in particular the molecular weight of the keratins formed is smaller than that of normal hair.
• the new compounds which are the subject of the invention have a higher free radical scavenging power acting as such and are at the origin of the vasodilator activity; they have significantly higher skin penetration and retention at the epidemic level.
• N " 11 - O" RI can be either -CH-X NH-Y or -CH- (CH 2 ) n -SZ
• X and Y can be hydrogen, a linear, branched, optionally hydroxylated alkyl group, an aryl group, an alkylaryl group, an aminoalkyl group, an aminoaryl group, a carboxyalkyl group, a carboxyaryl group.
• Z can be hydrogen, an alkyl group, an aryl group, n is 1 to 6, preferably 1 or 2.
• R 2 and R 3 may be hydrogen, a linear, branched, optionally hydroxylated alkyl group, an aryl group, an aminoalkyl group, an aminoaryl group, a heterocyclic group.
• - CO-R i may be a peptide structure comprising two or more amino acids whose terminal or branched acid or amino functions may be free or engaged in ester or amide groups. * 2 .
• - N can be a cyclic structure
• n is preferably 4 to 6 v —— ⁇
• ⁇ (CH 2 ) mm is preferably 2
• B is a heteroatom, preferably an O, NH or amine substituted by a linear, branched, optionally hydroxylated, alkyl group, an aryl group.
• the amino function -NH-Y can also exist in the form of mineral or organic salts, and in the form of an amide, either for Y the structure CO-R4, R4 being identical to R 2 excluding hydrogen .
• amides derive from monoamino-, diamino- and triamino-pyrimidines and from monoamino-, diamino- and triamino-pyridines.
• an amino-pyrimidine or an amino-pyridine and non-sulfur amino acids or peptides such as, for example, glutamic acid, pyroglutamic acid, tyrosine, histidine , arginine, citrulline or sulfur-containing amino acids or peptides such as methionine, cysteine, S-methylcysteine, S-benzylcysteine, cystine, glutathione, oxidized glutathione.
• minoxidil and non-sulfur amino acids or peptides such as, for example, glutamic acid, pyroglutamic acid, tyrosine, histidine, arginine, citrulline or amino acids or sulfur peptides such as methionine, cysteine, S-methylcysteine, S-benzylcysteine, cystine, glutathione, oxidized glutathione.
• the amino-substituted lazaroids in position 6 of 2,4-diaminopyrimidine (ain in primary aromatic amine form) being a piperazine substituted with a non-glucocorticoid 21-aminosteroid can replace minoxidil.
• the amides corresponding to formulas 1 to 4 are obtained by combination between a diaminopyrimidine and a diaminopyridine and a carboxyl function of an amino acid or peptide, leading to a monosubstituted derivative or to a disubstituted derivative.
• diaminopyrimidine minoxidil can be used, leading to a monosubstituted derivative or to a disubstituted derivative.
• amides having a pyrimidine or pyridine structure coupled to an amide structure, the carbonyl of which is of sulfur or non-sulfur amino acid or peptide origin have several properties; 1) very good fixation at the level of the skin, in particular at the level of the epidemic.
• Amides which have salified aminoalkyl or aminoaryl groups, for example in the form of hydrochloride, or organic or mineral salts of a free carboxylic function are soluble in water, the other compounds being rather liposoluble.
• alkyl denotes aliphatic hydrocarbon groups containing 1 to 12 carbon atoms, with a straight or branched chain. Preferred are lower alkyl groups, i.e., alkyl groups containing 1 to 4 carbon atoms.
• aryl denotes non-heterocyclic aromatic groups of the phenyl, phenole, benzyl type and higher homologs, substituted or not, as well as heterocyclic aromatic groups having 2 to 7 carbon atoms in the aromatic ring, and 1 to 4 hetero atoms which be oxygen, nitrogen, sulfur, of the furan, pyridine, oxazole type.
• aminoalkyl denotes aliphatic hydrocarbon groups containing 1 to 12 carbon atoms and 1 to 3 nitrogen atoms, straight or branched chain. Preference is given to groups containing 1 to 4 carbon atoms and 1 nitrogen atom.
• aminoaryl denotes nitrogen substituents of aromatic rings.
• mineral salt preferably designates a salt either of sodium, or of potassium, or of calcium.
• organic salt preferably designates a salt obtained by the action of a primary or secondary or tertiary amine on the carboxylic group; either an ethanolamine salt, a piperidine salt, a pyrrolidine salt or a pyridine salt or their derivatives are preferred.
• carboxyalkyl denotes a hydrocarbon group ending in a carboxylic function.
• carboxyaryl denotes an aromatic group with the presence of a carboxylic substituent.
• amino acid refers to ⁇ -alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, histidine, £ - hydroxylysine, hydroxyproline, leucine, isoleucine, lysine, methionine, norleucine, phenylalanine, praline, serine, threonine, tryptophan, tyrosine, valine, ⁇ -alanine, ⁇ - am ino acid n-butyric,% -amino n-butyric acid, ⁇ -amino-isobutyric acid, acid?
• the preparation of the amides corresponds to reacting an N-substituted amino acid
• a peptide synthesis reagent for example dicyclohexylcarbodiimide.
• the examples chosen are those of minoxidil with the
• Minoxidil monosubstituted and disubstituted by N-acetyl-D, L-methionine In a 100 ml ground flask, dissolve 0.5 g of minoxidil (0.0024 mole) in 40 ml of tetrahydrofuran and leave to stir for 5 minutes. Add 0.59 g of 40. dicyclohexylcarbodiimide (0.0029 mole) then 0.5 g of N-acetyl-D, L-methionine (0.0026 mole). Leave to stir at room temperature for one hour under an atmosphere of argon. Filter the reaction mixture, then evaporate the filtrate under reduced pressure. The residue is purified by chromatography on silica gel.
• the monosubstituted and disubstituted minoxidil are eluted with a MeOH / CH2Cl2 mixture (5/95) to obtain 0.20 g of monosubstituted minoxidil and 0.14 g of disubstituted minoxidil.
• the yields are 20 and 10.5% respectively.
• Minoxidil monosubstituted by pyroglutamic acid In a ground flask of 100 ml, introduce 0.5 g of minoxidil (0.0024 mole) in 40 ml of tetrahydrofuran and leave for 5 minutes with stirring.
• N-substituted amino acid for example N-acetylated on the amino group or groups of an aminopyrimidine N-oxide and an aminopyridine N-oxide by means of a peptide synthesis reagent, for example dicyclohexylcarbodiimide.
• a peptide synthesis reagent for example dicyclohexylcarbodiimide.
• aminopyrimidine N-oxide derivative and an aminopyridine N-oxide derivative can be transformed into its corresponding amine by reacting zinc in hydrochloric medium in ethanolic solution.
• the amides aminopyrimidine N-oxide and aminopyridine N-oxide can be prepared by reacting perhydrol in ethanolic solution.
• the new products described can be used as a medicament generally, for example as an antihypertensive agent in combination with excipients, suitable in the form of tablets, capsules for example.
• compositions can also be used in dermopharmaceutical or cosmetic compositions in combination with an appropriate vehicle, solution, emulsion, spray for example, the whole being to be applied to the surface of human skin.
• the detector must be able to collect all the RLs formed proportionally.
• the radical source provides the free radical which will react with a detector to form a modified detector.
• the latter can be quantified directly or after interaction with an additional analytical reagent by spectrophotometric analysis.
• adrenaline plays the double role of producer of the superoxide anion and detector.
• Adrenaline stable at acidic pH, oxidizes spontaneously at alkaline pH. This complex reaction gives after several stages the adrenochrome.
• the superoxide anion participates in it as an oxidizing agent. Adrenochrome formation is followed at 480 nm.
• the reaction medium consists of 3.1 ml of sodium carbonate (0.05 M) at pH 10.2 containing EDTA (0.1 mM).
• the oxidation reaction is initiated by the addition of 0.2 ml of adrenaline (0.01 M. in HC1 0.01N).
• the formation of adrenochrome is followed for 2 minutes at 480 nm.
• the compounds to be studied are added using 0.02 ml of DMSO, before the addition of adrenaline.
• the capacity of the substances to capture the superoxide anion is expressed in terms of percentage of inhibition (% I).
• AQ and A are respectively the absorbance of the modified detector in the absence and in the presence of the derivative studied.
• SOD superoxide dismutase
• N-acetyl-methionine The method of production and detection of the superoxide anion is validated by SOD which is the specific enzyme for the degradation of the superoxide anion. Besides SOD, cysteine is known to be the most reactive towards the superoxide anion. The concentration at which 50% inhibition is obtained is of the order of 0.051 M for cysteine, 0.25 mM for minoxidil and 0.67 mM for the compound disubstituted with N-acetyl-methionine. The monosubstituted compound at a concentration of 0.6 mM, the inhibition is 32%.
• hydroxyl radical has a very short lifespan in order to be able to detect it, an indirect method.
• k x term representing the reactivity of the OH ° radical reacting with the reactants of the Fenton reaction.
• Mannitol is known to be a good sensor of the hydroxyl radical, its rate constant is 1.8.10 ⁇ M ". S '*.
• the new synthesized derivatives have a greater speed constant compared to mannitol ranging from 5 times (reduced minoxidil) to 11 times more (disubstituted) and a significantly greater skin penetration of more than 10 times. 0 Capture of the hydroxyl radical
• the incubation medium consists of 2-deoxyribose (0.6 mM), H2O2 (0.85 mM) and thiobarbituric acid (0.6 mM) in 3 ml of phosphate buffer pH 7.4 (0.024 M Na2HP04 / NaH2P04 - 0.15 M NaCl).
• the reaction is initiated by the addition of the iron EDTA complex (0.13 mM (NH ⁇ Fe SO ⁇ ; 0.143 mM EDTA). After 15 minutes of incubation at 37 ° C, the reaction is stopped by the addition of 1 , 5 ml cold trichloroacetic acid (TCA) (2.8%).

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Cosmetics (AREA)
• Plural Heterocyclic Compounds (AREA)

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• 1993
  • 1993-06-23 FR FR9307821A patent/FR2706896B1/fr not_active Expired - Fee Related
• 1994
  • 1994-06-22 EP EP94920500A patent/EP0705252A1/fr not_active Ceased
  • 1994-06-22 WO PCT/FR1994/000753 patent/WO1995000495A1/fr not_active Application Discontinuation
  • 1994-06-22 US US08/571,832 patent/US5801150A/en not_active Expired - Fee Related

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