WO1986000616A1 - Oxydes de pyrimidine substitues utiles pour favoriser la croissance des cheveux - Google Patents

Oxydes de pyrimidine substitues utiles pour favoriser la croissance des cheveux Download PDF

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Publication number
WO1986000616A1
WO1986000616A1 PCT/US1985/001329 US8501329W WO8600616A1 WO 1986000616 A1 WO1986000616 A1 WO 1986000616A1 US 8501329 W US8501329 W US 8501329W WO 8600616 A1 WO8600616 A1 WO 8600616A1
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Prior art keywords
amino
ethyl
pyrimidine
oxamyl
ethoxy carbonyl
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PCT/US1985/001329
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English (en)
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Gail Sansone Bazzano
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Gail Sansone Bazzano
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Publication of WO1986000616A1 publication Critical patent/WO1986000616A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • 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

Definitions

  • Novel substituted diamino pyrimidine oxides and their salts processes for preparing the compounds as well as the preferred mode of applying the compounds are described. These compounds are used to increase the rate of hair growth and prolong the anagen phase of the hair cycle and as peripheral vasodilators.
  • Minoxidil a 2,4 diamino 6 piperidino pyrimidine-3-oxide is known in the art as an antihypertensive.
  • PCT application U.S. 85/00556 by G. Bazzano describes the use of substituted pyrimidine-oxides for hair growth promotion, particularly carbamate derivatives, and oxadiazolopyrimidine carbamates.
  • the compounds of this invention afford the following advantages: improved solubility, and improved stability of active compounds through in creased dispersion of charge; longer action of compounds; excellent penetration of skin due to the lipophilic substituents; and compatibility of compounds with non-polar solvents useful for the preservation of the polar groups, while in contact with the skin and useful for the encapsulation of the compounds within a syneresis-free hydrophobic polymeric network.
  • This invention relates to compositions of matter and to methods for producing them, their use and their application.
  • this invention relates to novel substituted diamino pyrimidine oxides and their salts of the general formula:
  • R 1 is a moiety selected from the group consisting of substituents of the formula
  • R 3 and R 4 are selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower aralkyl, and lower cycloalkyl, with the proviso that both R 3 and R 4 are not hydrogen, and the heterocyclic functionality systems, N-aziridinyl, N-piperidinyl, N-azetidinyl, N-pyrrolidinyl, hexahydro-1H-azepin-1-yl, 4-alkylpiperazinyl, hexahydro-1(2H)-azocinyl, (wherein the alkyl portion of the moiety is of one to 3 carbon atoms), 4-morpholinyl, 4-thiomorpholinyl, 3,6-dihydro-1(2H)-pyridinyl, 3-pyrrolindyl, 2,3,4,7-tetrahydro-1H-aze ⁇ ine-1-yl, and 3,4,7,8-tetrahydro-1(2H)-azocin
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkoxyalkyl, lower cycloalkyl, lower aryl, lower aralkyl, lower alkaryl, lower alkaralkyl, lower alkoxyaralkyl, and lower haloaralkyl.
  • R 2 can also be selected from the group consisting of chlorine, bromine, iodine, nitroso, nitro, amino, phenylthio, lower alkylphenylthio, and halphenylthio.
  • R 2 can also be assigned in accordance, with the definition applied for R 1 , above. R 1 and R 2 may be the same within the scope of that definition.
  • Precursors of Formulas I - V compounds can be the following :
  • R 1 is as defined above.
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkoxyalkyl, lower cycloalkyl, lower aryl, lower aralkyl, lower alkaralkyl, lower alkaralkyl, lower alkoxyaralkyl, and lower haloaralkyl.
  • R 2 can be selected from the group consisting of chlorine, bromine, iodine, nitroso, nitro, amino, phenylthio, lower alkylphenyithio, and halophenylthio.
  • R 2 is assigned the same definition as R 1 , above.
  • R 2 can be the same as or different than R 1 within the scope of that definition.
  • lower alkyl examples are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, ocyl and isomeric forms thereof.
  • lower alkenyl examples are allyl, 1-methylallyl, 2-methylallyl (methallyl), 2-butenyl (crotyl), 3-butenyl, 1,2-dimethylallyl, 1-dimethylallyl, 2-thylallyl, 1-methyl-2butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 3-pentenyl, 2,3-dimethyl2-butenyl, 1, 1, 2-trimethylallyl, 1, 3-dimethyl-2-butenyl, 1-ethyl-2-butenyl, 4-methyl-2- ⁇ etenyl, 2-ethyl-2-pentenyl, 4, 4-dimethyl-2-pentenyl, 2-heptenyl, 2-octenyl, 5-octenyl, 1, 4-di
  • lower alkoxyalkyl examples include 2-methoxyethyl, 2-ethoxyethyl, 2-butoxyethyl, 2-hexyloxyethyl, 2-octyloxyethyl, 2-methoxypropyl, 3-methoxypropyl, 3-propoxypropyl, 2-methoxybutyl, 3-ethoxybutyl, 4-butoxybutyx, 2-ethoxyhexy,, 3-methoxy-3-methylpentyl, 4-methoxyoctyl, and the like.
  • lower cycloalkyl examples include cyclopropyl, 2-methylcyclopropyl, 2, 2-dimethylcyclopro ⁇ yl, 2,3-diethyl-cyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, 2, 3, 4-trihylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 3-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl, 4-tert-butylcyclobexyl, 3-isopropylcyclohexyl, 2, 2-dimethylcyclohexyl, cycloheptyl, cycoctyl, and the like.
  • lower aryl examples are phenyl, 1-naphtyl, and 2-naphthyl.
  • lower alkaryl examples are o-tolyl, m-tolyl,p-tolyl, methylphenyl, p-tert butylphenyl, the isomeric forms of xylyl, the isomeric forms of trimethylphenyl, 4-methyl-1-naphthyl, 6-propyl-2-naphthyl, 2, 4, 5, 7-tetramethyl-1-naphthyl, and the like.
  • lower aralkyl examples include benzyl, phenethyl, 1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 6phenylhexyl, 5-phenyl-2-methylpentyl, 1-naphthylmethyl, 2-(1-naphthyl)ethyl, 2-(2-napthyl) ethyl and the like.
  • lower alkaralkyl examples include o-tolylmethyl, n-tolyl-methyl, p-tolylmethyl, 4-tert-butylphenylmethyl, 2-(ptolyl)ethyl, 1-(m-tolyl) ethyl, 3-(o-ethylphenyl)propyl, 4-methyl-1-naphthylmethyl, 6-tert-butyl-2-naphthylmethyl, and the like.
  • lower alkoxyaralkyl examples include o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl, 2(m-methoxyphenyl)ethyl,3-(p-ethoxyphenyl)propyl, 4-(p-tert-butoxyphenyl) butyl, 4-methoxyl-1-naphthylmethyl, and the like.
  • lower haloaralkyl examples include o-chloro-benzyl, m-fluorobenzyl, p-bromobenzyl, 2-(m-iodophenyl) ethyl, 2,4-dicloro-benzyl, 6-bromo-1-naphthylmethyl, 4-p-chlorophenyl)butyl and the like.
  • lower alkylphenylthio are o-tolylthio, p-tolylthio, the isomeric forms of xylylthio, p-ethylphenylthio, m-butylphenylthio and the like.
  • halophenylthio examples include p-chlorophenylthio, m-bromophenylthio, o-fluorophenylthio, 3,4-dichlorophenylthio and the like.
  • heterocyclic moieties within the scope of R 1 in addition to those already mentioned above are 2-methylaziridinyl, 2-ethylaziridinyl, 2-butylazirindinyl, 2,3-dimethylaziridinyl, 2, 2-dimethylaziridinyl, 2methylazetidinyl, 3-methylazetininyl, 2-octylazetidinyl, 2,2-dimethylazetidinyl, 3,3-diethylazetidinyl, 2, 4, 4-trimethylazetidinyl, 2, 3, 4-trimethylazetidinyl, 2-methylpyrrolidinyl, 3-butylpyrrolidinyl, 2-isohexylpyrrolidinyl, 2, 3-dimethyl-pyrrolidinyl,2, 2-dimethylpyrrolidinyl, 2,5-diethylpyrrolidinyl, 3-tert-butyl-pyrrolidinyl, 2,3,5-d
  • substituents B and X can be salts or A 1 , A 2 and A 3 represent amides derived by acylation. These can be formed from Ethyl oxallyl chloride or ethyl chloroformate or carboxylic acid anhydrides, carboxylic acid chlorides, as well as Ketene.
  • the compounds can be single compounds or mixtures of compounds depending on such factors as the nature of the reactants and the intermediates or the salts or the acylating agents, and the reaction conditions.
  • acylating agents derived from alkanoic (including half-acid chlorides of dibasic examples) as well as the anhydrides, mixed anhydrides and acid chlorides of alkanoic, cycloalkanoic, alkenoic, cycloalkenoic, aralkanoic, aromatic and heterocylic carboxylic acids.
  • alkanoic including half-acid chlorides of dibasic examples
  • anhydrides mixed anhydrides and acid chlorides of alkanoic, cycloalkanoic, alkenoic, cycloalkenoic, aralkanoic, aromatic and heterocylic carboxylic acids.
  • These anhydrides and acid chlorides can also be substituted on any carbon, but the carbonyl carbon with any of a wide variety of atomic or molecular moieties unreactive with the dihydropyrimidine reactants.
  • substituents are alkyl; e.g., methylthio, propylthio, heptylthio; dialkylamino; e.g., dimethylamino, diethylamino, dihexylamino; alkoxycarbonyl; e.g., methoxycarbonyl, propoxycarbonyl, nonoxycarbonyl; carboxyacyl; e.g., acetyl, butyryl; carboxamido; e.g., benzmido, acetamido; nitro, fluoro; cyano; and the like.
  • Chlorine, bromine and iodine can also be substituents on aromatic portions of the acylating agents.
  • Suitable anhydrides are acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, acrylic anhydride, crotonic anhydride, cyclohexane carboxylic anhydride, benzoic anhydride, naphthoic anhydride, furoic anhydride and the like, as well as the corresponding anhydrides substituted with one or more of the above-mentioned substituents.
  • Suitable acid chlorides are acetyl chloride, propionyl chloride, crotonyl chloride, cyclohexanecarbonyl chloride, 3cyclohexenecarbonyl chloride, phenylacetyl chloride, succinoyl chloride benzoyl chloride, naphthoyl chloride; furoyl chloride, 3-pyridinecarbonyl chloride, phthaloyl chloride and the like, as well as the corresponding acid chlorides substituted with one or more of the above mentioned substituents.
  • acylating agent One molecular equivalent of an acylating agent should be used for the introduction of each acyl moiety.
  • a reactive acylating agent such as ethyl oxalyl chloride
  • heating a cyclized compound is usually obtained.
  • These compounds can be hydrolyzed to the bis or mono acylates.
  • the acylation usually takes place rapidly in the range of -20°C to about +50°C.
  • Suitable diluents are CH 2 Cl 2 ; or, diethyl ether and tetrahydrofuran; ketones; e.g. acetone and methyl ethyl ketone; esters; e.g. methyl acetate and ethyl acetate; acetonitrile; pyridine and the like.
  • the desired acylated product often present from the reaction mixture in crystalline form can be separated in the usual manner; for example, by filtration or centrifugation. Alternately, the diluent can be evaporated, preferably at reduced pressure.
  • the acylates can be purified by conventional techniques; for example, by recrystallization from a suitable solvent or mixture of solvents.
  • the acylates can form salts.
  • the Formula IV through VII compounds can be salts when the cation is (X), represented by protonated primary, secondary or tertiary amines .
  • the amine compounds can be aliphatic and alicyclic in structure.
  • the aromatic and heteroaromatic amines can be substituted or unsubstituted .
  • the cation can be donated by any base stronger than an amine such as NaOH, barium hydroxide, etc. Where the bases constitute primary, secondary and tertiary amines or any base strong enough to remove the hydrogen on the activated urethane group in position 4.
  • the amines referred to above can be represented by the formulas: [1°] R 1 NH 2 [2°] R 1 R 2 NH [3°] R 1 R 2 R 3 N
  • the R groups can be aliphatic and alicyclic amines, aromatic and heteroaromatic amines can also be used.
  • novel compounds of Formulas I through V can also form the following carboxy derivatives:
  • the oxadiazino ring - Product A was opened by treating Product A in base with R 1 R 2 NH for 30 minutes.
  • the resultant Product B is shown below:
  • X will be Na+ if the base is KOH then X will be K+ if the base is NH 4 OH then X will be NH 4 if the base is a primary, soecondary or tertiary amine then X will be:
  • the R's on constituent Z constitute symmetrically and unsymmetrically substituted saturated aliphatic, olefinic, acetylenic, alicyclic, substituted and unsubstituted aromatic and heterocylic groups.
  • novel compounds of Formulas I through V can also form the following carboxy derivatives:
  • X OR where R can be H or CH 3 or any alkyl group or phenyl or other aromatic group or heterocylic group.
  • R 1 CH 3 or alkyl group or aromatic or heterocyclic group.
  • R 2 can be the same or different from R 1 .
  • X S-R where R is defined as R 1 or R 2 in the aforementioned.
  • novel compounds of Formulas I through V can also form the following carboxy derivatives: (Inner Salts)
  • X OR where R can H or CH 3 or any alkyl group or phenyl or other aromatic group or heterocylic group.
  • R 1 CH 3 or alkyl group or aromatic or heterocylic group.
  • R 2 can be the same or different from R 1
  • X S-R where R is defined as R 1 or R 2 above.
  • This invention relates to a method of preparing novel compounds of general formulas I and II.
  • R 3 is an alkyl oxalyl and R 1 is a heterocyclic moiety, or a substituted phenoxy group, or an 0-Tosyl group, and R 2 is hydrogen.
  • the process relates to compounds of the general Formula II, which comprises treating the compound of Formula I with a latent sulfate source such as sulfur trioxide pyridine complex, and sulfur trioxide triethy1 amine complex.
  • a latent sulfate source such as sulfur trioxide pyridine complex, and sulfur trioxide triethy1 amine complex.
  • alkyl oxalyl or an alkoxy carbonyl is used to define the RO- group in which R constitutes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like.
  • alkoxy carbonyl is referred to RO- in which R is the lower alkyl group.
  • R 1 is a heterocyclic moiety containing nitrogen including tetrahydropyridine, piperidine morpholine, pyrrolidine, thiomorpholine, diallylamine, or a substituted phenol such as p-cresol or an 0-tosyl group.
  • derivatives of Formula I are prepared readily by reacting a compound of the Formula III, where R 1 is as previously described.
  • Suitable solvents include chlorinated hydrocarbons, for example, methylene chloride and chloroform.
  • the reaction is spontaneous and is conducted in the temperature range of 0-5°C.
  • the reaction mixture is treated with an aqueous bicarbonate solution, for example, sodium bicarbonate and the two-phase system is then separated.
  • the organic phase is dried and the final product is precipitated using non-polar solvents such as toluene and hexane. See Scheme 1:
  • X, R 2 and R 1 are the same as previously mentioned
  • the majority of the oxamyl compounds have a bright yellow color and are somewhat light sensitive and may decompose to the parent compound on standing over a 6 month period in light on the laboratory shelf, in clear glass.
  • Another part of this invention deals with the synthesis, isolation and characterization of novel 4-[substituted]-2,6-bis (ethoxy carbonyl or alkoxy carbonyl amino)-1-(sulfooxy)-pyrimidinium hydroxide, inner salt of Formula II.
  • R 3 is hydrogen, or methoxy, ethoxy, propoxy-carbonyl and R, is diallylamine, pyrrolidine, piperidine, tetrahydropyridine, morpholino or thiomorpholino.
  • Example: The 4-(1,2,4,6-tetra hydro-1-pyridyl)-2,6-bis (ethoxy carbonyl amino)-pyrimidine-1-oxide (i.e., IV, R 3 is C 2 H 5 -O-Cand R 4 1,2,3,6-tetrahydro-pyridine) was reacted with sulfur trioxide pyridine complex in DMF at room temperature which afforded the 4-(1,2,3,6tetra hydro-1-pyridyl)-2,6-bis(ethoxy carbonyl amino)-1-(sulfooxy) pyrimidinium hydroxide, inner salt.
  • the last compound was synthesized from the parent compound 2,4-diamino-6(p-methylphenoxy)pyrimidine-3-oxide.
  • the parent compound was prepared in the following manner: a) Preparation of 2,4-Diamino-6-(p-methyl-phenoxy)pyrimidine A mixture of 54 g (0.5 mole)of p-Cresol, 7.2 g (0.05 mol) of 2,4-diamino-6-chloro ⁇ yrimidine and 3.5 g of potassium hydroxide was heated at 115-120° for a period of 5 hours. The resulting mixture was cooled slightly at (110°) and subsequently treated with a solution of 14 g of potassium hydroxide in 500 ml of water.
  • the pyrimidine oxides and salts of general Formula I or specific Formulas II through V, and pharmaceutically active inner salts thereof, have potent perpherial vasodilating properties, and are, therefore, useful in causing vasodilation. They are orally, topically and parenterally active. Standard pharmacological tests can be employed to demonstrate the vasodilation, particularly the use of Lazer Doppler Veloximetry. The desirable vasodilation is obtained with no adverse toxicity. (See Table I)
  • compositions which can be administered topically through encapsulation in a polymeric structure.
  • a rodent model of hypotrichosis has been developed. This variant is useful as an animal model of androgenetic alopecia. The variant displays all the characteristics of male pattern alopecia in humans.
  • Extreme hair loss is developed after puberty in males. It is typified by initial hair loss on the crown of the head, continuing to the development of hypotrichosis in these animals, as shown by fewer and smaller hair follicles and greatly enlarged sebaceous glands, especially over the crown of the head and the shoulders and upper back. The limbs tend to remain hairy. The females eventually develop male pattern alopecia but not to the same degree as the males,
  • An increased rate of hair growth is also associated with the administration of the active compounds, as measured by microscopic measurement of the outgrowth of hair after bleaching or dying.
  • topical as employed herein, relates to the use of a compound of the formulas, incorporated in a suitable pharmaceutical carrier, particularly the encapsulation process, and applied at the site of baldness for exertion of local action. Accordingly, such topical compositions include those pharmaceutical forms in which the compound is applied externally by contact with the skin surface to be treated.
  • Conventional pharmaceutical forms for this purpose include ointments, lotions, pastes, jellies, sprays, aerosols, and the like.
  • ointment embraces formulations (including creams) having oleaginous, absorption, water-soluble and emulsion-type bases; e.g., petrolatum, lanolin, polyethylene glycols, as well as mixtures of these.
  • the percentage by weight of the compound of the formulas herein utilized ranges from about 0.1% to about 20.0% of the pharmaceutical preparations; the aforesaid pharmaceutical carrier for topical application constitutes a major amount of the said preparation.
  • the preferred method of applying the compounds of this patent to the skin involves entrapment of the compounds of the instant invention within a syneresis-free hydrophobic polymeric network.
  • the active ingredients are either dissolved or dispersed in the monomer mix and in-situ polymerized.
  • the advantages to be derived are the ability to control the release of the active compounds and the ability to protect the active ingredients from non-specific hydrolysis due to the environmental conditions of contact with the applicant vehicle and with the skin.
  • Polymer entrapment systems such as Polytrap by Wicken Products, N.Y., are useful for this purpose.
  • emollients will provide a good plasticizer for the hydrophobic polymeric lattice, and an emollient base is excellent as a vehicle to apply the active ingredients of the formulation.
  • the active substrate is converted into a free flowing bead formulation by entrapment with a syneresis-free polymeric network which is hydrophobic. Loading as great as 60-80% should be achieved within the polymeric lattice. In this matrix the functional hair growth agent is held by microsorption and protected from hydrolysis and other modes of decomposition providing prolonged shelf-life and in a form superior to an emulsion.
  • the structural integrity of the polymer matrix can be disrupted by mechanical stress or force such as rubbing on application to produce continuous film of the released active component. This protection is particularly important when one or more of the active ingredients has a short half-life, in the absence of encapsulation and upon release.
  • Compound A* 10. o Distilled water q.s. to 100 Cetrimonium Chloride 5.0 Cetyl alcohol 4.0 Ethanol 4.0
  • Butylated hydroxytoluene 1.0 Hydrolized animal protein 0.5 Methylparaben, propylparaben 0.1 Stabilizer 0.1
  • All-trans retinoid acid 0.1 gram and 10 grams of Compound A are dissolved in 100 ml of acetone, and the solution admixed with 900 g of USP grade hydrophilic ointme-nt to a uniform consistency; one gram of butylated hydroxy-toluene is added.
  • the water washable cream ointment thus prepared consists of 0.1% retinoic acid and 10% of Compound A.
  • the active ingredients are entrapped within the polymer.
  • the hydrophobic polymer is plasticized by most entrapped ingredients. The degree of plasticization determines whether the heads are soft, spreadable and film forming with minimal pressure or hard with the ability to withstand shearing, of light intensity.
  • the unexpected novel advantages to be gained from the use of the instant invention are: improved solubility and improved stability and activity of active compounds through increased dispersion of charge; longer action of compounds; excellent penetration of skin due to the lipophilic substituents; and compatibility of compounds with non-polar solvents useful for the preservation of the polar groups while in contact with the skin and useful for the encapsulation of the compounds within a syneresisfree hydrophobic polymeric network.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Plural Heterocyclic Compounds (AREA)
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  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Nouveaux oxydes de pyrimidine substitués et leurs sels, ainsi que l'utilisation de ceux-ci en combinaison avec des rétinoïdes et/ou des analogues de la prostacycline afin d'accroître la vitesse de la croissance des cheveux et de prolonger la phase anagène du cycle des cheveux et de traiter certains types d'alopécies. Les nouveaux avantages inattendus à obtenir de l'utilisation de la présente invention sont: amélioration de la solubilité de la stabilité des composés actifs grâce à une augmentation de la dispersion de charge; prolongation de l'action des composés, excellente pénétration de la peau en raison de substituants lipophiles; compatibilité des composés avec des solvants non polaires utiles pour la préservation des groupes polaires lorsqu'ils sont en contact avec la peau et utiles pour l'encapsulage des composés dans un réseau polymère hydrophobe exempt de synérèse.
PCT/US1985/001329 1984-07-13 1985-07-15 Oxydes de pyrimidine substitues utiles pour favoriser la croissance des cheveux WO1986000616A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US63063984A 1984-07-13 1984-07-13
US630,639 1984-07-13
US72735785A 1985-04-25 1985-04-25
US727,357 1985-04-25

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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0242967A1 (fr) * 1986-03-14 1987-10-28 Unilever Plc Composition de traitement de la peau
WO1989000996A1 (fr) * 1987-07-31 1989-02-09 L'oreal Nouvelles oxadiazolo pyrimidinones, leur preparation et leur utilisation en cosmetique et dermopharmacie
FR2619309A1 (fr) * 1987-08-12 1989-02-17 Oreal Association de derives de pyrimidine et de retinoides en composants separes pour induire et stimuler la croissance des cheveux et diminuer leur chute
EP0327263A1 (fr) * 1988-01-29 1989-08-09 PROCTOR, Peter H. Stimulation de la croissance des cheveux avec nitroxide et autres radicaux
EP0353123A1 (fr) * 1988-07-29 1990-01-31 L'oreal Nouveaux dérivés d'uréylène triamino-2,4,6 pyrimidine oxyde-3, leur préparation et leur utilisation en cosmétique et dermopharmacie
EP0356271A1 (fr) * 1988-08-01 1990-02-28 L'oreal Nouveaux dérivés de diamino-2,4 pyrimidine oxyde-3 et leur utilisation pour le traitement et la prévention de la chute des cheveux
JPH02160710A (ja) * 1988-12-14 1990-06-20 Shiseido Co Ltd 養毛料
EP0408442A1 (fr) * 1989-07-12 1991-01-16 L'oreal Dérivés de pyrimidine oxyde-3 halogénés, leur utilisation pour le traitement et la prévention de la chute des cheveux et pour stimuler leur repousse
FR2657609A1 (fr) * 1990-01-31 1991-08-02 Oreal Nouveaux derives de pyrimidine oxyde-3 halogenes, leur utilisation pour le traitement et la prevention de la chute des cheveux et pour stimuler leur repousse.
EP0519819A1 (fr) * 1991-06-20 1992-12-23 L'oreal Composition pour freiner la chute des cheveux et pour induire et stimuler leur croissance à base de dérivés de pyrimidines N-oxyde trisubstitués en position 2,4 et 6 par une fonction amine, et nouveaux composés pyrimidines N-oxyde
US5352442A (en) * 1985-07-18 1994-10-04 Proctor Peter H Topical tempo
FR2706896A1 (fr) * 1993-06-23 1994-12-30 Caillot Jean Luc
US5470876A (en) * 1985-07-18 1995-11-28 Proctor; Peter H. Topical sod for treating hair loss
US5470861A (en) * 1994-08-04 1995-11-28 Hoffmann-La Roche Inc. Method of promoting hair growth
US5472687A (en) * 1985-07-18 1995-12-05 Proctor; Peter H. Topical pyridine N-oxides
US5714482A (en) * 1985-07-18 1998-02-03 Proctor; Peter H. Topical spin labels and method
US5714510A (en) * 1985-07-18 1998-02-03 Proctor; Peter H. Topical proxyl composition and method
US5716947A (en) * 1985-07-18 1998-02-10 Proctor; Peter H. Topical doxyl composition and method
US5723502A (en) * 1985-07-18 1998-03-03 Proctor; Peter H. Topical spin trap composition and method
US5728714A (en) * 1985-07-18 1998-03-17 Proctor; Peter H. Method for treating hair loss using tempo
US6150405A (en) * 1985-07-18 2000-11-21 Proctor; Peter H. Hair loss treatment with ascorbates
US6667028B2 (en) * 1998-10-01 2003-12-23 Wella Aktiengesellschaft Hair growth promoter
KR100738434B1 (ko) * 2005-09-13 2007-07-12 (주)아모레퍼시픽 피롤리디닐 디아미노피리미딘 옥사이드를 함유하는 화장료조성물
USRE43372E1 (en) 1999-03-05 2012-05-08 Duke University C16 unsaturated FP-selective prostaglandins analogs
US8906962B2 (en) 2000-03-31 2014-12-09 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US9346837B2 (en) 2000-03-31 2016-05-24 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2110111A1 (de) * 1970-03-05 1971-09-16 Sandoz Ag, Basel (Schweiz) Verfahren zur Herstellung von substituierten Pyrimidinen
US4150131A (en) * 1977-02-04 1979-04-17 Hoffmann-La Roche Inc. Substituted oxadiazolopyrimidines
US4150132A (en) * 1977-02-04 1979-04-17 Hoffmann-La Roche Inc. Oxadiazolopyrimidine derivatives
US4220772A (en) * 1978-07-21 1980-09-02 Hoffmann-La Roche Inc. Process for the preparation of oxadiazolopyrimidine derivatives
US4339453A (en) * 1979-07-23 1982-07-13 Merck & Co., Inc. Antimicrobial aminopyrimidinium salts
US4360521A (en) * 1980-12-19 1982-11-23 Hoffmann-La Roche Inc. 7[3,6-Dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate compounds

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0177581A4 (fr) * 1984-04-06 1987-08-10 Gail S Bazzano Compositions stimulant la croissance des cheveux.

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2110111A1 (de) * 1970-03-05 1971-09-16 Sandoz Ag, Basel (Schweiz) Verfahren zur Herstellung von substituierten Pyrimidinen
US4150131A (en) * 1977-02-04 1979-04-17 Hoffmann-La Roche Inc. Substituted oxadiazolopyrimidines
US4150132A (en) * 1977-02-04 1979-04-17 Hoffmann-La Roche Inc. Oxadiazolopyrimidine derivatives
US4220772A (en) * 1978-07-21 1980-09-02 Hoffmann-La Roche Inc. Process for the preparation of oxadiazolopyrimidine derivatives
US4339453A (en) * 1979-07-23 1982-07-13 Merck & Co., Inc. Antimicrobial aminopyrimidinium salts
US4360521A (en) * 1980-12-19 1982-11-23 Hoffmann-La Roche Inc. 7[3,6-Dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate compounds

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Helvetica Chimica Acta, issued 11 May 1982 1-4, 6 Vol. 65, Fasc, 5, Nr. 142, MULLER et al, "Regioselective Synthesis of 2-Oxo-2, 8-Dihydro-(1, 2, 4) -Oxadiazolo (2,3-a) Pyrimidine-7-Carbamates: A New Class of Antihypertensive Peripheral Vasodilators". *
Helvetica Chimica Acta, issued 11 May 1982 Fasc. 5, Nr. 143, MULLER et al "Structure of New 2-Oxo-2,8-Dihydro-(1, 2, 4) Oxadiazolo-(2, 3-a) Pyrimidinecarbamates". *
Helvetica Chimica Acta, issued 30 November 1982, Vol. 66, Fasc. 2 N. 61, MULLER et al "Synthesis of 2-Oxo-2H-(1, 2, 4) Oxadiazolo- (2, 3- c) Pyrimidine-5-Carbamates". pp. 669-672 *
See also references of EP0187854A4 *
The New England Journal of Medicine, issued 26 July 1973, Vol. 289, No. 4, PETTINGER et al, "Minoxidil-an Alternative to Nephrectomy for Refractory Hypertension", pp. 167-171. *

Cited By (45)

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US5728714A (en) * 1985-07-18 1998-03-17 Proctor; Peter H. Method for treating hair loss using tempo
US5714482A (en) * 1985-07-18 1998-02-03 Proctor; Peter H. Topical spin labels and method
US5470876A (en) * 1985-07-18 1995-11-28 Proctor; Peter H. Topical sod for treating hair loss
US5352442A (en) * 1985-07-18 1994-10-04 Proctor Peter H Topical tempo
US6150405A (en) * 1985-07-18 2000-11-21 Proctor; Peter H. Hair loss treatment with ascorbates
US5723502A (en) * 1985-07-18 1998-03-03 Proctor; Peter H. Topical spin trap composition and method
US5472687A (en) * 1985-07-18 1995-12-05 Proctor; Peter H. Topical pyridine N-oxides
US5716947A (en) * 1985-07-18 1998-02-10 Proctor; Peter H. Topical doxyl composition and method
US5714510A (en) * 1985-07-18 1998-02-03 Proctor; Peter H. Topical proxyl composition and method
EP0242967A1 (fr) * 1986-03-14 1987-10-28 Unilever Plc Composition de traitement de la peau
US4871839A (en) * 1986-03-14 1989-10-03 Lever Brothers Company Skin treatment composition
US5034387A (en) * 1987-07-31 1991-07-23 L'oreal 2,4-triaminopyrimidine-3-oxides used in cosmetic and pharmaceutical compositions
US4945093A (en) * 1987-07-31 1990-07-31 L'oreal Novel derivatives of ureylene, 2,4-triaminopyrimidine-3- oxide, their preparation and use in cosmetic and pharmaceutical compositions
EP0304665A1 (fr) * 1987-07-31 1989-03-01 L'oreal Dérivés d'uréylène triamino- 2, 4, 6 pyrimidine oxyde-3, leur préparation et leur utilisation en cosmétique et dermopharmacie
WO1989000996A1 (fr) * 1987-07-31 1989-02-09 L'oreal Nouvelles oxadiazolo pyrimidinones, leur preparation et leur utilisation en cosmetique et dermopharmacie
EP0303871A1 (fr) * 1987-07-31 1989-02-22 L'oreal Oxadiazolo pyrimidinones, leur préparation et leur utilisation en cosmétique et dermopharmacie
US5567702A (en) * 1987-08-12 1996-10-22 L'oreal Combination of pyrimidine derivatives and retinoids, as separate components, for inducing and stimulating hair growth and reducing its loss
BE1001056A3 (fr) * 1987-08-12 1989-06-20 Oreal Association de derives de pyrimidine et de retinoides en composants separes pour induire et stimuler la croissance des cheveux et diminuer leur chute.
GB2208601A (en) * 1987-08-12 1989-04-12 Oreal Combination of pyrimidine derivatives and retinoids, as separate components, for inducing and stimulating hair growth and reducing its loss
DE3827467A1 (de) * 1987-08-12 1989-02-23 Oreal Mittel auf basis von getrennt vorliegenden pyrimidin- und retinoidderivaten zur induktion und stimulation des haarwuchses und zur verringerung von haarausfall
GB2208601B (en) * 1987-08-12 1991-12-11 Oreal Combination of pyrimidine derivatives and retinoids, as separate components, for inducing and stimulating hair growth and reducing its loss
FR2619309A1 (fr) * 1987-08-12 1989-02-17 Oreal Association de derives de pyrimidine et de retinoides en composants separes pour induire et stimuler la croissance des cheveux et diminuer leur chute
DE3827467C2 (de) * 1987-08-12 1998-07-16 Oreal Pharmazeutisches oder kosmetisches Mittel auf Basis von getrennt vorliegenden Pyrimidin- und Retinoidderivaten zur Induktion und Stimulation des Haarwuchses und zur Verringerung von Haarausfall
EP0327263A1 (fr) * 1988-01-29 1989-08-09 PROCTOR, Peter H. Stimulation de la croissance des cheveux avec nitroxide et autres radicaux
EP0353123A1 (fr) * 1988-07-29 1990-01-31 L'oreal Nouveaux dérivés d'uréylène triamino-2,4,6 pyrimidine oxyde-3, leur préparation et leur utilisation en cosmétique et dermopharmacie
US4973474A (en) * 1988-08-01 1990-11-27 L'oreal 2,4-diaminopyrimidine 3-oxide derivatives and their use for the treatment and prevention of hair loss
EP0356271A1 (fr) * 1988-08-01 1990-02-28 L'oreal Nouveaux dérivés de diamino-2,4 pyrimidine oxyde-3 et leur utilisation pour le traitement et la prévention de la chute des cheveux
JPH02160710A (ja) * 1988-12-14 1990-06-20 Shiseido Co Ltd 養毛料
US5132106A (en) * 1989-07-12 1992-07-21 L'oreal Halogenated pyrimidine 3-oxide derivatives, their use for the treatment and prevention of hair loss and for stimulating its regrowth
EP0408442A1 (fr) * 1989-07-12 1991-01-16 L'oreal Dérivés de pyrimidine oxyde-3 halogénés, leur utilisation pour le traitement et la prévention de la chute des cheveux et pour stimuler leur repousse
FR2657609A1 (fr) * 1990-01-31 1991-08-02 Oreal Nouveaux derives de pyrimidine oxyde-3 halogenes, leur utilisation pour le traitement et la prevention de la chute des cheveux et pour stimuler leur repousse.
US5772990A (en) * 1991-06-20 1998-06-30 L'oreal Composition for slowing down the loss of hair based on pyrimidine N-oxides triaminosubstituted or their sulfoconjugated
FR2677884A1 (fr) * 1991-06-20 1992-12-24 Oreal Composition pour freiner la chute des cheveux a base de pyrimidines n-oxyde trisubstitues ou leurs derives sulfoconjugues, nouveaux composes pyrimidines n-oxyde ou leurs derives sulfoconjugues.
EP0519819A1 (fr) * 1991-06-20 1992-12-23 L'oreal Composition pour freiner la chute des cheveux et pour induire et stimuler leur croissance à base de dérivés de pyrimidines N-oxyde trisubstitués en position 2,4 et 6 par une fonction amine, et nouveaux composés pyrimidines N-oxyde
FR2706896A1 (fr) * 1993-06-23 1994-12-30 Caillot Jean Luc
US5801150A (en) * 1993-06-23 1998-09-01 Caillot; Jean-Luc Aminopyri(mi)dine derivatives combined with amino acids, and pharmacological activities thereof
WO1995000495A1 (fr) * 1993-06-23 1995-01-05 Louis Jung Derives d'aminopyri(mi)dines associes a des acides amines, et leurs activites pharmacologiques
US5470861A (en) * 1994-08-04 1995-11-28 Hoffmann-La Roche Inc. Method of promoting hair growth
US6667028B2 (en) * 1998-10-01 2003-12-23 Wella Aktiengesellschaft Hair growth promoter
USRE43372E1 (en) 1999-03-05 2012-05-08 Duke University C16 unsaturated FP-selective prostaglandins analogs
US8906962B2 (en) 2000-03-31 2014-12-09 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US9346837B2 (en) 2000-03-31 2016-05-24 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US9579270B2 (en) 2000-03-31 2017-02-28 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US9675539B2 (en) 2000-03-31 2017-06-13 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
KR100738434B1 (ko) * 2005-09-13 2007-07-12 (주)아모레퍼시픽 피롤리디닐 디아미노피리미딘 옥사이드를 함유하는 화장료조성물

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