EP0187854A1

EP0187854A1 - Substituted pyrimidine oxides useful for hair growth promotion

Info

Publication number: EP0187854A1
Application number: EP85903903A
Authority: EP
Inventors: Gail S Bazzano
Original assignee: Individual
Current assignee: Individual
Priority date: 1984-07-13
Filing date: 1985-07-15
Publication date: 1986-07-23
Also published as: EP0187854A4; WO1986000616A1

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.New substituted pyrimidine oxides and their salts, as well as their use in combination with retinoids and / or prostacyclin analogs to increase the rate of hair growth and prolong the anagen phase of the cycle hair and to treat certain types of alopecia. The new unexpected advantages to be obtained from the use of the present invention are: improvement in the solubility of the stability of the active compounds by virtue of an increase in the dispersion of charge; prolonged action of the compounds, excellent penetration of the skin due to lipophilic substituents; compatibility of the compounds with non-polar solvents useful for the preservation of the polar groups when they are in contact with the skin and useful for the encapsulation of the compounds in a hydrophobic polymer network free from syneresis.

Description

Substituted Pyrimidine Oxides Useful for Hair Growth Promotion

Brief Summary of the Invention

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.

Cross References to Related Applications

This application is related in part to application serial U.S. 235, 169, filed February 17, 1981; application serial U.S. 318,697, filed November 9, 1981; application serial U.S. 386,730 filed June 9, 1982, and: application serial U.S. 414,854 filed September 3, 1982, and patents listed as follows: German Offec. 2,804,518 filed August 17, 1978; U.S. Patents 4,220,772 and 4,256,886; German Offeiu 2,804,519 filed August 10, 1978; Swiss Applic. 78/7,910 filed July 21, 1978: Chimica Acta Vol. 65 Fasc. 5 (1983), pp. 669-672: U.S. Patents 4,150,131 and 4,360,521 and Belgium Patent No. 893,333 filed January 14, 1983 and CH application 81/4,640 filed July 15, 1981, as well as U.S. Pat. Nos. 3,461,461, 3,382, 248, 3,973,016, 4,287,338, 3,464,987 and the British Patent No. 1,486, 682.

Background of the Invention:

Minoxidil, a 2,4 diamino 6 piperidino pyrimidine-3-oxide is known in the art as an antihypertensive. U.S. Patent 4,139,619, to Chidsey, describes the use of minoxidil and derivatives as hair growth promoters.

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.

It is the purpose of the present invention to provide additional compounds which overcome some of the problems inherent in the use of previously described compounds.

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.

Field of the Invention:

This invention relates to compositions of matter and to methods for producing them, their use and their application. In particular, this invention relates to novel substituted diamino pyrimidine oxides and their salts of the general formula:

More specific salt forms of this compound could be written as follows;

wherein, in Formulas I through V, R₁ is a moiety selected from the group consisting of substituents of the formula;

wherein R₃ and R₄ are selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower aralkyl, and lower cycloalkyl, with the proviso that both R₃ and R₄ 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-azeρine-1-yl, and 3,4,7,8-tetrahydro-1(2H)-azocinyl, each of said heterocyclic groups having attached as substituents on carbon atoms thereof zero to 3 lower alkyls, inclusive, a nitrogen atom of each of said heterocyclic moieties being the point of attachment of R₁ to the ring in said formula. When R₁ is N-R₃R₄, R₃ and R₄ can be alike or different. When R₁ is a heterocyclic moiety, the alkyls which can be attached thereto can all be different, or any two or all of them can be alike.

In Formulas I - V, R₂ 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. In Formulas I - V, R₂ can also be selected from the group consisting of chlorine, bromine, iodine, nitroso, nitro, amino, phenylthio, lower alkylphenylthio, and halphenylthio. In Formulas I - V, R₂ can also be assigned in accordance, with the definition applied for R₁, above. R₁ and R₂ may be the same within the scope of that definition. Precursors of Formulas I - V compounds can be the following :

wherein, in each instance, R₁ is as defined above.

In Formulas VI and VII, R₂ 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. In Formulas VI and VII, R₂ can be selected from the group consisting of chlorine, bromine, iodine, nitroso, nitro, amino, phenylthio, lower alkylphenyithio, and halophenylthio. In Formulas VI and VII, R₂ is assigned the same definition as R₁, above. R₂ can be the same as or different than R₁ within the scope of that definition.

Examples of lower alkyl are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, ocyl and isomeric forms thereof. Examples of lower alkenyl 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-ρetenyl, 2-ethyl-2-pentenyl, 4, 4-dimethyl-2-pentenyl, 2-heptenyl, 2-octenyl, 5-octenyl, 1, 4-dimethyl, 4-hexenyl, and the like. Examples of lower alkoxyalkyl are 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. Examples of lower cycloalkyl are cyclopropyl, 2-methylcyclopropyl, 2, 2-dimethylcycloproρyl, 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. Examples of lower aryl are phenyl, 1-naphtyl, and 2-naphthyl. Examples of lower alkaryl 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. Examples of lower aralkyl are 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. Examples of lower alkaralkyl are 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. Examples of lower alkoxyaralkyl are 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. Examples of lower haloaralkyl are 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. Examples of lower alkylphenylthio are o-tolylthio, p-tolylthio, the isomeric forms of xylylthio, p-ethylphenylthio, m-butylphenylthio and the like. Examples of halophenylthio are p-chlorophenylthio, m-bromophenylthio, o-fluorophenylthio, 3,4-dichlorophenylthio and the like.

Examples of heterocyclic moieties within the scope of R₁ 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-trimethylpyrrolidinyl, 3,4-dioctylpyrrolidinyl, 2-methyl-piperidino, 3-methylpiperidino, 4-methylpiperidino, 3-isopropylpiperidino, 4-tert-butylpiperidino, 2-methyl-5-ethylpiperidino, 3, 5dipentylpiperidino, 2, 4, 6-trimethylpiperidino, 2, 6-dimethyl-4-octylpiperidino, 2, 3, 5-triethyl-piperidino, 2-ethylhexahydroazepinyl, 4-tertbutylhexalhydroazepinyl, 3-heptylhexa-hydroazepinyl, 2, 4-dimethylhexahydroazepinyl, 3, 3-dimethylhexahydroazepinyl, 2, 4, 6-triproρylhexahydro azepinyl, 2-methylheptamethylenimino, 5-butylheptamethylenimino, 2, 4diisopropylheptamethylenimino, 3, 3-diethylheptamethylenimino, 2, 5, 8trimethylheptamethylenimino, 3-methyloctamethylenimino, 2, 9-diethyloctamethylenimino, 4-isooctyloctamethylenimino, 2-ethylmorpholino, 2-methyl-5ethylmorpholino, 3, 3-dimethylmorpholino, 2, 6-ditert-bύtylmorpholino, 4-methylpiperazinyl, 4-isopropylpiperazinyl and the like. In each of the above examples of heterocyclic moieties, the free valence and hence the point of attachment to a carbon atom of the pyrimidine ring, is at the heterocyclic nitrogen atom.

In the novel Formulas I through V substituents B and X can be salts or A₁, A₂ and A₃ 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.

Although substantially any acylating agent can be used to produce these acylates, especially suitable are 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. 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. Examples of such 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.

Examples of 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. Examples of 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.

One molecular equivalent of an acylating agent should be used for the introduction of each acyl moiety. When a reactive acylating agent such as ethyl oxalyl chloride is used with 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 CH₂Cl₂; 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.

Example Page

Further Examples of Acyl Derivatives Alkoxyacyl Derivatives (Carbamates)

Alkoxyoxalyl Derivatives (Oxamates) or (Oxoacetates)

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°] R₁NH₂ [2°] R₁R₂NH [3°] R₁R₂R₃N the R groups can be aliphatic and alicyclic amines, aromatic and heteroaromatic amines can also be used.

The novel compounds of Formulas I through V can also form the following carboxy derivatives:

The X in the above Formula I can be represented by the following: X=OR where R can be H or CH₃ or any alkyl group or phenyl or other aromatic group or heterocylic group.

X = NR₁R₂ where R₁=R₂=H R₁ = CH ₃ or alkyl group or aromatic or heterocylic group. R₂ can be the same or different from R₁.

X = S-R where R is defined as R₁ or R₂ above. (11)

The oxadiazino ring - Product A was opened by treating Product A in base with R₁ R₂NH for 30 minutes. The resultant Product B is shown below:

Product B when treated with strong bases yields the product shown¬

If the base is NaOH then X will be Na+ if the base is KOH then X will be K+ if the base is NH₄OH then X will be NH₄ if the base is a primary, soecondary or tertiary amine then X will be:

NR₁, NR₁R₂ or (.U)

Z in the above formula can be :

Z - S-R

The R's on constituent Z constitute symmetrically and unsymmetrically substituted saturated aliphatic, olefinic, acetylenic, alicyclic, substituted and unsubstituted aromatic and heterocylic groups.

(Inner Salts)

The X in the above Formula II can be represented by the following: X = OR where R can be H or CH₃ or any alkyl group or phenyl or other aromatic group or heterocylic group.

X - NR₁R₂ where R₁ = R₂ = H

R₁ = CH₃ or alkyl group or aromatic or heterocyclic group. R₂ can be the same or different from R₁. X = S-R where R is defined as R₁ or R₂ in the aforementioned.

The novel compounds of Formulas I through V can also form the following carboxy derivatives: (Inner Salts)

III

The X in the above Formula III can be represented by the following: X = OR where R can H or CH₃ or any alkyl group or phenyl or other aromatic group or heterocylic group.

X = NR₁R₂ where R₁= R₂= H

R₁ = CH₃ or alkyl group or aromatic or heterocylic group. R₂ can be the same or different from R₁

X = S-R where R is defined as R₁ or R₂ above.

Invention Technical Process Data

This invention relates to a method of preparing novel compounds of general formulas I and II.

I ^"

where R₃ is an alkyl oxalyl and R₁ is a heterocyclic moiety, or a substituted phenoxy group, or an 0-Tosyl group, and R₂ is hydrogen.

In another aspect 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.

II where R₂ is hydrogen, R₃ is carbamate or alkyl oxalyl and R₁ is the same as that described above. Detailed Description of the Invention

The 4-[substituted]-2,6-bis(alkyl oxamyl)-pyrimidine-1-oxides and their corresponding inner salts, obtained according to the process of this invention, have the general Formula I and II, where R₃ is an

alkyl oxalyl or an alkoxy carbonyl. The term "alkyoxalyl" is used to define the RO- group in which R constitutes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like. The term "alkoxy carbonyl" is referred to RO- in which R is the lower alkyl group. R₁ 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.

According to the invention, derivatives of Formula I are prepared readily by reacting a compound of the Formula III, where R₁ is as previously described.

with an excess of an alkyl oxalyl halide of structure A, or with an excess of an alkyl halo formate, of structure B.

« in the presence of an amine such as pyridine or triethylamine.

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:

Scheme 1

X, R₂ and R₁ 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.

In general these compounds could be prepared by two different methods shown in Schemes II and III.

In Method II (Scheme II) the novel 4-[substituted]-2,6-bis (alkyl oxalyl amino)-pyrimidine 3-oxides are treated at room temerature with sources of sulfur trioxide such as sulfur trioxide pyridine complex, or sulfur trioxide triethyl amine complex, in an inert solvent such as dimethyl formamide (DMF) or acetonitrile at room temperature. The sulfur trioxide reacts directly to form a sulfate with the substituted pyrimidine N-1 oxides, and is used in excess, usually in ratio of 1:2 or 1:1.5. Alternatively in Method III (see Scheme III) the 2,4-diamino-6-[substituted]pyrimidine-3-oxide is converted to 2,6-diamino-4-[substituted-1-(sulfooxy) -pyrimidinium hydroxide, inner salt by a reaction with a latent sulfur trioxide source, which subsequently is treated with an alkyl oxalyl halide, preferably ethyl oxalyl chloride to yield the corresponding substituted pyrimidine-0-sulfates.

Also considering Formula IV (See Scheme IV)

wherein R₃ 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, R₃ is C₂H₅-O-Cand R₄ = 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.

This process must also include the preparation of the starting materials of Formula III, some of which have been claimed with a different method, in U.S. Patent 3,461,461, but surprisingly enough, no record of their syntheses and physical data is presented. These were all made and used as intermediate compounds in the invention of I and II. Another novel compound, 2,4-diamino-6-(para-methyl-phenoxy) pyrimidine was synthesized by reacting p-cresol with 2,4-diamino-6-chloropyrimidine which was subsequently oxidized to 6-amino-4 (Para-methyl-phenoxy) 1,2dihydro-1-hydroxy-2-amino pyrimidine using peracetic acid 40%. Further on reacting the above mentioned compound with ethyl oxalyl chloride at 0-5°, 4-[Para-methyl phenoxy]-2,6-bis (ethyl oxalyl amino)-pyrimidine-1oxide was found.

See Scheme V.

Examples

The following examples will furnish further illustrations of the synthesis. All temperatures are reported in degree centrigrade. The elemental analyses are within ± 0.4% of theory unless otherwise stated. The melting points are not corrected. All N → O compounds gave a positive test with ferric chloride solution.

Example 1

Preparation of 4-(1,2,3,6-Tetrahydro-1-pyridyl)-2,6-bis(ethyl oxamyl) pyrimidine-1-oxide. A 0.5 g (0.0024 mol), sample of 2,6-diamino-4 (1,2, 3,6-Tetrahydro-1-pyridyl) pyrimidine-1-oxide was suspended in (2.4 mmol), a solution of 15 ml of methylene chloride containing 1.5 ml of pyridine. The mixture was cooled to 5º and 1-3 ml (0.012 mol) of ethyl oxalyl chloride was added dropwise to the suspension and stirred. The reaction occurred instantaneously and a yellow precipitate deposited. The precipitate was collected on a filter, washed several times with an aqueous solution of sodium bicarbonate, and separated. The organic phase was then dried, concentrated in vacuo, and 10 ml of hexane was added to precipitate a bright yellow compound which was recrystallized from methylene chloride affording 0.54 g, (56.1%) of the product.

Melting point (194-195°) C₁₇H₂₁N₅O₇

C:H:N:O 50.1:5.15:17.1:27.5

Example 2

Preparation of 4-(Piperidinyl)-2,6-bis (ethyl oxamyl)-pyrimidine 1oxide. A solution of 1.0 g (0.4 mmol) Minoxidil in 15 ml methylene chloride and containing 7 ml of pyridine, was treated with 5 ml (0.04 mol) ethyl oxalyl chloride added over a period of 10 minutes at 0°. The mixture was washed with a solution of sodium bicarbonate and the organic phase was then separated, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. Upon addition of a mixture of toluene (3 ml) and hexane (5 ml), a precipitate was deposited and then collected on a filter and dried under reduced pressure to give 1.16 g (56%) of the title compound of melting point 165-168°.

C:H:N:O 49.8:5.62:17; 1 :27.3 Similar reactions were conducted on 2,6-diamino-4-(morpholinyl)pyrimidine 1-oxide, 2,6-diamino-4-(pyrrolidinyl)-pyrimidine-1-oxide. 2,6-diamino-4(p-methyl phenoxy)pyrimidine-1-oxide, and was treated with an excess of ethyl oxalyl chloride 4-(morpholinyl)-2,6 bis (ethyl oxamyl) -pyrimidine-1-oxide, which respectively afforded, with the melting point of 182-184°, C:H:N:O 46.7:5.10:17.0:31.1, C₁₆H₂₁N₅O₈, Wpyrrolidinyl) -2,6-bis (ethyl oxamyl)-pyrimidine-1-oxide, with a melting point of 222223°, C₁₅H₂₁N₅)₇. C:H:N:O, 48.6:5.3:17.7:28.3, as well as 4-(p-methyl phenoxy) 2,6-bis (ethyl oxamyl)-pyrimidine-1-oxide, melting point 172174°, C:H:N:O 52.6:4.71:13.13:29.5, respectively.

It is noteworthy, that 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-chloroρyrimidine 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. Upon addition of 50 ml of ethanol, a solid 6.0 g (57%) was deposited and collected and recrystallized from acetonitrile (melting point = 277-279°). b) Preparation of 2,4-Diamino-6-(p-methyl-phenoxy)pyrimidine 3-oxide A mixture of 4.0 g (0.02 mol) of 2,4-dxamino-6(p-methyl phenoxy) pyrimidine was suspended in 100 ml of methanol and cooled to 0-5°. A solution of 3.2 g (0.02 mol) of m-chloro perbenzoic acid in 30 ml of methanol and was then added over a period of 15 minutes to the suspension. The resulting mixture was stirred for three hours and the excess solvent removed under reduced pressure. The residue was then dissolved in 50 ml of ethylacetate, and the solution extracted 3 times with 2% aqueous sodium hydroxide. The organic phase was separated, dried and concentrated. Upon cooling to 0°, a precipitate deposit which was collected on filter and air-dried to give 1.9 g (45%) of the oxide, melting point 255-258°. C₁₁H₁₂N₄O₂, C:H:N:O, 56.8:5.17:24.1:13.7 Example 3

Preparation of 2,6-bis(ethyl oxamyl)-4-(pyrrolidinyl)-1-(sulfooxy)pyrimidinium hydroxide, inner salt. A mixture of 0.5 g (0.2 mmol) of 2,6diamino-4-(pyrrolidinyl)-1-(sulfooxy)-pyrimidinium hydroxide inner salt in 8 ml pyridine and 15 ml methylene chloride was cooled externally with ice. 2 ml (10.01 mol) of cold ethyl oxalyl chloride was added dropwise to the mixture. The reaction occurs instantly, with a yellow precipitate immediately forming. The resulting mixture was collected on a filter, washed several times with an aqueous solution of sodium bicarbonate and separated. The organic phase was then dried, concentrated and crystallized from toluene which afforded 0.6 g (65%) of a yellow product.

Example 4

Preparation of 2,6-bis(ethyl oxamyl)-4-(piperidinyl)-1-(sulfooxy)pyrimidinium hydroxide, inner salt. A mixture of 0.2 g (0.4 mmol) of 4(piperidinyl)2,6-bis(ethyl oxamyl)-pyridine-1-oxide and 0.4 g (0.2 mmol) of sulfur trioxide pyridine complex in 10 ml of dimethyl formamide (DMF) and was stirred at room temperature for a period of 4 hours. The organic phase was then dried, concentrated in vacuo, and hot acetonitrile was added to the residue to precipitate a bright yellow compound. The solid was washed with water and then washed repeatedly with ether. The yield was 0.07 g (28%), affording a bright yellow compound.

Example 5

Preparation of 2,6-bis(ethyl oxamyl)-4-(piperidinyl)-1-(sulfooxy) pyrimidinium hydroxide, inner salt. A mixture of 1.0 g (0.3 mmol) of 2,6diamino-4-(piperidinyl)-1(sulfooxy)-pyrimidinium hydroxide, inner salt (Minoxidil sulfate) was dissolved in 20 ml of dimethyl formamide and 3 ml of pyridine in 10 ml of cold methylene chloride was also added to the mixture dropwise. 20 ml of methylene chloride was added and the resulting mixture was washed several times with an aqueous solution of sodium bicarbonate. The methylene chloride layer was then separated, dried and concentrated. The product was then crystallized from hot acetonitrile which yielded 0.5 g (30%) of the product. Example 6

Preparation of 2,6-bis(ethyl oxamyl)-4-(1,2,3,6-Tetrahydro pyridyl)1-(sulfooxy)-pyrimidlnium hydroxide, inner salt. Following Example 5, and using 2,6-diamino-4(1,2,3,6-Tetrahydro pyridyl)-1-(sulfooxy)-pyrimidinium hydroxide, inner salt and ethyl oxalyl chloride, there was obtained, the title compound.

Example 7

Preparation of 2,6-bis (ethoxy carboxyl amino)-4-(1,2,3,6-Tetrahydro pyridyl)-1-(sulfooxy)-pyrimidinium hydroxide inner salt. 0.3 g (0.8 mmol) of 4-(1,2,3,6-Tetrahydro-1-pyridyl)-2,6-bis(ethoxy carbonyl amino)-pyrimidine-1-oxide was dissolved in a mixture of 15 ml of dimethyl formamide and 20 ml of CH₂Cl₂, The resulting mixture was reacted and stirred with 0.6 g (0.3 mmol) of sulfur trioxide pyridine complex at room temperature for a period of 2.5 hours and the excess solvents were removed under reduced pressure. The residue was cooled at 0-5° and was triturated with hot acetonitrile, affording 0.3 g (83%) of a white crystalline substance, with a melting point of 147-148°.

Example 8

Preparation of 2,6-dlamino-4-(1-pyrrolidinyl)-1-(sulfooxy)-pyrimidinium hydroxide, inner salt. A mixture of 1 g (0.5 mmol) of 2,6-diamino-4 (1-pyrrolidinyl)-pyrimidine 1-oxide and 1.6 grams (0.01 mol) of sulfur trioxide pyridine complex in 15 ml of dimethyl formamide were stirred at 25° for a period of 2 hours. The precipitate deposit was collected on a filter, washed with water and dried, which gave 1.2 g (86%) of the title compound, with a melting point of 225-227°.

C:H:N:O:S 34.9:4.72:25.4:23.2:11.6

Example 9

Also following Example 8, but using 2,6-diamino-4-(diallylamine)pyrimidine-1-oxide and sulfur trioxide pyridine complex and also reacting 2,6diamino-4-(1,2,3,6-Tetrahydro-1-pyridyl)pyrimidine-1-oxide with sulfur trioxide pyridine complex in dimethyl formamide, there were obtained respectively 2,6-diamino-4-(diallylamine)-1-(sulfooxy)-pyrimidinium hydroxide, inner salt with the melting point of 174-175° and 2,6-diamino-4(1,2,3,6-tetra hydro-1-pyridyl)-1-(sulfooxy)-pyrimidinium hydroxide, inner salt with the melting point of 207-209°. Example 10 Preparation of 4-(pyrrolydinyl)-2,6-bis (ethoxy carbonyl amino)-pyrimidine -1-oxide

A mixture of 1.0 g (0.5 mmol) of 2,6-diamino-4-(pyrrolydinyl)-pyrimidine-1-oxide in 15 ml methylene chloride containing 2 ml of pyridine was stirred and cooled in ice-bath. Ethyl chloroformate, 2.5 ml (0.02 mol) was added over a period of 15 minutes at 0°. The mixture was stirred for % hour in 0-5°C, and then over night at room temperature. The precipitate was washed with water, the organic phase was separated, dried and concentrated which afforded 1.2 g (70%) of a solid with the melting point of 155-157°. C:H:N:O 49.5:6.1:20.6:23.5

Example 11

Preparation of 2,6-bis (ethoxy carbonyl amino)-4-(pyrrolidinyl)-1-(sulfooxy) -pyrimidinium hydroxide inner salt

0.6 g (0.1 mmol) of 4-(pyrrolidinyl)-2,6-bis(ethoxy carbonyl amino)pyrimidine-1-oxide and 1 g (0.006 mol) of sulfur trioxide pyridine complex were reacted at room temperature in 10 ml of dimethyl formamide (DMF). The mixture was stirred overnight which afforded a precipitate. The solvent was removed under reduced pressure. The residue was coo Led in an ice bath and crystallized from hot acetonitrile, affording 0.7 g (95%) of a white crystalline substance with a melting point of 165-167°.

C:H:N:O 40.0:5.01:16.7:30.5:7.63

Example 12

Preparation of 4-(diallylamino)-2,6-bis(ethoxy carbonyl amino)-pyrimidine¬

1-oxide

1 g (0.004 mol) of 2,6-diamino-4-(diallylamino)-pyrimidine-1-oxide was suspended in 15 ml methylene chloride and cooled at 0-5°. 1.8 ml (0.022 mol) of pyridine was added to the suspension. Cold ethyl chloroformate, 2.1 ml (0.022 mol) was added dropwise over a period of ten minutes. The mixture was stirred for ½ hour at 0-5°C, and then washed several times with water (30 ml). The organic layer was dried and concentrated under reduced pressure which afforded 1.2 g (73%) of a white crystalline solid with the melting point of 134-135°. C:H:N:O 52.6:6.30:19.1:21.9 Example 13

Preparation of 2,6-bis(ethoxy carbonyl amino)-4-(diallylamino)-1-(sulfooxy) -pyrimidinium inner salt

100 mg (0.27 mmol) of 4-diallylamino-2,6-bis (ethoxy carbonyl amino)pyrimidine-1-oxide, and 200 mg (1.2 mmol) of sulfur trioxide pyridine complex were dissolved in 10 ml dimethyl formamide (DMF) and stirred at room temperature overnight. Dimethyl formamide was removed under reduced pressure. The residue was cooled at 0-5° and was triturated with hot acetonitrile, affording 95 mg (79%) of a white compound, with a melting point of 150-152°. C:H:N:O 43.1:5.16:15.7:28.7:7.19

Example 14

Preparation of 4-0-tosylyl-2,6-bis-(ethyl oxamyl)-pyrimidine-1-oxide

1 g (3.3 mmol) of 2,4-diamino-6-0-tosylated pyrimidine-3-oxide was suspended in 30 ml of methylene chloride containing 2 ml of pyrimidine. The mixture was stirred and cooled at 5° and 2 ml (16.8 mmol) of ethyl oxalyl chloride was added dropwise over a period of ten minutes. A yellow-orange solution was formed which on further stirring, yielded a yellow precipitate. The precipitate was washed several times with a solution of sodium bicarbonate. The organic phase was separated, dried, and concentrated, affording a yellow precipitate.

Using the method of the examples given above, and starting with the appropriate 3-oxide, all of the compounds of this invention are synthesized.

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)

It is the object of the present invention to provide improved compositions which are effective in increasing the rate of hairgrowth on mammalian skin.

It is also an object of this invention to provide such improved compositions in combination with retinoids and/or prostacyclin analogues for topical applications to mammalian skin in order to stimulate or improve the rate of hair growth thereon and to prolong the anagen phase of the hair cycle.

It is a further object of this invention to provide such compositions which can be administered topically through encapsulation in a polymeric structure.

900 = Minoxidil Sulfate

907 = 4-(morpholino)-2,6-bis(ethyl oxamyl)-pyrimidine-1-oxide

909 = 4-(pyrrolidinyl)-2,6-bis(ethyl oxamyl)-pyrimidine-1-oxide

1001 - 4-(1,2,3,6-tetrahydro-1-pyridyl)-2,6-bis(ethyl oxamyl)-pyrimidine-1oxide

1005 = 2,6-diamino-4(pyrrolidinyl)-1-(sulfooxy)-pyriminium hydroxide, inner salt

1009 = 2,6-diamino-4(1,2,3,6-tetra hydro-1-pyridyl)-1-(sulfooxy)-pyrimidinium hydroxide, inner salt

903 = 4-(piperidinyl)-2,6-bis(ethyl oxamyl)-pyrimidine-1-oxide

* - Laser Doppler,

Perimed Co ., SWEDEN Hairgrowth Data

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,

On subcutaneous implantation of a pellet of the active compounds a decrease in hair loss was observed. A significantly prolonged anagen phase of the hair cycle was observed, associated in a dose response fashion with the uptake of the implanted substance.

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.

The term "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. The term "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.

While the following examples describe the manner and process of making and using the invention and set forth the best mode contemplated by the inventor of carrying out the invention but are not to be construed as limiting.

Improved Method of Applying the Compounds of the Instant Invention:

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.

Amongst several available systems, the Polymer entrapment systems, such as Polytrap by Wicken Products, N.Y., are useful for this purpose.

Examples

Most 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.

In this manner it is possible to hold the functional materials under controlled conditions for availability on demand. This system offers the advantage that retinoids, see PCT U.S. 82/01593 can be incorporated as additional functional materials, within a similar polymeric network.

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.

An example of these entrapment systems for topical applications of the compositions is the Polytrap system of Wicken Products, N.Y. The following Examples illustrate the applicant vehicles for the present invention. The methods of administration may vary by lotion, cream, ointment, polymeric beadlets, supplement to chow, coating for seeds, etc. These Examples are only meant to be illustrative and do not limit the mode of administration nor the ingredients which can be admixed to the present invention, nor the amounts which may be used.

Example 1

Lotion formulation for the topical administration % wt to wt

Active ingredients:

I. All-trans retinoid acid 0.1

II. Compound A* 3.0

Ethanol q.s to 100.0

Propylene glycol 5.0

Butylated hydroxytoluene 0.1

Safflower oil 1.0

- tocopherol acetate 0.5

Stabilizer 0.1

Example II

Cream conditioner for Topical Administration

Active ingredients:

I. All-trans retinoid acid 1.0, (entrapped in polymeric beadlets)

II. 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

* bis-2,6-(ethyloxamyl)-4-(pyrrolidinyl)-pyrimidine-1-oxide Example III

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.

Example IV

Polymeric Beadlets for topical administration

Compound A 1 gram

Active ingredients all-trans retinoic acid and

Compound A entrapped in a acrylates copolymer 25 mg.

Emolient Base 100 ml.

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.

Claims

CLAIMS I claim:

1.) Substituted pyrimidine oxides useful for increasing the rate of hair growth and prolonging the anagen phase of the hair cycle, comprising compounds of the following formula:

wherein, a) R₁ and R₄ are alkoxy b) R₁ and R₄ = alkoxyacyl groups, such as ~ ~ ~ ~ 5 where the alkoxy R₅ moiety is derived from lower alcohols, c) R₂ and R₃ consist of lower alkyl substituents or hydrogen which may be the same or different, with the restriction that if R₂ is hydrogen, R₃ is neither hydrogen or methyl or the reverse; R₂ and R₃ can be alkenyl of

3 to 8 carbon atoms, cyclo alkyl groups incorporating 3 to 8 carbon atoms or phenylalkyl in which the alkyl moiety consists of 1 to 3 carbon atoms as well as R₂ and R₃ linked to form heterocyclic groups including the following: 1-pyrrolidinyl, 1-tetrahydropyridyl, 3-pyrrolidyl, aziridinyl, azetidinyl, piperidino, hexahydroazepinyl, heptamethylenemino, octamethylenimino, thiomorpholino, morpholino, 4-lower-alkyl-piperazinyl, and optionally bearing 1 to 3 alkyl groups including methyl, ethyl, npropyl and 2-propyl and butyl, and where X is oxide group o- or OSO-₃,

2. ) A process for the preparation of compounds of the general formula :

R

wherein R =~ - OR- or R = - O - R₃ where R₃ is a lower alkyl such as methyl, ethyl, propyl, butyl and wherein R₁ is a heterocyclic moiety such as pyrrolidino, morpholino, piperidino, diallylamine or tetrahydropyridyl, thiomorpholine or R₁ is diallylamino or R₁ is a substituted phenol or an 0-Tosyl group, which comprises reacting compounds of the formula:

with an alkyl oxalyl halide or an alkyl haloformate and optionally reacting the resultant compound with a latent sulfur source such as sulfur trioxide pyridine complex and sulfur trioxide triethylamine.

3.) A composition useful for increasing the rate of hair growth on mammalian skins, prolonging the anagen phase of the hair cycle and for treating various types of alopecias, comprising an effective amount of a compound selected from the series of Claim 1 and including:

6-amino-2-(ethyl oxamyl)-4-(thiomorpholinyl)-1-(sulfooxy)-pyrimidinium hydroxide inner salt.

6-amino-2-(ethyl oxamyl)-4-(pyrrolidinyl)-1-(sulfooxy)-pyrimidinium hydroxide inner salt.

6-amino-2-(ethyl oxamyl)-4-(piperidinyl)-1-(sulfooxy)-pyrimidinium hydroxide inner salt.

6-amino-2-(ethyl oxamyl)-4-(1,2,5,6-tetra hydro pyridyl)-1-(sulfooxy)-pyrimidinium hydroxide inner salt.

6-amino-2-(ethyl oxamyl)-4-(p-methyl-phenoxy)-1-(sulfooxy)-pyrimidinium hydroxide inner salt.

6-amino-2-(ethyl oxamyl)-4-(0-tosylyl)-1-(sulfooxy)-pyrimidinium hydroxide inner salt.

2-amino-6-(ethoxy carbonyl amino)-4-(pyrrolidinyl)-pyrimidine-1-oxide

2-amino-6-(ethoxy carbonyl amino)-4-(p-methyl phenoxy)-pyrimidine-1-oxxde

2-amino-6-(ehoxy carbonyl amino)-4-(diallyalamino)-pyrimidine-1-oxide

2-amino-6-(ethoxy carbonyl amino)-4-(morpholinyl)-pyrimidine-1-oxide

2-amino-6-(ethoxy carbonyl amino)-4-(thiomorpholinyl)-pyrimidine-1-oxide

2-amino-6-(ethoxy carbonyl amino)-4-(0-tosylyl)-pyrimidine-1-oxide

2-amino-6-(ethoxy carbonyl amino)-4-(piperidinyl)-pyrimidine-1-oxide

2-amino-6-(ethoxy carbonyl amino)-4-(1,2,5,6-tetra hydro pyyidyl) bis-2,6(ethyl oxamyl)-4-(diallylamino)-1-(sulfooxy)pyrimidinium hydroxide inner salt. bis 2,6(ethyl oxamyl)-4-(pyrrolidinyl)-1-(sulfooxy)pyrimidinium hydroxide inner salt. bis-2,6(ethoxy carbonyl amino)-4-(thiomorpholinyl)-pyrimidine-1-oxide bis-2,6(ethoxy carbonyl amino)-4-(morpholinyl)-pyrimidine-1-oxide bis-2,6(ethoxy carbonyl amino)-4-(piperidinyl)-pyrimidine-1-oxide bis-2,6(ethoxy carbonyl amino)-4-(p-methyl-phenoxy)-pyrimidine-1-oxide bis-2,6(ethoxy carbonyl amino)-4-(diallylamino)-pyrimidine-1-oxide bis-2,6(ethoxy carbonyl amino)-4-(pyrrolidinyl)-pyrimidine-1-oxide bis-2,6(ethoxy carbonyl amino)-4-(0-tosylyl)-pyrimidine-1-oxide

6-amino-2-(ethoxy carbonyl amino)-4-(piperidinyl)-1-(sulfooxy) pyrimidinium hydroxide inner salt.

6-amino-2-(ethoxy carbonyl amino)-4-(diallylamino)-1-(sulfooxy) pyrimidinium hydroxide inner salt.

6-amino-2-(ethoxy carbonyl amino)-4-(1,2,5,6-tetrahydropyridyl)-1-(sulfooxy)pyrimidinium hydroxide inner salt.

6-amino-2-(ethoxy carbonyl amino)-4-(thiomorpholinyl)-1-(sulfooxy)pyrimidinium hydroxide inner salt.

6-amino-2-(ethoxy carbonyl amino)-4-(morpholinyl)-1-(sulfooxy)pyrimidinium hydroxide inner salt.

6-amino-2-(ethoxy carbonyl amino)-4-(pyrrolidinyl)-1-(sulfooxy)pyrimidinium hydroxide inner salt.

6-amino-2-(ethyl oxamyl)-4-(pyrrolidinyl)-pyrimidine-1-oxide

6-amino-2-(ethyl oxamyl)-4-(p-methyl phenoxy)-pyrimidine-1-oxide

6-amino-2-(ethyl oxamyl)-4-(diallylamino)-pyrimidine-1-oxide

6-amino-2-(ethyl oxamyl)-4-(1,2,5,6-tetrahydropyridyl)-pyrimidine-1-oxide

6-amino-2-(ethyl oxamyl)-4-(piperidinyl)-pyrimidine-1-oxide

6-amino-2-(ethyl oxamyl)-4-(morpholinyl)-pyrimidine-1-oxide

6-amino-2-(ethyl oxamyl)-4-(thiomorpholinyl)-pyrimidine-1-oxide bis-2,6(ethoxy carbonyl amino)-4-(piperidinyl)-1-(sulfooxy) pyrimidinium hydroxide inner salt. bis-2,6(ethoxy carbonyl amino)-4-(diallylamino)-1-(sulfooxy) pyrimidinium hydroxide inner salt. bis-2,6(ethoxy carbonyl amino)-4-(1,2,5,6-tetrahydropyridyl)-1-(sulfooxy) pyrimidinium hydroxide inner salt. bis-2,6(ethoxy carbonyl amino-4-(morpholinyl)-1-(sulfooxy) pyrimidinium hydroxide inner salt. bis-2,6(ethoxy carbonyl amino)-4-(thiomorpholinyl)-1-(sulfooxy) pyrimidinium hydroxide inner salt. bis-2,6(ethoxy carbonyl amino)-4-(pyrrolidinyl)-1-(sulfooxy) pyrimidinium hydroxide inner salt. bis-2,6-(ethyloxamyl)-4-(piperidinyl)-pyrimidine-1-oxide bis-2,6-(ethyloxamyl)-4-(p-methyl-phenoxy)-pyrimidine-1-oxide bis-2,6-(ethyloxamyl)-4-(diallylamino)-pyrimidine-1-oxide bis-2,6-(ethyloxamyl)-4-(1,2,5,6-tetrahydropyridyl)-pyrimidine-1-oxide bis-2,6-(ethyloxamyl)-4-(morpholinyl)-pyrimidine-1-oxide bis-2,6-(ethyloxamyl)-4-(thiomorpholinyl)-pyrimidine-1-oxide bis-2,6-(ethyloxamyl)-4-(pyrrolidinyl)-pyrimidine-1-oxide bis-2,6-(ethyloxamyl)-4-(o-tosylyl)-pyrimidine-1-oxide bis-2,6(ethyl oxamyl)-4-(1,2,5,6-tetrahydropyridyl)-1-(sulfooxy)pyrimidinium hydroxide inner salt. bis-2,6(ethyl oxamyl)-4-(thiomorpholinyl)-1-(sulfooxy)pyrimidinium hydroxide inner salt. bis-2,6(ethyl oxamyl)-4-(morpholinyl)-1-(sulfooxy)pyrimidinium hydroxide inner salt. bis-2,6(ethyl oxamyl)-4-(piperidinyl)-1-(sulfooxy)pyrimidinium hydroxide inner salt. bis-2,6(ethyl oxamyl)-4-(p-methyl phenoxy)-1-(sulfooxy)pyrimidinium hydroxide inner salt. 6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(pyrrolidinyl)-pyrimidine-1oxide

6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(p-methyl phenoxy)-pyrimidine -1-oxide

6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(1,2,5,6-tetra-hydropyridyl)pyrimidine-1-oxide

6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(morpholinyl)-pyrimidine-1oxide

6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(thiomorpholinyl)-pyrimidine1-oxide

6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(piperidinyl)-pyrimidine-1oxide

6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(diallylamino)-pyrimidine-1oxide

6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(pyrrolindinyl)-1-(sulfooxy)pyrimidinium hydroxide inner salt.

6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(morpholinyl)-1-(suLfooxy)pyrimidinium hydroxide inner salt.

6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(thiomorpholinyl)-1-(sulfooxy) -pyrimidinium hydroxide inner salt.

6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(piperidinyl)-1-(sulfooxy)pyrimidinium hydroxide inner salt.

6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(1,2,5,6-tetra hydro pyridyl) -1-(sulfooxy-pyrimidinium hydroxide inner salt.

6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(diallylamino)-4-(pyrrolidinyl) -1-(sulfooxy)-pyrimidinium hydroxide inner salt.

6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(p-methyl-phenoxy)-1-(sulfoαxy) -pyrimidinium hydroxide inner salt.

6-amino-2-(ethyl oxamyl)-4-(diallylamino)-1-(sulfooxy)-pyrimidinium hydroxide inner salt.

6-amino-2-(ethyl oxamyl)-4-(morpholinyl)-1-(sulfooxy)-pyrimidinium hydroxide inner salt.

4.) A composition useful for improving the rate of hair growth on mammalian skins which comprises topically applying to the skin an effective amount of a compound selected from the group consisting of retinoids and retinoid analogs and/or prostacyclin analogues in combintaion with the compounds described in Claims 1 and 3,

5.) A composition of Claim 4 wherein the retinoid is selected from the group consisting of stereoisomers of vitamin A acid as well as the aldehydes, alcohols, esters, amides, ethers and salts of said compounds, or a retinoid analog, such as those listed in PCT U.S. 82/01593.

6.) A process for applying the compounds of Claims 1,3, and 4 to the skin, which consists of individual encapsulation of the compounds in a syneresis free, hydrophobic, polymeric network, the active ingredients are either dissolved or dispersed in the monomer mix and in-situ polymerized.