SUBSTITUTED PYRIMIDINE OXIDES USEFUL FOR HAIR GROWTH PROMOTION

Abstract: Novel substituted pyrimidine oxides and their salts and use of these in combination with retinoids and/or prostacyclin analogues to increase the rate of hair growth and to prolong the anagen phase of the hair cycle and to treat certain types of alopecias. The unexpected novel advantages to be gained from the use of the instant invention are: improved solubility and improved stability 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 syneresis-free hydrophobic polymeric network.

Description: Substituted Pyrimidine Oxides Useful for Hair Growth Promotion Brief Summary of the Invention Novel substituted diamino pyrimidine oxides and their salts, proces¬ ses 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 No¬ vember 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 4,256,8a6; German Offei 2,804 r 519 filed August 10, 1978; Swiss Applic. 78/7,910 filed July 21, 1978: He -tica 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 com¬ pounds which overcome some of the problems inherent in the use of previously described compounds. The compounds of this invention afford the following advantages: im¬ proved solubility, and improved stability of active compounds through in- (2) creased dispersion of charge; longer action of compounds; excellent pene¬ tration 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, R_ is a moiety selected from the group « consisting of substituents of the formula; \. \ wherein R, and R, are selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower aralkyl, and lower cycloalkyl, with the proviso that both R~ and R, are not hydrogen, and the heterocyclic functionality systems, N-aziridinyl, N-piperidinyl, N-azetidinyl, N-pyrrolidinyl, hexa- hydro-lH-azepin-1-yl, 4-alkylpiperazinyl, hexahydro-l(2H)-azocinyl, (where¬ in the alkyl portion of the moiety is of one to 3 carbon atoms) , 4-morpho- linyl, 4-thiomorpholinyl, 3,6-dihydro-l(2H)-pyridinyl, 3-pyrrolindyl, 2,3,4,7- etrahydro-lH-azeρine-1-y1, and 3,4,7,8-tetrahydro-l(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 R. to the ring in said formula. When R. is N-R-R, , R_ and R, can be alike or differ¬ ent. When R, 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, R„ is selected from the group consisting of hydro¬ gen, 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, R„ 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 R. , above. R. and R„ may be the same within the scope of that definition. Precursors of Formulas I - V compounds can be the following : wherein, in each instance, R. 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, R_ can be selected from the group consisting of chlorine, bromine, iodine, nitroso, nitro, amino, phenylthio, lower alkylphenyithio, and halophenylthio. In Formulas VI and VII, R~ is assigned the same definition as R, , above. R_ can be the same as or different than ~ * . within the scope of that defini¬ tion. 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, l-methyl-2- butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 3-pentenyl, 2,3-dimethyl- 2-butenyl, 1, 1, 2-trimethylallyl, 1, 3-dimethyl-2-butenyl, l-ethyl-2-bu- tenyl, 4-methyl-2-ρetenyl, 2-ethyl-2-pentenyl, 4, 4-di ethyl-2- e tenyl, 2-heptenyl, 2-octenyl, 5-octenyl, 1, 4-dimethyl, 4-hexenyl, and the like. Examples of lower alkoxyalkyl are 2-methoxyethyl, 2-ethoxyethyl, 2-butoxy- ethyl, 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-dime hylcycloproρyl, 2,3-diethyl-cyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, 2, 3, 4-trihylcyclobutyl, cyclopentyl, 2,2-dimethylcyclo- pentyl, 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, js-tolyl, methylphenyl, p-tert butylphenyl, the isomeric forms of xylyl, the isomeric forms of tri ethylphenyl, 4-methyl-l-naphthyl, 6-ρropyl-2-naphthyl, 2, 4, 5, 7-tetramethyl-l-naphthyl, and the like. Examples of lower aralkyl are benzyl, phenethyl, 1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 6- phenylhexyl, 5-phenyl-2-methylpentyl, 1-naρhthylmethyl, 2-(l-naphthyl)ethyl, 2-(2-napthyl) ethyl and the like. Examples of lower alkaralkyl are o-toly- lmethyl, jn-tolyl-methyl, j-tolylme hyl, 4-tert-butylphenylmethyl, 2-(p- tolyl)ethyl, l-(m_-tolyl)ethyl, 3-(o-ethylphenyl)propyl, 4-methyl-l-naphthy- lmethyl, 6-tert-butyl-2-naρhthylmethyl, and the like. Examples of lower alkoxyaralkyl are o-methoxybenzyl, _m-methoxybenzyl, p_-methoxybenzyl, 2- (m-methoxyphenyl)ethyl,3-(p_-ethoxyphenyl)ρropyl, 4-(p-tert-butoxyphenyl) butyl, 4-methoxyl-l-naphthylmethyl, and the like. Examples of lower halo- aralkyl are o-chloro-benzyl, m-fluorobenzyl, p-bromobenzyl, 2-(m-iodo- phenyl)ethyl, 2,4-dicloro-benzyl, 6-bromo-l-naphthylmethyl, 4-p_-chloro- phenyl)butyl and the like. Examples of lower alkylphenylthio are o-tolyl- thio, jv-tolylthio, the isomeric forms of xylylthio, p-ethylphenylthio, _m-butylphenylthio and the like. Examples of halophenylthio are _p-chloro- phenylthio, j a-bromophenylthio, o-fluorophenylthio, 3,4-dichlorophenylthio and the like. Examples of heterocyclic moieties within the scope of R, in addition to those already mentioned above, are 2-methylaziridinyl, 2-ethylaziridinyl, 2-butylazirindinyl, 2,3-dimethylaziridinyl, 2, 2-dimethylaziridinyl, 2- ethylazetidinyl, 3-methylazetininyl, 2-octylazetidinyl, 2,2-dimethylazeti- dinyl, 3,3-diethylazetidinyl, 2, 4, 4-trimethylazetidinyl, 2, 3, 4-trimethyl- azetidinyl, 2-methylρyrrolidinyl, 3-butylpyrrolidinyl, 2-isohexylpyrrolidinyl, 2, 3-dimethyl-pyrrolidinyl,2, 2-dimethylpyrrolidinyl, 2,5-diethylpyrrolidinyl, 3- ert-butyl-pyrrolidinyl, 2,3,5-trimethylpyrrolidinyl, 3,4-dioctylpyrrolid- inyl, 2-methyl-piperidino, 3-methylpiperidino, 4-methylpiperidino, 3-iso- propylpiperidino, 4-tert-butylpiperidino, 2-methyl-5-ethylpiperidino, 3, 5- dipentylpiperidino, 2, 4, 6-trimethylpiperidino, 2, 6-dimethyl-4-octylpip- eridino, 2, 3, 5-triethyl-piperidino, 2-ethylhexahydroazepinyl, 4-tert- butylhexalhydroazepinyl, 3-heptylhexa-hydroazepinyl, 2, 4-dimethylhexahy- droazepinyl, 3, 3-dimethylhexahydroazeρinyl, 2, 4, 6-triproρylhexahydro- azepinyl, 2-methylheptamethylenimino, 5-butylheptamethylenimino, 2, 4- diisopropylheptamethylenimino, 3, 3-diethylheptamethylenimino, 2, 5, 8- trimethylheptamethylenimino, 3-methyloctamethylenimino, 2, 9-diethylocta- me hyleni ino, 4-isooctyloctamethylenimino, 2-ethylmorpholino, 2-methyl-5- ethylmorpholino, 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 A-. , A_ and A-, 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 com¬ pounds 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. II III 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, cyclo- alkanoic, alkenoic, cycloalkenoic, aralkanoic, aromatic and heterocylic carboxylic acids. These anhydrides and acid chlorides can also be sub¬ stituted on any carbon, but the carbonyl carbon with any of a wide variety of atomic or molecular moieties unreactive with the dihydropyri idine re- actants. Examples of such substituents are alkyl; e.g., ethylthio, 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, bro¬ mine and iodine can also be substituents on aromatic portions of the acy¬ lating agents. Examples of suitable anhydrides are acetic anhydride, propionic anhy¬ dride, butyric anhydride, isobutyric anhydride, acrylic anhydride, cro- tonic anhydride, cyclohexane carboxylic anhydride, benzoic anhydride, naphthoic anhydride, furoic anhydride and the like, as well as the corres¬ ponding 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, 3- cyclohexenecarbonyl chloride, pheπylacetyl 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 sub¬ stituents. 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 CH 2 C1 2 ; or, diethyl ether and tetra- hydrofuran; 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 evapor¬ ated, 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) 9 A, C-0-methyl q -C-0-ethyl 0 -C-0-butyl -C-O-i-butyl q -C-0-benzyl 0 -C-0-2-methoxy-ethy1 Alkoxyoxalyl Derivatives (Oxamates) or (Oxoacetates) Q 0 or A. -C-C-O-methyl - 9C,-C9-O-benzyl - 9C-RC-0-2-methoxy-ethyl (10) 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 unsubstitu ed . 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 H 2 [2°] R-^ H. [3°] R j R 2 R 3 N τhe R gr°"PS 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 CH- or any alkyl group or phenyl or other aromatic group or heterocylic group. X - NR ι R 2 wtlere R ι =R 2 =H R ι * -~-~ or aik yl group or aromatic or heterocylic group. R- can be the „ _ . „ . same or different from R.. X » S-R where R is 1 defined as R. or R- above. (11) Product A The oxadiazino ring - Produc Ot A was opened by treating Product A iinn bbaassee wwiitthh R.R„NH for 30 minutes. The resultant Product B is shown below: Product B 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 H 4 0H then X will be NH if the base is a primary, soecondary or tertiary amine then X will be: NR χ , R χ R 2 or -O (. ) Z in the above formula can be : Z - N 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. The novel compounds of Formulas I through V can also form the following carboxy derivatives: (Inner Salts) R χ II The X in the above Formula II can be represented by the following: X ■ OR where R can be H or CH-. or any alkyl group or phenyl or other aromatic group or heterocylic group. X - R χ R £ where R. - 2 - H R ^ ■ CH-, or alkyl group or aromatic or heterocyclic group. R- can be the same or different from R.. X = S-R where R is defined as R. or R_ in the aforementioned. The novel compounds of Formulas I through V can also form the following carboxy derivatives: (Inner Salts) The X in the above Formula III can be represented by the following; X = OR where R can H or CH- or any alkyl group or phenyl or other aromatic group or heterocylic group. X = NR χ R 2 where R-_= R ∑ = H R. = CH-. or alkyl group or aromatic or heterocylic group. R„ can be the same or different from R. X = S-R where R is defined as R. or R„ above. Invention Technical Process Data This invention relates to a method of preparing novel compounds of general formulas I and II. where R- is an alkyl oxalyl and R. is a heterocyclic moiety, or a substi¬ tuted phenoxy group, or an 0-Tosyl group, and R„ 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. where R~ is hydrogen, R- is carbamate or alkyl oxalyl and R. is the same- as that described above. Detailed Description of the Invention The 4-[substituted]-2,6-bis(alkyl oxamyl)-pyrimidine-l-oxides and their corresponding inner salts, obtained according to the process of this invention, have the general Formula I and II, where R., is an alkyl oxalyl or an alkoxy carbonyl. The term "alkyoxalyl" is used to define the RO-C-C group in which R constitutes methyl, ethyl, v-propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like. The term "alkoxy carbonyl" is referred to RO-fi in which R is the lower alkyl group. R, 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 R, is as pre¬ viously described. Ill with an excess of an alkyl oxalyl halide of structure A, or with an excess of an alkyl halo formate, of structure B. 0 A. - 9c, - 9 " OR, or X - C - OR, R„ = lower alkyl X = Cl « 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 bicar¬ bonate 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, R_ and R 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)-l-(sulfooxy)-ρyrimidinium 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 di¬ methyl formamide (DMF) or acetonitrile at room temperature. The sulfur trioxide reacts directly to form a sulfate with the substituted pyrimidine N-l oxides, and is used in excess, usually in ratio of 1:2 or 1:1.5. Al¬ ternatively in Method III (see Scheme III) the 2,4-diamino-6-[substituted]- pyrimidine-3-oxide is converted to 2,6-diamino-4-[substituted-l-(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-O-sulf tes. wherein R is hydrogen, or methoxy, ethoxy, propoxy-carbonyl and R, is diallylamine, pyrrolidine, piperidine, tetrahydropyridine, morpholino or thiomorpholino. Example: The 4-(l,2,4,6-tetra hydro-l-pyridyl)-2,6 j =:bis (ethoxy carbonyl amino)-pyrimidine-l-oxide (i.e., IV, R„ is C ^ H..-0-C- and R, = 1,2,3,6-tetrahydro-pyridine) was reacted with sulfur trioxide pyridine complex in DMF at room temperature which afforded the 4-(l,2,3,6- tetra hydro-l-pyridyl)-2,6-bis(ethoxy carbonyl amino)-l-(sulfooxy) pyrimi¬ dinium 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. (19) 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) 1,2- dihydro-l-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-1- oxide was found. See Scheme V. 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 - 0 compounds gave a positive test with ferric chloride solution. ' Example 1 Preparation of 4-(l ,2,3,6-Tetrahydro-l-pyridyl)-2,6-bis(ethyl oxamyl) pyrimidine-1-oxide. A 0.S g (0.0024 mol), sample of 2,6-diamino-4 (1,2, 3,6-Tetrahydro-l-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 5" and 1-3 ml (0.012 mol) of ethyl oxalyl chlor¬ ide 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°) C 1? H 21 5 0 7 C:H:N:0 50.1:5.15:17.1:27.5 Example 2 Preparation of 4-(Piρeridinyl)-2,6-bis (ethyl oxamyl)-pyrimidine 1- oxide. 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 mix¬ ture was washed with a solution of sodium bicarbonate and the organic phase was then separated, dried over anhydrous Na-SO,, 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 fil¬ ter and dried under reduced pressure to give 1.16 g (56%) of the title compound of melting point 165-168°. C:H:N:0 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-l-oxide. 2,6-diamino-4(p-methyl phenoxy)pyrimidine-l-oxide, and was treated with an excess of ethyl oxalyl chloride 4-(morpholinyl)-2,6 bis(ethyl oxamyl) -pyrimidine-1-σxide, which respectively afforded, with the melting point of 182-184°, C:H:N:0 46.7:5.10:17.0:31.1, c 16 H 2 ι N 5°8' Wpyrrolidinyl) -2,6-bis (ethyl oxamyl)-pyrimidine-1-oxide, with a melting point of 222- 223°, c 1 H 2i N 5 ) 7- C ;H "N:0, 48.6:5.3:17.7:28.3, as well as 4-(p-methyl phenoxy)2,6-bis(ethyl oxamyl)-pyrimidine-l-oxide, melting point 172- 174°, C:H:N:0 52.6:4.71:13.13:29.5, respectively. It is noteworthy, that the last compound was synthesized from the parent compound 2, -diamino-6(ρ-methylphenoxy)pyrimidine-3-oxide. The parent compound was prepared in the following manner: a)' Preparation of 2,4-Diamino-6-(p-methyl- henoxy)pyrimidine A mixture of 54 g (0.5 mole)of p-Cresol, 7.2 g (0.05 mol) of 2,4-di- amino-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 etha- nol, 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) py¬ rimidine was suspended in 100 ml of methanol and cooled to 0-5°. A solu¬ tion 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 re¬ moved 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°. C 11 H 12 N 4°2» C:H:N:0, 56.8:5.17:24.1:13.7 Example 3 Preparation of 2,6-bis(ethyl oxamyl)-4-(pyrrolidinyl)-l-(sulfooxy)- pyrimidinium hydroxide, inner salt. A mixture of 0.5 g (0.2 mmol) of 2,6- diamino-4-(ρyrrolidinyl)-l-(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)-l-(sulfooxy)- pyrimidinium hydroxide, inner salt * A mixture of 0.2 g (0.4 mmol) of 4- (piperidinyl)2,6-bis(ethyl oxamyl)-pyridine-l-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)-l-(sulfooxy) pyrimidinium hydroxide, inner salt. A mixture of 1.0 g (0.3 mmol) of 2,6- diamino-4-(piperidinyl)-l(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 bi¬ carbonate. 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)- l-(sulfooxy)-pyrimidlnium hydroxide, inner salt. Following Example 5, and using 2,6-diamino-4(l,2,3,6-Tetrahydro pyridyl)-l-(sulfooxy)-pyrimi- diniu hydroxide, inner salt and ethyl oxalyl chloride, there was obtained, the title compound. Example 7 Preparation of 2,6-bis(ethoxy carboxyl amino)-4-(l,2,3,6-Tetrahydro pyridyl)-l-(sulfooxy)-pyrimidinium hydroxide inner salt. 0.3 g (0.8 mmol) of 4-(l,2,3,6-Tetrahydro-l-pyridyl)-2,6-bis(ethoxy carbonyl amino)-pyrimi- dine-1-oxide was dissolved in a mixture of 15 ml of dimethyl formamide and 20 ml of CH„C1_, 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 re¬ duced 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-(l-pyrrolidinyl)-l-(sulfooxy)-pyrimidin- ium hydroxide, inner salt. A mixture of 1 g (0.5 mmol) of 2,6-diamino-4 (l-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:0:S 34.9:4.72:25.4:23.2:11.6 Example 9 Also following Example 8, but using 2,6-diamino-4-(diallylamine)pyri- midine-1-oxide and sulfur trioxide pyridine complex and also reacting 2,6- diamino-4-(l,2,3,6-Tetrahydro-l-pyridyl)pyrimidine-l-oxide with sulfur tri¬ oxide pyridine complex in dimethyl formamide, there were obtained respec¬ tively 2,6-diamino-4-(diallylamine)-l-(sulfooxy)-pyrimidinium hydroxide, inner salt with the melting point of 174-175° and 2,6-diamino-4- (1,2,3,6-tetra hydro-l-pyridyl)-l-(sulfooxy)-pyrimidinium hydroxide, inner salt with the melting point of 207-209°. Example 10 Preparation of 4-(pyτrolydinyl)-2,6-bis(ethoxy carbonyl amino)-pyrimidine -1-oxide A mixture of 1.0 g (0.5 mmol) of 2,6-diamino-4-(pyrrolydinyl)-pyrimi- dine-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 concen¬ trated which afforded 1.2 g (70%) of a solid with the melting point of 155-157°. C:H:N:0 49.5:6.1:20.6:23.5 Example 11 Preparation of 2,6-bis(ethoxy carbonyl amino)-4-(pyrrolidinyl)-l-(sulfooxy) -pyrimidinium hydroxide inner salt 0.6 g (0.1 mmol) of 4-(pyrrolidinyl)-2,6-bis(ethoxy carbonyl amino)- ρyrimidine-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 sol¬ vent was removed under reduced pressure. The residue was cooLed 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:0 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-l-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 h hour at 0-5°C, and then washed several times with water (30 ml) . The organic layer was dried and concentrated under re¬ duced pressure which afforded 1.2 g (73%) of a white crystalline solid with the melting point of 134-135°. C:H:N:0 52.6:6.30:19.1:21.9 Example 13 Preparation of 2,6-bis(ethoxy carbonyl amino)-4-(diallylamino)-l-(sulfooxy) -pyrimidinium inner salt 100 mg (0.27 mmol) of 4-diallylamino-2,6-bis(ethoxy carbonyl amino)- pyrimidine-l-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:0 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 solu¬ tion 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, use¬ ful 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 compo¬ sitions which are effective in increasing the rate of hairgrowth on mamma¬ lian skin. It is also an object of this invention to provide such improved com¬ positions 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. Table 1 , Effect of compounds on vasodilation as measured by Laser Doppler* flow meter for microvascular perfusion in male rats (hypotrichotic) Compound Dose % Change Araa Time (Hours) #900 60 micrograms +15 Head 1 per kilogram +25 2 #903 +15 1 +10 2 +10 24 900 = Minoxidil Sulfate 907 = 4-(morpholino)-2,6-bis(ethyl oxamyl)-pyrimidine-1-oxide 909 = 4-(pyrrolidinyl)-2,6-bis(ethyl oxamyl)-pyrimidine-l-oxide 1001 - 4-(l,2,3,6-tetrahydro-l-pyridyl)-2,6-bis(ethyl oxamyl)-pyrimidine-1- oxide 1005 = 2,6-diamino-4(pyrrolidinyl)-l-(sulfooxy)-pyriminium hydroxide, inner salt 1009 = 2,6-diamino-4(l,2,3,6-tetra hydro-l-pyridyl)-l-(sulfooxy)-pyrimi¬ dinium 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 develop¬ ment 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 admini¬ stration 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 com¬ pound of the formulas, incorporated in a suitable pharmaceutical carrier, particularly the encapsulation process, and applied at the site of bald¬ ness for exertion of local action. Accordingly, such topical compositions include those pharmaceutical forms in which the compound is applied exter¬ nally by contact with the skin surface to be treated. Conventional pharma¬ ceutical forms for this purpose include ointments, lotions, pastes, jel¬ lies, sprays, aerosols, and the like. The term "ointment" embraces form¬ ulations (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 uti¬ lized ranges from about 0.1% to about 20.0% of the pharmaceutical prepa¬ rations; the aforesaid pharmaceutical carrier for topical application con¬ stitutes 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 polymer¬ ized. 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 con¬ tact 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 formula¬ tion by entrapment with a syneresis-free polymeric network which is hydro¬ phobic. Loading as great as 60-80% should be achieved within the polymeric lattice. In this matrix the functional hair growth agent is held by micro- sorption 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 ad¬ ditional 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 con¬ tinuous film of the released active component. This protection is par¬ ticularly 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 - tocσpherol 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-oχide .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 hydro¬ phobic 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 in¬ stant invention are: improved solubility and improved stability and acti¬ vity 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 use¬ ful 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.

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 com¬ pounds of the following formula: N R 3 R 2 wherein, a) R. and R, are alkoxy o b) R. and R, = alkoxyacyl groups, such as ~ ~ ~ ~ ~ 5 where the alkoxy , moiety is derived from lower alcohols, c) R» and R_ consist of lower alkyl substituents or hydrogen which may be the same or different, with the restriction that if R„ is hydrogen, R- is neither hydrogen or methyl or the reverse; R„ and R„ 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 R 2 and R_ linked to form heterocyclic groups including the following: 1-pyrrolidinyl, 1-tetrahydropyridyl, 3-pyrrolidyl, aziridinyl, azetidinyl, piperidino, hexahydroazepinyl, heptamethylenemino, octa- me hylenimino, thiomorpholino, morpholino, 4-lower-alkyl-piperazinyl, and optionally bearing 1 to 3 alkyl groups including methyl, ethyl, n- propyl and 2-propyl and butyl, and where X is oxide group 0 or OSO _, 2. ) A process for the preparation of compounds of the general formula : R 0 0 M II wherein R -~ C - C - OR- or R = C - 0 - , where R is a lower alkyl such as methyl, ethyl, propyl, butyl and wherein R. is a heterocyclic moiety such as pyrrolidino, morpholino, piperidino, diallylamine or tetrahydro- pyridyl, thiomorpholine or R^ is diallylamino or R 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 reac¬ ting 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 mam¬ malian skins, prolonging the anagen phase of the hair cycle and for treat¬ ing various types of alopecias, comprising an effective amount of a com¬ pound selected from the series of Claim 1 and including: 6-amino-2-(ethyl oxamyl)-4-(thiomorpholinyl)-1-(sulfooxy)-pyrimidinium hy¬ droxide inner salt. 6-amino-2-(ethyl oxamyl)-4-(pyrrolidinyl)-l-(sulfooxy)-pyrimidinium hydro¬ xide inner salt. 6-amino-2-(ethyl oxamyl)-4-(piperidinyl)-l-(sulfooxy)-pyrimidinium hydro¬ xide inner salt. 6-amino-2-(ethyl oxamyl)-4-(l,2,5,6-tetra hydro pyridyl)-l-(sulfooxy)-pyri- midinium 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)-l-(sulfooxy)-pyrimidinium hydro¬ xide inner salt. 2-amino-6-(ethoxy carbonyl amino)-4-(pyrrolidinyl)-pyrimidine-l-oxide 2-amino-6-(ethoxy carbonyl amino)-4-(p-methyl phenoxy)-pyrimidine-1-ox de 2-amino-6-(ehoxy carbonyl amino)-4—(diallyalamino)-pyrimidine-l-oxide 2-amino-6-(ethoxy carbonyl amino)-4-(morpholinyl)-pyrimidine-l-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-(ρiperidinyl)-pyrimidine-l-oxide 2-amino-6-(ethoxy carbonyl amino)-4-(l,2,5,6-tetra hydro pyridyl) bis-2,6(ethyl oxamyl)-4-(diallylamino)-1-(sulfooxy) yrimidinium hydroxide inner salt. bis 2,6(ethyl oxamyl)-4-(pyrrolidinyl)-l-(sulfooxy)pyrimidinium hydroxide inner salt. bis-2,6(ethoxy carbonyl amino)-4-(thiomorpholinyl)-pyrimidine-l-oxide bis-2,6(ethoxy carbonyl amino)-4-(morpholinyl)-pyrimidine-l-oxide bis-2,6(ethoxy carbonyl amino)-4-(piperidinyl)-pyrimidine-l-oxide bis-2,6(ethoxy carbonyl amino)-4-(p-methyl-phenoxy)-pyrimidine-l-oxide bis-2,6(ethoxy carbonyl amino)-4-(diallylamino)-pyrimidine-1-oxide bis-2,6(ethoxy carbonyl amino)-4-(pyrrolidinyl)-pyrimidine-l-oxide bis-2,6(ethoxy carbonyl amino)-4-(0-tosylyl)-pyrimidine-l-oxide 6-amino-2-(ethoxy carbonyl amino)-4-(piperidinyl)-l-(sulfooxy) pyrimidini¬ um hydroxide inner salt. 6-amino-2-(ethoxy carbonyl amino)-4-(diallylamino)-l-(sulfooxy)pyrimidini¬ um hydroxide inner salt. 6-amino-2-(ethoxy carbonyl amino)-4-(1,2,5,6-tetrahydropyridyl)-1-(sulfo- oxy)pyrimidinium hydroxide inner salt. 6-amino-2-(ethoxy carbonyl amino)-4-(thiomorpholinyl)-1-(sulfooxy) yrimidi¬ nium hydroxide inner salt. 6-amino-2-(ethoxy carbonyl amino)-4-(morpholinyl)-l-(sulfooxy)pyrimidinium hydroxide inner salt. 6-amino-2-(ethoxy carbonyl amino)-4-(pyrrolidinyl)-l-(sulfooxy)pyrimidinium hydroxide inner salt. 6-amino-2-(ethyl oxamyl)-4-(pyrrolidinyl)-pyrimidine-l-oxide 6-amino-2-(ethyl oxamyl)-4-(p-methyl phenoxy)-pyrimidine-1-oxide 6-amino-2-(ethyl oxamyl)-4-(diallylamino)-pyrimidine-l-oxide 6-amino-2-(ethyl oxamyl)-4-(l,2,5,6-tetrahydropyridyl)-pyrimidine-l-oxide 6-amino-2-(ethyl oxamyl)-4-(piperidinyl)-pyrimidine-1-oxide 6-amino-2-(ethyl oxamyl)-4-(morpholinyl)-pyrimidine-l-oxide 6-amino-2-(ethyl oxamyl)-4-(thiomorpholinyl)-pyrimidine-l-oxide bis-2,6(ethoxy carbonyl amino)-4-(piperidinyl)-l-(sulfooxy) pyrimidinium hydroxide inner salt. bis-2,6(ethoxy carbonyl amino)-4-(diallylamino)-l-(sulfooxy) pyrimidinium hydroxide inner salt. bis-2,6(ethoxy carbonyl amino)-4-(l,2,5,6-tetrahy'dropyridyl)-l-(sulfooxy) pyrimidinium hydroxide inner salt. bis-2,6(ethoxy carbonyl amino-4-(morpholinyl)-l-(sulfooxy) pyrimidinium hydroxide inner salt. bis-2,6(ethoxy carbonyl amino)-4-(thiomorpholinyl)-l-(sulfooxy) pyrimidinium hydroxide inner salt. bis-2,6(ethoxy carbonyl amino)-4-(pyrrolidinyl)-l-(sulfooxy) pyrimidinium hydroxide inner salt. bis-2,6-(ethyloxamyl)-4-(piperidinyl)-pyrimidine-l-oxide bis-2,6-(ethyloxamyl)-4-(p-methyl-phenoxy)-pyrimidine-1-oxide bis-2,6-(ethyloxamyl)-4-(diallylamino)-pyrimidine-l-oxide bis-2,6-(ethyloxamyl)-4-(1,2,5,6-tetrahydropyridyl)-pyrimidine-1-oxide bis-2,6-(ethyloxamyl)-4-(morpholinyl)-pyrimidine-l-oxide bis-2,6-(ethyloxamyl)-4-(thiomorpholinyl)-pyrimidine-1-oxide bis-2,6-(ethyloxamyl)-4-(pyrrolidinyl)-pyrimidine-1-oxide bis-2,6-(ethyloxamyl)-4-(0-tosylyl)-pyrimidine-1-oxide bis-2,6(ethyl oxamyl)-4-(l,2,5,6-tetrahydropyridyl)-1-(sulfooxy)pyrimidinium hydroxide inner salt. bis-2,6(ethyl oxamyl)-4-(thiomorpholinyl)-!-(sulfooxy)pyrimidinium hydro¬ xide inner salt. bis-2,6(ethyl oxamyl)-4-(morpholinyl)-l-(sulfooxy)pyrimidinium hydroxide inner salt. bis-2,6(ethyl oxamyl)-4-(piperidinyl)-l-(sulfooxy)pyrimidinium hydroxide inner salt. bis-2,6(ethyl oxamyl)-4-(p-methyl phenoxy)-l-(sulfooxy)pyrimidinium hydro¬ xide inner salt. 6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(pyrrolidinyl)-pyrimidine-l- oxide 6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(p-methyl phenoxy)-pyrimidine -1-oxide 6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(l ,2,5,6-tetra-hydropyridyl)- pyrimidine-1-oxide 6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(morpholinyl)-pyrimidine-l- oxide 6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(thiomorpholinyl)-pyrimidine- 1-oxide 6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(piperidinyl)-pyrimidine-1- oxide 6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(diallylamino)-pyrimidine-l- oxide 6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(pyrrolindinyl)-l-(sulfooxy)- pyrimidinium hydroxide inner salt. 6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(morpholinyl)-l-(suLfooxy)- pyrimidinium hydroxide inner salt. 6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(thiomorpholinyl)-l-(sulfooxy) -pyrimidinium hydroxide inner salt. 6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(piperidinyl)-l-(sulfooxy)- pyrimidinium hydroxide inner salt. 6-(ethoxy carbonyl amino)-2-(ethyl oxamyl)-4-(l,2,5,6-tetra hydro-pyridyl) -l-(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)-l-(sulfoαxy) -pyrimidinium hydroxide inner salt. 6-amino-2-(ethyl oxamyl)-4-(diallylamino)-l—(sulfooxy)-pyrimidinium hydro¬ xide inner salt. 6-amino-2-(ethyl oxamyl)-4-(morpholinyl)-l-(sulfooxy)-pyrimidinium hydro¬ xide inner salt. 4.) A composition useful for improving the rate of hair growth on mammal¬ ian 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 alde¬ hydes, 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.

Inventors: BAZZANO GAIL SANSONE, BAZZANO, GAIL, SANSONE
Applicants: BAZZANO GAIL SANSONE, BAZZANO, GAIL, SANSONE
Application year: 1985
Main classification: C07D239
IPC codes: A61K8, A61Q7, C07D239, C07D401