IL26578A - Pteridine compounds and their preparation - Google Patents
Pteridine compounds and their preparationInfo
- Publication number
- IL26578A IL26578A IL2657866A IL2657866A IL26578A IL 26578 A IL26578 A IL 26578A IL 2657866 A IL2657866 A IL 2657866A IL 2657866 A IL2657866 A IL 2657866A IL 26578 A IL26578 A IL 26578A
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- amino
- diamino
- chloro
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
- C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
PATENTS AND DESIGNS ORDINANCE SPECIFICATION Novel Pteridine Compounds and their ^reparation I (we) Merck & Co., Inc., a corporation of Hew Jersey, U.S.A. , of Rahway, New Jersey, U.S.A. do hereby declare the nature of this invention and in what manner the same is to be performed, to particularly described and ascertained in and by t following statement :- This invention is concerned with a novel method for preparing 2 ,4-diaminopteridine compounds having halo substituent attached to the 6-position and being either unsubstituted or having a substituent of the type herein-after described attached to the 7-position. The products produced by the novel method of this invention are them-selves novel and constitute an additional feature of this invention.
In the past it has been impossible to produce 2,4-diaminopteridine compounds having a 6-halo substituent.
Surprisingly it was found by applicants that these novel and useful 6-halo substituted 2 ,4-diaminopteridine (I) compounds could be obtained by a novel process that involves reaction of a 3-amino-5-X-6-halopyrazinonitrile (III) with guanidine. During the reaction the acyclic product, (3-amino-5-X-6-halopyrazinimidoyl)guanidine, (II) is formed but these intermediates generally are not isolated but rather generated and cyclized iri situ to the 2,4-diamino- 7 ^-X-6-halopteridine (I) Guanidine is generated by treating a guanidine salt, such as guanidine hydrochloride, with an alkali metal salt of a lower alkanol such as sodium ethoxide, sodium 2-propoxide or potassium tert . -butoxide advantageously in a solution of the corresponding alkanol. The 3-amino-5-X-6-halopyrazinonitrile can be added to this solution or the solvent can be removed by distillation first and the re-action conducted without a solvent or a different solvent can be added at this time. The reaction can be conducted at ambient temperature or at higher temperature such as the reflux temperature of the solvent which facilitates the cyclization of the acyclic intermediate (II) to the desired pteridine (I). When the reaction of a 3-amino-5-chloro-(or bromo) -6-halopyrazinonitrile is conducted with a guanidine solution of a lower primary or secondary alkanol the 5-chloro(or bromo) is replaced by alkoxy and the corres-ponding 2 ,4-diamino-6-halo-7-alkoxypteridine is isolated. However, when a lower tert. -alkanol is used the 5-chloro-(or bromo) group is uneffected and the 2 ,4-diamino-6-halo-7-chloro(or bromo) pteridine is obtained.
While an alcohol generally is employed as a solvent for the pyrazinonitrile and guanidine reactants, other solvents can be used in place of it such as tetrahydrofuran , dimethylformamide or other highly polar solvents.
The preferred products produced by the novel pro-cess of this invention are 2 ,4-diamino-6-halo-7-X-pteridine wherein the 6-position halo is chloro, bromo or iodo and X is hydrogen, lower alkoxy, benzyloxy, lower alk lthio, mereapto, lower alkyl, halogen, hydroxy, mononuclear aryl or •N " wherein R and are each independently hydrogen, lower .alkynyl, lower alkyl, lowe alkenyl,/cycloalkyl, halo-lowe alkyl, hydroxy«l©wer alkyl, lower akoxy-lower alkyl, loner eyeloalkyl* lower alkyl, mononuclear aryl-lower alkyl, (lower alkyl substituted mononuclear aryl)-lower alkyl, (ha o-monoa e ear -aryl)-lower alkyl, amino-lower alkyl, furyl-lower alkyl, py^ridyl-lower alkyl, mononuclear aryl optionally substituted with alkyl or halogen; or -I is a group -iQ¾B¾L wherein n is 4, 5 or 6· It has been found that the intermediate 3-amino-5-X-S=halopyraainonitriles (III) can be prepared by the reactions illustrated graphically below* (V) (III) The 3-amino-5-X-6-halopyrazinamide (IV) upon treat- iiient with either phosphoryl chloride or thionyl chloride in the presence of dimethylformamide, advantageously by warra- ing forms the corresponding Ν,Ν-dimethyl-N' -(3-cyano-5- halo.-6-X-2-pyrazinyl) ormaroidine (V), which can be hydro- lyzed in the presence of a strong mineral or organic acid (such as hydrochloric, sulfuric, methanesulfonic and the like acids) to produce the desired 3-amino-5-X-6-halo- pyrazinonitrile (III).
It is to be recognized that if X is amino in the starting amide (IV), in the intermediate (V) XwLll be N=CHN(CH3)2 but in the product (III) will be amino since hydrolysis will involve both the 3- and the 5-substituents . 3 4 An alternate route to the 3-amino-5-R R N-6-halo- pyrazinonitriles (III-B) involves the reaction of one of the nitrile compounds made by the above method, namely a 3-amino-5-chloro(or bromo) -6-halopyrazinonitrile (III-A), with ammonia, a primary amine or a secondary amine.
- - (III-A) (III-B) The reaction is advantageously conducted in a polar solvent, such as dimethylformamide, dimethyl sulfoxide, sulfolane and the like. The reaction can be carried out at ambient temperature; however, it is advantageous to conduct the re- action at higher temperatures such as 50°C. to 120°C. for a period of from 10 minutes to 6 hours. 3 4 This method has the advantage that the R R sub- 1 2 stituents cannot only be the same as the R and R groups described supra but also can be hydroxyalkyl , polyhydroxy- alkyl and amino.
A further alternative procedure can be employed to prepare 3-amino-5-X-6-iodopyrazinonitriles (Compound III where halo is iodo). This method involves catalytic hydro- genolysis of 3-amino-5-X-6-chloro(or bromo)pyrazinonitrile using a palladium on charcoal catalyst in the presence of magnesium oxide to form the corresponding 3-amino-5-X- pyrazinonitrile. A solvent such as a lower alkanol is advantageous. Iodination of the 3-amino-5-X-pyrazino- nitrile using iodine and mercuric acetate in a solvent such as aqueous dioxane or tetrahydrofuran preferably with heat- o o ing at 50 C. to 100 C. for a period of 5 to 30 minutes pro- duces the desired 3-amino-5-X-6-iodopyrazinonitrile.
The 3-amino-5-X1-6-halopyrazinamide (IV-A) inter- mediates (where X represents each of the X groups des- cribed supra except lower alkoxy and lower-alkylmercapto) advantageously are prepared by the reaction of the appro- priate alkyl 3-amino-5-X -6-halopyrazinoate (VI) with ammonia.
(VI) (IV-A) The reaction can be conducted using liquid ammonia at temperatures slightly below ambient temperature to slightly above ambient temperature. Alternatively, the ester can be dissolved in an inert solvent and ammonia gas admitted be- low the surface of the solution. With esters which have a 5-chloro or bromo substituent, lower temperatures and the use of liquid ammonia and a .non-polar solvent favor the formation of the desired amide (IV-A) while higher tempera- tures and polar solvents favor the formation of 3,5-diamino- 6-halopyrazinamide.
The 3-amino-5-X"-6-halopyrazinamide (IV-B) inter- mediates (where X" represents lower alkoxy, lower alkylthio 1 2 and R R N- ) can be prepared by the reaction of a 3-amino-5- chloro(or bromo) -6-halopyrazinamide ( IV-C) with an appro- priate reagent (VII) ( (IV-C) (IV-B) When the reagent (VII) is a lower alkanol (ROH) or lower alkyl mercaptan (RSH) and a base, such as triethylamine or pyridine in a solvent as dimethylforraamide or dimethyl sulfoxide is used, the product is a 3-amino-5-lower alkoxy- (or lower alkylthio) -6-halopyrazinamide. The reaction also can be carried out using ROM or RSM where M is derived from an alkali metal. When ROM is used ROH can be used as a 1 2 solvent. When VII is R R NH in a solvent such as dimethyl sulfoxide or dimethylformamide the product is a 3-amino-5- 1 2 R R N-6-halopyrazinamide. It is usually advantageous to conduct these reactions above ambient temperature, such as o at 50 C. to the reflux temperature of the solvent.
The novel 2 ,4-diamino-6-halo-7-X-pteridine products of this invention possess diuretic and saluretic properties and are useful in the treatment of edema or other con- ditions, associated with an abnormal retention of fluid and/or electrolytes especially sodium and chloride ions. As the products are effective upon oral or parenteral adminis- tration, they can be administered in any of the usual suit- able dosage forms such as admixed with lactose and encap- sulated and administered orally. Of particular importance are the 2 ,4-diamino-6-halo-7-( amino or substituted amino) - pteridine compounds which possess marked diuretic and saluretic properties. While the dosage will vary depending upon the age and condition of the patient and the particu-lar product used, effective dosages ranging between about 50-1000 mg. per day or more generally will produce the desired effect.
The novel methods for producing the novel products of this invention will be described in greater detail in the following examples which are to be considered illustra-tive and not limitative of the invention.
EXAMPLE 1 2 ,4-Diamino-6-chloropteridine Step A: Preparation of 3-amino-6-chloropyrazinamide Methyl 3-amino-6-chloropyrazinoate (25 g. , 0.133 mole) is suspended in concentrated ammonium hydroxide (500 ml.) and then stirred and heated on a steam bath for an hour. The reaction mixture is cooled and the product removed by filtration, washed with water and dried. The yield of 3-amino-6-chloropyrazinamide is 20 g. (88%) o m.p. 222-225 C. Recrystallization from a mixture of alcohol and water gives material melting at 231-232°C.
Analysis calculated for C5H5C1N40: C, 34.80; H, 2.92; N, 32.47; Found: C, 35.28; H, 3.38; N, 32.55.
Step B: Preparation of N ,N-dimethyl-N1 - ( 3-cyano-5-chloro- 2-pyraziny1) formamidine A suspension of 3-amino-6-chloropyrazinamide (17.2 g. , o.l mole) in dimethylformamide (170 ml.) is treated with phosphoryl chloride (17 ml.). The tempera-ture of the reaction mixture rises spontaneously, after which it is stirred for 10 minutes on a steam bath. After cooling the mixture is poured into ice-water (1 liter), and then neutralized with ammonium hydroxide. The yield of ,Ν-dimethyl-N* - (3-cyano-5-chloro-2-pyrazinyl) formamidine is 14.2 g. (69%), m.p. 110-114°C. Recrystallization from o cyclohexane gives material melting at 117-119 C.
Analysis calculated for CgHgClN5: C, 45.83; H, 3.84; N, 33.41; Found: C, 45.84; H, 3.65; N, 33.49.
Step C: Preparation of 3-amino-6-chloropyrazinonitrile A solution of Ν,Ν-dimethyl-N' - ( 3-cyano-5-chloro-2-pyrazinyl) formamidine (4 g. , 0.02 mole) in 5% aqueous hydrochloric acid (100 ml.) is heated on a steam bath for 10 minutes. A yellow solid separates during the heating. The reaction mixture is cooled and the 3-amino-6-chloro-pyrazinonitrile is separated by filtration, washed with water and dried. The yield is 2.8 g. (95%), m.p. 151-153°C.
Recrystallization from cyclohexane gives pure material, m.p. 151-153°C.
Analysis calculated for C5H3CIN4: C, 38.86; H, 1.96; N, 36.25; Found: C, 39.33; H, 2.24; N, 36.73.
Step D: Preparation of 2 ,4-diamino-6-chloropteridine Sodium (920 mg 0.O4 g. atoms) is dissolved in methanol (50 ml.), guanidine hydrochloride (4.0 g. , 0.043 mole) is added and the mixture refluxed under anhydrous conditions for 15 minutes. The mixture is cooled, filtered and 3-amino-6-chloropyra2inonitrile (2.0 g. , 0.013 mole) is added and the mixture refluxed for 15 minutes. The yellow solid that separates is removed by filtration and dried. The yield is 1.9 g. (75%), m.p. 295°C. (dec). The product is suspended in water (100 ml.), dissolved by the addition of the minimum amount of diluted hydrochloric acid and filtered. Th e filtrate is made basic to litmus paper by the addition of dilute ammonium hydroxide. The precipi-tated 2 , 4-diamino-6-chloropteridine is separated by filtration, washed with water, then with ethanol and dried; m.p. 295°C. (dec).
Analysis calculated for C6H5C1N6: C, 36.66; H, 2.56; N, 42.75; Found: C, 36.76; H, 2.65; N, 42.33.
EXAMPLE 2 2 ,4-Diamino-6-bromopteridine Step A; Preparation of 3-amino-6-bromopyra2inonitrile 3-Aminopyrazinonitrile (11.1 g., 0.093 mole) is dissolved in acetic acid (92 ml.) by warming to 60°C. and a solution of bromine (16 g. , 0.2 g. atom) in acetic acid (7 ml.) is added. The mixture is stirred for 15 minutes solid that separates is removed by filtration, washed with water and dried yielding 15.7 g. (85%) of product, m.p. 170-174°C. After recrystallization first from benzene and then from ethanol, the 3-amino-6-bromopyrazinonitrile melts at 181-183°C.
Analysis calculated for C5H3Br 4: C, 30.18; H, 1.52; N, 28.15; Found: C, 30.44; H, 1.69; N, 28.40.
Step B: Preparation of 2 ,4-diamino-6-bromopteridine Sodium (920 mg. , 0.04 g. atom) is dissolved in methanol (35 ml.), guanidine hydrochloride (4.0 g. , 0.043 mole) is added and the mixture refluxed for 30 minutes. After cooling and filtering, the filtrate is treated with 3-amino-6-bromopyrazinonitrile (2.0 g., 0.01 mole) and the mixture is refluxed for 30 minutes. The reaction mixture is cooled, diluted with water (75 ml.) and the solid re-moved by filtration; the yield is 1.2 g. (50%), m.p. > 300°C. The solid is suspended in water (75 ml.) and the minimum amount of dilute hydrochloric acid added to effect solution. The solution is treated with decolorizing charcoal and filtered. The filtrate is made slightly basic to litmus paper with 5% sodium hydroxide and the precipi-tated 2 ,4-diamino-6-bromopteridine is separated by filtra-tion, washed with water and dried, m.p. ^ 300°C.
Analysis calculated for C6H5BrN6: C, 29.82; H, 2.08; N, 34.77; Found: C, 30.29; H, 2.45; N, 34.58.
EXAMPLE 3 2 ,4-Diamino-6-iodopteridine Step A: Preparation of 3-amino-6-iodopyrazinonitrile By replacing the methyl 3-amino-6-chloropyrazino-ate of Example 1, Step A, by an equimolecular quantity of methyl 3-amino-6-iodopyrazinoate and following substan-tially the same procedure described in Step A of Example 1, there is obtained 3-amino-6-iodopyrazinamide. This product when treated with dimethylformamide and phosphoryl chloride, using equivalent quantities of reactants and substantially the same procedure described in Step B of Example 1 gives N,N-dimethyl-N' - (3-cyano-5-iodo-2-pyrazinyl) formamidine which when hydrolyzed with hydrochloric acid as described in Step C of Example 1 gives 3-amino-6-iodopyrazinonitrile. Step B; Preparation of 2 ,4-diamino-6-iodopteridine By replacing the 3-amino-6-chloropyrazinonitrile used in Step D of Example 1 by an equimolecular quantity of 3-amino-6-iodopyrazinonitrile and following substantially the same procedure described in Step D of Example 1 there is obtained 2 ,4-diamino-6-iodopteridine.
EXAMPLE 4 2 , 4-Diamino-6 , 7-dichloropteridine Step A: Preparation of 3-amino-5,6-dichloropyrazinamide A stainless steel autoclave is charged with methyl 3-amino-5,6-dichloropyrazinoate (11.1 g. , 0.05 mole) and liquid ammonia (100 ml.) and is kept at 25°C. for 24 hours. autoclave with methanol (200 ml.). The methanol insoluble fraction (4.0 g.) was recrystallized from dimethylformamide (40 ml.) to give the pure 3-amino-5,6-dichloropyrazinamide which melted at 291.5-293.5°C.
Analysis calculated for C5H4C12N40: C, 29.07; H, 1.95; N, 27.06; Found: C, 29.58; H, 1.87; N, 27.36.
Step B; Preparation of Ν,Ν-dimethyl-N* -( 3-cyano-5,6- dichloro-2-pyrazinyl)formamidine A suspension of 3~amino-5,6-dichloropyrazinamide (22 g. , 0.106 mole) in dimethylformamide (220 ml.) is stirred and treated with phosphoryl chloride (22 ml.). The temperature spontaneously rises to 65°C. after which it is o heated to 80 C. and then stirred with heating for 10 minutes. The solution is cooled and poured into water (500 ml.) to give 12.5 g. (48%) of N,N-dimethyl-N« -( 3-cyano-5,6-dichloro-2-pyrazinyl)forroamidine, ra.p. 116-118°C. After recrystallization from methylcyclohexane it melts at 117-119°C.
Analysis calculated for CgHyClgl^: C, 39.35; H, 2.89; N, 28.70; Found: C, 38.76; H, 3.05; N, 28.94.
Step C: Preparation of 3-amino-5>6-dichloropyrazinonitrile A solution of N ,Ν-dimethyl-N* -( 3-cyano-5 ,6-dichloro-2-pyra2inyl) formamidine (2.5 g. , 0.01 mole) in a solution of water (100 ml.) and 6N hydrochloric acid (10 ml.) is stirred and heated on a steam bath for an hour.
The mixture is cooled and the ale ellow solid recovered by filtration; the yield is 1.85 g. (95%) m.p. 213-215°C. After recrystallization from benzene the 3-amino-5,6-dichloropyrazinonitrile still melts at 213-215°C.
Analysis calculated for C5H2C14 4: C, 31.74; H, 1.06; N, 29.64; Found: C, 31.83; H, 1.34; N, 29.41.
Step Dt Preparation of 2.4-diamino-6t7-dichloropteridine Sodium (0.46 g. , 0.02 g. atom) is dissolved in tert . -butanol (100 ml.), guanidine hydrochloride (1.91 g., 0.02 mole) is added and the mixture is refluxed for 30 minutes and then filtered. The tert . -butanol is removed from the filtrate and the residual guanidine is treated with 3-amino-5,6-dichloropyrazinonitrile (3.78 g. , 0.02 o mole) . The reaction mixture is heated briefly at 60 C. to assure complete homogeneity and then stirred at room temperature for 2 hours. The addition of water (100 ml.) precipitates the product which is recovered by filtration, dried and purified by dissolving in dilute aqueous hydro- chloric acid and precipitating with dilute aqueous sodium hydroxide. The product melts at > 300°C.
Analysis calculated for C6H4N6C12: C, 31.19; H, 1.74; Found: C, 31.53; H, 2.09.
EXAMPLE 5 2 , 4-Piamino-6-bromo-7-chloropteridine Step A: Preparation of methyl 3-amino-6-bromopyrazinoate 4-oxide A solution of methyl 3-amino-6-bromopyrazinoate (4.6 g., 0.02 mole) and m-chloroperbenzoic acid (3.4 g. , 0.02 mole) in chloroform (75 ml.) is refluxed for one hour, then chilled. The solid that separates is recovered by filtration and recrystallized from ethanol to yield 5.0 g. (98%) of methyl 3-amino-6-bromopyrazinoate 4-oxide m.p. 200-202°C.
Analysis calculated for C6H6 303Br: C, 29.05; H, 2.44; N, 16.94; Found: C, 29.12; H, 2.27; N, 17.12.
Step B; Preparation of methyl 3-amino-5-chloro-6-bromo- pyrazinoate Methyl 3-amino-6-bromopyrazinoate 4-oxide (2.0 g., 0.008 mole) is dissolved in dimethylformamide (20 ml.), phosphoryl chloride (2.0 ml.) is added and the reaction is stirred vigorously for 30 minutes and then poured into water (100 ml.). The clear solution deposits reddish crystals after standing for several hours, which are re-crystallized from acetonitrile to yield 1.5 g. (71%) of methyl 3-amino-5-chloro-6-bromopyrazinoate, m.p. 225-228°C.
Analysis calculated for C6H5N302BrCl: C, 27.04; H, 1.89; N, 15.77; Found: C, 27.38; H, 2.21; N, 15.93.
Step Gt Preparation of 3-amino-5-chloro-6-bromopyrazino- nitrile By replacing the methyl 3-amino-5,6-dichloro- pyrazinoate employed in Step A of Example 4 by an equi- molecular quantity of methyl 3-amino-5-chloro-6-bromo- pyrazinoate and then following the same procedures and 1 using equivalent Quantities of reactants described in Steps A through C of Example l\ , there is produced suc- 3 cessively 3-ftfliino- -chloro-6-bromopyrazinaraide, N, - l[ d imethy1-N ' - ( 3-c ano-$-bromo- -chloro-2-pyraziny1 ) ormami- > dine and 3-amino-5>-chloro-6-bromopyraz inonitrile .
^ Step D: Preparation of 2,li -d iamino-6-broino-7-chloro- 7 pterid ine ^ This product is prepared following substantially 9 the same procedure described in Example l\ , Step D, except 3-ari)ii)o-5-chloro-6-broiiiopyrazinonitrile is substituted for 11 the 3-amino-5,6-dichloropyrazinonitrile. 12 EXAMPLE 6 16 By replacing the phosphoryl chloride used in Step 17 B of F.xarnple by an ecual quantity of phosphoryl bromide Ιί.' ami following substantially the same procedure described in 19 Τ·'\ample 5» Step B, there is obtained methyl 3-,¾η1ηο-5>>6- 20 d ibrornopyraz inoate . 21 Step B; Preparation of 2,]i-diamino-6,7-dibroinopteridine 22 By replacing the methyl 3-¾wino-5 , 6-d icliloro- -?3 pyrazinoate employed in Example h, Step A, by an equi- k molecular nuantity of methyl 3_a lno- , -d ibromopyrazinoate and then us In; the same procedures and 113 ing eouivalent 2b quantities of reagents and reactants described in Exfimple )| , 27 Steps Λ through , there is produced successively 3*"«i«ino- 2'i 5f '''-dibromopyra inami e, li , 1 -dimethyl- '-( 3-cyano- , 6- 29 d ibromo-2-pyra inyl ) ormamidine, 3-amino-^, -dibromopyra- 30 z inonitrile, and thereafter 2, -diamino-6,7-dibromopterid ine.
EXAMPLE 7 2 j 4-Diamino-6-chloro-7-bromopterldine Step A: Preparation of methyl 3-amino-6-chloropyrazinoate 4-oxlde .
A suspension of methyl 3-amino-6-chloropyrazinoate (3· 5 g. , 0.02 mole) and m-chloroperbenzoic acid (3.4 g., 0.02 mole) in chloroform (50 ml.) is stirred at room temperature until a solution is obtained (15 minutes).
Then the mixture is refluxed for one hour. The solid that separates upon cooling; is recovered by filtration; the yield is 3.0 g. {75%). After crystallization from methanol the product melts at 200-202°C.
Analysis calculated for C^Hg ^Cl: C, 35-40; H, 2.97; , 20.64; Found: C, 35-71; 11, 3-l4; N, 20.62.
Step B: Preparation of methyl 3-amino-5-bromo-6-chloro- pyrazlnoate This product is prepared as described in Example 5, Step 13, except that methyl 3-amino-6-bromopyrazinoate 4-oxide and phosphoryl chloride is replaced by an equi-molecular quantity of methyl 3-amino-6-chloropyrazinoate 4-oxide. and phosphoryl bromide.
Step C: Preparation of 2, 4-diamino-6-chloro-7-bromo- pteridine This product is prepared following substantially the same procedure described in Example 1, Steps A-D, except the methyl 3-amino-6-chloropyrazinoate employed in Step A of Example 1 is replaced by an equimolecular quan-tity of methyl 3-amino-5-bromo-6-chioropyrazinoate . By following the procedures described in Steps A through D of Example 1 there is prepared successively 3-amino-5-bromo-6-chloropyrazinamide, ,N-dimeth l-N ' -( 3-c ano-5-chloro-6- 1 bromo-2-pyrazinyl) formamidine, 3-amino-5-bromo-6-chloro- 2 pyrazinonitrile, ana 2,4-diamino-6-chloro-7-bromopteridine. 3 EXAMPLE 8 4 2,l-Diamino-6-chloro-7-lsopropoxypteridine Sodium (Jl60 rng. , 0.02 g. atom) is dissolved in 6 isopropyl alcohol (50 rriL) and guanidine hydrochloride 7 (1.91 g. , 0.02 mole) then is added and the mixture is re- 8 fluxed for 30 minutes. After cooling and filtering, the 9 filtrate is treated with 3-amino-5, 6-dichloropyrazino-.10 riitrile from Example 4 , Step C, (2.0 g. , 0.0106 mole). .11 The mixture is stirred for 2 hours and then refluxed for ,12 30 minutes. After cooling, the reaction mixture is poured .13 into water (200 ml.) and the solid that separates is re-l4 moved by filtration yielding 1.4 g. (52¾) of 2, -diamino-25 6-chloro-7-isopropoxypteriaine, m.p. 233-235°C. (dec). 16 After recrystallization from benzene the product melts at 17 238-240oC. 18 Analysis calculated for CQH..,ClNO : C, 42.40; H, 4.35; 19 N, 32.95 Found: C, 2.65 H, 't - 2 J N, 33-23. 21 EXAMPLE 9 22 , -Diamino-6-chloro-7-methoxypteridine 2 Step A: Preparation of 3-amino-5-methoxy-6-chloropyrazin- 4 amide Sodium (2.3 g., 0.1 mole) is dissolved in methanol 26 (100 ml.) and the solution evaporated to dryness at reduced 27 pressure. The solid sodium methoxicte is dissolved in di- 23 methylformamide and 3-amlno- ,6-dichloropyrazinamide (20.7g. 0.1 mole) (from Example l\ , Step Λ) added, and the mixture stirred and heated on a steam bath for 30 minutes. The solvent is removed by distillation at reduced pressure and the residue suspended in water, filtered, washed with water ana recrystallized from isopropyl alcohol.
Step B: Preparation of 2 , il-diamino-6-chloro-7-methoxy- pteridine This product is prepared as described in Example ' Steps B through D, except the 3-amino-5 , o-dichloro- pyrazinamide used in Step B is replaced by an equimoleeular quantity of 3-arnino-5-methoxy-6-chloropyrazinanide . By following substantially the same procedures described in Example 4, Steps B through D, there is obtained successively N,N-dimethyl- ' -( 3-cyano-5-chloro-6-methoxy-2-pyrazinyl) formamidi e, 3-amino-5-tnethoxy-6-chloropyrazirionitrile and 2, ^-diamino-6-chloro-7-niethoxypteridine.
EXAMPLE 10 2 „ l-Diamino-6-iodo-7-methoxypteridine Step A: Preparation of 3-amino- -methoxypyrazlnonitrile A mixture of 3-amino-5-methoxy-6-chloropyrazino- nitrile (12.9 g., 0.07 mole) (from Example 9), % palladium-on-charcoal catalyst (9 g.), magnesium oxide ( J.0 g., 0.1 mole) and methanol (2'jO ml.) is shaken in an atmosphere of hydrogen for 10 hours at room temperature at an initial pressure of 30 p.s.i. The pressure drop indicates an absorption of 0.07 mole of hydrogen. The mixture is filtered and the solids extracted with boiling methanol and the combined filtrates are evaporated to dry- ness at reduced pressure. The residual 3-amino-5-methoxy- pyrasinonltrile is purified by recrystaliization from a mixture of benzene and cyclohexane.
Step B: Preparation of 3-amlno-5-methoxy-6-iodopyrazino- nltrile A suspension of 3-amino-5-methoxypyrazinonitrile (14.9 g., 0.1 mole), in water (300 ml.) is heated to 70°C. Mercuric acetate (32 g., 0.1 mole) and a solution of iodine (25 g., 0.1 mole) in warm dioxane (200 ml.) is added quick-l and the mixture is stirred and heated on a steam bath for 5 minutes then allowed to cool and treated with an aqueous solution of potassium Iodide (500 ml. containing 75 g. of KI). The solid 3-amino-5-methoxy-6-iodopyrazino-nitrile that separates is removed by filtration, washed with water and dried.
Step C: Preparation of 2 , 4-diamino-6-iodo-7-methoxy- pteridine By replacing 3-amino-5, 6-dichloropyrazinonitrile of Example 4, Step D, by an equimolecular quantity of 3-amino-5-methoxy-6-iodopyrazinonitrile and following sub-stantlally the same procedure described in Example 4, Step D, there is obtained 2 , -diamino-6-iodo-7-methoxypteridine .
EXAMPLE 11 , 4-Diamino-6-chloro-7-meth lthiopteridine This compound is prepared as described in Example 9, Steps A and B, except that an equivalent quantity of the sodium salt of methyl mercaptan is substituted for sodium methoxide in Step A. Thus, the products obtained in order are 3-amino-5-methylthio-6-chloropyrazinamide, M,N-di-methyl-N ' -( 3-cyano-5-chloro-6-methylthio-2-pyrazinyl) formamidlne, 3-amino-5-methylthio-6-chloropyrazinonitrile and 2, -diamino-6-chloro-7-inethylthiopteridine, EXAMPLE 12 bromo 2, -Diamino-G--efeh>¾^--7-ethylthiopteridine This compound is prepared as described in Example 9, Steps A and B, except that an equivalent quantity of the sodium salt of ethyl mercaptan is substituted for the sodi-urn methoxide used in Step A. Thus, the products obtained bromo in order are 3-amino-5-ethylthio-6-ekie.?epyrazinamide , bromo Ν,Ν-dimethyl- ' -( 3-cyano-5-9^1<*-ae--6-ethylthio-2-pyrazinyl ) r bromo formamidine, 3-amino-5-ethylthio-6-&&i^.a«pyrazinonitrile . bromo and 2,Jl-diamino-6-G^«U>iso--7-eth lthiopteridlne.
EXAMPLE 13 2 , 4-Diamlno-u-chloro-7-hydroxypterldine Step A: Preparation of 2, 4-diamino-6,7-dichloropteridine Sodium (0.46 g., 0.02 g. atom) is dissolved in tert . -butanol (100 ml.), guanidine hydrochloride (1.91 g., 0.02 mole) is added and the mixture is refluxed for 30 minutes and then filtered. The tert . -butanol is removed from the filtrate and the residual guanidine is treated with 3-amino-5,C-dichloropyrazinonitrile (3-72 g., 0.02 mole, from Example 4, Step C). The reaction mixture is heated briefly at G0°C. to assure complete homogeneity and then stirred at room temperature for 2 hours. The addition of water (100 ml.) precipitates the product which is re-covered by filtration, dried and purified by dissolving in dilute aqueous hydrochloric acid and precipitating with dilute aqueous sodium hydroxide. The product melts at > 300°C.
Analysis calculated for CgH^NgClgt C, 31.19; H, 1.74 Found: C, 31.53; H, 2.09-Step B: Preparation of 2 , -diamino-6-chloro-7-hydroxy- pterldine 2, 4-Diamino-6,7-dichloropteridine (2.31 g. , 0.01 mole) is dissolved in dimethyiformamide (50 ml.) and sodium acetate (902 gin., 0.011 mole) is added and the mixture stirred and heated on a steam bath for 2 hours. The solvent is removed by distillation at reduced pressure, the residue 3s suspended in water, IN sodium hydroxide (10 ml., 0.01 mole) is added and the mixture stirred and heated to effect solution. The solution is filtered and the filtrate acidified with acetic acid. The 2 , -diamino-6-chloro-7-hydroxypteridine that precipitates is removed by filtration, washed with water and dried.
EXAMPLE 1 , 4-Dlamino-6-chloro-7-mercaptopterldine This compound is prepared as described in Example 13, Step B except that a mixture of sodium sulfide mono-hydrate (2.4 g., 0.01 mole) and sulfur (2.5 g.) in ethanol (20 ml.) which had been refluxed for 30 minutes is sub-stituted. for the sodium acetate and dimethyiformamide .
EXAMPLE 15 , 4-Diamino-6-chloro-7-benzyloxypteridine This product is prepared in the same manner des-cribed in Example 8 except that benzyl alcohol is substi-tuted for isopropyl alcohol.
This product also can be prepared by the method described in Example 9 by replacing the methanol used in EXAMPLE 16 2 , Jl-Diamino-6-bromo-7-phenylpteridine This product is prepared following the procedure of Example 1, Steps A through D, except the methyl 3-amino- 6-chloropyrazinoate employed in Step A of Example 1 is replaced by an equimolecular quantity of methyl 3-amino-5- phenyl-6-bromopyrazinoate . By following the procedures described in Steps A through D of Example 1, there is pro- duced successively 3-amino-5-phenyl-6-bromopyrazinamide , ,N-dimethyl-N 1 -( 3-cyano-5-bromo-6-phenyl-2-pyrazinyl) formamidine, 3-amino-5-phenyl-6-bromopyrazinonitrile and 2, 4-diamino-6-bromo-7-phenylpteridine.
EXAMPLE 17 23 -Diamino-6-bromo-7-methylpteridine This product is prepared following the procedure of Example 1, Steps A through D, except the methyl 3-amino- u-chloropyrazinoate employed in Step A of Example 1 is re- placed by an equimolecular quantity of methyl 3-amino-5- methyl-6-bromopyrazinoate. By following the procedures described in Steps A through D of Example 1, there is pro- duced successively 3-amino-5-methyl-6-bromopyrazinamide , N,Ν-dimethyl-N' -( 3-cyano-5-bromo-6-methyl-2-pyrazinyl) formamidine, 3-amino-5-methyl-6-bromopyrazinonitrile and 2 , 4-diamino-6-bromo-7-methylpteridine .
EXAMPLE 18 23 Jl , 7-Triaiaino-6-chloropteridirie Step A: Preparation of 3 ¾ 5-diamlno-6-chloropyrazinonitrile A solution of 3-amino-5,6-dichloropyrazinonitrile, from Example 4, Step C, (10.0 g., 0.0rj mole) in dimethyl 1 sulfoxide (50 ml.) is stirred and heated on a steam bath 2 while ammonia gas is admitted below the surface of the 3 solution. The addition requires 30 minutes, after which 4 the solution is cooled and poured into water (150 ml.).
The solid that separates is removed by filtration washed ΰ with water and dried yielding 5.1 g. ( 60% ) of 3,5- 7 diamino-6-chloropyrazinonitril , m.p. 2 5°C. After re- 8 crystallisation from water the melting point remains un- 9 changed. 0 Analysis calculated for C^H^CI ^: C, 35-41; H, 2.43; 1' N, 41.30; 2 Found: C, 35-69; H, 2.30; N, 41.10. 3 Step B: Preparation of 2, 4 , 7-triamino-6-chloropteridine 4 Sodium (690 mg. , 0.03 g. atom) is dissolved in 5 isopropyl alcohol (100 ml.) then guanidine hydrochloride 6 (2.36 g., O.03I mole) is added and the mixture refluxed for 7 3 minutes. The mixture is cooled, filtered and 3,5-3 diamino-6-chloropyrazinonitrile (2.6. g., 0.015 mole) in 9 isopropyl alcohol (300 ml.) is added to the filtrate. The Q solution is refluxed for an hour and cooled. The solid 1 that separates is removed by filtration, washed with water 2 and dried yielding 3.0 g. (92%) of 2 , , 7-triamino-6-3 chloropteridine, m.p. \> 310°C. Purification was effected 4 by dissolving in dilute aqueous hydrochloric acid followed 5 by precipitation with dilute aqueous sodium hydroxide. 6 Analysis calculated for Cgh^ClN^ C, 3^.09 II, 2.86; 7 N , 46.42; 8 Found: C, 34.03; H, 3.l6; N, 46.35. 1 l.'f'AM i'Li'l 19 ■ '- , l\ , 7"' 1' am1no-6 -\ romopter1d 1 no 3 ' e Λ: Preparat Ion of 3 , 5~d iamlno-6-bromopyraz inonlfarlie l\ This product Is prepared by the method described in Example 18, Step A, by replacing the 3-amino-5, 6-di- 6 chloropyrazinonitrile by an equimolecular quantity of 7 3-amino-5-chloro-6-broiiiopyrazinonitrile, from Example 5> (\ Step G. 9 .te V< : Preparation of 2,)i , 7-trlaiiiino-6-broniopterid ine This product is prepared as described in Example 11 1 , Step B, by replacing the 3 ,5-d iarnino-6-chloropyrazino- 12 nitrile by an e imolecular quantity of 3,5-d iamino-6- 13 bromopyrazinonitrile .
Ik EXAMPLE 20 2,1.) , 7-'Elriamino-6--iodoptorid ine 16 Step A: Preparation of 3j3'-»ia.minopyrazinonitrile 17 A mixture of 3» _^iamino-6-chloropyrazirionifar ile 18 from !'.x..ample 18, Step A, (11.9 g., 0.07 mole), 19 pallad lum-on-charcoal catalyst (9 g · ) , magnesium oxide (J|..0 g., 0.1 mole) and methanol (2>0 ml.) is shaken in an 21 atmosphere of hydrogen for 18 hours at room temperature at 22 an initial pressure of 30 p.s.i. The pressure drop in-2,3 dicates an absorption of 0.07 mole of hydrogen. The 2l| inixture is filtered and the solids extracted with a boiling 5 solution of 2-propanol ( 5'00 ml.) and water (¾'J ml.). The 1 methanol filtrate and the 2-propanol-water extract are 2 united and concentrated to a volume of 50 ml. and cooled. 3 The 3 j 5-diaminopyrazinonitrile that separates is removed J by filtration, dried and recrystallized from a mixture of 2-propanoi and water.
Step b: Preparation of 3 , 5-diamino-6-iodopyra¾lnonitrile 7 A suspension of 3 , 5-dlaminopyrazinonitrile (13. Ί r,., 8 0.1 mole) in water ( 300 ml.) is heated to 70°C, then 9 mercuric acetate (3· 2 g. , 0.1 mole) and a solution of iodine (25 g. , 0.1 mole) in warm dioxane (200 ml.) is added 11 quickly. The mixture is stirred and heated on a steam 12 bath for 5 minutes, then allowed to cool to room tempera- 13 ture and" treated with an aqueous solution of potassium 14 iodide (500 ml. containing 75 Z> of potassium iodide). The red solution quickly deposits a crystalline product which lb is separated by filtration, dried ana recrystallized from 1/ a mixture of 2-propanol and water. iu Step C: Preparation of , j4 , -triamino-6-iodopteridine 19 This product is prepared as described in Example 10, Step B, by replacing the 3 , 5-diamino-6-chloropyrazino- 21 nitrile by an equimolecular quantity of 3 , -diamino-6- 22 iodopyrazinonitrile . 23 EXAMPLE 21 2^ , ^-Dlamino-6-chloro-7-ethylaininopteriQlne Step A: Preparation of 3-amino-5-ethylamino-6-chloro- 26 pyrazinonitrile 27 3-Amino-5,6-dichloropyrazinonitrile from Example 28 i|, Step C, (5.0 g., 0.0255 mqle) is dissolved in dimethyl 29 sulfoxide (50 ml.) at 65°C, then aqueous ethylamine (3·5 mi., 0.05 mole) is added and the solution stirred at 1 tliis temperature for 15 minutes. After cooling it is 2 poured into water (I'jO ml.) and the solid that separates 3 is removed by filtration, washed with water and dried 1 yielding 3-2 g. (62%) of product, m.p. 100-105°C After recrystallization from a mixture of water and Isopropyl 6 alcohol, the 3-amino-5-ethylamlno-6-chloropyrazinonitrile 7 melts at 107-109°C 3 Analysis calculated for C7HPC1KV: C, 12.55; H, 1.11; 9 N , 35.15 Found: C, 12.21; ii, 3.92; N, 35-31. 11 Step B: Preparation of , 1-diamino-6-chloro-7-ethylamino- 12 pteridine 13 Soaiu (IbO mg. , 0.02 g. atom) is dissolved in I'-l isopropyl alcohol (50 ml.). Then guanidine hydrochloride (1.91 ε·> 0.02 mole) is added and the mixture refluxed for lb 30 minutes. The mixture is cooled, filtered and then 17 3-amino-5-ethylamino-6-chloropyrazinonitrile (2.0 g., IS 0.01 mole) is added to the filtrate. The mixture is re- 19 fluxed for an hour and cooled. The solid that separates is removed by filtration, washed with water and dried 21 yielding 1.9 g. ( 2/ of , 1-diamino-6-chloro-7-ethylamino- 22 pteridine, in. p. 256-259°C. After recrystallization from 23 ethanol the melting point of the product remains unchanged. 21 Analysis calculated for C,H C1H,.: C, 10.10; H, 1.21; , 10.90; 26 Found: C, 10.12; II, 1.17; , 10.69- 27 EXAMPLE 22 28 2, -Diamino-b-chloro-7-anillnopteridine 29 Step A: Preparation of 3-amino-5-anilino-6-chloroOyrazino- 30 " nitrile - - - 1 from Example *l , Step C, (10 p., O.O'JJ mole), aniline 2 (l'K9 R. , 0.16 mole), aniline hyurochloride (13.7 > 3 0.116 mole) and dimethyl sulfoxide (100 mi.) is heated at 4 5°C for 3 hours and then cooled and diluted with water '3 (100 ml.). The solid that separates is removed by 6 filtration, washed with water, dried and washed with 7 methylcyciohexane . After recrystallization from iso- 8 propyl alcohol there is obtained 3-ainino-5-anilino-6- 9 chloropyrazinonitril . 0 St B: Preparation of 2, 1J-diamino-6-chloro-7-anilino-1 pteriaine 2 This proauct is prepared by substantially the 3 same procedure described in Example 21, Step B, except the ^ 3-amino-5-ethylamino-b-ehloropyrazinonitrile used there is 5 replaced by an equimolecular quantity of 3-amino-5-anilino-6 6-chloropyrazinonltrile . 7 EXAMPLE 23 Q 2 , Jl-Diamino-G-chloro-7-p-mothylanilinopteridine 9. Step A: Preparation of 3-amino-5-p-niethylanilino-6-chloro-0 pyrazinonltrile 1 This proauct is prepared by the process described 2 in Example 22, Step A, except the aniline and the aniline 3 hydrochloride employed there are replaced by equimolecular *1 quantities of p-toluidine and p-toluidine hydrochloride respectively. 6 Step B: Preparation of 2 , il-diamino-6-chioro-7-p-rnethyl- anilinopterlaine 8 This product is prepared following substantially 9 the same procedure described' in Example 21, Step B, except 0 the 3-amino-5-ethylamino-6-chloropyra'2inonitrile used there I is replaced by an equimoiecular quantity of 3-amino-5-p- methylanllino-6~-chloropyrazinonitrile . 3 EXAMPLE ^ 2 , ^-Dlaniino-G-chloro-T-p-c loroanilinopteridine Step A: Preparation of 3-amino-5-p-chloroanilino-6- 6 chloropyrazinonitrile 7 This product is prepared by the process described 8 in Example 22, Step A, except the aniline and the aniline 9 hydrochloride employed there are replaced by equimoiecular 0 quantities of p-chloroaniline and p-chloroaniline hydro-1 chloride respectively. 2 Step b: Preparation of , it-diamino-6-chloro-7-p-chloro-3 anllinopteriaine 4 This product is prepared following substantially 5 the same procedure described in Example 21, Step B, except b the 3-amino-5-ethylamino-b-chloropyrazinonitrile used there 7 is replaced by an equimoiecular quantity of 3-amino~5-p-6 chloroanilino-o-chloropyrazinonitrile . 9 Table A identifies other 2 , 4-diamino-6-chloro-7-0 RR½-pteridlnes prepared by the process described in 1 Example 21, Steps A and B , except the ethylamine used in 2 Example 21, Step A, is replaced by an equimoiecular quan-3 tity of the RR½i identified in the table. The variable ^1 radicals R and of the amine reactant remain unchanged 5 during the reaction and are the same in the 5-positlon .6 RR½-groups of the intermediate pyrazlnonitriie (A) and 7 pyrazinimidoylRuanidirie (B) and in the 7-position RR½-3 groups of the pteridine enu product (C) and are identified 1 9 in the columns headed R and R in Table A. isopropyl H Pyrazinonitrile (A) 92 126-3 45. 46 4 Pteridine (C) 79 233-5 42. 60 4 26 allyl Pyrazinonitrile (A) 56 103-5 45. 79 "3 Pteridine (C) 33 245-7 42. 92 4 27 methyl meth l Pyrazinonitrile (A) 79 119-20 42. 5 4 Pteridine (C) 66 263(dec.) 40. 10 4 ethyl ethyl Pyrazinonitrile (A) 70 114-6 47. 90 5 Pteridine (C) 84 26S-71(dec.) 44. 95 5 1 Other 2 , | -diamine-6-chloro-7 ( substltuted-amino ) - 2 pterldlne compounds that are prepared by the procedures j described in xample 21, Steps A and B, are identified in •'-I the following table. In each example the 3-amino-5,6- 5 dichloropyrazinonitrile is heated with the required amine 6 RR½H at 50°C. to 100°C. for 10 to 30 minutes in a solvent 7 such as dimethyl sulfoxide, dimeth Iformamide or ethanol to 8 produce the corresponding 3-amino-5-MRR^"-pyrazinonitrile 9 which is refiuxed with a 2-propanol solution of guanidine 0 to produce the corresponding , 4-diamino-6-chloro-7-NRR'1'-1 pteridine according to the procedure described in Example 2LL. 2 The following table identifies other 2,4-diamino-3 6-chloro-7-( substituted-amino)-pteridines that are repre-4 sentative of the products that are and can be prepared by 5 substituting equivalent quantities of the appropriate amine 6 for ethylamirie employed in Example 21, Step Λ, and of the 7 corresponding 3-amino-5-substituted aminopyraainonitrile 8 for the 3-amino-ij-ethylaminopyrazinonitrile in Example 21, 9 Step B.
TA LsLli ϋ Ex. υ. R R 29 benz l hydrogen 2,2, 2-trifl oroeth 1 1 cyclopropylmethyl 32 cyclobutyl 33 p-methylbenzyl 3 2-hydroxyethyl 31 -pyridylmeth 1 36 2-furylmethyl 37 methyl allyl 3& n-propyl n-butyl 39 p-chlorobenzyl hydrogen 40 2-arninoethyl Ml 2-dimethylaninoethyl '1 propargy1 3 meth l 44 methoxy 45 tetram thylene 46 hexamcthylene -3.3- 26578/2 9
Claims (1)
1. carried out in presence of an A proeess as in 1 wherein the is added to a of guanidine in a secondary A process as claimed in Claim 1 wherein the is added to a solution of guanidine in tertiary A process as claimed in Claim 4 wherein the nitrile reactant is A process as claimed in Claia 4 wherein the nitrile reactant is A as claimed in Claim 4 wherein the nitrile reactant is pyrazinonitrile in which the lover alkyl group may be substituted as herein A process as in Claim 4 wherein the nitrile reactant is A process as claimed in Claim 4 wherein the nitrile reactant is alkyl A process as claimed in Claim 4 wherein the nitrile reactant is wherein halo and X have the same as in wherein the halo is selected and 2 wherein the halo radicals are separately selected from and compounds wherein each of the variables and is lower alkyl optionally substituted as herein lower aryl or lower and substituent is or 1 p eridine wherein substituent is or is lower alkyl or and Y is oxygen or 2 2 2 opt eridine 2 insufficientOCRQuality
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US49289865A | 1965-10-04 | 1965-10-04 |
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IL26578A true IL26578A (en) | 1970-11-30 |
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IL2657866A IL26578A (en) | 1965-10-04 | 1966-09-26 | Pteridine compounds and their preparation |
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BE (1) | BE687730A (en) |
BR (1) | BR6683209D0 (en) |
CH (1) | CH479601A (en) |
DE (1) | DE1620034A1 (en) |
ES (1) | ES332322A1 (en) |
FR (1) | FR6028M (en) |
GB (1) | GB1149640A (en) |
IL (1) | IL26578A (en) |
NL (1) | NL6613936A (en) |
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WO2007127366A2 (en) | 2006-04-25 | 2007-11-08 | Targegen, Inc. | Kinase inhibitors and methods of use thereof |
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1966
- 1966-09-26 IL IL2657866A patent/IL26578A/en unknown
- 1966-09-27 BR BR18320966A patent/BR6683209D0/en unknown
- 1966-09-28 CH CH1397766A patent/CH479601A/en not_active IP Right Cessation
- 1966-09-28 GB GB4340166A patent/GB1149640A/en not_active Expired
- 1966-09-29 ES ES0332322A patent/ES332322A1/en not_active Expired
- 1966-10-03 BE BE687730D patent/BE687730A/xx unknown
- 1966-10-03 NL NL6613936A patent/NL6613936A/xx unknown
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FR6028M (en) | 1968-05-13 |
CH479601A (en) | 1969-10-15 |
BE687730A (en) | 1967-04-03 |
ES332322A1 (en) | 1967-07-16 |
BR6683209D0 (en) | 1973-12-26 |
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