CA1216587A - 1,2-dihydropyrido [3,4-b]-pyrazines and method and intermediates for preparing same - Google Patents

Abstract

Abstract Of The Disclosure:

1,2-Dihydropyrido[3,4-b]pyrazines are provided which possess antifungal and anticancer activity. The compounds have the structure:

I

wherein x has a value of 1, 2 or 3; R1 is a lower alkyl group, e.g., an alkyl group containing up to six carbon atoms such as methyl, ethyl, propyl, butyl, etc.; R2 is a member selected from the group consisting of hydrogen, alkyl radicals having from about one to about 12 carbon atoms, preferably from about one to about 6 carbon atoms; alkenyl radicals having from about two to about 15 carbon atoms, preferably from about two to about 10 carbon atoms; cycloalkyl radicals having from about three to about 20 carbon atoms, preferably from about three to about 15 carbon atoms; aralkyl and alkaryl radicals having from about six to about 20 carbon atoms, preferably from about six to about 15 carbon atoms; a halogen radical, e.g., chlorine, fluorine, bromine and iodine, provided that when x has a value of 1 and R2 is in the para position and R3 and R4 are both hydrogen, R2 is not chlorine, a hydroxyl group; an amino group; an alkoxy or aryloxy group; a carboxyl group or an alkylcarboxyl group having from about one to about 10 carbon atoms, preferably from about one to about 5 carbon atoms; an alkylthio group or an arylthio group having from about one to about 20 carbon atoms, preferably from about one to about 15 carbon atoms; a sulfonic acid group or alkyl- or arylsulfonyl group having from about one to about 20 carbon atoms, preferably from about one to about 15 carbon atoms; an alkyl- or arylsulfinyl group having from about one to about 20 carbon atoms, preferably from about one to about 15 carbon atoms; an alkyl- or aryl mono- or diamino group having from about one to about 20 carbon atoms, preferably from about one to about 15 carbon atoms; a hydrocarbyl group, such as defined above, carrying halogen, hydroxyl, amino, alkoxy or aryloxy; and, when taken together with the aromatic ring to which it is attached, a fused ring structure such as naphthyl;
and R3 and R4 are either both hydrogen or one is hydrogen and the other is a lower alkyl group.
Compounds of Formula I wherein R3 is hydrogen are prepared by aminating a lower alkyl ester of 6-amino-4-chloro-5-nitropyridin-2-ylcarbamate having the structure:

II

with the oxime of an alpha-amino ketone having the structure:

III

to give a lower alkyl ester of a 6-amino-5-nitro-4-[(2-oxo-ethyl)amino]pyridin-2-ylcarbamate oxime having the structure:

IV
wherein R1, R2, R4 and x are the same as previously defined, further provided that R2 may be a nitro group. The compound of Formula IV is hydrolyzed, e.g., by acid hydrolysis to give the correpsonding ketone having the formula:

V
wherein R1, R2, R4 and x are the same as previously defined, further provided that R2 may be a nitro group. The compound of Formula V is converted to the compound of Formula I by catalytic hydrogenation. An intermediate product formed during hydrogena-tion has the formula:

VI

wherein R1, R2, R4 and x are the same as previously defined.
Compounds of Formula I wherein R4 is hydrogen may also be prepared by aminating the compound of Formula II with an alpha-amino alcohol having the structure:

IIIA
to give a compound having the structure:

VII;

which is oxidized to give a ketone having the structure:

VA

wherein R1, R2, R3 and x are the same as previously defined, further provided that R2 may be a nitro group. The compound of Formula VA is converted to a compound of Formula I by catalytic hydrogenation.

Description

This application is a divisional of S.N. 399,081 filed 23 March 1982 and is directed to the preparation of intermediates and the compounds so produced. The pa~ent application is concerned with the preparation of the end products and the products so produced.

This invention relates to novel 1,2~dihydropyridol3,4 b]pyrazines, also known as 1-deaza-7,8-dihydropteridines. This invention alco relates to a process for making such compounds and to novel intermediates obtained in said process.
The antimitotic chemical agents commonly known as spindle poisons are plant products of which the best known are colchicine, podophyllotoxin, and the vinca alkaloids. [L.
Wilson, J.R. Bamburg, S.B. Mizel, L.M. Grisham and K.M. Cres-well, Federation Proceedings, 33, 158 (1974~]. Two members of the latter, vincristine and vinblastine, are currently use~
clinically in the treatment of neoplasmsO Although these agents produce a number of biochemical actions such as the inhibition of macromolecular synthesis, their primary effect is to prsvent mitosis by interfering with the function of microtubules, which result~ in the acc~mulation o~ cells in metaphase. In addition, several benzimidazol-2-yl carbamates have been introduced as fungicides, anthelmintics and antitumoral agent~. lL.C. Davidse and WO Flach, J. Cell Biol., 72, 174 (1977)]~ These compounds ~O also prevent mitosis and their biological activity can probably be attributed to interference with the formation or functioning of microtubules.
The development of procedures for the preparation of 1-deazapteridines is reported by J.A. Montgomery and N.F. Wood, J. Or~ Chem., 29, 734 (1964); R.D. Elliott, C. Temple, Jr. and 5~
1 J.A. Montgomery, J. Org. Chem., 33, 533 (1968); R.D. Elliott, C.
Temple, Jr., J.L. Frye and J.A. Montgomery, J. Org. Chem., 36, 2818 (1971), and R.D. Elliott, C. Temple, Jr. and J.A. Mont-gomery, J. Med. Chem., 17, 553 (1974~. These references dis-close the preparation and use of various 1,2-dihydro[3,4-b]-pyrazine derivatives. Thus, the 1964 J. Org. Chem. reference discloses the compounds:

N~IC02C2H5 N~ ~- 3

2 5 2 \ N J

and I ~ N ~,- CH3 KO2CKN- ~ H

qo The 1968 J. Org. Chem. reference d.iscloses the compound:

N ~ N q ~ 2 6 5 C2H52CHN/~ NJ
H

~!~

5~37 The 1971 J. Org. Chem. reference discloses the cornpoundso ~ , CH2N ~ C2CH3 H

and lo N " ~ N ~ / CH2NH - ~ 2C2H5 C2H5o2cHN H

The J. Med. Chem. reference discloses that a dihydro-l-deaza-pteridine precursor of l-deazamethotrexate showed activity against leukemia L1210 in mice. An abstract presented at the 28th Southeast Regional Meeting of the American Chemical Society in Gaithinburg, Tennessee, October 27-29, 1976 discloses that the compound ~ N~ 2N ~ C2CH3 showed cytotoxicity in the KB cell culture screen and activity against leukemia L1210 in mice.

;s~

Sunmary Of 17he Invention It has now been found that certain 1,2-dihydropyrldo-[3,4-b]pyrazines which are not disclosed in any of the refer-ences discussed in the preceding section possess antifungal and anticancer activity. The compounds of this invention nave the structure:

NH ~R2)x ~ N
N ~ ~ \

RlO2CHN ~ ~ N \ R

wherein x has a value of 1, 2 or 3; Rl is a lower alkyl group, e.g., an alkyl group containing up to six carbon atoms such as methyl, ethyl, propyl, butyl, etc.; R2 is a member selected from the group consisting of hydrogen, alkyl radicals having from about one to about 12 carbon acoms, preferably from about one to about 6 carbon atoms; alkenyl radicals having from about two -to about 15 carbon atoms, preferably rom about two to about 10 carbon atoms; cycloalkyl radicals having from about three to about 20 carbon atoms, preferably from about three to about 15 carbon atoms; aralkyl and alkaryl radicals having from about six to about 20 carbon atoms, preferably from about six to about 15 carbon atoms; a halogen radical, e.g., chlorine, fluorine, bromine and iodine, provided that when x has a value of 1 and R2 is in the para position and R3 and R4 are both hydrogen, R2 is not chlorine; a hydroxyl group; an amino group; an alkoxy or aryloxy group; a carboxyl group or an alkylcarboxyl group having from about one to about 10 carbon atoms, preferably from about 7~' .,~,.

5~7 one to about 5 carbon atoms; an alkylthio group or an arylthio group having from about one to about 20 carbon atoms, preferably from about one to about 15 carbon atoms; a sulfonic acid group or alkyl- or arylsulfonyl group having from about one to about 20 carbon atoms, preferably from about one to about 15 carbon atoms; an alkyl- or arylsulfinyl group having from about one to about 20 carbon atoms, preferably from about one to about 15 carbon atoms, an alkyl- or aryl mono- or diamlno group having from about one to about 20 carbon atoms, preferably from about 1 one to about 15 carbon atoms; a hydrocarbyl group, such as defined above, carrying halogen, hydroxyl, amino, alkoxy or aryloxy; and, when taken together with the aromatic ring to which it is attached, a fused ring structure such as naphthyl;
and R3 and R4 are either both hydrogen or one is hydrogen and the other is a lower alkyl group~
Compounds of Formula I wherein R3 is hydrogen may be prepared by amlnating a lower alkyl ester of 6-amino-4-chloro-5-nitropyridin-2-ylcarbamate having the structure:

~0 ~, N02 RlO2CHN / ~ \ Cl with the oxime of an alpha-amino ketone having the structure:

5&~

H2NCHC ~R2 ) x III

to give a lower alkyl ester of a 6-amino-5-ni~ro-4-[~2-oxo-ethyl)amino]pyridin-2-ylcarbama~e oxime having the structure:

N ~ / 2 J,OH ~ ~2)x 102CHN ~ NHCHC--~

IV

wherein Rl, R2, R4 and x are the same as previously defined, further provided that R2 may be a nitro group. The compound of Formula IV is hydrolyzed, e~g., by acid hydrolysis to give the correpsonding ketone having the formula:

N~I2 RlO2CHN ~ ~ NHCHC ~ R2)x R~

wherein Rl, R2, R4 and x are the same as previously defined, further provided that R2 may be a nltro group. The compound of Formula V is converted to the compound of Formula I by catalytic hydrogenation or the compound of Formula IV may be hydrogenated directly. An intermediate product formed during hydrogenation has the formula:

~ NH2 RlO2CHN / ~ NHCHC ~ R2)x VI

wherein Rl, R2, R4 and x are the same as previously defined.
Compounds of Formula I wherein R4 is hydrogen may be prepared by aminating the compound of Formula II with an alpha-amino alcohol having the structure:

HNCH2CH--~R2) x IIIA

to give a compound having the structure:

,,~,~ ~ N2 ,/~R2) X

R i 2 C HN ~ ~, \ N C H 2 C {~) VII;
which is oxidized to give a ketone having the s-tructure:

5~

~ N02 R12C~IN / ~ \ ~lCH2C ~ R2~x VA

wherein Rl, R2, R3 and x are the same as previously defined, further provided that R2 may be a nitro group. The compound of Formula VA is converted to a compound of Formula I by catalytic hydrogenation.
In broadest scope, the compounds of Formula I can be prepared by catalytic hydrogenation of a compound of Formulae V, VA or IV.

Detailed Description_of the Invention A preferred lower alkyl ester of 6-amino-4-chloro-5-nitropyridin-2-ylcarbamate is the ethyl ester, i.e., ethyl 6-amino-4-chloro-5-nitropyridin-2-ylcarbamate. This compound is prepared according the procedure described by R.D. Elliott, C. Temple, Jr. and J.A. Montgomery, J. Or~. Chem., 31, 1890 (1966).
Oximes of alpha-amino ketones, i.e., compounds of Formula III, may be prepared by k~own prior art procedures.
Thus, they can be prepared by reacting the corresponding alpha~
bromoacetophenone with hexamethylenetetramine to glve the corresponding ammonium salt which is hydrolyzed by ethanolic hydrochloric acid to give the corresponding alpha-aminoaceto-phenone hydrochloride [LoM. Long and H.D. Troutman, J. Amer.
lo Chem. Soc., 71, 2473 (1949); and A.B. Sen and D.D. Mukerji, J.
Indian Chem. 50c., 28, 401 (1951)]. The condensation of these alpha-amino ketones with hydroxylamine hydrochloride in a refluxing mixture of pyridine and ethanol gives the oxime derivatives [R.D. Elliott, C. Temple, Jr. and J.A. Montgomexy, J. Org. Chem., 35, 1676 (1970)].
The compounds of Formula III can also be prepared by alkylation of phthalimide with the corresponding alpha-bromo-acetophenone, treatment of the alpha-(phthalimido)-acetophenone product [G.C. Schweiker, Dissertation Abstracts, 21, 464 ~1953)]
with hydroxylamine, and removal of the phthaloyl protecting group from the resulting oxime with hydrazine [R.D. Elliott, C.
Temple, Jr. and J.A. Montgomery, J. Ox~O ChemO, 35, 1676 (1970)].

Examples of these two procedures for the preparation of compounds of Formula III follow:

i5~7 Method I. a-Amino-2~4-dlchloroacetophenone Oxime.

~,2,4-Trichloroacetophenone (15 g, 67 mmol) was added with stirring to a suspension of potassium phthalimide (16 g, 86 mmol) in N,N-dimethylformamide (68 ml) at 5C. After 5 minutes, the resulting solution was allowed to warm to room temperature followed by heating at 50C for 15 minutes. The solution was mixed successively with CHC13 (103 ml) and H2O (341 ml), and the H20 phase was sepaxated and extracted with additional CHC13 l3 x 46 ml). The combined CHC13 extracts were washed with 2~ NaOH
(57 ml) and H2O (57 ml), and evaporated to a small volume ~n 1~
vacuo ~40C). The residue was diluted with cold H20 (225 ml), and the mixture was chilled to deposit a semisolid, which was separated by decantation. The residue was washed with C2H50H
and (C2H5)20 and dried to give the phenacyl phthalimide: yield, 9.2 g. A solution of this solid (28 mmol) and hydroxylamine hydrochloride 12.9 g, 41 mmol) in a mixture of pyridine (28 ml) and C2H50H (117 ml) was stirred at reflux for 1.5 hours. The solvent was evaporated ln vacuo, and the resulting oily ketone oxime was washed with H20: mass spectrum, m/e 348 (M ). A

solution of the oxime in ethanol (332 ml) at 70C. was treated ~`
dropwise during 20 minutes with a solution of 95% hydrazine (2.0 g) in ethanol (25 ml). The resulting solution was heated at 40C. for 22 hours, and the cooled reaction mixture was treated with l N HCl (30 ml). After stirring in an ice bath for 1 hour, the precipitated phthalhydrazide was removed by filtration and washed with 1:1 ethanol-water (36 ml1. The combined filtxate and wash was evaporated to dryness in vacuo (40C), the residue wa~ extracted with warm water (120 ml), and the filtrate was treated with concentrated NH40H (2 ml) to deposit the product:
yield, 3.2 g.

3~

3~2~5~7 1 Method II. ~ -Amino-p-nitro-_ _ acetophenone Oxime A solution of ~-bromo-~-nitroacetophenone (20 g., 82 mmol) and hexamethylenetetramine (12 g., 86 mmol) in chloroform (300 ml) was stirred at room temperature for 24 hours. The quaternary salt (34 g.) was collected by filtration and stirred in a mixture of ethanol (175 ml) and concentrated hydrochloric acid (55 ml) for 19 hours to give the hydrochloride salt:
yield, 9.0 g. A suspension of this product and hydroxylamine 10 hydrochloride (10 g.) in 1:1 ethanol-pyridine (135 ml) was re-fluxed with stirring for two hours, evaporated to dryness ln vacuo, and the resulting residue was dissolved in water and treated with 50% sodium hydroxide to deposit the product:
yield, 3.2 g.
The oximes set forth in Table I were prepared by Method I or Method II, as indlcated in Table I. The first column of Table I sets forth the structure of the group ~ 2)x in Formula III. Known compounds are referenced with superscript 2~letters in Table I.

5~7 The alpha-amino alcohol of Form~la IIIA wherein R2 is hydrogen a~d R3 is CH3 was prepared in accordance with the pro~
~edure described by S,P. ~cManus, C.~. Larson and ~.A. Hearn, '-Synthetic Col~mun., 3, 17~ (1973~o The product, having th~
empirical formula CgH13NO/ m/e 151 (M ), and a melting point of 75-77C, was obtained in a 52~ ov~rall yield.
~ compound of Formula II is aminated with a compound of Formula III under nitrogen in refluxing ethanol containing triethylamine as an acid accep~or to give a compound of Formula IV. ~n example of this procedure follows:
1(~
Example 1 Ethyl 6-Amino-~-nitro-4-~(2-oxo-2-phenylethyl)amino]-pyridin-2-ylcarbamate oxime (IV: R1=C2H5; R~=H; R4=H) A solution of ethyl 6-amino-4-chloro-S-nitropyridin-2-ylcarbamate (14.0 g., S3.8 mmoles), alpha-aminoacetopnenone oxime ~8.07 g., ~3.8 mmoles), and triethylamine (5.43 g~, 53.8 mmolesj in ethyl alcohol (300 ml.) was refluxed under N2 with stirring for eight hours. The solid that deposited from the cooled xeaction mixture was collected by filtration and dried in 2~ vacuo over P2O : yïeld 10~4 g. The properties are set forth in Table II.
~ dditional compounds wexe prepared similarly wherein the alpha-aminoacetopnenone oxime was replaced with substituted alpha-aminoacetophenone oximes. The propertie~ of these com-pounds are set fortn in Table II. The first column of Table II
Gets ~orth the ,tructure of the group ~ (~2)x in the starting alpha-aminoacetophenone oxime and in the final ~ product, the formula for which appears in Table II

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U ~r ~ rY ~ ~ r~ ~ ~ r~ r r~J U r~

~65~3~

Treatment of a compound of Formula IV with a 1:1 mixture of 1 N hydrochloric acid and dioxane at 60C. hydrolyzes the oxime function to give a compound of Formula V. An example of this procedure follows:

Exam~le 2 Ethyl 6-Amino-5~nitro-4-[(2-oxo-2-phenyl-ethyl)amino]pyridin-2-ylcarbamate dioxanate (V,: Rl=C2H5; R2 H; R4 A solution of ethyl 6-amino-5-nitro-4-[(2-oxo-2-lo phenylethyl)amino]pyridin-2-ylcarbamate oxime ~4.72 g., 12.6 mmoles) in a 1:1 mixture of 1 N HCl~dioxane (170 ml.) was heated with stirring at 60C. for two hours. The yellow solid that deposited from the chilled solution was collected by filtration and recrystallized from a 1:1 mixture of H2O-dioxane ~1 L.):
yield, 3.13 g. The properties of the compound thus obtained are set forth in Table III.
Additional compounds were prepared similarly wherein the oxime starting material was replaced with substituted ethyl 6-amino-5-nitro-4-[~2 oxo-2-phenylethyl)amino]pyridin-2-ylcar-bamate oximes. The properties of these compounds are set forth in Table III. The first column of Table III sets forth the structure of the group ~ R2)x in the starting oxime, the formula for which appears in Table II, and in the final product, the formula for which appears in Table III.

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a u~ ~1 ~ ~ In ~ Ln o ~ ~ ~ co ~

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H'-- ~t O--C~
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H~r t~l ~ C )--~ U) . CO ~I ~1 0 ~1 0 Oz ~ ~ O O O t`J U~ 0 V ~ \ / ~~ U~ U) O Z ~ ~ ~
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U ~r f~ ~ ~ ~ ~ ~ ~ ~r r 5~t7 1 Amination of the compound of Formula II with a com pound of Formula IIIA in refluxing ethanol containing triethyl-amine as an acid acceptor gives a compound of Formula VII.
O~idation of a compound of Formula VII gives a ketone of Formula VA. An example of thls procedure follows:

Example 3 A. Ethyl 6-Amino-4-[(N-(2-hydroxy-2-phenylethyl-N-methyl)amino]5-nitropyridin-2 ylcarbamate (VII: Rl=C2H5; R2 H; 3 3 A solution of ethyl 6-amino-4-chloro-5-nitropyridin 2-ylcarbamate (3.40 g., 13.1 mmol), 2-(methylamino)-1-phenyl-ethanol (2017 g,, 14.4 mmol), and triethylamine (1.32 g., 13.1 mmol) in ethanol (75 ml) was refluxed with protection by a drying tube for 2 hours and evaporated to dryness in vacuo. The resldue was stirred with 1 N HCl for l hour followed by neutral-ization (pH 7) with 1 N NaOH. The product was collected by ~iltration and used without further purification: yield, 4.81 108 10C FormUla: C17H21N5 5 B. Ethyl 6-Amino-4-[(N-methyl-N-2-oxo-2-phenyl-ethyl)amino]-5-nitro-pyridin-2-ylcarbamate (VA: R1=C2H5; R2=H; R3=CH3) To a solution of pyridine (8.70 g., 110 mmol) in CH2C12 ~131 ml), protected with a drying tube, chromium ~VI) oxide (5.52 g., 55.2 mmol) was added with stirring. After 15 minutes, a solution of ethyl 6-amino-4-[[(N-(2-hydroxy-2-phenyl-ethyl3-N-methyl]amino]-5-nitropyridin-2-ylcarbamate (3.45 g., 9.20 mmol) in CH2Cl2 (35 ml.) was added. After an additional 20 minutes, the residue was separated by decantation and washed with (C2H5)2O (242 ml3. The combined decant and wash was evaporated to dryness, the residue was dissolved in (C2H5)2O
(1700 ml.~, and the solution was washed with aqueous 5~ NaHCO3 ~:3l65~3~

l (200 ml), H2O (200 ml) and saturated NaCl solution (200 ml.).
Concentration of the (C2H5)2O solution to a small volume fol-lowed by cooling in an ice bath gave the product: yield, 1.99 g ; m.p. 139-40C; Anal. Calcd- for Cl7Hl9N5o5 C, S4.69; H~
5.13; N, 18.76. Found: C, 54.88; H, 5 49; ~l, 18.50.
The catalytic hydrogenation of a compound of Formula V
or VA with a three-fold amount of Raney nickel in a large volume of ethanol li.e., more than one liter per gram~ at atmospheric pressure at room temperature or with intermittent warming (e.g., to no higher than 60C.) with a water bath gi~es the inter-mediate compound of Formula VI which is cyclized ln situ with the elimination of water to give a compound of ~ormula I. Such reaction is shown in Example 4O The compounds of Formula I can also he prepared directly by hydrogenation of a compound of Formula IV in the presence of Raney nickel as shown in Example 5.

Example 4 Ethyl 5-Amino-1,2-dihydro-3-phenyl-pyrido(3,4-b)pyrazin-7-ylcarbamate (I: R1=C2H5; R2=H; R3=H; R4=H) A solution of ethyl 6-amino-5-nitro-4-[(2-oxophenyl-~-ethyl)amino]pyridin-2-ylcarbamate dioxanate (10:7) obtained in Example 2 (3.10 g., 7.25 mmoles) in ethyl alcohol (4 L.) was hydrogenated in the presence of Raney nickel (9 g., weighed wet after washing with ethyl alcohol) at atmospheric pressure with intermittent warming with a water bath. After six hours the catalyst was removed by filtration, and the filtrate was con-centrated in vacuo (<40C.) to 1/16 volume. The solid that deposited ~rom the chilled mixtuxe was collected by filtration and dried ln vacuo over P2O5: yield, 1.82 y. From the filtrate a second crop was obtained: yield, 0.17 g. The total yield was 1.99 g. The properties are set forth in Table IVo ~658~

l Example 5 Hydrogenatlon of Ethyl 6-Amino-5-nitro-4-[[2-[4'-(trifluoromethyl)phenyl]-2-oxo~
ethyl] amino]pyrldin-2-carbamate oxime A solution of the oxime (0.5 g.) in ethanol (1000 ml.) contalning Raney nickel (1.5 g. wet, washed successively with H2O and ethanol) was hydrogenated at room temperature and atmospheric pressure for 7 hours. The catalyst was removed by filtration through Celite under nitrogen, and the filtrate was concentrated in vacuo to 1/20 volume to deposit ethyl 5-amino-1,2-dihydro-3-[4'-(trifluoromethyl)phenyl]pyrido~3,4-b]pyrazin-7-ylcarbamate. The product was collected by filtration, washed with ether, and dissolved in a mixture of ethanol (35 ml.) and 1 N HCl (15 ml.) with warming. After filtration through Celite, the filtrate was neutralized with 1 N NaOH and concentrated ln vacuo to deposit the product: yield, 0.20 g. (47%). This material was identical by thin-layer chromatography with that prepared by hydrogenation of the corresponding ketone.
The compounds set forth in Table IV were prepared by 20 the procedure of Example 4 or Example 5, as indicated in Table IV. The propexties of these compounds are set forth in Table IV. The first column of Table IV sets forth the structure of the group ~ R2)x in the starting material, the formula for which appears in Table II or III ~except as noted), and in the final product, the formula for which appears in Table IV.

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1 The 1,2-dihydropyrido[3,4-b]pyrazines of this ~nven-tion are powerEul inhibitors o~ the prolif~ration o~ cultured lymphoid luekemia L1210 cells as shown in Table V. The concen-tration causing a 50% inhibition of proliferation of the cells during 24 hours is similar to that observed for vincristine, vinblastine, and colchicine. Also, the addition to the test medium of inosine, thymidine, glycine, citrovorum factor, individually and in combinations, and elevated concentrations of amino acids and vitamins did not overcome the inhibitions.

1() In addition to cell cyto~oxicity, the 1,2-dihydro-pyrido[3,4-b]pyrazines showed activity ayainst lymphocytic leukemia P388 cells (1061 implanted intraperitoneally in mice.
Ethyl 5-amino-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-ylcar-bamate was also active in mice against P388 cells that were resistant to vincristine.
The 1,2-dihydropyrido[3,4-b]pyrazines at concentra-tions that prevented any increase in the cell number during a 24 hour period had little effect upon the synthesis of DNA, RNA, and protein by cultured L1210 cells during exposure for four hours. This result and those described above led to the deter-2n mination of the effect of the 1,2~dihydropyrido[3,4-b]pyrazines upon cell division. Exposure of cultured L1210 cells to the 1,2-dihydropyrido[3,4-b]pyrazines inhibited cell division as measured by the mitotic index (MI) (Table V), which is the fraction of the cell population that is made up o~ metaphase cells. Subsequent experiments showed that these agents caused the accumulation in metaphase of human epidermoid carcinoma ~2 cells, P388 cells, and P388 cells resistant to vincristine grown in cuspension culture and of colon tumor #26 cells and colon tumor #38 cells grown on plastic surfaces. Further experiments 5~7 1 showed that the 1-deaza-7,8-dihydropteridines of this invention possess antifungal activity against both human and plant patho~
gens. For example, 5-amino-1,2-dihydro~3-phenylpyrido[3,4-b]-pyrazin-7-ylcarbamate was active against Saccharomyces cere-vlslae, Asperigillus niger~ Penicillium italicum and Botrytis clnereae .
Table V sets forth biological data for l-deaza-7,8-dihydropteridines of this invention and for two prior art compounds. The first column of Table V sets forth the structure of the group ~ ~

in the formula in the heading of the table for the l-deaza-7,8-dihydropteridines tested.

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~J~5~

The data in Table V shows that the l-deaza-7,8-dl-hydropteridines of this in~ention are active against leukemia in laboratory animals.
The compounds of the invention form pharmaceutically acceptable salts with both organic and inorganic acids. Ex-amples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, sali-cyclic, malic, fumaric, succinic, ascorbic, maleic, methanesul-fonic, and the like. The salts are prepared by contacting the free base form with an equivalent amount of the desired acid in the conventional mannerO The free base forms may be regenerated by treating the salt form with a base. For example, dilute aqueous base solutions may be utilized. Dilute aqueous sodium hydroxide, potassium carbonate, ammonia, and sodium bicarbonate solutions are suitable for this purpose. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.
Also embraced within the purview of the present invention are therapeutic composi~ions of matter useful for ameliorating cancer diseases in mammals and containing the l-deaza-7,8-dihydropteridines of this invention or pharmaceu-tically acceptable salts thereof.
The active ingredients of the therapeutic compositions and the novel compounds of the present invention inhibit trans-planted mouse tumor growth when administered in amounts ranging from about 5 mg to about 200 mg per kilogram of body weight per day. A preferred dosage regimen for optimum results would be 30 from about 5 mg to about 50 mg per kilogram of body weight per day, and such dosage units are employed that a total of fxom 5~

1 about 350 mg to about 3.5 grams of the active compound for a subject of about 70 kg of body weight are administered in a 24-hour period. This dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportion-ally reduced as indicated by the exigencies of the therapeutic situation. A decided practical advantage is that the active compound may be adminlstered ln any convenlent manner such as by the oral, intravenous, intramuscular or subcutaneous routes.
The active compounds may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds may be incor-porated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspen-sions, syrups, wafers and the like. Such compositions and preparations should contain at least 0.1% of active compound.

The percentage of the compositions and preparations may, of 2~
course, be varied and may conveniently be between about 2 and about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the pxesent invention are prepared so that an oral dosage unit form contains between about 5 and about 200 milligrams of active compound.
The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, 30acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn skarch, pokato 1 starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoriny agent such as peppermint, oil of wintergreen or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills or capsules may be coated with shellac, sugar or both. ~ syrup or elixir 1~ may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoxing such as cherry or orange flavor. ~f course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compounds may be incorporated into sustained-release preparations and formulations.
The active compounds may also be administered paren-terally or intraperitoneally. Solutions of the active compound as a free base or pharmaceutically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in ~lyGerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The phar~aceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile 3~ and must be fluid to the extent that easy syringability exists.
It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium contalning, for example, water, ethanol, polyol (for example, gl~cerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof and vegetable oils. The proper fluidity can be main-tained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various anti-bacterial and antifungal agents, for example, parabens, chloro-~utanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, alum-inum monostearate and gelatin.
Sterile injectable solutions are prepared by incor-porating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered steriliza-tio~. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-Eiltered solution thereof.
3() s~

As used herein, "pharmaceutically acceptable carrier"
includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art.
Except insofar as an~ conventional media or agent is incompat-ible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
It is especially advantageous to formulate parenteral 1~
compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the mammalian sub~ects to be treated; each unit containing a pre-determined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the novel dosage unit ~orms of the invention are dictated by and directly de-pendent on (a) the unique characteristics of the active material and the particular therapeutic e~fect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodil~ health is impaired as herein disclosed in detail.
The principal active ingredient is compounded for convenient and effective administration in ef~ective amounts with a suitahle pharmaceutically-acceptable carrier in dosage unit form as hereinbefore disclosed. ~ unit dosage form can, for example, contain the principal active compound in amounts ranging from about 0.1 to about 400 mg, with ~rom about one to about 30 mg being preferred. Expressed in proportions, the ;5~

1 active compound is generally present in from about 0.1 to about 400 mg/ml of carrier. In the case of compositions containing supplementary acti~e ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.

Claims (70)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE
IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of wherein x has a value of 1,2 or 3, R1 is a lower alkyl group, R2 is a member selected from the group consisting of hydrogen, alkyl radicals having from about one to about 12 carbon atoms, alkenyl radicals having from about two to about 15 carbon atoms, cycloalkyl radicals having from about three to about 20 carbon atoms, aralkyl and alkaryl radicals having from about six to about 20 carbon atoms, a halogen radical, hydroxyl, amino, thiol nitro, alkoxy, aryloxy, carboxyl, alkylcarboxyl radicals having from about one to about 10 carbon atoms, alkylthio and arylthio radicals having from about one to about 20 carbon atoms, sulfonyl, alkylsulfonyl and arylsulfonyl radicals having from about one to about 20 carbon atoms, alkylsulfinyl and arylsulfinyl radicals having from about one to about 20 carbon atoms, alkylamino and arylamino radicals having from about one to about 20 carbon atoms, or a hydrocarbyl group carrying halogen, hydroxyl, amino, alkoxy or aryloxy, and, when taken together with the aromatic ring to which it is attached, a fused ring structure; and R4 is hydrogen or a lower alkyl group, which comprises aminating a lower alkyl ester of 6-amino-4-chloro-5-nitro pyridin-2-yl carbamate with the oxime of an ?-amino ketone of structure wherein R2, R4 and x are as already defined and recovering the required compound.

2. A compound of formula wherein x has a value of 1,2 or 3, R1 is a lower alkyl group, R2 is a member selected from the group consisting of hydrogen, alkyl radicals having from about one to about 12 carbon atoms, alkenyl radicals having from about two to about 15 carbon atoms, cycloalkyl radicals having from about three to about 20 carbon atoms, aralkyl and alkaryl radicals having from about six to about 20 carbon atoms, a halogen radical, hydroxyl, amino, thiol, nitro, alkoxy, aryloxy, carboxyl, alkylcarboxyl radicals having from about one to about 10 carbon atoms, alkylthio and arylthio radicals having from about one to about 20 carbon atoms, sulfonyl, alkylsulfonyl and arylsulfonyl radicals having from about one to about 20 carbon atoms, alkylsulfinyl and arylsulfinyl radicals having from about one to about 20 carbon atoms, alkylamino and arylamino radicals having from about one to about 20 carbon atoms, or a hydrocarbyl group carrying halogen, hydroxyl, amino, alkoxy or aryloxy, and, when taken together with the aromatic ring to which it is attached, a fused ring structure; and R4 is hydrogen or a lower alkyl group, when prepared by the process of claim 1 or an obvious chemical equivalent.

3. A process as claimed in claim 1 wherein the reactants are chosen so that R1 is ethyl.

4. A process as claimed in claim 3 wherein the reactants are chosen so that R4 is hydrogen and the group is selected from those having the following structure: C6H5, 4-CH3C6H4, 2,4-(CH3)2C6H3, 3,4-(CH3)2C6H3, 4-FC6H4, 2,4-(Cl)2C6H3, 3,4-(Cl)2C6H3, 3-CH3OC6H4, 4-CH3O6H4, 3,4,5-(CH3O)3C6H2, 4-O2NC6H4, 4-CF3C6H4 and 2-C10H7.

5. A process as claimed in claim 3 wherein the reactants are chosen so that R2 is hydrogen and R4 is methyl.

6. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(2-oxo-2-phenylethyl)amino]pyridin-2-yl carbamate oxime, which comprises reacting ethyl 6-amino-4-chloro-5-nitropyridin-2-yl carbamate in a solvent with ?-aminoacetophenone oxime in the presence of triethylamine and recovering the required compound.

7. Ethyl 6-amino-5-nitro-4-[(2-oxo-2-phenylethyl)amino]pyridin-2-yl carbamate oxime, when prepared by the process of claim 6 or an obvious chemical equivalent.

8. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(2-oxo-2(4-methylphenyl)ethyl)amino]pyridin-2-yl carbamate oxime which comprises reacting ethyl 6-amino-4-chloro-5-nitropyridin-2-yl carbamate in a solvent with 4-methylphenyl aminomethyl ketone oxime in the presence of triethylamine and recovering the required compound.

9. Ethyl 6-amino-5-nitro-4-[(2-oxo-2(4-methylphenyl)ethyl)amino]-pyridin-2-yl carbamate oxime when prepared by the process of claim 8 or an obvious chemical equivalent.

10. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(2-oxo-2(2,4-dimethylphenyl)ethyl)amino]pyridin-2-yl carbamate oxime which comprises reacting ethyl 6-amino-4-chloro-5-nitropyridin-2-yl carbamate in a solvent with 2,4-dimethylphenyl aminomethyl ketone oxime in the presence of triethylamine and recovering the required compound.

11. Ethyl 6-amino-5-nitro-4-[(2-oxo-2(2,4-dimethylphenyl)ethyl)amino]-pyridin-2-yl carbamate oxime when prepared by the process of claim 10 or an obvious chemical equivalent.

12. A process for the preparation of the compound 6-amino-5-nitro-4[(2-oxo-2(3,4-dimethylphenyl)ethyl)amino]pyridin-2-yl carbamate oxime which comprises reacting ethyl 6-amino-4-chloro-5-nitropyridin-2-yl carbamate in a solvent with 3,4-dimethylphenyl aminomethyl ketone oxime in the presence of triethylamine and recovering the required compound.

13. 6-amino-5-nitro-4[(2-oxo-2(3,4-dimethylphenyl)ethyl)amino]pyridin-2-yl carbamate oxime when prepared by the process of claim 12 or an obvious chemical equivalent.

14. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(2-oxo-2-(4-fluorophenyl)ethyl)amino]pyridin-2-yl carbamate oxime which comprises reacting ethyl 6-amino-4-chloro-5-nitropyridin-2-yl carbamate in a solvent with 4-fluorophenyl aminomethyl ketone oxime in the presence of triethylamine and recovering the required compound.

15. Ethyl 6-amino-5-nitro-4-[(2-oxo-2-(4-fluorophenyl)ethyl)-amino]pyridin-2-yl carbamate oxime when prepared by the process of claim 14 or an obvious chemical equivalent.

16. A process for the preparation of the compound ethyl 6-amino-5-nitro-4 [(2-oxo-2-(2,4-dichlorophenyl)ethyl)amino]pyridin-2-yl carbamate oxime which comprises reacting ethyl 6-amino-4-chloro-5-nitropyridin-2-yl carbamate in a solvent with 2,4-dichlorophenyl aminomethyl ketone oxime in the presence of triethylamine and recovering the required compound.

17. Ethyl 6-amino-5-nitro-4-[(2-oxo-2-(2,4 dichlorophenyl)ethyl)amino]-pyridin-2-yl carbamate oxime when prepared by the process of clsim 16 or an obvious chemical equivalent.

18. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(2-oxo-2(3,4-dichlorophenyl)ethyl)amino]pyridin-2-yl carbamate oxime, which comprises reacting ethyl 6-amino-4-chloro-5-nitropyridin-2-yl carbamate in a solvent with 3,4-dichlorophenyl aminomethyl ketone oxime in the presence of triethylamine and recovering the required compound.

19. Ethyl 6-amino-5-nitro-4-[(2-oxo-2(3,4-dichlorophenyl)ethyl)amino]-pyridin-2-yl carbamate oxime when prepared by the process of claim 18 or an obvious chemical equivalent.

20. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(2-oxo-2(3-methoxyphenyl)ethyl)amino]pyridin-2-yl carbamate oxime which comprises reacting ethyl 6-amino-4-chloro-5-nitropyridin-2-yl carbamate in a solvent with 3-methoxyphenyl aminomethyl ketone oxime in the presence of triethylamine and recovering the required compound.

21. Ethyl 6-amino-5-nitro-4-[(2-oxo-2(3-methoxyphenyl)ethyl)amino]-pyridin-2-yl carbamate oxime when prepared by the process of claim 20 or an obvious chemical equivalent.

22. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(2-oxo-2(4-methoxyphenyl)ethyl)amino]pyridin-2-yl carbamate oxime which comprises reacting ethyl 6-amino-4-chloro-5-nitropyridin-2-yl carbamate in a solvent with 4-methoxyphenyl aminomethyl ketone oxime in the presence of triethylamine and recoverin~ the required compound.

23. Ethyl 6-amino-5-nitro-4-[(2-oxo-2(4-methoxyphenyl)ethyl)amino]-pyridin-2-yl carbamate oxime when prepared by the process of claim 22 or an obvious chemical equivalent.

24. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(2-oxo-2-(3,4,5-trimathoxyphenyl)ethyl)amino]pyridin-2-yl carbamate oxime which comprises reacting ethyl 6-amino-4-chloro-5-nitropyridin-2-yl carbamate in a solvent with 3,4,5-trimethoxyphenyl aminomethyl ketone oxime in the presence of triethylamine and recovering the required product.

25. Ethyl 6-amino-5-nitro-4-[(2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl)-amino]pyridin-2-yl carbamate oxime when prepared by the process of claim 24 or an obvious chemical equivalent.

26. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(2-oxo-2-(4-nitrophenyl)ethyl)amino]pyridin-2-yl carbamate oxime which comprises reacting ethyl 6-amino-4-chloro-5-nitropyridin-2-yl carbamate in a solvent with 4-nitrophenyl aminomethyl ketone oxime in the presence of triethylamine and recovering the required compound.

27. Ethyl 6-amino-5-nitro-4-[(2-oxo-2-(4-nitrophenyl)ethyl)amino]-pyridin-2-yl carbamate oxime when prepared by the process of claim 26 or an obvious chemical equivalent.

28. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(2-oxo-2-(4-trifluoromethyl)ethyl)amino]pyridin-2-yl carbamate oxime which comprises reacting ethyl 6-amino-4-chloro-5-nitropyridin-2-yl carbamate in a solvent with 4-trifluoromethylphenyl aminomethyl ketone oxime in the presence of triethylamine and recovering the required compound.

29. Ethyl 6-amino-5-nitro-4-[(2-oxo-2-(4-trifluoromethyl)ethyl)amino]-pyridin-2-yl carbamate oxime when prepared by the process of claim 28 or an obvious chemical equivalent.

30. A process for the preparation of the compound ethyL 6-amino-5-nitro-4-[(2-oxo-2-(2-naphthyl)ethyl)amino]pyridin-2-yl carbamate oxime which comprises reacting ethyl 6-amino-4-chloro-5-nitropyridin-2-yl carbamate in a solvent with 2-naphthylphenyl aminomethyl ketone oxime in the presence of triethylamine and recovering the required compound.

31. Ethyl 6-amino-5-nitro-4-2-[(2-oxo-(2-naphthyl)ethyl)amino]pyridin-2-yl carbamate oxime when prepared by the process of claim 30 or an obvious chemical equivalent.

32. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(1-methyl-2-oxo-2-phenylethyl)amino]pyridin-2-yl carbamate oxime which comprises reacting ethyl 6-amino-4-chloro-5-nitropyridin-2-yl carbamate in a solvent with ?-amino ?-methyl acetophenone oxime in the presence of triethylamine and recovering the require compound.

33. Ethyl 6-amino-5-nitro-4-[(1-methyl-2-oxo-2-phenylethyl)amino]-pyridin-2-yl carbamate oxime when prepared by the process of claim 32 or an obvious chemical equivalent.

34. A process for the preparation of the compound wherein x has a value of 1,2 or 3, R1 is a lower alkyl group, R2 is a member selected from the group consisting of hydrogen, alkyl radicals having from about one to about 12 carbon atoms, alkenyl radicals having from about two to about 15 carbon atoms, cycloalkyl radicals having from about three to about 20 carbon atoms, aralkyl and alkaryl radicals having from about six to about 20 carbon atoms, a halogen radical, hydroxyl, amino, thiol, nitro, alkoxy, aryloxy, carboxyl, alkylcarboxyl radicals having from about one to about 10 carbon atoms, alkylthio and arylthio radicals having from about one to about 20 carbon atoms, sulfonyl, alkylsulfonyl and arylsulfonyl radicals having from about one to about 20 carbon atoms, alkylsulfinyl and arylsulfinyl radicals having from about one to about 20 carbon atoms, alkylamino and arylamino radicals having from about one to about 20 carbon atoms, or a hydrocarbyl group carrying halogen, hydroxyl, amino, alkoxy or aryloxy, and, when taken together with the aromatic ring to which it is attached, a fused ring structure; and R3 is hydrogen or a lower alkyl group, which comprises aminating a lower alkyl ester of 6-amino-4-chloro-5-nitropyridin-2-yl carbamate with an ?-amino alcohol of formula wherein R2, R3 and x are as defined and recovering the required compound.

35. A compound of formula wherein x has a value of 1,2 or 3, R1 is a lower alkyl group, R2 is a member selected from the group consisting of hydrogen, alkyl radicals having from about one to about 12 carbon atoms, alkenyl radicals having from about two to about 15 carbon atom , cycloalkyl radicals having from about three to about 20 carbon atoms, aralkyl and alkaryl radicals having from about six to about 20 carbon atoms, a halogen radical t hydroxyl, amino, thiol, nitro, alkoxy, aryloxy, carboxyl, alkylcarboxyl radicals having from about one to about 10 carbon atoms, alkylthio and arylthio radicals having from about one to about 20 carbon atoms; sulfonyl, alkylsulfonyl and arylsulfonyl radicals having from about one to about 20 carbon atoms, alkylsulfinyl and arylsulfinyl radicals having from about one to about 20 carbon atoms, alkylamino and arylamino radicals having from about one to about 20 carbon atoms, or a hydrocarbyl group carrying halogen, hydroxyl, amino, alkoxy or aryloxy, and, when taken together with the aromatic ring to which it is attached, a fused ring structure; and R3 is hydrogen or a lower alkyl group, when prepared by the process of claim 34 or an obvious chemical equivalent.

36. A process as claimed in claim 34 wherein the reactants are chosen so that R1 is ethyl, R2 is hydrogen and R3 is methyl.

37. A process for the preparation of the compound ethyl 6-amino-4-[(N-(2-hydroxy-2-phenylethyl-N-methyl)amino]5-nitropyridin-2-yl carbamate which comprises reacting ethyl 6-amino-4-chloro-5-nitro-pyridin-2-yl carbamate in a solvent with 2-(methylamino)-1-phenylethanol in the presence of triethylamine and recovering the required compound.

38. Ethyl 6-amino-4-[(N-(2-hydroxy-2-phenylethyl-N-methyl)amino]-5-nitropyridin-2-yl carbamate when prepared by the process of claim 37 or an obvious chemical equivalent.

39. A process for the preparation of the compound wherein x has a value of 1,2 or 3, R1 is a lower alkyl group, R2 is a member selected from the group consisting of hydrogen, alkyl radicals having from about one to about 12 carbon atoms, alkenyl radicals having from about two to about 15 carbon atoms, cycloalkyl radicals having from about three to about 20 carbon atoms, aralkyl and alkaryl radicals having from about six to about 20 carbon atoms, a halogen radical, provided that when x has a value of 1 and R2 is in the para position and R3 and R4 are both hydrogen, R2 is not chlorine; hydroxyl, amino, thiol nitro, alkoxy, aryloxy, carboxyl, alkylcarboxyl radicals having from about one to about 10 carbon atoms, alkylthio and arylthio radicals having from about one to about 20 carbon atoms, sulfonyl, alkylsulfonyl and arylsulfonyl radicals having from about one to about 20 carbon atoms, alkylsulfinyl and arylsulfinyl radicals having from about one to about 20 carbon atoms, alkylamino and arylamino radicals having from about one to about 20 carbon atoms, or a hydrocarbyl group carrying halogen, hydroxyl, amino, alkoxy or aryloxy, and, when taken together with the aromatic ring to which it is attached, a fused ring structure; and R3 and R4 are either both hydrogen or one is hydrogen and the other is a lower alkyl group,, which comprises (i) when R4 is hydrogen, oxidizing a compound of formula wherein R1, R2, R3 and x are as defined, or (ii) when R3 is hydrogen, hydrolyzing a compound of formula wherein R1, R2, R4 and x are as defined, and recovering the required compound.

40. A compound of formula wherein x has a value of 1,2 or 3, R1 is a lower alkyl group, R2 is a member selected from the group consisting of hydrogen, alkyl radicals having from about one to about 12 carbon atoms, alkenyl radicals having from about two to about 15 carbon atoms, cycloalkyl radicals having from about three to about 20 carbon atoms, aralkyl and alkaryl radicals having from about six to about 20 carbon atoms, a halogen radical, provided that when x has a value of 1 and R2 is in the para position and R3 and R4 are both hydrogen, R2 is not chlorine; hydroxyl, amino, thiol, nitro, alkoxy, aryloxy, carboxyl, alkylcarboxyl radicals having from about one to about 10 carbon atoms, alkylthio and arylthio radicals having from about one to about 20 carbon atoms, sulfonyl, alkylsulfonyl and arylsulfonyl radicals having from about one to about 20 carbon atoms, alkylsulfinyl and arylsulfinyl radicals having from about one to about 20 carbon atoms, alkylamino and arylamino radicals having from about one to about 20 carbon atoms, or a hydrocarbyl group carrying halogen, hydroxyl, amino, alkoxy or aryloxy, and, when taken together with the aromatic ring to which it is attached, a fused ring structure; and R3 and R4 are either both hydrogen or one is hydrogen and the other is a lower alkyl group, when prepared by the process of claim 39 or an obvious chemical equivalent.

41. A process as claimed in claim 39 wherein the reactants are chosen so that R1 is ethyl.

42. A process as claimed in claim 41 wherein the reactants are chosen so that R3 and R4 are each hydrogen and the group.

is selected from those having the following structures: C6H5, 4-CH3C6H4, 3,4-(CH3)2C6H3, 4-FC6H4, 3,4-(Cl)2C6H3, 3-CH3OC6H4, 4-CH3OC6H4, 3,4,5-(CH3O)3C6H2, 4?O2NC6H4, 4-CF3C6H4 and 2-C10H7.

43. A process as claimed in claim 41 wherein the reactants are chosen so that R2 and R4 are each hydrogen and R3 is methyl.

44. A process as claimed in claim 41 wherein the reactants are chosen so that R2 and R3 are each hydrogen and R4 is methyl.

45. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(2-oxo-2-phenylethyl)amino]pyridin-2-yl carbamate which comprises acid hydrolysis of ethyl 6-amino-5-nitro-4-[(2-oxo-2-phenylethyl)amino]pyridin-2-yl carbamate oxime, in a solvent and recovery of the required compound.

46. Ethyl 6-amino-5-nitro-4-[(2-oxo-2-phenylethyl)amino]pyridin-2-yl carbamate when prepared by the process of claim 45 or an obvious chemical equivalent.

47. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(2-oxo-2(4-methylphenyl)ethyl)amino]pyridin-2-yl carbamate which comprises acid hydrolysis of ethyl 6-amino-5-nitro-4-[(2-oxo-2(4-methylphenyl)ethyl)-amino]pyridin-2-yl carbamate oxime, in a solvent and recovery of the required compound.

48. Ethyl 6-amino-5-nitro-4-[(2-oxo-2(4-methylphenyl)ethyl)-amino]pyridin-2-yl carbamate when prepared by the process of claim 47 or an obvious chemical equivalent.

49. A process for the preparation of the compound ethyl 5-amino-4-nitro-4-[2-oxo-2-(4-fluorophenyl)ethylamino]pyridin-2-yl carbamate which comprises acid hydrolysis of ethyl 6-amino-5-nitro-4-[(2-oxo-2-(4-fluorophenyl)ethyl)-amino]pyridin-2-yl carbamate oxime, in a solvent and recovery of the required compound.

50. Ethyl 6-amino-5-nitro-4-[2-oxo-2-(4-fluorophenyl)ethylamino]-pyridin-2-yl carbamate when prepared by the process of claim 49 or an obvious chemical equivalent.

51. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[2-oxo-2-(3,4-dichlorophenyl)ethylamino]pyridin-2-yl carbamate which comprises acid hydrolysis of ethyl 6-amino-5-nitro-4-[(2-oxo-2(3,4-dichlorophenyl)ethyl)-amino]pyridin-2-yl carbamate oxime, in a solvent and recovery of the required compound.

52. Ethyl 6-amino-5-nitro-4-[2-oxo-2-(3,4-dichlorophenyl)ethylamino]-pyridin-2-yl carbamate when prepared by the process of claim 51 or an obvious chemical equivalent.

53. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[2-oxo-2-(3-methoxyphenyl)ethylamino]pyridin-2-yl carbamate which comprises acid hydrolysis of ethyl 6-amino-5-nitro-4-[(2-oxo-(3-methoxyphenyl)-ethyl)amino]pyridin-2-yl carbamate oxime in a solvent and recovery of the required compound.

54. Ethyl 6-amino-5-nitro-4-[2-oxo-2-(3-methoxyphenyl)ethylamino]-pyridin-2-yl carbamate when prepared by the process of claim 53 or an obvious chemical equivalent.

55. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[2-oxo-2-(4-methoxyphenyl)ethylamino]pyridin-2-yl carbamate which comprises acid hydrolysis of ethyl 6-amino-5-nitro-4-[(2-oxo-2(4-methoxyphenyl)ethyl)-amino]pyridin-2-yl carbamate oxime in a solvent and recovery of the required compound.

56. Ethyl 6-amino-5-nitro-4-[2-oxo-2-(4-methoxyphenyl)ethylamino]-pyridin-2-yl carbamate when prepared by the process of claim 55 or an obvious chemical equivalent.

57. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl)amino]pyridin-2-yl carbamate which comprises acid hydrolysis of ethyl 6-amino-5-nitro-4-[(2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl)amino]pyridin-2-yl carbamate oxime in a solvent and recovery of the required compound.

58. Ethyl 6-amino-5-nitro-4-[)2-oxo-2-(3,4,5-trimethoxyphenyl)-ethyl)amino]-pyridin-2-yl carbamate when prepared by the process of claim 57 or an obvious chemical equivalent.

59. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(2-oxo-2-(4-nitrophenyl)ethyl)amino]pyridin-2-yl carbamate which comprises acid hydrolysis of ethyl 6-amino-5-nitro-4-[(2-oxo-2(4-nitrophenyl)ethyl)-amino]pyridin-2-yl carbamate oxime in a solvent and recovery of the required compound.

60. Ethyl 6-amino-5-nitro-4-[(2-oxo-2-(4-nitrophenyl)ethyl)amino]-pyridin-2-yl carbamate when prepared by the process of claim 59 or an obvious chemical equivalent.

61. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(2-oxo-2-(4-trifluoromethyl)ethyl)amino]pyridin-2-yl carbamate which comprises acid hydrolysis of ethyl 6-amino-5-nitro-4-[(2-oxo-2-(4-tri-fluoromethyl)ethyl)amino]pyridin-2-yl carbamate oxime in a solvent and recovery of the required compound.

62. Ethyl 6-amino-5-nitro-4-[2-oxo-2-(4-trifluoromethyl)ethyl)-amino]pyridin-2-yl carbamate when prepared by the process of claim 61 or an obvious chemical equivalent.

63. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(2-oxo-2-(2-naphthyl)ethyl)amino]pyridin-2-yl carbamate which comprises acid hydrolysis of ethyl 6-amino-5-nitro-4-[(2-oxo-2-(2-naphthyl)ethyl)amino]-pyridin-2-yl carbamate oxime in a solvent and recovery of the required compound.

64. Ethyl 6-amino-5-nitro-4-[(2-oxo-2-(2-naphthyl)ethyl)amino]pyridin-2-yl carbamate when prepared by the process of claim 63 or an obvious chemical equivalent.

65. A process for the preparation of the compound ethyl 6-amino-4-[(N-methyl-N-2-oxo-2-phenylethyl)amino]-5-nitro-pyridin-2-yl carbamate which comprises oxidizing ethyl 6-amino-4-[(N-(2-hydroxy-2-phenylethyl-N-methyl)-amino]5-nitropyridin-2-yl carbamate in a solvent with chromium oxide in the presence of pyridine and recovering the required compound.

66. Ethyl 6-amino-4-[(N-methyl-N-2-oxo-2-phenylethyl)amino]-5-nitro-pyridin-2-yl carbamate when prepared by the process of claim 65 or an obvious chemical equivalent.

67. A process for the preparation of the compound ethyl 6-amino-5-nitro-4-[(1-methyl-2-oxo-2-phenylethyl)amino]pyridin-2-yl carbamate which comprises acid hydrolysis of ethyl 6-amino-5-nitro-4-[(1-methyl-2-oxo-2-phenylethyl)-amino]pyridin-2-yl carbamate oxime in a solvent and recovery of the required compound.

68. Ethyl 6-amino-5-nitro-4-[(1-methyl-2-oxo-2-phenylethyl)amino]-pyridin-2-yl carbamate when prepared by the process of claim 67 or an obvious chemical equivalent.

69. A process for the preparation of the compound wherein x has a value of 1,2 or 3, R1 is a lower alkyl group, R2 is a member selected from the group consisting of hydrogen, alkyl radicals having from about one to about 12 carbon atoms, alkenyl radicals having from about two to about 15 carbon atoms, cycloalkyl radicals having from about three to about 20 carbon atoms, aralkyl and alkaryl radicals having from about six to about 20 carbon atoms, a halogen radical, hydroxyl, amino, thiol nitro, alkoxy, aryloxy, carboxyl, alkylcarboxyl radicals having from about one to about 10 carbon atoms, alkylthio and arylthio radicals having from about one to about 20 carbon atoms, sulfonyl, alkylsulfonyl and arylsulfonyl radicals having from about one to about 20 carbon atoms, alkylsulfinyl and arylsulfinyl radicals having from about one to about 20 carbon atoms, alkylamino and arylamino radicals having from about one to about 20 carbon atoms, or a hydrocarbyl group carrying halogen, hydroxyl, amino, alkoxy or aryloxy, and, when taken together with the aromatic ring to which it is attached, a fused ring structure;
X is H or lower alkyl, Y is H or lower alkyl and Z is =0, =N ? OH or CZ
is HCOH with the proviso that when Z is =N ? OH, X is H and Y is H or lower alkyl, when CZ is HCOH, X is H or lower alkyl and Y is H, and when Z is =0, X and Y are both H or one is H and the other lower alkyl, with the further proviso that when Z is =0, X has a value of 1 and R2 is in the para position both X and Y are H and R2 is not chlorine, which comprises (1) when Z is =N ? OH, X is H and Y is H or lower alkyl, aminating a lower alkyl ester of 6-amino-4-ohloro-5-nitro pyridin-2-yl carbamate with the oxime of an .alpha.-amino ketone of structure wherein R2, Y and x are as already defined and recovering the required compound, (ii) when CZ is HCOH, X is H or lower alkyl and Y is H, aminating a lower alkyl ester of 6-amino-4-chloro-5-nitropyridin-2-yl carbamate with an ?-amino alcohol of formula.

wherein R2, X and x are as defined and recovering the required compound, or (iii) when Z is =O, and X and Y are both H or one is H and the other lower alkyl, which comprises (A) when Y is hydrogen, oxidizing a compound of formula wherein R1, R2, X and x are as defined, or (B) when X is hydrogen, hydrolyzing a compound of formula wherein R1, R2, Y and x are as defined, and recovering the required compound.

70. A compound of the formula wherein x has a value of 1,2 or 3, R1 is a lower alkyl group, R2 is a member selected from the group consisting of hydrogen, alkyl radicals having from about one to about 12 carbon atoms, alkenyl radicals having from about two to about 15 carbon atoms, cycloalkyl radicals having from about three to about 20 carbon atoms, aralkyl and alkaryl radicals having from about six to about 20 carbon atoms, a halogen radical, hydroxyl, amino, thiol nitro, alkoxy, aryloxy, carboxyl, alkylcarboxyl radicals having from about one to about 10 carbon atoms, alkylthio and arylthio radicals having from about one to about 20 carbon atoms, sulfonyl, alkylsulfonyl and arylsulfonyl radicals having from about one to about 20 carbon atoms, alkylsulfinyl and arylsulfinyl radicals having from about one to about 20 carbon atoms, alkylamino and arylamino radicals having from about one to about 20 carbon atoms, or a hydrocarbyl group carrying halogen, hydroxyl, amino, alkoxy or aryloxy, and, when taken together with the aromatic ring to which it is attached, a fused ring structure;
X is H or lower alkyl, Y is H or lower alkyl and Z is =O, =N?OH or CZ
is HCOH with the proviso that when Z is =N?OH, X is H and Y is H or lower alkyl, when CZ is HCOH, X is H or lower alkyl and Y is H, and when Z is =O, X and Y are both H or one is H and the other lower alkyl, with the further proviso that when Z is =O, X has a value of 1 and R2 is in the para position both X and Y are H and R2 is not chlorine, when prepared by the process of claim 69 or an obvious chemical equivalant.