FI77449B - 5-NITRO-4 - / (2-PHENYLTHYL) AMINO / PYRIDINE DERIVATIVES. - Google Patents

Description

This invention relates to novel 5-nitro-4- ([2-phenylethyl) amino] pyridine derivatives which can be used as intermediates in the preparation of 1,2-nitro-4 - [(2-phenylethyl) amino] pyridine derivatives which are separated from application 820982 (patent 75567). -dihydropyrido / 3,4-b7pyrazines (also known as 1-deaza-7,8-dihydropteridines).

Antinitotic chemicals commonly referred to as spindle creams are plant products, the best known of which are colchicine, podophyllotoxin, and winter alkaloids. / L. Wilson, J.R. Bamburg, S.B. Mizel, L.M.

Grisham and K.M. Creswell, Federation Proceedings, 3J3> 158 (1974j_7 · The last two members of the group, vincristine and vinblastine, are commonly used clinically for the treatment of tumors. micropores are the result of cell accumulation in metaphase, and numerous benzimidazol-2-yl carbamates have been reported as antifungals, anthelmintics, and antitumor agents./ LC Davidise and W. Flach, J. Cell Biol., 72. »174 (1977) These compounds also inhibit mitosis and their biological effect is likely due to their interference with micropore formation or function.

The development of methods for the preparation of 1-deazapapteridines has been reported by J.A. Montgomery and N.F. Wood, J. Org. Chem., 29, 734 (1964); R.D. Elliott, C. Temple, Jr., and J.A. Montgo-mety, J. Org. Chem., 21, 533 (1968); R.D. Elliott, C. Temple, Jr., J.L. Frye and J.A. Montgomery, J. Org. Chem., 21, 2818 (1971); and R.D. Elliott, C. Temple, Jr., and J.A. Montgomery, J. Med. Chem., 12/553 (1974). These references include the preparation and use of numerous 1,2-dihydro / 3,4-b7-pyrazine derivatives. Thus, reference J. Org. Chem. from 1964 comprises compounds: nhco2c2h5 C2H5 ° 2CHN?

B

and nhco2k KO, CKN ^

B

The 1968 J. Org. Chem. Reference comprises the compound: NHC0oCoHc I 225 ch3 N ^ γΟΗ2Νε6Η5 C2H5 ° 2CHN'X ^^ Ns'n ^

B

The 1971 J. Org. Chem. Reference comprises the compounds: Γ2 “3_ / ~ v_ N ifNY ™ 2" C ° 2CH3 c2h5o2chn / ^ AN? ^

B

NH2 / - CH2NH - <^ Jh-CO2C2H5

C2H502CHtr ^ / JNSvN

B

li 3 77449

In J. Med. Chem. it has been shown that the dihydro-1-deaza-pteridine precursor of 1-deaza-methotrexate has anti-leukemic L1210 activity in mice. Abstract presented in 2Θ. The Southeastern Area of the American Chemical Society in Gaitinburg, Tennessee, October 27-29, 1976, revealed that the compound nh2 CH3 / - \ -ft V) -CO2CH3

g2H5 ° 2CHN

B

had eolumotoxicity against KB cell culture screening assay and activity against leukemia L1210 in mice.

The main application 820982 (patent 75567) relates to a process for the preparation of certain 1,2-dihydropyrido [3,4-b] pyrazines, which are not disclosed in the above publications and which have antifungal and anti-cancer properties and have the formula (R2) χ R102CHNX '\ ^ Ss' r4 r3 wherein x is 1, 2 or 3; R 1 is a lower alkyl group such as methyl, ethyl, propyl, butyl, etc .; R 3 and R 4 are either both hydrogen or one is hydrogen and the other is a lower alkyl group and R 2 is hydrogen, a lower alkyl group; halogen, e.g. chlorine, fluorine, bromine or iodine, provided that when x is 1 and R 2 is in the para position and R 3 and R 4 are both hydrogen, R 2 is not chlorine; a hydroxyl group; amino group; lower alkoxy group; , 77449 or a trifluoromethyl group or, taken together with the aromatic ring to which it is attached, a naphthyl ring.

The present invention relates to novel 5-nitro-4- [72-phenylethyl] amino] pyridine derivatives which can be used as intermediates in the preparation of compounds of formula I.

The compounds of the invention have one of the following formulas nh2

o2 ^ OH

?Α? Av * 2 ’* r1o2chn ^ NHCHC— (y R4 H”,

OF

I I H, -. (R2> x VI1 r1o2chn y: r3 OH \ = - / nh2 Ν '^ Αγ--' n02

L 11 * 3 0 / -y / <> <2> * V 'VA

R 10 2 CHN / Al 2 H 1 wherein x is 1, 2 or 3, R 1 is a lower alkyl group, R 8 and R 2 are either both hydrogen or one is hydrogen and the other is a lower alkyl group and R 2 is hydrogen, a lower alkyl group , halogen, provided that when x is 1 and R 2 is in the para position and R 8 and R 6 are both hydrogen, R 2 is not chlorine; hydroxy, amino, nitro, lower alkoxy or trifluoro

II

5 77449 methyl group or taken together with the aromatic ring to which it is attached, a naphthyl ring.

The preparation of the compounds of the invention and their utility as intermediates for the preparation of the compounds of formula I will become apparent from the following description of the preparation of the compounds of formula I.

Compounds of formula I may be prepared as follows: a) To form compounds of formula I wherein R 9 is hydrogen, a lower alkyl ester of 6-amino-4-chloro-5-nitro-pyridin-2-ylcarbamate of formula: NH 2 is aminated.

I il II

R ^ OgCHN

ai fa-aminoketone oxime of the formula:

Ϊ / ~ V <R2> X

h2nchc-t y III

6-Amino-5-nitro-4 - [(2-oxoethyl) amino] pyridin-2-ylcarbamate oxime to form a lower alkyl ester of the formula: «2

Ν <^ ν_Ν02 ^ OH

XJk ϊ / Πκ ™> 2 x

Rj ^ OjCHN ^ NHCHC - (/) IV

R 4 wherein R 1, R 2, R 2 and x are as defined above, wherein R 2 may also be a nitro group, the compound of formula IV 6 77449 is hydrolysed, e.g. by acid hydrolysis to form the corresponding ketone of formula: nh 2 N iTN ° 2

Ϊ / “^ <R2> X

R102CHN NHCHC-C y V

R 4 wherein R 1, R 2, R 4 and x are as defined above, wherein R 2 may also be a nitro group and the compound of formula V is converted to the compound of formula I by catalyst hydrogenation. The intermediate formed during the hydrogenation has the formula: NH2 L jl y / r2} x

RiO ^ CHN ^^^ NHCHC — V VI

i4 \ = / wherein R1, R2, R4 and x have the same meaning as above.

b) To form compounds of formula I wherein R 3 is hydrogen, the compound of formula IV is catalytically hydrogenated.

c) To form compounds of formula I wherein R 4 is hydrogen, the compound of formula II is aminated with an alpha-amino alcohol of formula:

HNCHjCH-T '\ II IA

r3 oh Vr = y to give a compound of formula: 11 7 77449 NH2 n ^ Ono2 r1o2chn xnch2c — r \\ vii r3 oh oxidizes a compound of formula VII to form a ketone of formula: nh2 »ΓΎ ™ 2 '*

R, CH, CH, C— ('VA

R 3 = = wherein R 1, R 2, R 3 and x are as defined above, wherein R 2 may be a nitro group and the compound of formula VA is converted to the compound of formula I by catalytic hydrogenation.

The preferred lower alkyl ester of 6-amino-4-chloro-5-yltropyridin-2-ylcarbamate is the ethyl ester, i. ethyl 6-amino-4-chloro-5-nitro-pyridin-2-ylcarbamate. This compound is prepared by R.D. Elliot, C. Temple Jr., and J.A. In Montgome, J. Org. Chem., 3L1 # 1890 (1966).

8 77449

Oximes of alpha-aminoketones, i. compounds of formula III may be prepared according to procedures known in the art. Thus, they can be prepared by reacting the corresponding alpha-bromoacetophenone with hexamethylenetetramine to give the corresponding ammonium salt, which is hydrolyzed with ethanol hydrochloric acid to give the corresponding alpha-aminoacetophenone hydrochloride. Long and H.D. Troutman, J. Amer. Chem. Soc., 71y 2473 (1949); and A.B. Sen and D.D. Mukerji, J. Indian Chem. Soc., 28_, 401 (1951J_). Condensation of these alpha-aminoketones with hydroxylamine hydrochloride in a reflux mixture of pyridine and ethanol gives oxime derivatives (R.D. Elliott, C. Temple, Jr. and J.A. Montgomery, J. Org.

Chem., 35, 1676 (1970).

Compounds of formula III may also be prepared by alkylation of a phthalimide with the corresponding alpha-bromoacetophenone by treatment of the alpha- (phthalimido) acetophenone product /G.C. Schweiker, Dissertation Abstracts, 21, 464 (1953J_7 with hydroxylamine and removing the phthaloyl protecting group from the resulting oxime with hydrazine /R.D. Elliott, C. Temple, Jr. and J.A. Montgomery, J. Org. Chem., 3J5, 1676 (1970-7.

The following are examples of these two procedures for the preparation of compounds of formula III:

Method I. α-Amino-2,4-dichloroacetophenone oxime α, 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 5 °. At a temperature of C.

After 5 minutes, the resulting solution was allowed to warm to room temperature, followed by heating to 50 ° C for 15 min. The solution was then stirred with CHCl 3 (103 mL) and H 2 O (341 mL) and the aqueous phase was separated and extracted with additional CHCl 3 (3 x 46 mL). Combined CHCl 3 -

II

The extracts were washed with 2% sodium hydroxide (57 ml) and water (57 ml) and evaporated to a small volume in vacuo (40 ° C). The residue was diluted with cold water (225 ml) and the mixture was cooled to semi-solid, which semi-solid was separated by decantation. The residue was washed with ethyl alcohol and diethyl ether and dried to give phenacyl phthalimide: yield 9.2 g. A solution of this solid (28 mmol) and hydroxylamine hydrochloride (2.9 g, 41 mmol) in a mixture of pyridine (28 mL) and ethyl alcohol (117 mL) was stirred at reflux for 1.5 h. The solvent was evaporated off in vacuo and the resulting oily ketone oxime was washed with water .: m / e 348 (M +) was obtained in the mass spectrum. A solution of the oxime in ethanol (332 ml) at 70 ° C was treated dropwise over 20 min with a 95% solution of hydrazine (2.0 g) in ethanol (25 ml). The resulting solution was heated at 40 ° C for 22 hours and the cooled reaction mixture was treated with 1 N hydrochloric acid (30 mL). After the mixture was stirred in an ice bath for 1 hour, the precipitated phthalic hydrazine was removed by filtration and washed with 1: 1 ethanol-water (36 ml). The combined filtrate and washings were evaporated to dryness in vacuo (40 ° C), the residue was extracted with warm water (120 ml) and the filtrate was treated with concentrated ammonium hydroxide (2 ml) to precipitate the product: yield 3.2 g.

Method II, α-Amino-p-nitroacetophenone oxime A solution of α-bromo-p-nitroacetophenone (20 g, 82 mmol) and hexamethylenetetramine (12 g, 86 mmol) in chloroform (300 mL) was stirred at room temperature for 24 h. 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 hydrochloride (10 g) in 1: 1 ethanol-pyridine (135 ml) was refluxed with stirring for 2 hours, evaporated to dryness in vacuo and the resulting residue dissolved in water and treated with 50%; with sodium hydroxide to precipitate the product: yield 3.2 g.

The oximes given in Table I were prepared by Method I and Method II as indicated in Table I. The first column of Table I shows the group structure in Formula III. Known compounds are indicated by superscript letters in Table I.

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An α-amino alcohol of formula IIIA wherein R 2 is hydrogen and R 1 is a methyl group was prepared according to the procedure described in S.P. McManus, C.A. Larson and R.A. Hearn, Synthetic Commun., 3, 177 (1973). The product with the empirical formula CgH13NO, m / e 151 (M +) and a melting point of 75-77 ° C was obtained with a total yield of 52%.

A compound of formula II was aminated with a compound of formula III under reflux in ethanol containing triethylamine as an acid acceptor to provide a compound of formula IV. An example of this procedure is as follows:

Example 1

Ethyl 6-amino-5-nitro-4 - [(2-oxo-2-phenylethyl) amino] pyridin-2-ylcarbamate oxime (IV: ri = C2H5 'R2 = H' R4 = H)

Ethyl 6-amino-4-chloro-5-nitropyridin-2-ylcarbamate (14.0 g, 53.8 mol), alpha-aminoacetophenone oxime (8.07 g, 53.8 mmol) and triethylamine (5.43 g, 53.8 mmol) in ethyl alcohol (300 mL) was refluxed under nitrogen with stirring for 8 h. The solid which precipitated from the cooled reaction mixture was collected by filtration and dried in vacuo over phosphorus pentoxide: yield 10.4 g. The properties are given in Table II.

Excipients were prepared in a similar manner in which alpha-aminoacetophenone oxime was replaced with substituted alpha-aminoacetophenone oximes. The properties of these compounds are given in Table II. The first column of Table II shows the structure of the group: "D \ -σ" in the starting alpha-aminoacetophenone oxime and in the final product, the formula of which is shown in Table II.

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

Example 2

Ethyl 6-amino-5-nitro-4 - [(2-oxo-2-phenylethyl) amino] pyridin-2-ylcarbamate dioxanoate (V: R1 = C2H5; R2 = H; R4 = H).

Ethyl 6-amino-5-nitro-4- (2-oxo-2-phenylethyl) amino] pyridin-2-ylcarbamate oxime (472 g, 12.6 mmol) in 1: 1 HCl-dioxane solution (170 mL) heated with stirring at 60 ° C for two hours. The yellow solid which precipitated from the cooled solution was collected by filtration and recrystallized from 1: 1 H 2 O-dioxane (1 L): yield 3.13 g. The properties of the compound thus obtained are given in Table III.

Other compounds were prepared in a similar manner, substituting substituted ethyl 6-amino-5-nitro-4- (2-oxo-2-phenylethyl) amino] pyridin-2-ylcarbamate oxime for the oxime starting material. The properties of these compounds are given in Table III. The first column of Table III shows the structure of the group, f \ '**' *, in the oxime used as starting material, the formula of which is shown in Table II, and in the final product, the formula of which is shown in Table III.

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Amination of a compound of formula II with a compound of formula IIIA under reflux in ethanol containing triethylamine as an acid acceptor provides a compound of formula VII. Oxidation of a compound of formula VII results in a ketone of formula VA. An example of this procedure is given below.

Example 3 A. Ethyl 6-amino-4 - [(N- (2-hydroxy-2-phenylethyl-N-methyl) amino] -5-nitropyridin-2-ylcarbamate (VII: R1 = C2H5; R2 = H; R3 = CH3)

Ethyl 6-amino-4-chloro-5-nitropyridin-2-ylcarbamate (3.40 g, 13.1 mmol), 2- (methylamino) -1-phenylethanol (2.17 g, 14.4 mmol) and a solution of triethylamine (1.32 g, 13.1 mmol) in ethanol (75 ml) was refluxed under protection with a drying tube for 2 hours and the mixture was then evaporated to dryness in vacuo. The residue was stirred with 1 N HCl for 1 h, followed by neutralization (pH 7) with 1N NaOH. The product was collected by filtration and used without further purification: yield 4.81 g; mp. 108-110 ° C. Formula C17H21N5O3 m / e 375 (M +).

B. Ethyl 6-amino-4 - [(N-methyl-N-2-oxo-2-phenylethyl) amino] -5-nitropyridin-2-ylcarbamate (VA: R1 = C2H5; R2 = H; R3 = CH 3)

To a solution of pyridine (8.70 g, 110 mmol) in CH 2 Cl 2 (131 mL) protected by a drying tube was added chromium (VI) oxide (5.52 g, 55.2 mmol) with stirring. After 15 min, a solution of ethyl 6-amino- [N- (2-hydroxy-2-phenylethyl) -N-methyl] amino] -5-nitropyridin-2-ylcarbamate (3.45 g, 9.20 mmol) in CH 2 Cl 2 was added: in (35 mL). The residue was separated after a further 20 min by decantation and washed with diethyl ether (242 ml). The combined decantation solution and washings were evaporated to dryness, the residue was dissolved in diethyl ether (1700 ml) and the solution was washed with 5% aqueous sodium bicarbonate solution (200 ml), water (200 ml) and saturated sodium chloride solution (200 ml). diethyl

II

17 77449 Concentration of the ether solution to a small volume followed by cooling in an ice bath gave the product: yield 1.99 g? mp. 139-140 ° C; Analysis calculated for C 17 H 19 N 5 O 5: C 54'69 'H 5'13; N 18.76. Found: C, 54.88; 5.49; N 18.50.

Catalytic hydrogenation of a compound of formula V or VA with three times the volume of Raney nickel in a large volume of ethanol (i.e. more than 1 / g) at normal pressure at room temperature with heating (e.g. up to 60 ° C) in a water bath gives an intermediate of formula VI, which are cyclized in situ to give water to give a compound of formula I. Such a reaction is shown in Example 4. Compounds of formula I can also be prepared directly by hydrogenation of compounds of formula IV in the presence of Raney nickel as shown in Example 5.

Example 4

Ethyl 5-amino-1,2-dihydro-3-phenylpyrido [1,4-b] pyrazin-7-ylcarbamate (I: R2 = H; R3 = H 'R4 = H)

Ethyl 6-amino-5-nitro-4- ([2-oxophenyl-2-ethyl) amino] pyridin-2-ylcarbamate dioxanate (10: 7) obtained in Example 2 (3.10 g, 7.25 mmol) as a solution 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 occasional heating in a water bath. After 6 hours, the catalyst was removed by filtration and the filtrate was concentrated in vacuo (<40οΟ) to 1/16 volume. The solid which precipitated from the cooled mixture was collected by filtration and dried in vacuo over phosphorus pentoxide: yield 1.82 g. A second crop of filtrate was obtained: yield 0.17 g. The total yield was 1.99 g. The properties are shown in Table IV.

18 77449

Example 5

Hydrogenation of ethylamino-5-nitro-4 - ['- [2- (4' - (trifluoromethyl) phenyl] -2-oxoethyl] amino] aminopyridine-2-carbamate oxime

A solution of oxime (0.5 g) in ethanol (1000 ml) containing Raney nickel (1.5 g wet weight and washed successively with water and ethanol) was hydrogenated at room temperature and atmospheric pressure for 7 h. The catalyst was removed by filtration through Celite under nitrogen and the filtrate was concentrated in vacuo to 1/20 volume of ethyl 5-amino-1,2-dihydro-3- [4 '- (trifluoromethyl) phenyl] pyrido / 3.4 to precipitate -b7pyrazin-7-ylcarbamate. The product was collected by filtration, washed with ether and dissolved with heating in a mixture of ethanol (35 mL) and 1 N HCl (15 mL). After filtration through "Celite", the filtrate was neutralized with 1 N NaOH and concentrated in vacuo to precipitate the product: Yield 0.20 g. (47%).

This material was identified by thin layer chromatography compared to the product prepared by hydrogenation of the corresponding ketone.

The compounds shown in Table IV were prepared according to the procedure of Example 4 'or Example 5, as indicated in Table IV. The properties of these compounds are shown in Table IV. The first column of Table IV shows the structure of the group, _v / (r2) v, in the starting material, the starting material formula of which is shown in Table II or III (except for those items marked separately) and in the final product, the formula of which is shown in Table IV.

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21 77449

The pharmacological properties of the 1,2-dihydropyrido [3,4-f] pyrazines of the formula I are described in more detail in parent application 820982 (patent 75567).

Claims (11)

A compound of the formula: nh2 I I N / -V / (R,) Y R 2 wherein x is 1, 2 or 3, R 6 is a lower alkyl group, R 4 is hydrogen or a lower alkyl group and R 2 is hydrogen, a lower alkyl group, halogen, provided that where x is 1 and R 2 is in para lation and R 4 is hydrogen, R 2 is not chlorine; a hydroxyl, amino, nitro, lower alkoxy or trifluoromethyl group or taken together with the aromatic ring to which it is attached a naphthyl ring. A compound according to claim 1, characterized in that R 2 is ethyl. 3. A compound according to claim 1 or 2, characterized in that R 4 is hydrogen and that the group <RTIgt; <R2> x </RTI> is C6H5, 4-CH3C6H4, 2.4- (CH3) 2CgH3, 3.4- <CH , 4-CFgH4, 2.4- (Cl> 2C6H3, 3.4- <Cl) 2C6H3, 3-CH30C6H4, 4-CH30CgH4, 3,4,5- <CH 2-C10H7. A compound according to claim 1 or 2, characterized in that R 2 is hydrogen and R 4 is methyl. 26, p 77449 5. Compound of the formula: nh2 n ^ Ono2 JLJjL i / T ~ v <R2> x r102chn "^^^ v'nch2c - // & 3 OH V = V wherein x is 1, 2 or 3, R 2 is a lower alkyl group, R 3 is hydrogen or a lower alkyl group Q 2 and R 2 is hydrogen, a lower alkyl group, halogen, provided that χ is 1 and R 2 is in para and R 3 is hydrogen, R 2 is not chlorine; , lower alkoxy or trifluoromethyl group or taken together with the aromatic ring to which it is attached a napyl ring. · Compound according to claim 5, characterized in that R 1 is ethyl, R 2 is hydrogen and R 3 is methyl. A compound of the formula:; V2 V Ν ^ γ-Ν02 i4 w / wherein x is 1, 2 or 3, R 2 is a lower alkyl group, R 3 and R 2 are either both hydrogen or one is hydrogen and the other is a lower alkyl group and R 2 is hydrogen , a lower alkyl group, halogen, provided that x is 1 and R2 is in para and R3 and R4 are each hydrogen, R2 is not chlorine; a hydroxyl, amino, nitro, lower alkoxy or trifluoromethyl group or taken together with the aromatic ring to which it is attached a naphthyl ring. Il