CA1036605A - Amino derivatives of pyrido (3,4-b) pyrazine carboxylic acids and esters - Google Patents
Amino derivatives of pyrido (3,4-b) pyrazine carboxylic acids and estersInfo
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- CA1036605A CA1036605A CA230,146A CA230146A CA1036605A CA 1036605 A CA1036605 A CA 1036605A CA 230146 A CA230146 A CA 230146A CA 1036605 A CA1036605 A CA 1036605A
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- lower alkyl
- compound
- hydrogen
- methyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
ABSTRACT
New derivatives of pyrido[3,4-b]pyrazine carboxylic acids and esters and their acid addition salts, useful as anti-inflammatory agents and central nervous system depressants, have the general formula wherein R, R3, R4 and R5 each is hydrogen or lower alkyl; R1 and R2 each is hydrogen, lower alkyl, lower alkanoyl, di(lower alkylamino)lower alkyl, or
New derivatives of pyrido[3,4-b]pyrazine carboxylic acids and esters and their acid addition salts, useful as anti-inflammatory agents and central nervous system depressants, have the general formula wherein R, R3, R4 and R5 each is hydrogen or lower alkyl; R1 and R2 each is hydrogen, lower alkyl, lower alkanoyl, di(lower alkylamino)lower alkyl, or
Description
-~ MT84 ` 1~)366QS
The invention relates to the new amino derivatives of pyrido[3,4-b]pyrazine carboxylic acids and esters and acid addition salts thereof having the general formula COOR
- (I) R3 ~ ` X R
~ N R
':' / \
R R
wherein R, R3, R4 and R5 each is hydrogen or lower alkyl;
Rl and R2 each is hydrogen, lower alkyl, lower alkanoyl, di(lower alkylamino)lower alkyl, phenyl, substituted phenyl, or _~ ~ 1 is an unsubstituted or substituted heterocyclic . ~ R2 of the group consisting of pyrrolidinyl, piperidinyl, pyrimidinyl, pyridazinyl or piperazinyl; wherein the substituted phenyl bears one or two lower alkyl, lower alkoxy, halogen, trifluoro-methyl, amino or carboxy groups, and the substituted hetero-cyclics bear a hydroxy-lower alkyl, one or two lower alkyl or a phenyl group.
The symbols have the above meanings in formula I and throughout this specification.
The basic nitrogen group -~ < 1 is an acyclic amino moiety or a heterocyclic of 5 or 6 members in which an additional nitrogen may be present.
.. . .
.;" ' ' ' .
~, .
':. ;: .
~ 10366~S
.:
The lower alkyl groups in any of the foregoing radicals include straight or branched chain hydrocarbon groups containing 1 to 7 carbon atoms. The lower alkanoyl groups are of the same type. Examples of the groups con-templated are methyl, ethyl, propyl, isopropyl, etc. Lower - alkyl groups of 1 to 4 carbon atoms are preferred, especially - the 1 and 2 carbon members of this grou~. The substituted phenyl groups include one or two simple substituents (pre-ferably only one substituent, but they are the same groups if disubstituted), i~e., lower alkyl, lower alkoxy, halogen (F, Cl, Br or I, preferably Cl or Br), CF3, amino or carboxy.
Examples of the types of groups contemplated are o-, m- or p-chlorophenyl, o-, m- or p-tolyl, 2,5-dichlorophenyl, 3,5-dimethylphenyl or 3,4-dimethoxyphenyl.
Preferred embodiments of this invention are as follows: --R is hydrogen or lower alkyl of 1 to 4 carbon atoms, especially ethyl.
Rl and R2 each is hydrogen or lower alkyl of 1 to 4 carbon atoms, especially butyl; or -N \ 1 is N-(lower alkyl)-piperazinyl, especially N-methylpiperazinyl.
R3 is lower alkyl, especially methyl.
R4 and R5 each is hydrogen or lower alkyl, especially hydrogen and methyl.
;i.' ' ' ~', '~ ' :' "' , ~Q366 Q 5 MT84 The new compounds of formula I are formed by the following series of reactions. The symbols in the structural formulas have the same meaning as previously described.
A 4,6-dihydroxypyridine carboxylic acid ester of the formula (II) OH
02N~COOR ~
HO~ N R3 [produced analogous to the procedure described in Chem. Ber.
99, 244 (1966)] wherein R is lower alkyl is made ~Q react with an inorganic acid chloride like phosphorus oxychloride, producing a compound of the formula:
(III) Cl 02N~:OOR
Cl N R3 with two chlorine atoms in the 4- and 6- positions of the molecule. This compound is now treated with an amine like -~ tert. butylamine in a solvent like alcohol ~n the presence of a base, e.g., an alkylamine like triethylamine, forming a compound of the formula:
(IV) HN-C(CH3)3 . 02N \~( COOR
Cl N R3 _3 ' 366(~5 ' Heating of this compound in an inert high boiling solvent like diphenylether, or without any solv,ent at a temperature of about 240-260C produces a compound , -of the formula: ,' - (V) ; . :
, 1 2 Cl N 3 -which is next treated with ammonia or the appropriate , - primary or secondary amine of the formula: ~' , (VI) . ~ 1 :
~, HN
. R2 in a solvent like alcohol in the presence of a base, e.g., ,~
an alkylamine like triethylamine. By this procedure a ~,~, compound of the formula: ~ -(VII) ' , ' ' O2N~ ~ COOR
R
,, N N
~ R2~ 3 .. . .
`,~' is formed. The p~oduct is now hydrogenated~either c~talytically '~, or with a metal-acid pair like zinc in acetic acid. This . . .
results in the formation of a compound of the formula:
'~ (VIII) ; 2 N N R ' ' , 30 R2 ."
'. ' : . . .
~;
`` ~0366~5 . The compound of formula I is now produced by reacting the compound of formula VIII with an appropriate 1,2-diketone ; of the formula:
(IX) 0 O
The water formed by this reaction is removed by a water-separator using an aromatic solvent like benzene or toluene.
Compounds of formula VII wherein Rl and R2 are other than hydrogen can also be produced by an alternate process by reaction of a compound of formula III with an amine of formula VI (wherein Rl and R2 are not hydrogen) forming a compound of the formula (X) Cl 02N ~
,. 'R2 A product of formula VII is now produced by treatment of the compound of formula X with gaseous or aqueous ammonia in an autoclave in a solvent, e.g., an a~c ohol like ethanol.
The ester can be converted to the a'cid, i.e., wherein R is hydrogen, with a dilute alkali hydroxide like sodium hydroxide.
The bases of formula I form physiologically acceptable acid addition salts by reaction with an equivalent amount of the common inorganic and organic acids. Such salts include the hydrohalides, e.g., hydrobromide, hydrochloride, sulfate, nitrate, phosphate, acetate, citrate, oxalate, ~0366~5 MT84 tartrate, maleate, succinate, benzoate, ascorbate, alkanesulfonate, e.g., methanesulfonate, arylsulfonate, e.g., benzenesulfonate, etc. It is frequently convenient to purify or isolate the product by forming an insoluble salt which is not necessarily physiologically acceptable.
The base is then obtained by neutralizatlon and another salt can then be formed by treatment with the appropriate inorganic and organic acid.
The new compounds of this invention have anti-inflammatory properties and are useful, for example, to reduce local inflammatory conditions such as those of an edematous nature or resulting from proliferation of connective tissue in various mammalian species such as rats, dogs and the like when given orally in dosages of about 5to 50 mg/kg/day, preferably 5 to ~5 mg/kg/day, in single or 2 to 4 divided -~
doses, as indicated by the carageenan edema assay in rats.
- The active substance can be utilized in compositions such as tablets, capsules, solutions or suspensions containing up to about 300 mg. per unit of dosage of a compound or mixture of compounds of formula I or physiologically acceptable acid addition salt thereof. They are compounded in conventional manner with a physiologically acceptable vehicle or carrier, - excipient, binder, preservative, stabilizer, flavor, etc. as called for by accepted pharmaceutical practice. Topical preparations containing about 0.01 to 3 percent by weight of active substance in a lotion, salve or cream can also be used.
The compounds of this invention are also central nervous system depressants and can be used as tranquilizers or ataractic agents for the relief of anxiety and tension - 30 states, for example, in mice, cats, rats, dogs and other ~ -6--: :
.
` 1(~36605 mammalian-species. For this purpose a compound or mixture of compounds of formula I, or non-toxic, physiologically acceptable acid addition salt thereof, is administered orally or parenterally in a conventional dosage form such as tablet, capsule, injectable or the like. A single dose, or preferably
The invention relates to the new amino derivatives of pyrido[3,4-b]pyrazine carboxylic acids and esters and acid addition salts thereof having the general formula COOR
- (I) R3 ~ ` X R
~ N R
':' / \
R R
wherein R, R3, R4 and R5 each is hydrogen or lower alkyl;
Rl and R2 each is hydrogen, lower alkyl, lower alkanoyl, di(lower alkylamino)lower alkyl, phenyl, substituted phenyl, or _~ ~ 1 is an unsubstituted or substituted heterocyclic . ~ R2 of the group consisting of pyrrolidinyl, piperidinyl, pyrimidinyl, pyridazinyl or piperazinyl; wherein the substituted phenyl bears one or two lower alkyl, lower alkoxy, halogen, trifluoro-methyl, amino or carboxy groups, and the substituted hetero-cyclics bear a hydroxy-lower alkyl, one or two lower alkyl or a phenyl group.
The symbols have the above meanings in formula I and throughout this specification.
The basic nitrogen group -~ < 1 is an acyclic amino moiety or a heterocyclic of 5 or 6 members in which an additional nitrogen may be present.
.. . .
.;" ' ' ' .
~, .
':. ;: .
~ 10366~S
.:
The lower alkyl groups in any of the foregoing radicals include straight or branched chain hydrocarbon groups containing 1 to 7 carbon atoms. The lower alkanoyl groups are of the same type. Examples of the groups con-templated are methyl, ethyl, propyl, isopropyl, etc. Lower - alkyl groups of 1 to 4 carbon atoms are preferred, especially - the 1 and 2 carbon members of this grou~. The substituted phenyl groups include one or two simple substituents (pre-ferably only one substituent, but they are the same groups if disubstituted), i~e., lower alkyl, lower alkoxy, halogen (F, Cl, Br or I, preferably Cl or Br), CF3, amino or carboxy.
Examples of the types of groups contemplated are o-, m- or p-chlorophenyl, o-, m- or p-tolyl, 2,5-dichlorophenyl, 3,5-dimethylphenyl or 3,4-dimethoxyphenyl.
Preferred embodiments of this invention are as follows: --R is hydrogen or lower alkyl of 1 to 4 carbon atoms, especially ethyl.
Rl and R2 each is hydrogen or lower alkyl of 1 to 4 carbon atoms, especially butyl; or -N \ 1 is N-(lower alkyl)-piperazinyl, especially N-methylpiperazinyl.
R3 is lower alkyl, especially methyl.
R4 and R5 each is hydrogen or lower alkyl, especially hydrogen and methyl.
;i.' ' ' ~', '~ ' :' "' , ~Q366 Q 5 MT84 The new compounds of formula I are formed by the following series of reactions. The symbols in the structural formulas have the same meaning as previously described.
A 4,6-dihydroxypyridine carboxylic acid ester of the formula (II) OH
02N~COOR ~
HO~ N R3 [produced analogous to the procedure described in Chem. Ber.
99, 244 (1966)] wherein R is lower alkyl is made ~Q react with an inorganic acid chloride like phosphorus oxychloride, producing a compound of the formula:
(III) Cl 02N~:OOR
Cl N R3 with two chlorine atoms in the 4- and 6- positions of the molecule. This compound is now treated with an amine like -~ tert. butylamine in a solvent like alcohol ~n the presence of a base, e.g., an alkylamine like triethylamine, forming a compound of the formula:
(IV) HN-C(CH3)3 . 02N \~( COOR
Cl N R3 _3 ' 366(~5 ' Heating of this compound in an inert high boiling solvent like diphenylether, or without any solv,ent at a temperature of about 240-260C produces a compound , -of the formula: ,' - (V) ; . :
, 1 2 Cl N 3 -which is next treated with ammonia or the appropriate , - primary or secondary amine of the formula: ~' , (VI) . ~ 1 :
~, HN
. R2 in a solvent like alcohol in the presence of a base, e.g., ,~
an alkylamine like triethylamine. By this procedure a ~,~, compound of the formula: ~ -(VII) ' , ' ' O2N~ ~ COOR
R
,, N N
~ R2~ 3 .. . .
`,~' is formed. The p~oduct is now hydrogenated~either c~talytically '~, or with a metal-acid pair like zinc in acetic acid. This . . .
results in the formation of a compound of the formula:
'~ (VIII) ; 2 N N R ' ' , 30 R2 ."
'. ' : . . .
~;
`` ~0366~5 . The compound of formula I is now produced by reacting the compound of formula VIII with an appropriate 1,2-diketone ; of the formula:
(IX) 0 O
The water formed by this reaction is removed by a water-separator using an aromatic solvent like benzene or toluene.
Compounds of formula VII wherein Rl and R2 are other than hydrogen can also be produced by an alternate process by reaction of a compound of formula III with an amine of formula VI (wherein Rl and R2 are not hydrogen) forming a compound of the formula (X) Cl 02N ~
,. 'R2 A product of formula VII is now produced by treatment of the compound of formula X with gaseous or aqueous ammonia in an autoclave in a solvent, e.g., an a~c ohol like ethanol.
The ester can be converted to the a'cid, i.e., wherein R is hydrogen, with a dilute alkali hydroxide like sodium hydroxide.
The bases of formula I form physiologically acceptable acid addition salts by reaction with an equivalent amount of the common inorganic and organic acids. Such salts include the hydrohalides, e.g., hydrobromide, hydrochloride, sulfate, nitrate, phosphate, acetate, citrate, oxalate, ~0366~5 MT84 tartrate, maleate, succinate, benzoate, ascorbate, alkanesulfonate, e.g., methanesulfonate, arylsulfonate, e.g., benzenesulfonate, etc. It is frequently convenient to purify or isolate the product by forming an insoluble salt which is not necessarily physiologically acceptable.
The base is then obtained by neutralizatlon and another salt can then be formed by treatment with the appropriate inorganic and organic acid.
The new compounds of this invention have anti-inflammatory properties and are useful, for example, to reduce local inflammatory conditions such as those of an edematous nature or resulting from proliferation of connective tissue in various mammalian species such as rats, dogs and the like when given orally in dosages of about 5to 50 mg/kg/day, preferably 5 to ~5 mg/kg/day, in single or 2 to 4 divided -~
doses, as indicated by the carageenan edema assay in rats.
- The active substance can be utilized in compositions such as tablets, capsules, solutions or suspensions containing up to about 300 mg. per unit of dosage of a compound or mixture of compounds of formula I or physiologically acceptable acid addition salt thereof. They are compounded in conventional manner with a physiologically acceptable vehicle or carrier, - excipient, binder, preservative, stabilizer, flavor, etc. as called for by accepted pharmaceutical practice. Topical preparations containing about 0.01 to 3 percent by weight of active substance in a lotion, salve or cream can also be used.
The compounds of this invention are also central nervous system depressants and can be used as tranquilizers or ataractic agents for the relief of anxiety and tension - 30 states, for example, in mice, cats, rats, dogs and other ~ -6--: :
.
` 1(~36605 mammalian-species. For this purpose a compound or mixture of compounds of formula I, or non-toxic, physiologically acceptable acid addition salt thereof, is administered orally or parenterally in a conventional dosage form such as tablet, capsule, injectable or the like. A single dose, or preferably
2 to 4 divided daily doses, provided on ~ basis of about 1 to 50 mg. per kilogram per day, preferably about 2 to 15 mg. per . kilogram per day, is appropriate. A conventional dosage in oral or parenteral form is compoundedby incorporating about 10 to 250 mg. per unit of dosage with conventional vehicle, excipient, binder, preservative, stabilizer, flavor or the like as called for by accepted pharmaceutical practice.
The following examples constitute preferred ~ embodiments and also illustrate how these and other members : of the group are produced. Simple variation of the reactants and substitution in the reaction sequences described below readily yield other compounds within the scope of the invention. All temperatures are in degrees celsius.
Example 1 7-Methyl-5-(4-methyl-1-piperazinyl)pyrido[3,4-b]pyrazine-8-carboxylic acid, ethyl ester a) 4,6-Dichloro-2-methyl-5-nitropyridine-3-carboxylic acid_ethyl ester :
~ 242 g. of 4,6-dihydroxy-2-methyl-5-nitropyridine-: 3-carboxylic acid ethyl ester (1 mol.) are heated at 120 ;
~ with 500 ml. of phosphorus oxychloride for 3 hours. After - this time, the excess phosphorus oxychloride is removed - in vacuo and the black residue is decomposed by pouring ; into ice-water. About 1 liter of chloroform is added and the ~, .:: .
~ 30 mixture is filtered to remove undissolved material. The '' ~
' ' ,'~:
~, ~5)36605 organic layer is separated and the aqueous phase is extracted twice with 100 ml. portions of chloroform. The extract is dried over calcium chloride, filtered and evaporated to dryness. The resulting oil is crystallized with about 500 ml. of petroleum ether yielding 153 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (55~);
m.p. 45-46.
b)_ 4-Chloro-2-methY1~6-(4-methYl-l-PiPeraz nyl)-5-nitro-PYridine-3-carboxylic acid ethyl ester 55.8 g. of 4,6-dichloro-2-methyl-5-nitropyridine- ~ -
The following examples constitute preferred ~ embodiments and also illustrate how these and other members : of the group are produced. Simple variation of the reactants and substitution in the reaction sequences described below readily yield other compounds within the scope of the invention. All temperatures are in degrees celsius.
Example 1 7-Methyl-5-(4-methyl-1-piperazinyl)pyrido[3,4-b]pyrazine-8-carboxylic acid, ethyl ester a) 4,6-Dichloro-2-methyl-5-nitropyridine-3-carboxylic acid_ethyl ester :
~ 242 g. of 4,6-dihydroxy-2-methyl-5-nitropyridine-: 3-carboxylic acid ethyl ester (1 mol.) are heated at 120 ;
~ with 500 ml. of phosphorus oxychloride for 3 hours. After - this time, the excess phosphorus oxychloride is removed - in vacuo and the black residue is decomposed by pouring ; into ice-water. About 1 liter of chloroform is added and the ~, .:: .
~ 30 mixture is filtered to remove undissolved material. The '' ~
' ' ,'~:
~, ~5)36605 organic layer is separated and the aqueous phase is extracted twice with 100 ml. portions of chloroform. The extract is dried over calcium chloride, filtered and evaporated to dryness. The resulting oil is crystallized with about 500 ml. of petroleum ether yielding 153 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (55~);
m.p. 45-46.
b)_ 4-Chloro-2-methY1~6-(4-methYl-l-PiPeraz nyl)-5-nitro-PYridine-3-carboxylic acid ethyl ester 55.8 g. of 4,6-dichloro-2-methyl-5-nitropyridine- ~ -
3-carboxylic acid ethyl ester (0.2 mol.) are dissolved in 300 ml. of alcohol. After addition of 25 g. of triethylamine (0.25 mol.), the mixture is heated at reflux temperature and then 20 g. of N-methylpiperazine are dropped in with stirring.
When the addition is completed, the temperature is maintained for 30 minutes. The solvent is distilled off, the residue is ; dissolved in benzene and the precipitated triethylammonium chloride filtered off. After evaporation of the solvent, ~ the residual 4-chloro-2-methyl-6-(4-methyl-1-piperazinyl)-5-- 20 nitropyridine-3-carboxylic acid ethyl ester is recrystallized from methanol, yield 40 g. (60%), m.p. 59-61.
c) 4-Amino-2-methYl-6-(4-methyl-l-piperazinyl)-5-nitropyridine 3-carboxylic acid ethyl ester 33.3 g. of 4-chloro-2-methyl-6-(4-methyl-1-pipera-zinyl)-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 mol) are dissolved in about 100 ml. of alcohol. 50 ml. of aqueous ammonia solution (30~) are added and the mixture is heated in an autoclave at 80 for 10 hours. After this time, the solution is evaporated to dryness and the residue is extracted with hot alcohol. On cooling, 25.2 g. of 4-amino-2-methyl-:, .
, . - . -- - . , .
. ........... . . .
- - : .
. .. . : .
1~366(~5 6-(4-methyl-1-piperazinyl)-5-nitropyridine-3-carboxylic acid ethyl ester precipitate, (78%), m.p. 73-75 (methanol).
d) 4,5-Diamino-2-methyl-6-(4-methyl-1-piperazinylpyridine-3-carboxylic acid ethyl ester 25.2 g. of 4-amino-2-methyl-6-(4-methyl-1-piperazinyl)-5-nitropyridine-3-carboxylic acid ethyl ester (0.078 mol.) are dissolved in 100 ml. of butyl alcohol and 0.5 g. of palladium on charcoal are added. The mixture is hydrogenated at 80 and a hydrogen pressure of 2 atmos. After 4 hours, the reaction is complete. The catalyst is filtered off and the solvent removed. The remaining oil comprising 4,5-diamino-2-methyl-6-(4-methyl-1-piperazinyl)pyridine-3-carboxylic acid ethyl ester is not purified further.
e) 7-MethYl-5-(4-methYl-l-Piperazinyl)pyrido[3,4-b]pyrazine-8-carboxylic acid ethyl ester .~ , .
2.9 g. of 4,5-diamino-2-methyl-6-(4-methyl-1-piperazinyl)-pyridine-3-carboxylic acid ethyl ester (O.Ol mol.) are dissolved in~
I0 ml. of toluene and 1 g. of glyoxal monohydrate is added.
The mixture is refluxed for 8 hours with stirring. The .: . .
~ 20 solvent is distilled off and the black residue is extracted ; with benzene after charcoal has been added. The benzene layer `
is evaporated and the residue distilled in vacuo. The 7-methyl-5-(4-methyl-l-piperazinyl)pyrido[3~4rb]pyrazine-8-carboxylic acid ethyl ester boils at 200 (0.05mm), yield 18 g. (56%).
f) 7-MethYl-5-(4-methYl-l-piperazinyl)pyrido[3,4-b]pyrazine-8-carboxylic acid .
10 gm. of 7-methyl-5-(4-methyl-1-piperazinyl)pyrido- ~ ;
[3,4-b]pyrazine-8-carboxylic acid ethyl ester are hydrolyzed with dilute sodium hydroxide solution to obtain 7-methyl-5-;
: ~ -g- .: ::
.:. .
:''.
- . :. ~ . . . . :
. ~ .: - . , . :
1~)36ti0s (4-methyl-1-piperazinyl)pyrido[3,4-b]pyrazine-8-carboxylic acid.
Example 2 .
- 7-Methyl-5-~1-piperidinyl)pyrido[3,4-b]pyrazine-8-carboxylic acid ethyl ester By substituting piperidine for N-methylpiperazine -in Example 1 b and the resulting 4-chloro-2-methyl-6-(1-piperidinyl)-5-nitropyridine-3-carboxylic acid ethyl ester -is processed according to the procedure in Example 1 c-e, 7-methyl-5-(1-piperidinyl)pyrido[3,4-b]pyrazine-B-carboxylic acid ethyl ester is obtained, m.p. 73-74 (petroleum ether).
Example 3 7-Methyl-5-(4-phenyl-l-piperazinyl)pyrido[3/4-b]pyrazine 8-carboxylic acid ethyl ester - By substituting N-phenylpiperazine for N-methyl-piperazine in Example 1 b and the resulting 4-chloro-2-methyl-6-(4-phenyl-1-piperazinyl)-5-nitropyridine-3-carboxylic acid ethyl ester is processed as described in Example 1 c-e, 7-methyl-5-(4-phenyl-1-piperazinyl)pyrido-[3,4-b]pyrazine-8-carboxylic acid ethyl ester is formed, m.p. 85-87 (ligroin).
Example 4 5-Butylamino 7-methylpyrido[3/4-b]pyraziner8-carboxylic acid ethyl ester a) 6-Chloro-4[(1,1-dimethylethyl)amino]-2-methyl-5-nitro-pyridine-3-carboxylic acid ethyl ester 55.8 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-;. carboxylic acid ethyl ester (0.2 mol.) are dissolved in 300 ml. of alcohol and 25 g. of triethylamine. At reflux temperature, 14.6 g. of tert. butylamine are slowly added .:
16)366~S
dropwise-and the mixture is heated with stirring for an additional 30 minutes. The solvent is distilled off in vacuo and the residue is dissolved in benzene. The precipitated triethylamine hydrochloride is filtered off and the benzene layer is evaporated to dryness. The remaining oil, 6-chloro-
When the addition is completed, the temperature is maintained for 30 minutes. The solvent is distilled off, the residue is ; dissolved in benzene and the precipitated triethylammonium chloride filtered off. After evaporation of the solvent, ~ the residual 4-chloro-2-methyl-6-(4-methyl-1-piperazinyl)-5-- 20 nitropyridine-3-carboxylic acid ethyl ester is recrystallized from methanol, yield 40 g. (60%), m.p. 59-61.
c) 4-Amino-2-methYl-6-(4-methyl-l-piperazinyl)-5-nitropyridine 3-carboxylic acid ethyl ester 33.3 g. of 4-chloro-2-methyl-6-(4-methyl-1-pipera-zinyl)-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 mol) are dissolved in about 100 ml. of alcohol. 50 ml. of aqueous ammonia solution (30~) are added and the mixture is heated in an autoclave at 80 for 10 hours. After this time, the solution is evaporated to dryness and the residue is extracted with hot alcohol. On cooling, 25.2 g. of 4-amino-2-methyl-:, .
, . - . -- - . , .
. ........... . . .
- - : .
. .. . : .
1~366(~5 6-(4-methyl-1-piperazinyl)-5-nitropyridine-3-carboxylic acid ethyl ester precipitate, (78%), m.p. 73-75 (methanol).
d) 4,5-Diamino-2-methyl-6-(4-methyl-1-piperazinylpyridine-3-carboxylic acid ethyl ester 25.2 g. of 4-amino-2-methyl-6-(4-methyl-1-piperazinyl)-5-nitropyridine-3-carboxylic acid ethyl ester (0.078 mol.) are dissolved in 100 ml. of butyl alcohol and 0.5 g. of palladium on charcoal are added. The mixture is hydrogenated at 80 and a hydrogen pressure of 2 atmos. After 4 hours, the reaction is complete. The catalyst is filtered off and the solvent removed. The remaining oil comprising 4,5-diamino-2-methyl-6-(4-methyl-1-piperazinyl)pyridine-3-carboxylic acid ethyl ester is not purified further.
e) 7-MethYl-5-(4-methYl-l-Piperazinyl)pyrido[3,4-b]pyrazine-8-carboxylic acid ethyl ester .~ , .
2.9 g. of 4,5-diamino-2-methyl-6-(4-methyl-1-piperazinyl)-pyridine-3-carboxylic acid ethyl ester (O.Ol mol.) are dissolved in~
I0 ml. of toluene and 1 g. of glyoxal monohydrate is added.
The mixture is refluxed for 8 hours with stirring. The .: . .
~ 20 solvent is distilled off and the black residue is extracted ; with benzene after charcoal has been added. The benzene layer `
is evaporated and the residue distilled in vacuo. The 7-methyl-5-(4-methyl-l-piperazinyl)pyrido[3~4rb]pyrazine-8-carboxylic acid ethyl ester boils at 200 (0.05mm), yield 18 g. (56%).
f) 7-MethYl-5-(4-methYl-l-piperazinyl)pyrido[3,4-b]pyrazine-8-carboxylic acid .
10 gm. of 7-methyl-5-(4-methyl-1-piperazinyl)pyrido- ~ ;
[3,4-b]pyrazine-8-carboxylic acid ethyl ester are hydrolyzed with dilute sodium hydroxide solution to obtain 7-methyl-5-;
: ~ -g- .: ::
.:. .
:''.
- . :. ~ . . . . :
. ~ .: - . , . :
1~)36ti0s (4-methyl-1-piperazinyl)pyrido[3,4-b]pyrazine-8-carboxylic acid.
Example 2 .
- 7-Methyl-5-~1-piperidinyl)pyrido[3,4-b]pyrazine-8-carboxylic acid ethyl ester By substituting piperidine for N-methylpiperazine -in Example 1 b and the resulting 4-chloro-2-methyl-6-(1-piperidinyl)-5-nitropyridine-3-carboxylic acid ethyl ester -is processed according to the procedure in Example 1 c-e, 7-methyl-5-(1-piperidinyl)pyrido[3,4-b]pyrazine-B-carboxylic acid ethyl ester is obtained, m.p. 73-74 (petroleum ether).
Example 3 7-Methyl-5-(4-phenyl-l-piperazinyl)pyrido[3/4-b]pyrazine 8-carboxylic acid ethyl ester - By substituting N-phenylpiperazine for N-methyl-piperazine in Example 1 b and the resulting 4-chloro-2-methyl-6-(4-phenyl-1-piperazinyl)-5-nitropyridine-3-carboxylic acid ethyl ester is processed as described in Example 1 c-e, 7-methyl-5-(4-phenyl-1-piperazinyl)pyrido-[3,4-b]pyrazine-8-carboxylic acid ethyl ester is formed, m.p. 85-87 (ligroin).
Example 4 5-Butylamino 7-methylpyrido[3/4-b]pyraziner8-carboxylic acid ethyl ester a) 6-Chloro-4[(1,1-dimethylethyl)amino]-2-methyl-5-nitro-pyridine-3-carboxylic acid ethyl ester 55.8 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-;. carboxylic acid ethyl ester (0.2 mol.) are dissolved in 300 ml. of alcohol and 25 g. of triethylamine. At reflux temperature, 14.6 g. of tert. butylamine are slowly added .:
16)366~S
dropwise-and the mixture is heated with stirring for an additional 30 minutes. The solvent is distilled off in vacuo and the residue is dissolved in benzene. The precipitated triethylamine hydrochloride is filtered off and the benzene layer is evaporated to dryness. The remaining oil, 6-chloro-
4{(1,1-dimethylethyl)amino]-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester crystallizes with methanol, yield 38.4 g. (61%), m.p. 40-43.
b) 4-Amino-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester 31.6 g. of 6-chloro-4[(1,1-dimethylethyl)amino]-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 mol.) are heated with stirring at 250-260 for 5 minutes. The - dark oil is cooled to room temperature and 50 ml. of methyl alcohol are added. 18.2 g. of 4-amino-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester crystallize on cooling (70%), m.p. 89-91 (methanol).
c) 4-Amino-6-butvlamino-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester 26 g. of 4-amino-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 mol.) in 300 ml. of . alcohol and 15 g. of triethylamine are treated with 7.3 g.
of butylamine for 30 minutes at reflux temperature. After this time, the solution is evaporated to dryness and 100 ml.
of ethyl acetate are added to the residue. The triethyl-ammonium chloride is filtered off, the solvent is evaporated and the remaining oil recrystallized from methanol. The yield of 4-amino-6-butylamino-2-methyl-5-nitropyridine-3-.... .
carboxylic acid ethyl ester is 25 g. (84%), m.p. 74-76 (methanol).
--11 -- .
~ la3660s d) 4,5-~iamino-6-butylamino-2-methYlPYridine-3-carboxYlic acid ethyl ester -.,: . .
6 g. of 4-Amino-6-butylamino-2-methyl-5-nitro-pyridine-3-carboxylic acid ethyl ester are hydrogenated in .; . .
butyl alcohol with 0.1 g. of palladium on charcoal at 90 ``
and 2 atmos. hydrogen pressure for 3 h~urs. The catalyst is filtered off, the butyl alcohol is removed and the residual 4,5-diamino-6-butylamino-2-methylpyridine-3-carboxylia acid ethyl ester is recrystallized from ethyl acetate, yield
b) 4-Amino-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester 31.6 g. of 6-chloro-4[(1,1-dimethylethyl)amino]-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 mol.) are heated with stirring at 250-260 for 5 minutes. The - dark oil is cooled to room temperature and 50 ml. of methyl alcohol are added. 18.2 g. of 4-amino-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester crystallize on cooling (70%), m.p. 89-91 (methanol).
c) 4-Amino-6-butvlamino-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester 26 g. of 4-amino-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 mol.) in 300 ml. of . alcohol and 15 g. of triethylamine are treated with 7.3 g.
of butylamine for 30 minutes at reflux temperature. After this time, the solution is evaporated to dryness and 100 ml.
of ethyl acetate are added to the residue. The triethyl-ammonium chloride is filtered off, the solvent is evaporated and the remaining oil recrystallized from methanol. The yield of 4-amino-6-butylamino-2-methyl-5-nitropyridine-3-.... .
carboxylic acid ethyl ester is 25 g. (84%), m.p. 74-76 (methanol).
--11 -- .
~ la3660s d) 4,5-~iamino-6-butylamino-2-methYlPYridine-3-carboxYlic acid ethyl ester -.,: . .
6 g. of 4-Amino-6-butylamino-2-methyl-5-nitro-pyridine-3-carboxylic acid ethyl ester are hydrogenated in .; . .
butyl alcohol with 0.1 g. of palladium on charcoal at 90 ``
and 2 atmos. hydrogen pressure for 3 h~urs. The catalyst is filtered off, the butyl alcohol is removed and the residual 4,5-diamino-6-butylamino-2-methylpyridine-3-carboxylia acid ethyl ester is recrystallized from ethyl acetate, yield
5.0 g., m.p. 66-68.
e) 5-ButYlamino-7-methylpyrido[3,4-b]pyrazine-8-carboxylic acid ethyl ester 2.6 g. of 4,5-diamino-6-butylamino-2-methylpyridine-3-carboxylic acid ethyl ester and 1 g. of glyoxal monohydrate are refluxed for 5 hours in toluene with stirring. The .,~ ~ . ;
- mixture is evaporated to dryness and after addition of charcoal : .
;; the residue is extracted with boiling ligroin. The charcoal is filtered off and the 5-n-butylamino-7-methylpyrido[3,4-b]- ;
- .
pyrazine-8-carboxylic acid ethyl ester crystallizes on :: .
cooling, yield 1.9 g. (65%), m.p. 50-52 (ligroin). Treatment ` of this product with one equivalent of dilute hydrochloric acid yields 5-butylamino-7-methylpyrido[3,4-b]pyrazine-8-carboxylic acid ethyl ester, hydrochloride! The toluene-; sulfonate is similarly obtained using toluenesulfonic acid.
, . . .
Example 5 5-(3-dimethylaminoProPyl)amino-7-methylpyrido[3,4-b]pyrazine~
~` 8-carboxylic acid t~l ester . . .
By substituting for butylamine in Example 4 c ` (3-dimethylamino)propylamine, 4-amino-6-(3-dimethylamino-propyl)amino-2-methyl-5-nitropyridine-3-carboxylic acid ethyl .,.. ~
.
-12- ~ ~
.
10366(~5 - . ester is obtained which is then processed as described in Example 4 d - e. 5-(3-dimethylaminopropyl)amino-7-methylpyrido[3,4-b]pyrazine-8-carboxylic acid ethyl ester is formed, m.p. 55-57 (ligroin).
The ollowing additional products are obtained - by the procedure of Example 1:' -,' :-:: 10 , .:' ' ' ~ :
'`. ' ' :
''.~. ' ' .. ` ' ' ,' .
. ' .
'' ~' ... .
- . : : . . , ~ :
: .; ,.. . .: . :
1 .
. ¦ 11 l N ~ ~ N ~j ' . ~"' ' ', '.
¦ \ Ss / l b ~ b b ,, l l ~; ~ ~ c,)N
~I
~ ~ o . ~ .. . : .
.
`::" . . : .
,.' . ` 10366QS
. .
: ~ ~ .
.. U~ ~
,: ' : ' :' ..:
. ,~ . . .
10 ' ., , ' , -.......... , ~ ~-~ ~ U~
:, ~
-.~. ' ~ ' . :::
. ;' -::
.., .... . , ..~
~ ~ N
.., ::
~1 ~ 5~ U C ~ ~N ~
. ,.' . . ';' '.
., ~.,, '. ` . ' " : .
~. ~ ' . ,' .
3 0 Iq ~ ~ ~D ,,al ,, o ' .
. ..
; -15-;: - . . . . - . ` - - , -, . .
,. . .
.' . .' ~, X
'' ~
. . '' .: '-, '.
;
., ~) ~ N
, ~ ,'' ' '~
`,.,' ''~
.,~', . ' . ' '.
~ !
.,., . ' ~
'~' . ^,"
. ' ~
~ y, --I h Z ..
<
.' . . , ,'' "; .
.
.. , ~ .
':'' . :-,` . :
3 n x N
.' t~
.'. ' . . .
. .-: , - . , - :. . ~` :; .: -`' .
.: ~ :c ~ r .
.:
1 ;;
., .. :''. :.
'~ 10 .~ :~
~ ~ Z ~ ~ ~ ~ N
.- '~
,. . ;'' ' ; ' . ..
~ .
O ~
~N -- ;
.. t~ z rr) ~ N
~z~ æ
. ''.'' :,.,, . ' .:
N N N N N
~' . ' ~:,''' ' ., . ' ~.
"~ ~: ' 3 0 x ~ ~ o ,, ~ ~
.. r}J N ~ . . . : ~ .
' ' :. ''.~' . .:
- ' .: : . ,, :' ',: ,.' . . ~. . . ' ' : ~ ' , ; . . ' . :
. , ~ ,, . . . . . - . . . . . .
`: lQ3~iiO~
.`
',.' ~. .
,.
.' ~ ~
,:,. " . ~ ' , '~ '~
:, U~
... ~ ~ ~ r~
, , '.
:. .
.' :
,~ ~
N U
~
~-1 N Z~ J ; ' ''' ::;;
u~ In ~
U~
,.',.," ' .
.,',.
. .
:
.". ,~
30 ~s~ ~
~.,, . ~, . , .. . ~ ., . ,.. , ~..... . . . . ..
:
,
e) 5-ButYlamino-7-methylpyrido[3,4-b]pyrazine-8-carboxylic acid ethyl ester 2.6 g. of 4,5-diamino-6-butylamino-2-methylpyridine-3-carboxylic acid ethyl ester and 1 g. of glyoxal monohydrate are refluxed for 5 hours in toluene with stirring. The .,~ ~ . ;
- mixture is evaporated to dryness and after addition of charcoal : .
;; the residue is extracted with boiling ligroin. The charcoal is filtered off and the 5-n-butylamino-7-methylpyrido[3,4-b]- ;
- .
pyrazine-8-carboxylic acid ethyl ester crystallizes on :: .
cooling, yield 1.9 g. (65%), m.p. 50-52 (ligroin). Treatment ` of this product with one equivalent of dilute hydrochloric acid yields 5-butylamino-7-methylpyrido[3,4-b]pyrazine-8-carboxylic acid ethyl ester, hydrochloride! The toluene-; sulfonate is similarly obtained using toluenesulfonic acid.
, . . .
Example 5 5-(3-dimethylaminoProPyl)amino-7-methylpyrido[3,4-b]pyrazine~
~` 8-carboxylic acid t~l ester . . .
By substituting for butylamine in Example 4 c ` (3-dimethylamino)propylamine, 4-amino-6-(3-dimethylamino-propyl)amino-2-methyl-5-nitropyridine-3-carboxylic acid ethyl .,.. ~
.
-12- ~ ~
.
10366(~5 - . ester is obtained which is then processed as described in Example 4 d - e. 5-(3-dimethylaminopropyl)amino-7-methylpyrido[3,4-b]pyrazine-8-carboxylic acid ethyl ester is formed, m.p. 55-57 (ligroin).
The ollowing additional products are obtained - by the procedure of Example 1:' -,' :-:: 10 , .:' ' ' ~ :
'`. ' ' :
''.~. ' ' .. ` ' ' ,' .
. ' .
'' ~' ... .
- . : : . . , ~ :
: .; ,.. . .: . :
1 .
. ¦ 11 l N ~ ~ N ~j ' . ~"' ' ', '.
¦ \ Ss / l b ~ b b ,, l l ~; ~ ~ c,)N
~I
~ ~ o . ~ .. . : .
.
`::" . . : .
,.' . ` 10366QS
. .
: ~ ~ .
.. U~ ~
,: ' : ' :' ..:
. ,~ . . .
10 ' ., , ' , -.......... , ~ ~-~ ~ U~
:, ~
-.~. ' ~ ' . :::
. ;' -::
.., .... . , ..~
~ ~ N
.., ::
~1 ~ 5~ U C ~ ~N ~
. ,.' . . ';' '.
., ~.,, '. ` . ' " : .
~. ~ ' . ,' .
3 0 Iq ~ ~ ~D ,,al ,, o ' .
. ..
; -15-;: - . . . . - . ` - - , -, . .
,. . .
.' . .' ~, X
'' ~
. . '' .: '-, '.
;
., ~) ~ N
, ~ ,'' ' '~
`,.,' ''~
.,~', . ' . ' '.
~ !
.,., . ' ~
'~' . ^,"
. ' ~
~ y, --I h Z ..
<
.' . . , ,'' "; .
.
.. , ~ .
':'' . :-,` . :
3 n x N
.' t~
.'. ' . . .
. .-: , - . , - :. . ~` :; .: -`' .
.: ~ :c ~ r .
.:
1 ;;
., .. :''. :.
'~ 10 .~ :~
~ ~ Z ~ ~ ~ ~ N
.- '~
,. . ;'' ' ; ' . ..
~ .
O ~
~N -- ;
.. t~ z rr) ~ N
~z~ æ
. ''.'' :,.,, . ' .:
N N N N N
~' . ' ~:,''' ' ., . ' ~.
"~ ~: ' 3 0 x ~ ~ o ,, ~ ~
.. r}J N ~ . . . : ~ .
' ' :. ''.~' . .:
- ' .: : . ,, :' ',: ,.' . . ~. . . ' ' : ~ ' , ; . . ' . :
. , ~ ,, . . . . . - . . . . . .
`: lQ3~iiO~
.`
',.' ~. .
,.
.' ~ ~
,:,. " . ~ ' , '~ '~
:, U~
... ~ ~ ~ r~
, , '.
:. .
.' :
,~ ~
N U
~
~-1 N Z~ J ; ' ''' ::;;
u~ In ~
U~
,.',.," ' .
.,',.
. .
:
.". ,~
30 ~s~ ~
~.,, . ~, . , .. . ~ ., . ,.. , ~..... . . . . ..
:
,
Claims (46)
1. A process for the preparation of a compound of the formula wherein R, R3, R4 and R5 each is hydrogen or lower alkyl, R1 and R2 each is hydrogen, lower alkyl, lower alkanoyl, di(lower alkyl-amino)lower alkyl, or is an unsubstituted or substituted heterocyclic of the group consisting of piperidinyl and pipera-zinyl; wherein the substituted heterocyclic bears a hydroxy-lower alkyl, one or two lower alkyl or a phenyl group; or an acid addition salt thereof, which comprises reacting a compound of the formula with a 1,2-diketone of the formula wherein R, R1, R2, R3, R4 and R5 have the meaning stated above, and recovering the desired compound or an acid addition salt thereof.
2. The process as in claim 1 wherein R is hydrogen.
3. The process as in claim 1 wherein R is lower alkyl.
4. The process as in claim 1 wherein R is lower alkyl of 1 to 4 carbon atoms.
5. The process as in claim 1 wherein R1 is hydrogen.
6. The process as in claim 1 wherein R1 is lower alkyl.
7. The process as in claim 1 wherein R1 is lower alkyl of 1 to 4 carbon atoms.
8. The process as in claim 1 wherein R1 is di(lower alkylamino)lower alkyl.
9. The process as in claim 1 wherein R2 is hydrogen.
10. The process as in claim 1 wherein R2 is lower alkyl.
11. The process as in claim 1 wherein R2 is lower alkyl of 1 to 4 carbon atoms.
12. The process as in claim 1 wherein R2 is di(lower alkylamino)lower alkyl.
13. The process as in claim 1 wherein is N-(lower alkyl)piperazinyl.
14. The process as in claim 1 wherein is piperidinyl.
15. The process as in claim 1 wherein is 4-phenylpiperazinyl.
16. The process as in claim 1 wherein R3 is lower alkyl.
17. The process as in claim 1 wherein R4 is hydrogen.
18. The process as in claim 1 wherein R5 is hydrogen.
19. The process as in claim 1 wherein R is ethyl, R4 and R5 each is hydrogen, is 4-methyl-1-piperazinyl and R3 is methyl.
20. The process as in claim 1 wherein R is ethyl, R4 and R5 each is hydrogen, is piperidinyl and R3 is methyl.
21. The process as in claim 1 wherein R is ethyl, R4 and R5 each is hydrogen, is 4-phenyl-1-piperazinyl and R3 is methyl.
22. The process as in claim 1 wherein R is ethyl, R1, R4 and R5 each is hydrogen, R2 is butyl and R3 is methyl.
23. The process as in claim 1 wherein R is ethyl, R1, R4 and R5 each is hydrogen, R2 is 3-dimethylaminopropyl and R3 is methyl.
24. A compound of the formula wherein R, R3, R4 and R each is hydrogen or lower alkyl;
R1 and R2 each is hydrogen, lower alkyl, lower alkanoyl, di(lower alkylamino)lower alkyl, of is an unsubsti-tuted or substituted heterocyclic of the group consisting of piperidinyl and piperazinyl; wherein the substituted hetero-cyclic bears a hydroxy-lower alkyl, one or two lower alkyl or a phenyl group; or an acid addition salt thereof, whenever prepared by the process of claim 1.
R1 and R2 each is hydrogen, lower alkyl, lower alkanoyl, di(lower alkylamino)lower alkyl, of is an unsubsti-tuted or substituted heterocyclic of the group consisting of piperidinyl and piperazinyl; wherein the substituted hetero-cyclic bears a hydroxy-lower alkyl, one or two lower alkyl or a phenyl group; or an acid addition salt thereof, whenever prepared by the process of claim 1.
25. A compound as in claim 24 wherein R is hydrogen, whenever prepared by the process of claim 2.
26. A compound as in claim 24 wherein R is lower alkyl, whenever prepared by the process of claim 3.
27. A compound as in claim 24 wherein R is lower alkyl of 1 to 4 carbon atoms, whenever prepared by the process of claim 4.
28. A compound as in claim 24 wherein R1 is hydrogen, whenever prepared by the process of claim 5.
29. A compound as in claim 24 wherein R1 is lower alkyl, whenever prepared by the process of claim 6.
30. A compound as in claim 24 wherein R1 is lower alkyl of 1 to 4 carbon atoms, whenever prepared by the process of claim 7.
31. A compound as in claim 24 wherein R1 is di(lower alkylamino)lower alkyl, whenever prepared by the process of claim 8.
32. A compound as in claim 24 wherein R2 is hydrogen, whenever prepared by the process of claim 9.
33. A compound as in claim 24 wherein R2 is lower alkyl, whenever prepared by the process of claim 10.
34. A compound as in claim 24 wherein R2 is lower alkyl of 1 to 4 carbon atoms, whenever prepared by the process of claim 11.
35. A compound as in claim 24 wherein R2 is di(lower alkylamino)lower alkyl, whenever prepared by the process of claim 12.
36. A compound as in claim 24 wherein is N-(lower alkyl)piperazinyl, whenever prepared by the process of claim 13.
37. A compound as in claim 24 wherein is piperidinyl, whenever prepared by the process of claim 14.
38. A compound as in claim 24 wherein is 4-phenylpiperazinyl, whenever prepared by the process of claim 15.
39. A compound as in claim 24 wherein R3 is lower alkyl, whenever prepared by the process of claim 16.
40. A compound as in claim 24 wherein R4 is hydrogen, whenever prepared by the process of claim 17.
41. A compound as in claim 24 wherein R5 is hydrogen, whenever prepared by the process of claim 18.
42. A compound as in claim 24 wherein R is ethyl, R4 and R5 each is hydrogen, is 4-methyl-1-piperazinyl and R3 is methyl, whenever prepared by the process of claim 19.
43. A compound as in claim 24 wherein R is ethyl, R4 and R5 each is hydrogen, is piperidinyl and R3 is methyl, whenever prepared by the process of claim 20.
44. A compound as in claim 24 wherein R is ethyl, R4 and R5 each is hydrogen, is 4-phenyl-1-piperazinyl and R3 is methyl, whenever prepared by the process of claim 21.
45. A compound as in claim 24 wherein R is ethyl, R1, R4 and R5 each is hydrogen, R2 is butyl and R3 is methyl, whenever prepared by the process of claim 22.
46. A compound as in claim 24 wherein R is ethyl, R1, R4 and R5 each is hydrogen, R2 is 3-dimethylaminopropyl and R3 is methyl, whenever prepared by the process of claim 23.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US49188474A | 1974-07-25 | 1974-07-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1036605A true CA1036605A (en) | 1978-08-15 |
Family
ID=23954069
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA230,146A Expired CA1036605A (en) | 1974-07-25 | 1975-06-25 | Amino derivatives of pyrido (3,4-b) pyrazine carboxylic acids and esters |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS5136495A (en) |
| CA (1) | CA1036605A (en) |
| DE (1) | DE2530681A1 (en) |
| FR (1) | FR2279405A1 (en) |
| GB (1) | GB1513432A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1197661B (en) * | 1982-07-22 | 1988-12-06 | Sandoz Ag | 1-Phenalkyl-4-imidazo:pyridyl or pyrido:pyrazinyl piperazine derivs. |
| GB201309508D0 (en) * | 2013-05-28 | 2013-07-10 | Redx Pharma Ltd | Compounds |
-
1975
- 1975-05-14 GB GB2037775A patent/GB1513432A/en not_active Expired
- 1975-06-25 CA CA230,146A patent/CA1036605A/en not_active Expired
- 1975-07-09 DE DE19752530681 patent/DE2530681A1/en not_active Withdrawn
- 1975-07-25 JP JP50091506A patent/JPS5136495A/en active Pending
- 1975-07-25 FR FR7523373A patent/FR2279405A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| FR2279405A1 (en) | 1976-02-20 |
| DE2530681A1 (en) | 1976-02-05 |
| GB1513432A (en) | 1978-06-07 |
| JPS5136495A (en) | 1976-03-27 |
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