CA1330802C - Process for the preparation of n,n'-bis-(alkoxyalkyl)-pyridine-2,4-dicarboxamides - Google Patents
Process for the preparation of n,n'-bis-(alkoxyalkyl)-pyridine-2,4-dicarboxamidesInfo
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- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
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- 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
- C07D213/81—Amides; Imides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
Abstract
Abstract of the disclosure:
An improved process for the preparation of N,N'-bis-(alkoxyalkyl)-pyridine-2,4-dicarboxamides The invention relates to an improved process for the preparation of N,N'-bis(alkoxyalkyl)-pyridine-2,4-di-carboxamides and to the use of these compounds for the preparation of pharmaceuticals which can be administered orally.
In the process according to the invention the compounds of the formula I
(I) in which R1 denotes C1-C4-alkyl which is monosubstituted by C1-C4-alkoxy are obtained by firstly A) reacting pyridine-2,4-dicarboxylic acid in toluene with a 2-3-fold excess of SOCl2 at temperatures of 90-110°C, dissolving the resulting intermediate in dioxane, and B) adding dioxane to 4 times the molar amount of alkoxyalkylamine of the formula II
An improved process for the preparation of N,N'-bis-(alkoxyalkyl)-pyridine-2,4-dicarboxamides The invention relates to an improved process for the preparation of N,N'-bis(alkoxyalkyl)-pyridine-2,4-di-carboxamides and to the use of these compounds for the preparation of pharmaceuticals which can be administered orally.
In the process according to the invention the compounds of the formula I
(I) in which R1 denotes C1-C4-alkyl which is monosubstituted by C1-C4-alkoxy are obtained by firstly A) reacting pyridine-2,4-dicarboxylic acid in toluene with a 2-3-fold excess of SOCl2 at temperatures of 90-110°C, dissolving the resulting intermediate in dioxane, and B) adding dioxane to 4 times the molar amount of alkoxyalkylamine of the formula II
Description
DeBcription 1 3 3 0 ~ ~ ~
An improved process for the preparstion of N,N'-bi~-(alko y alkyl)-pyridine-2,4-dicarboxAmides Compounds which inhibit proline hydroxyla~e and lysine hydroxylase bring about very selective inhibition of collagen biosynthesis by influencing the collagen-specific hydroxylation reactions. During these protein-bound proline or lysine is hydroxylated by the enzymes proline hydroxylase and lysine hydroxylase respectively.
If this reaction i~ ~uppressed by inhibitors, the col-lagen molecule which is produced is underhydroxylated nnd unable to function and can be released from the cells into the-extracellular ~pace only in small amount. ~ore-over, the underhydroxylated collagen cannot be incor-porated into the collagen matrix and very readily under~
goes proteolytic degradation. The consequence of these effects is an overall reduction in the amount of collagen deposited outside the cell.
It i~ known that inhibition of proline hydroxylase by known inhibitors such as ~,~'-dipyridyl results in inhibition of the Clq biosynthesi6 by macrophages (W. N~ller et al., FEBS Lett. 90 (1978), 218; Immuno-biology 155 (1978) 47). This leads to the classical pathway of complement activation becomin~ inoperative.
This is why inhibitors of proline hydroxylase also act as immuno~uppressants, for example in immune complex diseases.
It is known that proline hydroxylase i8 efficiently inhibited by pyridina-2,4- and -2,5-dicarboxylic acid (R. Ma~amaa et al., Eur. J. Biochem. 138 (1984) 239-245).
Howevex, ~hese compounds are effective inhibitors in the cell culture only in very high concQntrations (Tschank, G. et al., Biochem. J. 238, 625-633, 1987).
--- 2 - 1 3~
EP-A-o 176 741 describQs pyridine-2,4- and -2,5-dicar-boxylic diesters with 1-6 carbon atoms in the ester alkyl moiety a8 pharmaceuticals for inhiblting proline hy-droxylase and lysine hydroxylase.
However, these low-alkylated diesters have the disad-vantage that they are rapidly cleaved in the body to give the acids and do not re~ch their site of action in the cell in sufficiently high concentration, and thus are less suitable for possible ad~inistration as pharmaceuticals.
It has already been proposed (EP-A-O 278 453, EP-A-O 278 454, EP-A-O 278 452 and EP-A-O 281 94~)to use mixed ester~amides, higher alkylated diesters and di-amides of pyridine-2,4- and -2,5-dicarboxylic acid in order effectively to inhibit collagen biosynthesis in the animal model.
European Patent Application EP-A-0 278 453 propo~es inter alia the synthesis of N,N'-bis(2-~etho~yethyl)-pyrldine-2,~-d$carbox~m$de (III) ~ONH-CH2-CH2-0-CH3 ~ (IIl) N ~ CONH- N2-CH2-0-CH3 ~nd N,N'-bis(3-isopropoxypropyl)-pyridins-2,~-dicarboxamide (IV) CH
An improved process for the preparstion of N,N'-bi~-(alko y alkyl)-pyridine-2,4-dicarboxAmides Compounds which inhibit proline hydroxyla~e and lysine hydroxylase bring about very selective inhibition of collagen biosynthesis by influencing the collagen-specific hydroxylation reactions. During these protein-bound proline or lysine is hydroxylated by the enzymes proline hydroxylase and lysine hydroxylase respectively.
If this reaction i~ ~uppressed by inhibitors, the col-lagen molecule which is produced is underhydroxylated nnd unable to function and can be released from the cells into the-extracellular ~pace only in small amount. ~ore-over, the underhydroxylated collagen cannot be incor-porated into the collagen matrix and very readily under~
goes proteolytic degradation. The consequence of these effects is an overall reduction in the amount of collagen deposited outside the cell.
It i~ known that inhibition of proline hydroxylase by known inhibitors such as ~,~'-dipyridyl results in inhibition of the Clq biosynthesi6 by macrophages (W. N~ller et al., FEBS Lett. 90 (1978), 218; Immuno-biology 155 (1978) 47). This leads to the classical pathway of complement activation becomin~ inoperative.
This is why inhibitors of proline hydroxylase also act as immuno~uppressants, for example in immune complex diseases.
It is known that proline hydroxylase i8 efficiently inhibited by pyridina-2,4- and -2,5-dicarboxylic acid (R. Ma~amaa et al., Eur. J. Biochem. 138 (1984) 239-245).
Howevex, ~hese compounds are effective inhibitors in the cell culture only in very high concQntrations (Tschank, G. et al., Biochem. J. 238, 625-633, 1987).
--- 2 - 1 3~
EP-A-o 176 741 describQs pyridine-2,4- and -2,5-dicar-boxylic diesters with 1-6 carbon atoms in the ester alkyl moiety a8 pharmaceuticals for inhiblting proline hy-droxylase and lysine hydroxylase.
However, these low-alkylated diesters have the disad-vantage that they are rapidly cleaved in the body to give the acids and do not re~ch their site of action in the cell in sufficiently high concentration, and thus are less suitable for possible ad~inistration as pharmaceuticals.
It has already been proposed (EP-A-O 278 453, EP-A-O 278 454, EP-A-O 278 452 and EP-A-O 281 94~)to use mixed ester~amides, higher alkylated diesters and di-amides of pyridine-2,4- and -2,5-dicarboxylic acid in order effectively to inhibit collagen biosynthesis in the animal model.
European Patent Application EP-A-0 278 453 propo~es inter alia the synthesis of N,N'-bis(2-~etho~yethyl)-pyrldine-2,~-d$carbox~m$de (III) ~ONH-CH2-CH2-0-CH3 ~ (IIl) N ~ CONH- N2-CH2-0-CH3 ~nd N,N'-bis(3-isopropoxypropyl)-pyridins-2,~-dicarboxamide (IV) CH
3" ~ 3 (IV) N NH C~2-CH2-CH2-0-C~
However, either these compounds are produced in only very low yields (III about 5~ and I~ about 59~ yield based on pyridine-2,4-dicarboxylic acid used) or the processes proposed for the preparat:ion thereof are, in terms of C
~, :
, . . .
.
~ -- ,~ ~ , . .
~ 3 ~ 1 3 3 ~ 8 ~2 process technology, li~tle suited for m~ss production because, on the one hand, the preparation of the com-pounds compri~e~ too many synthetic steps and, on the other hand, production is rather energy-intensive (re-moval of SOC12 by distillation, evaporation to dryne~swith toluene, dropwise addition at -30 to -20C) and, finally, a chromatographic purification step is al~o nece~sary too.
A process which make~ it po~sible for compounds of the formula I
CONH-~ CONH-R
in which Rl denotes Cl-C~-alkyl which i~ ~ono~ubstituted by C,-C~-alkoxy to be ~ynthQsized in yields of over 70~
(based on pyridine-2,4-dicarboxylic acid used) and which i6 considerably les~ energy-intensiv~ than ~he process proposed in EP-A-0 278 453 and, in particular, makes do without a chromatographi~ purifi-cation, because th~ final product is obtained directly a~
20 a solid, has now be~n found.
The ~elected compounds Are able to be v~ry well ab~orbed in the intestine3, for which reason thay are particularly well suited for an oral administration form. The pharma-cological activity of the compound~ of the formula I
correspond~ to that of the ~ompvunds proposed in EP-A-O 278 453.
Hence the invention relhte~ to:
A proc~ss for the preparation of N,~'-bi~-(alkoxyalkyl)- `
pyridine-2,4-dic~rboxamides of th~ for~ul~ I
ONH- Rl -~ CONH-Rl (I) in which Rl denotes C,-C~-alkyl which i~ ~onosubstituted by A
-. . .
~ ~ . . . .
~ .
~ ~ 4 ~ ~3308~2 C~-C4-alkoxy, entailing reaction of pyridine-2,4-dicarbonyl chloride with an alkoxyalkylamine, which comprises firstly A) pyridine-2,4-dicarboxylic acid being suspended in toluene, a 2-3-fold molar exce~s of SOCl2 being added at room temperature, the mixture being heated at 90-110C
until evolution of gas cea~es, the clear solution being evaporated, and the resulting intermediate being dis-solved in dioxane, and B) dioxane being added to 4 tLmes the molar amount of alkoxyalkylamine of the formula II
H H-(R2~ oR3 (II) in which R2 denotes C,-C~-alkylene and R3 denotes Cl-C4-alkyl, and then, at a temperature of -5 to +5C, either the solution prepared as in A) being added dropwise to the ~olution prepared as in B), or the solution prepared as in B) being added dropwise to the solution prepared as in A), reaction subsequently being allow~d to take place at room temperature, and then the reaction product being acidi-fied, and subsequently the organic phase being separated off, washed with water, dried and then freed of solven~.
The said alkyl and alkoxy radicals having 3 and more carbon atoms can be both straight-chain and branched. A
C1-C~-alkylene radical means methylene, ethylene, n-propylene or n-butylene, as well as alkyl-substituted alkylenes. ~xamples of these are methylmethylene, ethyl-methylene, n-propylmethylene, i-propylmethylene, methyl-ethylene or ethylethylene.
In the proces6 according to the invention the pyridine-2,4-dicarboxylic acid, which can be bought as starting ~ubstance, ifi ~uspended in toluene, and SOCl2 i~ added at room temperature. 2-3-fold molar amounts of SOC12, prefer-ably 2-fold molar amount~, based on the molax amount of ;' ' ' ~' ' ~' ' , _ 5 _ 1 33 ~ ~ ~2 pyridine-2,4-dicarboxylic acid used, are used. The resulting reaction mixture iB heated at 90-110C, prefer-ably at 100C, until no more evolution of gaseous HCl i~
observable and a clear solution hs~ been produced. The solution is subsequently evaporated - preferably under high vacuum (down to about 10-3 ~orr) - and the re~ulting carbonyl ~hloride is then dissolved in dioxane.
Now 4 times the molar amount of commercially available alkoxyalkylamine (compound of the formula II), based on the molar amount of pyridine-2,4-dicarboxylic acid used, iB dis~olved in dioxane. The alkoxyalkylamine is then preferably added dropwise to the dissolved pyridine-2,4-dicarbonyl chloride. However, it i~ also possible to add the solution of the carbonyl chloride dropwise to the solution of the alkoxyalkylamine. In both cases the addition takes place at a temperature of -5 to +5C, preferably at 0C. The reaction mixture i8 then allowed to warm to room temperature and is fitirred for a further 2-5 hours, preferably 3 hours. The resulting product is then acidified in order to remove excess alkoxyalkylamine from the desired product. The acidification can be carried out, for example, with 0.2 molar citric acid. The organic phase i8 then ~eparated off and washed with water. The organic pha~e is subse~quently dried - prefer-ably over magnesium sulfate - and finally freed of solvent. The product - N,~'-bis(alkoxyalkyl)-pyridine-2,4-dicarboxamide - is obtained as a white solid when the solvent i8 removed.
It has been found that the compounds of the formula I are able to be exceptionally well absorbed in the intestines.
The ability to be absorbed wa~ investigated in Wistar rats which received intragastric administration of N,N'-bis-(2-methoxyethyl)pyridine-2,4-dicarboxamide.Theserum level fell in the first few hours after admini~tration of 3S the substance and, after about 5 hour~, reached a plat-eau, still with a slight decreasing trend. The initial very high seruM level immediately after administration of .~.
~ . .. - .. :
, - 6 - ~ 33 ~ 8 ~2 the substance Ruggests that the ~ubstance is able to be absorbed well.
The invention is explained in more detail hereinafter by means of examples.
Ability to be absorbed in the intestines Female Wi~tar rats of about 150 g body weight receive 50 mg~kg N,N'-bis(2-methoxyethyl)pyridine-2,4-dicarbox-amide admini6tered intragastrically by gavage. Group~ of 4 rats are anesthetized after 0, 0.25, 0.5, 1, 3, 4, 5, 6, 8 and 14 hours and exsanguinated via the vena cava.
The blood is immediately centrifuged and N,N'-bis(2-methoxyethyl)pyridine-2t4-dicarboxamide is extracted from the serum using ether. The ether is evaporated off and then the residue is taken up in 100 ml of mobile phase.
The mobile phase is composed of 0.05 N phosphoric acid and acetonitrile (4:1).
50 ~1 of this sample are in~ected into an HPLC column.
Detection takes place at W 200 nm and a retention time of 2.2 min. The re~ults are documented in Table 1 and Figure 1.
Table 1: Serum levels of N,N'-bis(2-methoxyethyl)pyri-dine-2,4-dicarboxamide after oral admini-~ration of 50 mg/kg Time (h) Serum 1eVQ18 ~g/ml 5D ~EM
0 . 2 53 8 . 7 ~ 2 . 2 1 . 6 0.5 32.4 ~ 3.1 2.1 15.6 1 1.5 3 0.7 ~ 0.07 0.04 4 3.3 ~ 2.2 1.6 0.5 ~ 0.3 0.2 6 ~.6 ~ 0.1 0.1 8 0.5 ~ 0.3 0.2 14 0.3 ~ 0.2 0.1 x = ~an of 4 me~surements .
. ~ , ~' ''- '' ~
..
. -~` _ 7 _ 133~802 SD = Standard deviation SEM = Standard error of the mean Example 1 Preparation of N,N'-bis(2-methoxyethyl)pyridine-2,4-dicarboxamide 10 g of pyridine-2,4-dicarboxylic acid are suspended in 150 ml of toluene, and 9.1 ml of SOC12 are added at room temperature. The reaction mixture is then heated at 100C
until the solution is clear and no further gas evolution 0 i8 observable. The solution i8 evaporated under high vacuum, the re~idue i8 dissolved in 100 ml of dioxane, and 21 ml of 2-methoxyethylamine in 100 ~1 of dioxane are added dropwi~e at 0C. After the solution has been ~tirred at room temperature for 3 hours, 0.2 M citric acid is added (pH 4), and the organic phase i~ sepArated off and washed with water. After the solution has been dried with magensium sulfate it i8 freed of ~olvent, yielding 12.8 g (76% yield based on pyridine-2,4-dicarboxylic acid~ of a white solid.
Nelting point 86C
` ' , - ' -: - ' , i , . .
However, either these compounds are produced in only very low yields (III about 5~ and I~ about 59~ yield based on pyridine-2,4-dicarboxylic acid used) or the processes proposed for the preparat:ion thereof are, in terms of C
~, :
, . . .
.
~ -- ,~ ~ , . .
~ 3 ~ 1 3 3 ~ 8 ~2 process technology, li~tle suited for m~ss production because, on the one hand, the preparation of the com-pounds compri~e~ too many synthetic steps and, on the other hand, production is rather energy-intensive (re-moval of SOC12 by distillation, evaporation to dryne~swith toluene, dropwise addition at -30 to -20C) and, finally, a chromatographic purification step is al~o nece~sary too.
A process which make~ it po~sible for compounds of the formula I
CONH-~ CONH-R
in which Rl denotes Cl-C~-alkyl which i~ ~ono~ubstituted by C,-C~-alkoxy to be ~ynthQsized in yields of over 70~
(based on pyridine-2,4-dicarboxylic acid used) and which i6 considerably les~ energy-intensiv~ than ~he process proposed in EP-A-0 278 453 and, in particular, makes do without a chromatographi~ purifi-cation, because th~ final product is obtained directly a~
20 a solid, has now be~n found.
The ~elected compounds Are able to be v~ry well ab~orbed in the intestine3, for which reason thay are particularly well suited for an oral administration form. The pharma-cological activity of the compound~ of the formula I
correspond~ to that of the ~ompvunds proposed in EP-A-O 278 453.
Hence the invention relhte~ to:
A proc~ss for the preparation of N,~'-bi~-(alkoxyalkyl)- `
pyridine-2,4-dic~rboxamides of th~ for~ul~ I
ONH- Rl -~ CONH-Rl (I) in which Rl denotes C,-C~-alkyl which i~ ~onosubstituted by A
-. . .
~ ~ . . . .
~ .
~ ~ 4 ~ ~3308~2 C~-C4-alkoxy, entailing reaction of pyridine-2,4-dicarbonyl chloride with an alkoxyalkylamine, which comprises firstly A) pyridine-2,4-dicarboxylic acid being suspended in toluene, a 2-3-fold molar exce~s of SOCl2 being added at room temperature, the mixture being heated at 90-110C
until evolution of gas cea~es, the clear solution being evaporated, and the resulting intermediate being dis-solved in dioxane, and B) dioxane being added to 4 tLmes the molar amount of alkoxyalkylamine of the formula II
H H-(R2~ oR3 (II) in which R2 denotes C,-C~-alkylene and R3 denotes Cl-C4-alkyl, and then, at a temperature of -5 to +5C, either the solution prepared as in A) being added dropwise to the ~olution prepared as in B), or the solution prepared as in B) being added dropwise to the solution prepared as in A), reaction subsequently being allow~d to take place at room temperature, and then the reaction product being acidi-fied, and subsequently the organic phase being separated off, washed with water, dried and then freed of solven~.
The said alkyl and alkoxy radicals having 3 and more carbon atoms can be both straight-chain and branched. A
C1-C~-alkylene radical means methylene, ethylene, n-propylene or n-butylene, as well as alkyl-substituted alkylenes. ~xamples of these are methylmethylene, ethyl-methylene, n-propylmethylene, i-propylmethylene, methyl-ethylene or ethylethylene.
In the proces6 according to the invention the pyridine-2,4-dicarboxylic acid, which can be bought as starting ~ubstance, ifi ~uspended in toluene, and SOCl2 i~ added at room temperature. 2-3-fold molar amounts of SOC12, prefer-ably 2-fold molar amount~, based on the molax amount of ;' ' ' ~' ' ~' ' , _ 5 _ 1 33 ~ ~ ~2 pyridine-2,4-dicarboxylic acid used, are used. The resulting reaction mixture iB heated at 90-110C, prefer-ably at 100C, until no more evolution of gaseous HCl i~
observable and a clear solution hs~ been produced. The solution is subsequently evaporated - preferably under high vacuum (down to about 10-3 ~orr) - and the re~ulting carbonyl ~hloride is then dissolved in dioxane.
Now 4 times the molar amount of commercially available alkoxyalkylamine (compound of the formula II), based on the molar amount of pyridine-2,4-dicarboxylic acid used, iB dis~olved in dioxane. The alkoxyalkylamine is then preferably added dropwise to the dissolved pyridine-2,4-dicarbonyl chloride. However, it i~ also possible to add the solution of the carbonyl chloride dropwise to the solution of the alkoxyalkylamine. In both cases the addition takes place at a temperature of -5 to +5C, preferably at 0C. The reaction mixture i8 then allowed to warm to room temperature and is fitirred for a further 2-5 hours, preferably 3 hours. The resulting product is then acidified in order to remove excess alkoxyalkylamine from the desired product. The acidification can be carried out, for example, with 0.2 molar citric acid. The organic phase i8 then ~eparated off and washed with water. The organic pha~e is subse~quently dried - prefer-ably over magnesium sulfate - and finally freed of solvent. The product - N,~'-bis(alkoxyalkyl)-pyridine-2,4-dicarboxamide - is obtained as a white solid when the solvent i8 removed.
It has been found that the compounds of the formula I are able to be exceptionally well absorbed in the intestines.
The ability to be absorbed wa~ investigated in Wistar rats which received intragastric administration of N,N'-bis-(2-methoxyethyl)pyridine-2,4-dicarboxamide.Theserum level fell in the first few hours after admini~tration of 3S the substance and, after about 5 hour~, reached a plat-eau, still with a slight decreasing trend. The initial very high seruM level immediately after administration of .~.
~ . .. - .. :
, - 6 - ~ 33 ~ 8 ~2 the substance Ruggests that the ~ubstance is able to be absorbed well.
The invention is explained in more detail hereinafter by means of examples.
Ability to be absorbed in the intestines Female Wi~tar rats of about 150 g body weight receive 50 mg~kg N,N'-bis(2-methoxyethyl)pyridine-2,4-dicarbox-amide admini6tered intragastrically by gavage. Group~ of 4 rats are anesthetized after 0, 0.25, 0.5, 1, 3, 4, 5, 6, 8 and 14 hours and exsanguinated via the vena cava.
The blood is immediately centrifuged and N,N'-bis(2-methoxyethyl)pyridine-2t4-dicarboxamide is extracted from the serum using ether. The ether is evaporated off and then the residue is taken up in 100 ml of mobile phase.
The mobile phase is composed of 0.05 N phosphoric acid and acetonitrile (4:1).
50 ~1 of this sample are in~ected into an HPLC column.
Detection takes place at W 200 nm and a retention time of 2.2 min. The re~ults are documented in Table 1 and Figure 1.
Table 1: Serum levels of N,N'-bis(2-methoxyethyl)pyri-dine-2,4-dicarboxamide after oral admini-~ration of 50 mg/kg Time (h) Serum 1eVQ18 ~g/ml 5D ~EM
0 . 2 53 8 . 7 ~ 2 . 2 1 . 6 0.5 32.4 ~ 3.1 2.1 15.6 1 1.5 3 0.7 ~ 0.07 0.04 4 3.3 ~ 2.2 1.6 0.5 ~ 0.3 0.2 6 ~.6 ~ 0.1 0.1 8 0.5 ~ 0.3 0.2 14 0.3 ~ 0.2 0.1 x = ~an of 4 me~surements .
. ~ , ~' ''- '' ~
..
. -~` _ 7 _ 133~802 SD = Standard deviation SEM = Standard error of the mean Example 1 Preparation of N,N'-bis(2-methoxyethyl)pyridine-2,4-dicarboxamide 10 g of pyridine-2,4-dicarboxylic acid are suspended in 150 ml of toluene, and 9.1 ml of SOC12 are added at room temperature. The reaction mixture is then heated at 100C
until the solution is clear and no further gas evolution 0 i8 observable. The solution i8 evaporated under high vacuum, the re~idue i8 dissolved in 100 ml of dioxane, and 21 ml of 2-methoxyethylamine in 100 ~1 of dioxane are added dropwi~e at 0C. After the solution has been ~tirred at room temperature for 3 hours, 0.2 M citric acid is added (pH 4), and the organic phase i~ sepArated off and washed with water. After the solution has been dried with magensium sulfate it i8 freed of ~olvent, yielding 12.8 g (76% yield based on pyridine-2,4-dicarboxylic acid~ of a white solid.
Nelting point 86C
` ' , - ' -: - ' , i , . .
Claims (8)
1. A process for the preparation of N,N'-bis-(alkoxyalkyl)-pyridine-2,4-dicarboxymides of the formula I
I) in which R1 denotes C1-C4-alkyl which is monosubstituted by C1-C4-alkoxy, entailing reaction of pyridine-2,4-dicarbonyl chloride with an alkoxyalkylamine, which comprises firstly A) pyridine-2,4-dicarboxylic acid being suspended in toluene, a 2-3-fold molar excess of SOCl2 being added at room temperature, the mixture being heated at 90-110°C
until evolution of gas ceases, the clear solution being evaporated, and the resulting intermediate being dis-solved in dioxane, and B) dioxane being added to 4 times the molar amount of alkoxyalkylamine of the formula II
(II) in which R1 is as defined above then, at a temperature of -5 to +5°C, either the solution of the intermediate prepared as in A) being added dropwise to the solution prepared as in B), or the solution prepared as in B) being added dropwise to the solution of the intermediate prepared as in A), reaction subsequently being allowed to take place at room temperature, and then the reaction product being acidified, and subsequently the organic phase being separated off, washed with water, dried and then freed of solvent.
I) in which R1 denotes C1-C4-alkyl which is monosubstituted by C1-C4-alkoxy, entailing reaction of pyridine-2,4-dicarbonyl chloride with an alkoxyalkylamine, which comprises firstly A) pyridine-2,4-dicarboxylic acid being suspended in toluene, a 2-3-fold molar excess of SOCl2 being added at room temperature, the mixture being heated at 90-110°C
until evolution of gas ceases, the clear solution being evaporated, and the resulting intermediate being dis-solved in dioxane, and B) dioxane being added to 4 times the molar amount of alkoxyalkylamine of the formula II
(II) in which R1 is as defined above then, at a temperature of -5 to +5°C, either the solution of the intermediate prepared as in A) being added dropwise to the solution prepared as in B), or the solution prepared as in B) being added dropwise to the solution of the intermediate prepared as in A), reaction subsequently being allowed to take place at room temperature, and then the reaction product being acidified, and subsequently the organic phase being separated off, washed with water, dried and then freed of solvent.
2. The process as claimed in claim 1, wherein a 2-fold molar excess of SOCl2 is used.
3. The process as claimed in claim 1, wherein the pyridine-2,4-dicarboxylic acid and the SOCl2 are heated at 100°C.
4. The process as claimed in claim 2, wherein the pyridine-2,4-dicarboxylic acid and the SOCl2 are heated at 100°C.
5. The process as claimed in any one of claims 1 to 4, wherein the solution prepared as in A) is added dropwise to the solution prepared as in B), or the solution prepared as in B) is added dropwise to the solution prepared as in A), at a temperature of 0°C.
6. The process as claimed in any one of claims l to 4, wherein the two solutions prepared as in A) and prepared as in B) are subsequently allowed to react at room temperature for 3 hours.
7. The process as claimed in any one of claims l to 4, wherein in the alkoxyalkylamine of the formula II
R1 denotes C1-C3-alkyl which is monosubstituted by C1-C3-alkoxy.
R1 denotes C1-C3-alkyl which is monosubstituted by C1-C3-alkoxy.
8. The process as claimed in any one of claims 1 to 4, wherein in the alkoxyalkylamine of the formula II
R1 denotes 2-methoxyethyl.
R1 denotes 2-methoxyethyl.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3826471.4 | 1988-08-04 | ||
| DE3826471A DE3826471A1 (en) | 1988-08-04 | 1988-08-04 | Improved process for the preparation of N,N'-bis(alkoxyalkyl)pyridine-2,4-dicarboximides |
| DE3828140A DE3828140A1 (en) | 1988-08-19 | 1988-08-19 | Improved process for the preparation of N,N'-bis(alkoxyalkyl)pyridine-2,4-dicarboxamides and use of these compounds for the preparation of orally administrable medicaments |
| DEP3828140.6 | 1988-08-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1330802C true CA1330802C (en) | 1994-07-19 |
Family
ID=25870814
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000607509A Expired - Fee Related CA1330802C (en) | 1988-08-04 | 1989-08-03 | Process for the preparation of n,n'-bis-(alkoxyalkyl)-pyridine-2,4-dicarboxamides |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0353668B1 (en) |
| JP (1) | JP2683423B2 (en) |
| KR (1) | KR0137789B1 (en) |
| AT (1) | ATE113036T1 (en) |
| AU (1) | AU615324B2 (en) |
| CA (1) | CA1330802C (en) |
| DE (1) | DE58908519D1 (en) |
| DK (1) | DK170748B1 (en) |
| ES (1) | ES2065355T3 (en) |
| HU (1) | HU208423B (en) |
| IE (1) | IE64673B1 (en) |
| IL (1) | IL91185A (en) |
| PT (1) | PT91361B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3703963A1 (en) * | 1987-02-10 | 1988-08-18 | Hoechst Ag | PYRIDINE-2,4- AND 2,, 5-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE THEREOF, AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
| DE3703959A1 (en) * | 1987-02-10 | 1988-08-18 | Hoechst Ag | PYRIDINE-2,4- AND 2,5-DICARBONIC ACID AMIDES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
| DE3703962A1 (en) * | 1987-02-10 | 1988-08-18 | Hoechst Ag | PYRIDINE-2,4- AND 2,5-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
| DE3707429A1 (en) * | 1987-03-07 | 1988-09-15 | Hoechst Ag | SUBSTITUTED PYRIDINE-2,4-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
| DE3924093A1 (en) * | 1989-07-20 | 1991-02-07 | Hoechst Ag | N, N'-BIS (ALKOXY-ALKYL) -PYRIDINE-2,4-DICARBONESAUREDIAMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| DE4031000A1 (en) * | 1990-10-01 | 1992-04-09 | Hoechst Ag | 4- OR 5-SUBSTITUTED PYRIDINE-2-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
| YU9492A (en) * | 1991-02-05 | 1995-03-27 | Hoechst Ag. | 2,4- and 2,5-BIS-TETRAZOLYL pyridines and the process for their preparation |
| TW199147B (en) * | 1991-03-18 | 1993-02-01 | Hoechst Ag | |
| EP0533130A1 (en) * | 1991-09-19 | 1993-03-24 | Hoechst Aktiengesellschaft | 2-Hydroxymethylpyridines, the corresponding pyridine-N-oxides and derivatives thereof, process for their preparation and their use |
| EP0541042A1 (en) * | 1991-11-05 | 1993-05-12 | Hoechst Aktiengesellschaft | 2,4- and 2,5-pyridine-dicarboxylic acid derivatives, process for their preparation and their use |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1235348A (en) * | 1968-12-16 | 1971-06-09 | Dufour Claude | Pyridine carboxylic acid amides |
| DE3703959A1 (en) * | 1987-02-10 | 1988-08-18 | Hoechst Ag | PYRIDINE-2,4- AND 2,5-DICARBONIC ACID AMIDES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
| DE3924093A1 (en) * | 1989-07-20 | 1991-02-07 | Hoechst Ag | N, N'-BIS (ALKOXY-ALKYL) -PYRIDINE-2,4-DICARBONESAUREDIAMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
-
1989
- 1989-07-29 DE DE58908519T patent/DE58908519D1/en not_active Expired - Fee Related
- 1989-07-29 AT AT89114031T patent/ATE113036T1/en not_active IP Right Cessation
- 1989-07-29 EP EP89114031A patent/EP0353668B1/en not_active Expired - Lifetime
- 1989-07-29 ES ES89114031T patent/ES2065355T3/en not_active Expired - Lifetime
- 1989-08-02 IL IL91185A patent/IL91185A/en not_active IP Right Cessation
- 1989-08-03 JP JP1200441A patent/JP2683423B2/en not_active Expired - Lifetime
- 1989-08-03 IE IE252089A patent/IE64673B1/en not_active IP Right Cessation
- 1989-08-03 AU AU39263/89A patent/AU615324B2/en not_active Ceased
- 1989-08-03 KR KR1019890011072A patent/KR0137789B1/en not_active IP Right Cessation
- 1989-08-03 DK DK380989A patent/DK170748B1/en not_active IP Right Cessation
- 1989-08-03 CA CA000607509A patent/CA1330802C/en not_active Expired - Fee Related
- 1989-08-03 PT PT91361A patent/PT91361B/en active IP Right Grant
- 1989-08-04 HU HU893966A patent/HU208423B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK170748B1 (en) | 1996-01-08 |
| PT91361B (en) | 1995-05-04 |
| JP2683423B2 (en) | 1997-11-26 |
| ATE113036T1 (en) | 1994-11-15 |
| PT91361A (en) | 1990-03-08 |
| KR900003125A (en) | 1990-03-23 |
| EP0353668A3 (en) | 1991-03-27 |
| EP0353668A2 (en) | 1990-02-07 |
| AU3926389A (en) | 1990-02-08 |
| IE892520L (en) | 1990-02-04 |
| JPH0283371A (en) | 1990-03-23 |
| HU208423B (en) | 1993-10-28 |
| ES2065355T3 (en) | 1995-02-16 |
| HUT52057A (en) | 1990-06-28 |
| DK380989A (en) | 1990-02-05 |
| KR0137789B1 (en) | 1998-05-15 |
| IL91185A (en) | 1993-06-10 |
| AU615324B2 (en) | 1991-09-26 |
| IE64673B1 (en) | 1995-08-23 |
| EP0353668B1 (en) | 1994-10-19 |
| DE58908519D1 (en) | 1994-11-24 |
| DK380989D0 (en) | 1989-08-03 |
| IL91185A0 (en) | 1990-03-19 |
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