CA2021529C - N,n'-bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamides, preparation and their use - Google Patents
N,n'-bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamides, preparation and their useInfo
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- CA2021529C CA2021529C CA002021529A CA2021529A CA2021529C CA 2021529 C CA2021529 C CA 2021529C CA 002021529 A CA002021529 A CA 002021529A CA 2021529 A CA2021529 A CA 2021529A CA 2021529 C CA2021529 C CA 2021529C
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- pyridine
- dicarboxylic acid
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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
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
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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
- C07D213/82—Amides; Imides in position 3
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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
Abstract
N,N'-Bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamides, preparation and their use The invention relates to N,N'-bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamides of the formula I
(I) wherein R1, R2, n, R1', R2' and n' have the meanings given.
The compounds inhibit proline hydroxylase and lysine hydroxylase and are suitable as fibrosuppressants and immunosuppressants.
(I) wherein R1, R2, n, R1', R2' and n' have the meanings given.
The compounds inhibit proline hydroxylase and lysine hydroxylase and are suitable as fibrosuppressants and immunosuppressants.
Description
HOECHST AXTIENGESELL5CHAFT Dr.SN/fe MOE 89/F 241 Description N,N'-Bis(alkoxyalkyl)-pyridine-2,4-dicarbo~ylic acid di-amides, preparation and their use Compounds which inhiblt proline hydroxyla~e and ly~ine hydroxylase cause a very selective inhibition of collagen biosynthesis by influencing the collagen-specific hydroxylation reactions. In the course of these, protein-bound proline or ly~ine is hydroxylate~ by the enzymes proline hydroxylase or lysine hydro~ylase. If this reaction is sup~essed by inhibitor~, Zl non-functional, hypohydroxylated collagen molecule iR formed, which can be released by the cells into the extracellular space in only a small amount. The hypohydroxylated collagen also cannot be incorporated into the collagen matrix and is very easily degraded by proteolysis. As a con~eguence of these e~fect~, the amount of extracellularly deposited collagen overall is reduced.
It is known that the inhibition of proline hydroxylase by known inhibitors, such as ~ dipyridyl, leads to an inhibition o~ the Clq biosynthesis of macrophages (W. Muller et al., FEBS Lett. 90 (1978), 218; and Immun-biolo~y 155 (1978) 47). This result~ in a failure of the classical route of complement activation. Inhibitors of proline hydroxylase therefore also act as i ~oSuppL~s-sants, for example in cases of immune complex diseases.
It is known that proline hydlo~ylase is inhibited effec-tively by pyridine-2,4- and -2,5-dicarboxylic acid (K. Ma~amaa et al., Eur. J. Biochem. 138 (1984) 239-245).
However, in the cell culture the~e compounds are effec-tive as inhibitors only in very high concentrations (Tschank, G. et al., Biochem. J. 238, 625-633, 1987).
Ge -n Patent A-3,432,09A describes pyridine-2,4- and -2,5-dicarboxylic acid diasters having 1-6 carbon atoms in the ester alXyl part as pharmaceutical& for inhibition of proline hydroxylase and lys.ine hydroxylase.
Howeverl ~hese lower alkylated diesters have the dis-advantage that they are split too rapidly in the organism ~o give the acids and do not arrive at their site of action in the cell in a sufficiently high concentration, and are therefore of little suitability fvr possible a~ri n istra~ion as pharmaceu~icals.
G~rr-n Patent A-3,703,959, ~7e ~n Patent A-3,703,962 and ~erm~n Patent A-3,7~3,963 describe, in general form, mi~ed ester/amides, higher alkylated diesters and di-amides of pyridine-2,4- and -2,5-dicarboxylic acid which effectively inhibit collagen biosynthe~is in the ~ni~l model.
,.
German Patent A-3,703,959 thus describes, inter alia, the synthesis o~ N,N'-bis(2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide (III) CON~-CH2-CH2-O-C~3 ~ CONH-CH~-CH2-O-CH3 (III) and N,N'-bis(3-isopropoxypropyl)-pyridine-2,4-dicarboxylic acid diamide (IV) ~ CH3 CONH-CH2-CH2-CH~-O-CH
~H3", CH3 ~IV) N ~ CONH CH2-CH2-C~2-~-CX ~
An improved proce~ for the preparation of N,N'-bis~2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide ~5 (III) is proposed in German Patent Applications P 38 26 471.4 and P 38 28 140.6.
2&J~ 2~
-- 3 ~
The enteral absorbability of many of the compounds described in German Patent A-3,703,959 i~ still un~atis-factory, however, 80 ~hat there i~ a need to provide compounds which effec~ively inhibit proline hydroxyla~e S and lysine hydro~ylase after oral al' ini~tration even in low dosagesr It has been found that compounds of the formula I
CONH-(R~ O~ 3~
CO~H-(R~ oR2 ~n'~ (I) N
wherein R1 denotes linear or branched Cl-c4-alk~nediylt R2 denotes unbranched Cl-C4-alkyl or hydrogen, n denotes 1 or 2 and R1, R~ and n~ have the ~ame ~anings as Rl, R2 and n, Rl and R1, and RZ and R2 and n and n~ being identical or different, and physiologically tolerated 8alt8 thereof, excluding N,N~-bis~2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide and N,N'-bi~ hydroxyethyl)-pyridine-2,4-dicar-boxylic acid diamide, achieve the abov~- ~ntioned ob~e~t.
~0 In compari~on with the compounds N,N'-bis~2-methoxy-ethyl)-pyridine-2,4-dicarboxylic aci~ diamide and N,N~-bis(3-isopropoxypropyl)-pyridine-2,4-dicarboxylic acid diamide de~cribed in Ge- -n Patent A-3,703,959, the compounds of the formula I have both a better ph~rr-clo-logical activity and a bekter enteral ab~orbability.
The invention furth~ Le relates to a process for thepreparation of N,N'-bi~-(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamides of the formula I
CONH- ~ R~ . ( OR2 ) n ~ CONH-~R~ (OR2 )n~ (I) J ~ t) wherein R1 denotes linear ox branched C,-C4-~lk~ne~iyl, R2 denotes unbranched Cl-C4-alkyl or hydrogen, n denotes l or 2 and Rl, RZ and n' have the same ~nin~s as Rl, R2 and n, R1 and R1, and R2 and R2 and n and n' being identical or differant, excluding ~tN'-bis(2-methoxyethyl~-pyridine-2,4-dicar-boxylic acid diamide and N,N'-bis(2-hydroxyethyl)-pyridine-2,4-dicarboxylic acid ~ de, which compri6es reacting a pyridine-2,4-dicarboxylic acid halide with an alkoxyalkylamine or hydroxyalkylamine.
The invention likewise relates to a proce~s for the preparation of N,N~-bis-(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamide~ of the formula I
CON~ Rl ) - ( oR2 ~ n ~ CONH-(R~ (OR~ )n~
wherein R} denotes linear or branched Cl-c4-~kAnedi R2 denotes unbr~nched Cl-C4-alkyl or hydrogen, n denotes 1 or 2 and Rl, R2 and n' have the same meanings as Rl, R2 and n, Rl and Rl, and R2 and R2 and n and n' being identical or different, 2~ which compri~es first A) ~ i ng at least two equivalents of a halogenating agent to pyridine-2,4-dicarboxylic acid and 2. dissolving at least 2 equivalent8 of a hydroxyalXyl-amine or alkoxyalkylamine of the formula II or II' H2N-(R )-(OR )n (II) H2~ 1 )--( oR2 ) n ~
ln which Rl and R1 denote linear or branched Cl-C4-alkanediyl, R2 and R2 denote unbranched C1-C4-alkyl or hydrogen, n and n' denote l or 2 and Rl and Rl, R2 and R2 and n and n~ are identical or different, but II and II~ are differen , in a solvent and then reacting the solution prepared according to l.
with the solution prepared according to 2., or B) converting the resulting N,N~-bis(alkoxyal~yl~-pyri-dine-2,4-dicarboxylic acid ~ e into the bis(hydro~y-alkyl) compound, or C) reacting the pyridine-2,4-dicarboxylic acid halide prepared according to A) 1. with a substituted or un~ub-stituted benzyl alcohol to give the benzyl pyridine-2~4-dicarboxylate, hydrolyzing the benzyl ester selectively in the 2-position of the pyridine, converting the free carboxylic acid in the 2-position into the acid halide again in accordance with proces6 variant A) l. and adding a solution prepared according to A~ 2. using a compound of the formula II~ to the c~ -und thus obtAin~ a pyridine-4-(carboxylic acid benzyl ester)-2-carboxylic acid ~mide being formed, and then splitting off the benzyl protective group in the 4-position by hydrogenoly-25 ~i8 ~ converting the free carboxylic acid into the acidchloride again in accordance with process variant A) 1., and subsequently adding a solution prepared according to A) 2. using a compound of the formula II, an unsymmetri-cally substituted compcund of the formula I being formed, and if appropriate then converting the resulting compound of the formula I into its physiologically tolerated salt.
In the process for the preparation of the compound~ of the formula I, the pyridine-2,4-dicarboxylic acid commer-cially available 2S a starting subskance is suspended in a solvent, such as toluene, and a halogenating agent, preferably a chlorinating agent, ~uch as, for example, SOCl2, i8 added at room temperature. 2-3 eguivalents, preferably 2.5 equivalents, of a halogenating agent, ," ,i. ~ ~" ;,) based on the molar amount of pyridine-2,4-dicarbo~ylic acid employed, are used. The resulting reaction mixture is heated at 90-110~C, preferably at lOO~C, until no further evolution of gas is tu be observed and a clear solution has formed. 10% of the solution is then evapora-ted off - preferably under a hlgh vacuum (down to about 10-3 mm Hg) - and the resulting carboxylic acid halide i8 reacted further.
2-4 times the molar amount of commercially available lQ alkoxyalkylamine ox hydroxyalkylamine, based on ~he molar amount of pyridine-2,4-dicarboxylic acid employ~d~ is now dissolved in a solvent, such as toluene, and 2-4 times the molar amount of a base, such as triethyli i n~ ~ is pr~ferably added. The carbo~ylic acid halide is reacted with the alkoxyalkylamine or the hydroxyalkylamine. ~his i5 preferably done by ~in~ the solution of the alkyl-amine mentioned dropwise to the dissol~ed pyridine-2,4-dicarboxylic acid halide. However, it is also pos3ible to add the solution of the carboxylic acid halide dropwi~e to the solution of the alkoxyalkylamine or hydroxyalkyl-amine~ The addition is carried out at a temperature of -5 to ~5~C, pxeferably at 0~C. The reaction mixture ca~
then be after-reacted, for example, by warming it to room temperature and subsequently stirring it fox a further 2-5 hours, preferably 3 hours. The resulting product isthen acidified in order to ~ -ve excess hydroxy- or alkoxyalkylamine from the desired product. The acidifica-tion can be carried out, for example, with 0.2 molar citric acid. The organic phase is then separated off and washed with water. The or~anic phase i~ ~ub~equently dried - pre~erably over magnesium sulfate - and finally freed ~rom the solvent. On removal of the solvent, the product is obt~;ne~ as a white solid or as an oil.
To prepare the N,N'-bis(hydroxyalkyl)-pyridine-2,4-dicarboxylic acid diamides, a procedure i8 preferablyfollowed in which a correspo~ing bis(alkoxyalkyl)di-amide, preferably bis(methoxyalkyl)~ ;de, is converted ~ 7 ~
into the corre~ponding bi~(hydroxyalkyl)diamide by proce~es which are known from ~he litera~ure, for example u~ing boron tribromide.
Unsymmetrically substituted compounds of the formula I
can be synthe~ized, for example, as followss reaction of a pyrldine-2,4-dicarboxylic acld halide, preferably the chlor~de, with ~ub~tituted or unsub~tituted benzyl alcohol to give benzyl pyridine-2,4-clicarboxylate, subsequent sslective hydroly~i~ of the ester in the 2-position (for example in the presence of a copper cata-lyst, Acta Helv. 44, 1963, page 637), conver~ion of the free acid in the 2-position into the acid halide, reac-tion with a compound of the formula (II') ~o give the pyxidine~4-(carboxylic acid benzyl ester)-2-car~o~ylic acid amide, splitting off of the remain~ng benzyl pxotec-tive group by hydrogenolysi~ (for example with H~Pd, see Houben-Wey} Volume IV/lc ~1980), pages 381-82) and subsequent conversion of the free acid in the 4-po~ition of the pyridine ring into the acid halide.
~he acid halide can now be converted into the mixed diamide ~I) with an amine II (see Figure 1).
If appropriate, the product~ can be worked up, for example, by extraction or by chromatography, for example over silica gel. The product isolated can be Lecly~tal-lized and if appropriate reacted with a suitable acid togive a physiologically tolerated salt. Example6 of possible suitable acid~ are: mineral acids, such as hydrochloric and hydrobromic acid as well a~ ~ulfuric, phosphoric, nitric or perchloric acidt or organic acid~, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, fumaric, phenyl-acetic, benzoic, methanesulfonic~ toluene~ulfonic, oxalic, 4-aminobenzoic, naphthalene-1,4-di~ulfonic or ascorbic acid.
l'he compounds o~ the formula I can be used ae medicaments in the form of phA -ceutical preparations which contain -- 8 ~
them, if appropriate toge~her with tolerated pharmaceuti-cal excipients. The compound~ can be used as medicines, for example in the form o~ pharmaceutical preparations which contain these compounds as a mixture with a pharmaceutical/ organic or inorganic excipient suitable for enteral, percutaneous or parenteral admini~tration, such as, for example, water, gum axabic, gelatin, lac-tose, starch, ma~nesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline and the :Like.
The ph~ ~?utical preparation~ can be in solid form, for example as tablets, coated tablets, suppositorie~ or capsules; in semi-solid form, for e~ample as ointments, or in liquid form, for example as solutions, ~uspensions or emulsions. If a~loyliate, they are ~terilized and/or contain auxiliaries, such as pre~ervatives, s$abilizers, wetting agents or emulsifiers/ salts for modifying the osmotic pressure or buffers. They can al~o additionally contain other ther~peutically active substances.
It has been found that the c~ ~)ounds of the formula T
have exceptionally good enteral ~bsorbabilities. ~he absorbability was inve~tigated on Wis~ar ra~s to whi~h the compounds according to the invention were ~ ni~ter-ed intragastrally. ~he serum level dropped in the first hours after administration of the substance, and after about 5 hours ~eached a plateau which 5till fell only slightly. The good absorbability of the substances can be conclude~ from the initially very high serum level directly after ~-' i n~ stration of the substances.
The invention i~ illustrated in more detail below with the aid o~ examples.
rJ ~ 5; ~ éJJ
Exampl~ 1 Pyridine-2,4-dicarboxylic acid bis-N,N~-(metho~ opyl)-amide 3 g of pyridine-2,4-dicarboxylic acid are initially S introduced into 50 ml of toluene and 1 ml of dimethyl-formamide, and 2.7 ml of thionyl chloride are added dropwi~e to the solution. The mixture i~ heated until no further evolution of gas is to be ob~erved (about 2.5 hours~. It i5 cooled, 5 ml of toluene are di~tillsd off and 4.6 ml of 3-methoxypropylamine and S ml of triethyl-amine are added dropwise to the solution. ~fter the solution has been 6tirred at room temperature for 4 hours, it is evaporated, the residue is taken up in water and the mixture is extracted 4 tLmes with methylene lS chloride. The combined organic phase~ are dried over magne~ium sulfate and evaporated. The crude product i~
chromatographed with silica gel ~solvent: ethyl acetate).
Yield: 4.3 g; oil 1H-NMR ~CDCl3): ~ = 1.6-2.3 (4H, m); 3.2-3.8 (14H, m);
7.8-8.0 (lH, m); 8.3-8.5 (lH, m); 8.6-8.8 (lH, m).
~xample 2 Pyridine-2,4-dicarboxylic acid bis-N,N'-(etho~y~Lo~yl)-amide Yor instructions see Example l; amine component: ethoxy-propylamine Yield: 4.5 g, melting point: 46-48~C.
H-NMR (CDCl3): 6 - 1.3 (6H, tr); 1.7-2.1 (4H, m); 3.3-3.8 (12H, m); 7.8-B.0 (lH, m); 8.4-8.5 (lH, m); B . 5-8 . 8 ( lH, m) .
2~3~ r~
~xample 3 Pyridine-2/4-dicarboxylic acid bi~-M,N'~(2-dimetho~y~
ethyl)amide For instructions see Example 1 amine component: 2-S dimethoxyethylamine Yield: 1.6 g (~rom 3 g of pyridine~-2,4-dicarboxylic acid), oil H-NMR (CDC13): ~ = 3.4 (12H, ~); 3.7 (4H, m); 4.5 (2H, m); 7.9-8.0 (lH, m); 8~4-8.5 (lH, m);
8.7-8.8 (lH, m).
r - ~le 4 Pyridine-2,4-dicarboxylic acid bis-N,N'-(2-m0thoxy-isoprop~l)a~ide For instructions ~ee Example 1; amine component: 2-methoxyisopropylamine;
Yield: 3.3 g tfrom 3 g of pyridine-2,4-dicarboxylic acid), oil H-NMR (CDCl3): 6 = 1.3 (6H, d); 3-2 (6H~ ~); 3-5 (4H~
It is known that the inhibition of proline hydroxylase by known inhibitors, such as ~ dipyridyl, leads to an inhibition o~ the Clq biosynthesis of macrophages (W. Muller et al., FEBS Lett. 90 (1978), 218; and Immun-biolo~y 155 (1978) 47). This result~ in a failure of the classical route of complement activation. Inhibitors of proline hydroxylase therefore also act as i ~oSuppL~s-sants, for example in cases of immune complex diseases.
It is known that proline hydlo~ylase is inhibited effec-tively by pyridine-2,4- and -2,5-dicarboxylic acid (K. Ma~amaa et al., Eur. J. Biochem. 138 (1984) 239-245).
However, in the cell culture the~e compounds are effec-tive as inhibitors only in very high concentrations (Tschank, G. et al., Biochem. J. 238, 625-633, 1987).
Ge -n Patent A-3,432,09A describes pyridine-2,4- and -2,5-dicarboxylic acid diasters having 1-6 carbon atoms in the ester alXyl part as pharmaceutical& for inhibition of proline hydroxylase and lys.ine hydroxylase.
Howeverl ~hese lower alkylated diesters have the dis-advantage that they are split too rapidly in the organism ~o give the acids and do not arrive at their site of action in the cell in a sufficiently high concentration, and are therefore of little suitability fvr possible a~ri n istra~ion as pharmaceu~icals.
G~rr-n Patent A-3,703,959, ~7e ~n Patent A-3,703,962 and ~erm~n Patent A-3,7~3,963 describe, in general form, mi~ed ester/amides, higher alkylated diesters and di-amides of pyridine-2,4- and -2,5-dicarboxylic acid which effectively inhibit collagen biosynthe~is in the ~ni~l model.
,.
German Patent A-3,703,959 thus describes, inter alia, the synthesis o~ N,N'-bis(2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide (III) CON~-CH2-CH2-O-C~3 ~ CONH-CH~-CH2-O-CH3 (III) and N,N'-bis(3-isopropoxypropyl)-pyridine-2,4-dicarboxylic acid diamide (IV) ~ CH3 CONH-CH2-CH2-CH~-O-CH
~H3", CH3 ~IV) N ~ CONH CH2-CH2-C~2-~-CX ~
An improved proce~ for the preparation of N,N'-bis~2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide ~5 (III) is proposed in German Patent Applications P 38 26 471.4 and P 38 28 140.6.
2&J~ 2~
-- 3 ~
The enteral absorbability of many of the compounds described in German Patent A-3,703,959 i~ still un~atis-factory, however, 80 ~hat there i~ a need to provide compounds which effec~ively inhibit proline hydroxyla~e S and lysine hydro~ylase after oral al' ini~tration even in low dosagesr It has been found that compounds of the formula I
CONH-(R~ O~ 3~
CO~H-(R~ oR2 ~n'~ (I) N
wherein R1 denotes linear or branched Cl-c4-alk~nediylt R2 denotes unbranched Cl-C4-alkyl or hydrogen, n denotes 1 or 2 and R1, R~ and n~ have the ~ame ~anings as Rl, R2 and n, Rl and R1, and RZ and R2 and n and n~ being identical or different, and physiologically tolerated 8alt8 thereof, excluding N,N~-bis~2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide and N,N'-bi~ hydroxyethyl)-pyridine-2,4-dicar-boxylic acid diamide, achieve the abov~- ~ntioned ob~e~t.
~0 In compari~on with the compounds N,N'-bis~2-methoxy-ethyl)-pyridine-2,4-dicarboxylic aci~ diamide and N,N~-bis(3-isopropoxypropyl)-pyridine-2,4-dicarboxylic acid diamide de~cribed in Ge- -n Patent A-3,703,959, the compounds of the formula I have both a better ph~rr-clo-logical activity and a bekter enteral ab~orbability.
The invention furth~ Le relates to a process for thepreparation of N,N'-bi~-(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamides of the formula I
CONH- ~ R~ . ( OR2 ) n ~ CONH-~R~ (OR2 )n~ (I) J ~ t) wherein R1 denotes linear ox branched C,-C4-~lk~ne~iyl, R2 denotes unbranched Cl-C4-alkyl or hydrogen, n denotes l or 2 and Rl, RZ and n' have the same ~nin~s as Rl, R2 and n, R1 and R1, and R2 and R2 and n and n' being identical or differant, excluding ~tN'-bis(2-methoxyethyl~-pyridine-2,4-dicar-boxylic acid diamide and N,N'-bis(2-hydroxyethyl)-pyridine-2,4-dicarboxylic acid ~ de, which compri6es reacting a pyridine-2,4-dicarboxylic acid halide with an alkoxyalkylamine or hydroxyalkylamine.
The invention likewise relates to a proce~s for the preparation of N,N~-bis-(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamide~ of the formula I
CON~ Rl ) - ( oR2 ~ n ~ CONH-(R~ (OR~ )n~
wherein R} denotes linear or branched Cl-c4-~kAnedi R2 denotes unbr~nched Cl-C4-alkyl or hydrogen, n denotes 1 or 2 and Rl, R2 and n' have the same meanings as Rl, R2 and n, Rl and Rl, and R2 and R2 and n and n' being identical or different, 2~ which compri~es first A) ~ i ng at least two equivalents of a halogenating agent to pyridine-2,4-dicarboxylic acid and 2. dissolving at least 2 equivalent8 of a hydroxyalXyl-amine or alkoxyalkylamine of the formula II or II' H2N-(R )-(OR )n (II) H2~ 1 )--( oR2 ) n ~
ln which Rl and R1 denote linear or branched Cl-C4-alkanediyl, R2 and R2 denote unbranched C1-C4-alkyl or hydrogen, n and n' denote l or 2 and Rl and Rl, R2 and R2 and n and n~ are identical or different, but II and II~ are differen , in a solvent and then reacting the solution prepared according to l.
with the solution prepared according to 2., or B) converting the resulting N,N~-bis(alkoxyal~yl~-pyri-dine-2,4-dicarboxylic acid ~ e into the bis(hydro~y-alkyl) compound, or C) reacting the pyridine-2,4-dicarboxylic acid halide prepared according to A) 1. with a substituted or un~ub-stituted benzyl alcohol to give the benzyl pyridine-2~4-dicarboxylate, hydrolyzing the benzyl ester selectively in the 2-position of the pyridine, converting the free carboxylic acid in the 2-position into the acid halide again in accordance with proces6 variant A) l. and adding a solution prepared according to A~ 2. using a compound of the formula II~ to the c~ -und thus obtAin~ a pyridine-4-(carboxylic acid benzyl ester)-2-carboxylic acid ~mide being formed, and then splitting off the benzyl protective group in the 4-position by hydrogenoly-25 ~i8 ~ converting the free carboxylic acid into the acidchloride again in accordance with process variant A) 1., and subsequently adding a solution prepared according to A) 2. using a compound of the formula II, an unsymmetri-cally substituted compcund of the formula I being formed, and if appropriate then converting the resulting compound of the formula I into its physiologically tolerated salt.
In the process for the preparation of the compound~ of the formula I, the pyridine-2,4-dicarboxylic acid commer-cially available 2S a starting subskance is suspended in a solvent, such as toluene, and a halogenating agent, preferably a chlorinating agent, ~uch as, for example, SOCl2, i8 added at room temperature. 2-3 eguivalents, preferably 2.5 equivalents, of a halogenating agent, ," ,i. ~ ~" ;,) based on the molar amount of pyridine-2,4-dicarbo~ylic acid employed, are used. The resulting reaction mixture is heated at 90-110~C, preferably at lOO~C, until no further evolution of gas is tu be observed and a clear solution has formed. 10% of the solution is then evapora-ted off - preferably under a hlgh vacuum (down to about 10-3 mm Hg) - and the resulting carboxylic acid halide i8 reacted further.
2-4 times the molar amount of commercially available lQ alkoxyalkylamine ox hydroxyalkylamine, based on ~he molar amount of pyridine-2,4-dicarboxylic acid employ~d~ is now dissolved in a solvent, such as toluene, and 2-4 times the molar amount of a base, such as triethyli i n~ ~ is pr~ferably added. The carbo~ylic acid halide is reacted with the alkoxyalkylamine or the hydroxyalkylamine. ~his i5 preferably done by ~in~ the solution of the alkyl-amine mentioned dropwise to the dissol~ed pyridine-2,4-dicarboxylic acid halide. However, it is also pos3ible to add the solution of the carboxylic acid halide dropwi~e to the solution of the alkoxyalkylamine or hydroxyalkyl-amine~ The addition is carried out at a temperature of -5 to ~5~C, pxeferably at 0~C. The reaction mixture ca~
then be after-reacted, for example, by warming it to room temperature and subsequently stirring it fox a further 2-5 hours, preferably 3 hours. The resulting product isthen acidified in order to ~ -ve excess hydroxy- or alkoxyalkylamine from the desired product. The acidifica-tion can be carried out, for example, with 0.2 molar citric acid. The organic phase is then separated off and washed with water. The or~anic phase i~ ~ub~equently dried - pre~erably over magnesium sulfate - and finally freed ~rom the solvent. On removal of the solvent, the product is obt~;ne~ as a white solid or as an oil.
To prepare the N,N'-bis(hydroxyalkyl)-pyridine-2,4-dicarboxylic acid diamides, a procedure i8 preferablyfollowed in which a correspo~ing bis(alkoxyalkyl)di-amide, preferably bis(methoxyalkyl)~ ;de, is converted ~ 7 ~
into the corre~ponding bi~(hydroxyalkyl)diamide by proce~es which are known from ~he litera~ure, for example u~ing boron tribromide.
Unsymmetrically substituted compounds of the formula I
can be synthe~ized, for example, as followss reaction of a pyrldine-2,4-dicarboxylic acld halide, preferably the chlor~de, with ~ub~tituted or unsub~tituted benzyl alcohol to give benzyl pyridine-2,4-clicarboxylate, subsequent sslective hydroly~i~ of the ester in the 2-position (for example in the presence of a copper cata-lyst, Acta Helv. 44, 1963, page 637), conver~ion of the free acid in the 2-position into the acid halide, reac-tion with a compound of the formula (II') ~o give the pyxidine~4-(carboxylic acid benzyl ester)-2-car~o~ylic acid amide, splitting off of the remain~ng benzyl pxotec-tive group by hydrogenolysi~ (for example with H~Pd, see Houben-Wey} Volume IV/lc ~1980), pages 381-82) and subsequent conversion of the free acid in the 4-po~ition of the pyridine ring into the acid halide.
~he acid halide can now be converted into the mixed diamide ~I) with an amine II (see Figure 1).
If appropriate, the product~ can be worked up, for example, by extraction or by chromatography, for example over silica gel. The product isolated can be Lecly~tal-lized and if appropriate reacted with a suitable acid togive a physiologically tolerated salt. Example6 of possible suitable acid~ are: mineral acids, such as hydrochloric and hydrobromic acid as well a~ ~ulfuric, phosphoric, nitric or perchloric acidt or organic acid~, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, fumaric, phenyl-acetic, benzoic, methanesulfonic~ toluene~ulfonic, oxalic, 4-aminobenzoic, naphthalene-1,4-di~ulfonic or ascorbic acid.
l'he compounds o~ the formula I can be used ae medicaments in the form of phA -ceutical preparations which contain -- 8 ~
them, if appropriate toge~her with tolerated pharmaceuti-cal excipients. The compound~ can be used as medicines, for example in the form o~ pharmaceutical preparations which contain these compounds as a mixture with a pharmaceutical/ organic or inorganic excipient suitable for enteral, percutaneous or parenteral admini~tration, such as, for example, water, gum axabic, gelatin, lac-tose, starch, ma~nesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline and the :Like.
The ph~ ~?utical preparation~ can be in solid form, for example as tablets, coated tablets, suppositorie~ or capsules; in semi-solid form, for e~ample as ointments, or in liquid form, for example as solutions, ~uspensions or emulsions. If a~loyliate, they are ~terilized and/or contain auxiliaries, such as pre~ervatives, s$abilizers, wetting agents or emulsifiers/ salts for modifying the osmotic pressure or buffers. They can al~o additionally contain other ther~peutically active substances.
It has been found that the c~ ~)ounds of the formula T
have exceptionally good enteral ~bsorbabilities. ~he absorbability was inve~tigated on Wis~ar ra~s to whi~h the compounds according to the invention were ~ ni~ter-ed intragastrally. ~he serum level dropped in the first hours after administration of the substance, and after about 5 hours ~eached a plateau which 5till fell only slightly. The good absorbability of the substances can be conclude~ from the initially very high serum level directly after ~-' i n~ stration of the substances.
The invention i~ illustrated in more detail below with the aid o~ examples.
rJ ~ 5; ~ éJJ
Exampl~ 1 Pyridine-2,4-dicarboxylic acid bis-N,N~-(metho~ opyl)-amide 3 g of pyridine-2,4-dicarboxylic acid are initially S introduced into 50 ml of toluene and 1 ml of dimethyl-formamide, and 2.7 ml of thionyl chloride are added dropwi~e to the solution. The mixture i~ heated until no further evolution of gas is to be ob~erved (about 2.5 hours~. It i5 cooled, 5 ml of toluene are di~tillsd off and 4.6 ml of 3-methoxypropylamine and S ml of triethyl-amine are added dropwise to the solution. ~fter the solution has been 6tirred at room temperature for 4 hours, it is evaporated, the residue is taken up in water and the mixture is extracted 4 tLmes with methylene lS chloride. The combined organic phase~ are dried over magne~ium sulfate and evaporated. The crude product i~
chromatographed with silica gel ~solvent: ethyl acetate).
Yield: 4.3 g; oil 1H-NMR ~CDCl3): ~ = 1.6-2.3 (4H, m); 3.2-3.8 (14H, m);
7.8-8.0 (lH, m); 8.3-8.5 (lH, m); 8.6-8.8 (lH, m).
~xample 2 Pyridine-2,4-dicarboxylic acid bis-N,N'-(etho~y~Lo~yl)-amide Yor instructions see Example l; amine component: ethoxy-propylamine Yield: 4.5 g, melting point: 46-48~C.
H-NMR (CDCl3): 6 - 1.3 (6H, tr); 1.7-2.1 (4H, m); 3.3-3.8 (12H, m); 7.8-B.0 (lH, m); 8.4-8.5 (lH, m); B . 5-8 . 8 ( lH, m) .
2~3~ r~
~xample 3 Pyridine-2/4-dicarboxylic acid bi~-M,N'~(2-dimetho~y~
ethyl)amide For instructions see Example 1 amine component: 2-S dimethoxyethylamine Yield: 1.6 g (~rom 3 g of pyridine~-2,4-dicarboxylic acid), oil H-NMR (CDC13): ~ = 3.4 (12H, ~); 3.7 (4H, m); 4.5 (2H, m); 7.9-8.0 (lH, m); 8~4-8.5 (lH, m);
8.7-8.8 (lH, m).
r - ~le 4 Pyridine-2,4-dicarboxylic acid bis-N,N'-(2-m0thoxy-isoprop~l)a~ide For instructions ~ee Example 1; amine component: 2-methoxyisopropylamine;
Yield: 3.3 g tfrom 3 g of pyridine-2,4-dicarboxylic acid), oil H-NMR (CDCl3): 6 = 1.3 (6H, d); 3-2 (6H~ ~); 3-5 (4H~
4.4 (2H, m~; 7.9 8.0 (lH, m); 8.4-8.5 (lH, m); 8.7~8.8 (lH, m).
Rxample 5 Pyridine-2,4-dicarboxylic acid bis -N, N ' - ( 2-ethoxyethyl)-amide For in~truction6 ~ee Example 1; ~mine c~ nent: etho~y-ethyli- Ine~
Yields 7.8 g (from 10 g of pyridine-2,4-dicarboxylic acid), melting point: 42-44~C
H-NMR (CDCl3): ~ = 1.2 (3H, tr); 3.3-3.8 (12H, qu. and m); 7.9 (lH, m); 8.4-8.S (lH, m); 8.7-8.8 (lH, m).
Example 6 Pyridine-2,4~dicarboxylicacidbi~-N,N'-(3-hydroxyethyl)-amide 0.5 g of pyridine-2,4-dicarboxylic acid bis-N,N'-(3-methoxyethyl)~mide are dis~olved in lO ml of methylene chloride, and boron tribromide (11 ml~ 1 molar .501ution in methylene chloride) is added dropwisle at ~78~C. When the addition ha~ ended, the mixture i8 allowed to come to room temperature and is subsequen~ly stirxed for 3 hours.
It is poured onto 109 ml of saturated bicarbonate solu-tion and extracted 3 times with ethyl acetate. The combined organic phases are dried with magnesium ~ulfate and evaporated. The crude product is chromatographed on silica gel.
Yield: 0.45 g; oil H-NMR (CDCl3): ~ - 1.5-2.2 t4H/ m); 3.4 (4H, m); 3.6 (4H, m); 7.9-8.0 (lH, m); 8.4-B.5 (lH, m);
8.7-8.8 (lH, m).
Example 7a Pyridine-2,4-dicarboxylic acid dibenzyl e~ter 30g of pyridine-2,4-dicarboxylic acid are coJ-v~lLed illtO
the acid chloride using 30 ml of thionyl chloride analo-gously to Example 1 and the acid chloride is reacted with 43.8 g of benzyl alcohol. The product is recrystallîzed from diisopropyl ether.
Yield: 42.1 g Melting point 63-65~C
Rxample 7b Pyridine-2-(carboxylic acid)-4-carboxylic acid benzyl ester 40 g of pyridine-2,4-dicarboxylic acid dibenzyl ester from Example 7a are added to a suspension of 27.8 g of copper-II nitrate in 700 ml of methanol. The mixture i~
boiled under reflux for one hour and, after cooling, the copper complex is ~iltered off. The comple~ is su~pended in dioxane and carbon disulfide is pa~sed in. The copper sulfide which has precipitated is filtered off and ths organic phase is concentrated. The product i~ ~tirred with petroleum ether.
~ield: 25.3 g Melting point 113-115~C
~ample 7c Pyridine-2-[(3-methoxypropyl)-carboxylic acid amide]-4-carboxylic acid benzyl ester 3.9 g of pyridine-2-tcarboxylic acid)-4-carboxylic acid benzyl ester from Example 7b are converted into the acid chloride using 1.2 ml of thionyl chloride analogously to Example 1 and the acid chloride is reacted with 3-meth-oxypropylamine to give the amide. For purification, the product is chromatographed over silica gel using a mi~ture of cyclohe~A~/ethyl acetate (1:1).
Yield. 4.3 g Oil r _le 7d Pyridine-4-(carboxylic acid)-2-(3-methoxypropyl)-car-boxylic acid amide 4.3 g of the e, ~ur.d from ~xample 7c are dissolved in 100 ml of dio~ane and hydrogenated using 50n mg of palladium/charcoa]. (10% strength) catalyst under normal pressure for 4 hours. When the uptake of hydrogen has ended, the catalyst i~ filtered off with suction and the solvent i3 stripped of~.
Yield: 3.5 g Melting point 124-126~C
2 ~ s~ Ji ~xample 7e Pyridine~4-[carboxylic acid-(2-me~hoxyethyl)~amide]-2-carboxylic acid t3-metho~ypropyl)-amide 1.8 g of the compound from Example 7d are converted into S ~he acid chloride using 0.B ml of thionyl chloride in accordance with ~xample 1 and the acid chloride i~ then reacted with 2-me~hoxyethyl, inP. For purification, the product is chromatographed over silica gel using a mixture of methylene chloride/methanol (20:1).
Yield: 1.0 g Oil ~-NMR ~CDCl3)~ 9-2.0 (2H~ qui); 3.4 (6H, ~); 3.5-3.7 (8H, m); 6.9 ~lH, s, br); 8.0 (lH, dd); 8.4 (lH, s, br); 8.5 (lH, s); 8.7 (lHt d)-~xa~ple 8 Pyridine-2-[carboxylic acid-(2-metho~yethyl)-amide]-4-carboxylic acid (3-methoxypropyl)-amide The compound according to Example 8 is prepared analo-gously to Examples 7a-e by using 2-methoxyethy~ n~ in the reaction step of Example 7c and 3-metho~y~ o~ylamine in the reaction step of Example 7e.
Melting point: 69-72~C
H-NMR ~CDCl3): ~ = 1.9-2.0 (2H, qui); 3.4 (3H, s); 3.45 (3H, s); 3.6-3.7 (~H~ m); 7.4 (lH, br); 7.9 (lH, ddl; 8.3 (lH, br); 8.4 (lH, d); 8.7 ~lH, d).
E~ampl~ 9 ~nteral absorbability Female Wistar rat~ of about 150 g body weight are given an intragastral administration of 50 mg/kg of the sub~
stance under investigation by means of a stomach probe.
2 ~ 5 ~ ~) In each case 4 rats are anesthetized after 5; lO; 15; 30;
60; 120; 180 and 240 minutes and exsanguinated via the Vena Cava. The blood i8 cen~ri~uged immediately and the compound a.~ stered i8 extracted from the serum using ether. A~ter the ether ha~ been evaporatRd, the residue is taken up in 100 ml of mobile phase. ~he mobile phase consists of 0.05 ~ phosphoric acid and acetonitrile (4:1). 50 ~l ~f thi~ sample are in~ected into a high performance liquid chromatography column. Detection is performed under W of 200 nm with a retention time of 2.2 minutes. The results are documented in Table l.
Table 1: Serum levels of the compounds according to the invention from Examples 1-3 after a~inistra tion of 50 mg/kg perorally 1~
Tlme Substance from Substance from Substance ~rom (minutes) Example 1Example 2 Example 3 x SD x SD x SD
~.3 + 15.451.4 ~ 11.2 8.9 t 3.1 ~9.8 + 3.639.2 + 4.0 11.5 + 0.6 39.9 + 11.029.4 ~ ~.71~.7 ~ 1.9 28.1 ~ 3.215.2 + 5.6 10.7 ~ 1.9 9.~ ~ 5.51.4 + 1.0 11.3 ~ 1.5 120 0.3 + 0.3<DL 5.5 ~ 0.9 180 <DL <DL 2.9 + 0.5 240 ~DL <DL 1.7 i 0.4 x = mean value of 4 measurements SD = stAn~rd deviation <DL = below the detection lLmit ~xample 10 ph~ ~cological activity To demonstrAte the effective inhibition of proline hydroxyla~e and lysine hydroxylase by the compounds - 15 ~
according to the invention, the hydroxyproline concentra-tion~ in the liv2r and the 7s 5IV)-collagen concentra-tions in the serum o~
a) untreated rats (control) b~ rats to which carbon tetrachloride had been ~ini~-tered ~ CC14 control) c) rat~ to which first Cc14 and then a compound according to the invention had been ~r 1 n i ~tered were measured (this ~ast method is described by 1~ ~ouiller, C., experimental toxic injury of the liver; in The Liver, C. Rouiller, Volume 2, pages 335-476, New York, Academic Press, 1964)o The action potency of the compounds according to the invention was det~rrined as the percentage inhibition of the liver hydroxyproline synthesis and serum 7s-(IV)-collagen synthesis following oral administration in comparison with control ~ni 9l B to which only carbon tetrachloride had been A~' i n i Rtered ~ CC14 control). ~he result~ are shown in Table 2. The compounds from E~amples 2 and 3 of Ge ~n Patent ~~3r703~559 ~,N'-bis(2-methoxy-ethyl)-pyri~ine-2,4-dicarboxylic acid diamide and N,N'-bis(3-isopropox~propyl)-pyridine-2,4-dicarboxylic acid diamide) are likewise also ~hown as comparison ~ubstan-ces. Surprisingly, the compounds according to the inven-tion show a better activity, even after oral ~-' ini~t:ra-tion, than the intraperitoneally ~l inistered compound from Example 2 of Germ~n Patent A-3~703,959.
2 ~ 1 .J i~ ~ i f J r -- 16 ~
Table 2:
SubstancQ Dosage Liver Serum 7B- Admini~-from hydxo~y~ (IV)-collagen tration Example proline ~% [% inhibition~
inhibition~
1 2x2 mg 62 28 p.o.
2xlO m~ 90 67 p.o.
2 2x2 mg 25 2 p.o.
2xlO mg 60 35 p.o.
2 (from 2x25 mg 55 48 i.p.
DE-A-3,703,959 3 (from 2x25 mg 49 11 p.o.
DE-A-3,703,~59' p.o. = peroral i.p. = intraperitone~l
Rxample 5 Pyridine-2,4-dicarboxylic acid bis -N, N ' - ( 2-ethoxyethyl)-amide For in~truction6 ~ee Example 1; ~mine c~ nent: etho~y-ethyli- Ine~
Yields 7.8 g (from 10 g of pyridine-2,4-dicarboxylic acid), melting point: 42-44~C
H-NMR (CDCl3): ~ = 1.2 (3H, tr); 3.3-3.8 (12H, qu. and m); 7.9 (lH, m); 8.4-8.S (lH, m); 8.7-8.8 (lH, m).
Example 6 Pyridine-2,4~dicarboxylicacidbi~-N,N'-(3-hydroxyethyl)-amide 0.5 g of pyridine-2,4-dicarboxylic acid bis-N,N'-(3-methoxyethyl)~mide are dis~olved in lO ml of methylene chloride, and boron tribromide (11 ml~ 1 molar .501ution in methylene chloride) is added dropwisle at ~78~C. When the addition ha~ ended, the mixture i8 allowed to come to room temperature and is subsequen~ly stirxed for 3 hours.
It is poured onto 109 ml of saturated bicarbonate solu-tion and extracted 3 times with ethyl acetate. The combined organic phases are dried with magnesium ~ulfate and evaporated. The crude product is chromatographed on silica gel.
Yield: 0.45 g; oil H-NMR (CDCl3): ~ - 1.5-2.2 t4H/ m); 3.4 (4H, m); 3.6 (4H, m); 7.9-8.0 (lH, m); 8.4-B.5 (lH, m);
8.7-8.8 (lH, m).
Example 7a Pyridine-2,4-dicarboxylic acid dibenzyl e~ter 30g of pyridine-2,4-dicarboxylic acid are coJ-v~lLed illtO
the acid chloride using 30 ml of thionyl chloride analo-gously to Example 1 and the acid chloride is reacted with 43.8 g of benzyl alcohol. The product is recrystallîzed from diisopropyl ether.
Yield: 42.1 g Melting point 63-65~C
Rxample 7b Pyridine-2-(carboxylic acid)-4-carboxylic acid benzyl ester 40 g of pyridine-2,4-dicarboxylic acid dibenzyl ester from Example 7a are added to a suspension of 27.8 g of copper-II nitrate in 700 ml of methanol. The mixture i~
boiled under reflux for one hour and, after cooling, the copper complex is ~iltered off. The comple~ is su~pended in dioxane and carbon disulfide is pa~sed in. The copper sulfide which has precipitated is filtered off and ths organic phase is concentrated. The product i~ ~tirred with petroleum ether.
~ield: 25.3 g Melting point 113-115~C
~ample 7c Pyridine-2-[(3-methoxypropyl)-carboxylic acid amide]-4-carboxylic acid benzyl ester 3.9 g of pyridine-2-tcarboxylic acid)-4-carboxylic acid benzyl ester from Example 7b are converted into the acid chloride using 1.2 ml of thionyl chloride analogously to Example 1 and the acid chloride is reacted with 3-meth-oxypropylamine to give the amide. For purification, the product is chromatographed over silica gel using a mi~ture of cyclohe~A~/ethyl acetate (1:1).
Yield. 4.3 g Oil r _le 7d Pyridine-4-(carboxylic acid)-2-(3-methoxypropyl)-car-boxylic acid amide 4.3 g of the e, ~ur.d from ~xample 7c are dissolved in 100 ml of dio~ane and hydrogenated using 50n mg of palladium/charcoa]. (10% strength) catalyst under normal pressure for 4 hours. When the uptake of hydrogen has ended, the catalyst i~ filtered off with suction and the solvent i3 stripped of~.
Yield: 3.5 g Melting point 124-126~C
2 ~ s~ Ji ~xample 7e Pyridine~4-[carboxylic acid-(2-me~hoxyethyl)~amide]-2-carboxylic acid t3-metho~ypropyl)-amide 1.8 g of the compound from Example 7d are converted into S ~he acid chloride using 0.B ml of thionyl chloride in accordance with ~xample 1 and the acid chloride i~ then reacted with 2-me~hoxyethyl, inP. For purification, the product is chromatographed over silica gel using a mixture of methylene chloride/methanol (20:1).
Yield: 1.0 g Oil ~-NMR ~CDCl3)~ 9-2.0 (2H~ qui); 3.4 (6H, ~); 3.5-3.7 (8H, m); 6.9 ~lH, s, br); 8.0 (lH, dd); 8.4 (lH, s, br); 8.5 (lH, s); 8.7 (lHt d)-~xa~ple 8 Pyridine-2-[carboxylic acid-(2-metho~yethyl)-amide]-4-carboxylic acid (3-methoxypropyl)-amide The compound according to Example 8 is prepared analo-gously to Examples 7a-e by using 2-methoxyethy~ n~ in the reaction step of Example 7c and 3-metho~y~ o~ylamine in the reaction step of Example 7e.
Melting point: 69-72~C
H-NMR ~CDCl3): ~ = 1.9-2.0 (2H, qui); 3.4 (3H, s); 3.45 (3H, s); 3.6-3.7 (~H~ m); 7.4 (lH, br); 7.9 (lH, ddl; 8.3 (lH, br); 8.4 (lH, d); 8.7 ~lH, d).
E~ampl~ 9 ~nteral absorbability Female Wistar rat~ of about 150 g body weight are given an intragastral administration of 50 mg/kg of the sub~
stance under investigation by means of a stomach probe.
2 ~ 5 ~ ~) In each case 4 rats are anesthetized after 5; lO; 15; 30;
60; 120; 180 and 240 minutes and exsanguinated via the Vena Cava. The blood i8 cen~ri~uged immediately and the compound a.~ stered i8 extracted from the serum using ether. A~ter the ether ha~ been evaporatRd, the residue is taken up in 100 ml of mobile phase. ~he mobile phase consists of 0.05 ~ phosphoric acid and acetonitrile (4:1). 50 ~l ~f thi~ sample are in~ected into a high performance liquid chromatography column. Detection is performed under W of 200 nm with a retention time of 2.2 minutes. The results are documented in Table l.
Table 1: Serum levels of the compounds according to the invention from Examples 1-3 after a~inistra tion of 50 mg/kg perorally 1~
Tlme Substance from Substance from Substance ~rom (minutes) Example 1Example 2 Example 3 x SD x SD x SD
~.3 + 15.451.4 ~ 11.2 8.9 t 3.1 ~9.8 + 3.639.2 + 4.0 11.5 + 0.6 39.9 + 11.029.4 ~ ~.71~.7 ~ 1.9 28.1 ~ 3.215.2 + 5.6 10.7 ~ 1.9 9.~ ~ 5.51.4 + 1.0 11.3 ~ 1.5 120 0.3 + 0.3<DL 5.5 ~ 0.9 180 <DL <DL 2.9 + 0.5 240 ~DL <DL 1.7 i 0.4 x = mean value of 4 measurements SD = stAn~rd deviation <DL = below the detection lLmit ~xample 10 ph~ ~cological activity To demonstrAte the effective inhibition of proline hydroxyla~e and lysine hydroxylase by the compounds - 15 ~
according to the invention, the hydroxyproline concentra-tion~ in the liv2r and the 7s 5IV)-collagen concentra-tions in the serum o~
a) untreated rats (control) b~ rats to which carbon tetrachloride had been ~ini~-tered ~ CC14 control) c) rat~ to which first Cc14 and then a compound according to the invention had been ~r 1 n i ~tered were measured (this ~ast method is described by 1~ ~ouiller, C., experimental toxic injury of the liver; in The Liver, C. Rouiller, Volume 2, pages 335-476, New York, Academic Press, 1964)o The action potency of the compounds according to the invention was det~rrined as the percentage inhibition of the liver hydroxyproline synthesis and serum 7s-(IV)-collagen synthesis following oral administration in comparison with control ~ni 9l B to which only carbon tetrachloride had been A~' i n i Rtered ~ CC14 control). ~he result~ are shown in Table 2. The compounds from E~amples 2 and 3 of Ge ~n Patent ~~3r703~559 ~,N'-bis(2-methoxy-ethyl)-pyri~ine-2,4-dicarboxylic acid diamide and N,N'-bis(3-isopropox~propyl)-pyridine-2,4-dicarboxylic acid diamide) are likewise also ~hown as comparison ~ubstan-ces. Surprisingly, the compounds according to the inven-tion show a better activity, even after oral ~-' ini~t:ra-tion, than the intraperitoneally ~l inistered compound from Example 2 of Germ~n Patent A-3~703,959.
2 ~ 1 .J i~ ~ i f J r -- 16 ~
Table 2:
SubstancQ Dosage Liver Serum 7B- Admini~-from hydxo~y~ (IV)-collagen tration Example proline ~% [% inhibition~
inhibition~
1 2x2 mg 62 28 p.o.
2xlO m~ 90 67 p.o.
2 2x2 mg 25 2 p.o.
2xlO mg 60 35 p.o.
2 (from 2x25 mg 55 48 i.p.
DE-A-3,703,959 3 (from 2x25 mg 49 11 p.o.
DE-A-3,703,~59' p.o. = peroral i.p. = intraperitone~l
Claims (20)
1. An N,N'-bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamide of the formula I
wherein R1 denotes linear or branched C1-C4-alkanediyl, R2 denotes unbranched C1-C4-alkyl or hydrogen, n denotes 1 or 2 and R1, R2 and n' have the same meanings as R1, R2 and n, R1 and R1', and R2 and R2' and n and n' being identical or different, or a physiologically tolerated salt thereof, excluding N,N'-bis(2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide and N,N'-bis(2-hydroxyethyl)-pyridine-2,4-dicarboxylic acid diamide.
wherein R1 denotes linear or branched C1-C4-alkanediyl, R2 denotes unbranched C1-C4-alkyl or hydrogen, n denotes 1 or 2 and R1, R2 and n' have the same meanings as R1, R2 and n, R1 and R1', and R2 and R2' and n and n' being identical or different, or a physiologically tolerated salt thereof, excluding N,N'-bis(2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide and N,N'-bis(2-hydroxyethyl)-pyridine-2,4-dicarboxylic acid diamide.
2. A compound of the formula I as claimed in claim 1, in which in each case R1 and R1', R2 and R2' and n and n' have the same meaning.
3. A compound of the formula I as claimed in claim 1, in which the substituents -(R1)-(OR2)n and -(R1')-(OR2')n' are different.
4. A compound of the formula I as claimed in any one of claims 1, 2 and 3, in which R1 denotes linear or branched C1-C3-alkyl and R2 denotes unbranched C1-C2-alkyl or hydrogen.
5. The compound of the formula or one of its physiologically tolerated salts.
6. The compound of the formula or one of its physiologically tolerated salts.
7. The compound of the formula or one of its physiologically tolerated salts.
8. The compound of the formula or one of its physiologically tolerated salts.
9. The compound of the formula or one of its physiologically tolerated salts.
10. The compound of the formula or one of its physiologically tolerated salts.
11. The compound of the formula or one of its physiologically tolerated salts.
12. The compound of the formula or one of its physiologically tolerated salts.
13. A process for the preparation of an N,N'-bis-(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamide of the formula I
wherein R1 denotes linear or branched C1-c4-alkanediyl, R2 denotes unbranched C1-C4-alkyl or hydrogen, n denotes 1 or 2 and R1', R2 and n' have the same meanings as R1, R2 and n, R1 and R1', and R2 and R2' and n and n' being identical or different, excluding N,N'-bis(2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide and N,N'-bis(2-hydroxyethyl)-pyridine-2,4-dicarboxylic acid diamide, which comprises reacting a pyridine-2,4-dicarboxylic acid halide with an alkoxyslkylamine or hydroxy-alkylamine.
wherein R1 denotes linear or branched C1-c4-alkanediyl, R2 denotes unbranched C1-C4-alkyl or hydrogen, n denotes 1 or 2 and R1', R2 and n' have the same meanings as R1, R2 and n, R1 and R1', and R2 and R2' and n and n' being identical or different, excluding N,N'-bis(2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide and N,N'-bis(2-hydroxyethyl)-pyridine-2,4-dicarboxylic acid diamide, which comprises reacting a pyridine-2,4-dicarboxylic acid halide with an alkoxyslkylamine or hydroxy-alkylamine.
14. A process for the preparation of an N,N'-bis-(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamide of the formula I
wherein R1 denotes linear or branched C1-C4-alkanediyl, R2 denotes unbranched C1-C4-alkyl or hydrogen, n denotes 1 or 2 and R1', R2' and n' have the same meanings as R1, R2 and n, R1 and R1', and R2 and R2' and n and n' being identical or different, which comprises first A) 1. adding at least two equivalents of a halogenating agent to pyridine-2,4-dicarboxylic acid and 2. dissolving at least 2 equivalents of a hydroxy-alkylamine or alkoxyalkylamine of the formula II or II' H2N-(R1)-(OR2)n (II) H2N-(R1')-(OR2')n' (II') in which R1 and R1' denote linear or branched C1-C4-alkanediyl, R2 and R2' denote unbranched C1-C4-alkyl or hydrogen, n and n' denote 1 or 2 and R1 and R1', R2 and R2' and n and n' are identical or different, but II and II' are different, in a solvent and then reacting the solution prepared according to 1. with the solution prepared according to 2., or B) converting the resulting N,N'-bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamide into the bis(hydroxyalkyl) compound, or C) reacting the pyridine-2,4-dicarboxylic acid halide prepared according to A) 1. with a substituted or unsubstituted benzyl alcohol to give the benzyl pyridine-2,4-dicarboxylate, hydrolyzing the benzyl ester selectively in the 2-position of the pyridine, converting the free carboxylic acid in the 2-position into the acid halide again in accordance with process variant A) 1. and adding a solution prepared according to A) 2. using a compound of the formula II' to the compound thus obtained, a pyridine-4-(carboxylic acid benzyl ester)-carboxylic acid amide being formed, and then splitting off the benzyl protective group in the 4-position by hydrogenolysis, converting the free carboxylic acid into the acid chloride again in accordance with process variant A) 1., and subsequently adding a solution prepared according to A) 2. using a compound of the formula II, an unsymmetrically substituted compound of the formula I being formed, and if appropriate then converting the resulting compound of the formula I into its physiologically tolerated salt.
wherein R1 denotes linear or branched C1-C4-alkanediyl, R2 denotes unbranched C1-C4-alkyl or hydrogen, n denotes 1 or 2 and R1', R2' and n' have the same meanings as R1, R2 and n, R1 and R1', and R2 and R2' and n and n' being identical or different, which comprises first A) 1. adding at least two equivalents of a halogenating agent to pyridine-2,4-dicarboxylic acid and 2. dissolving at least 2 equivalents of a hydroxy-alkylamine or alkoxyalkylamine of the formula II or II' H2N-(R1)-(OR2)n (II) H2N-(R1')-(OR2')n' (II') in which R1 and R1' denote linear or branched C1-C4-alkanediyl, R2 and R2' denote unbranched C1-C4-alkyl or hydrogen, n and n' denote 1 or 2 and R1 and R1', R2 and R2' and n and n' are identical or different, but II and II' are different, in a solvent and then reacting the solution prepared according to 1. with the solution prepared according to 2., or B) converting the resulting N,N'-bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamide into the bis(hydroxyalkyl) compound, or C) reacting the pyridine-2,4-dicarboxylic acid halide prepared according to A) 1. with a substituted or unsubstituted benzyl alcohol to give the benzyl pyridine-2,4-dicarboxylate, hydrolyzing the benzyl ester selectively in the 2-position of the pyridine, converting the free carboxylic acid in the 2-position into the acid halide again in accordance with process variant A) 1. and adding a solution prepared according to A) 2. using a compound of the formula II' to the compound thus obtained, a pyridine-4-(carboxylic acid benzyl ester)-carboxylic acid amide being formed, and then splitting off the benzyl protective group in the 4-position by hydrogenolysis, converting the free carboxylic acid into the acid chloride again in accordance with process variant A) 1., and subsequently adding a solution prepared according to A) 2. using a compound of the formula II, an unsymmetrically substituted compound of the formula I being formed, and if appropriate then converting the resulting compound of the formula I into its physiologically tolerated salt.
15. A compound as claimed in any one of claims 1 to 12 for inhibition of proline hydroxylase and lysine hydroxylase.
16. A compound as claimed in any one of claims 1 to 12 for use as a fibrosuppressant and immunosuppressant.
17. A pharmaceutical containing a compound of the formula I as claimed in any one of claims 1-12 and/or one of its physiologically tolerated salts with tolerated pharmaceutical excipients.
18. The use of a compound of the formula I as claimed in any one of claims 1-12 and/or a physiologically tolerated salt thereof for influencing the biosynthesis of collagen and collagen-like substances or the biosynthesis of Clq.
19. The use of a compound of the formula I as claimed in any one of claims 1-12 and/or a physiologically tolerated salt thereof for the treatment of disturbances in the biosynthesis of collagen and collagen-like substances or the biosynthesis of Clq.
20. A process for the preparation of pharmaceuticals for influencing the biosynthesis of collagen and collagen-like lagen-like substances or the biosynthesis of Clq, which comprises incorporating a compound of the formula I as claimed in any one of claims 1-12 and/or a physiologically tolerated salt of this compound into the pharmaceutical.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3924093.2 | 1989-07-20 | ||
| DE3924093A DE3924093A1 (en) | 1989-07-20 | 1989-07-20 | N, N'-BIS (ALKOXY-ALKYL) -PYRIDINE-2,4-DICARBONESAUREDIAMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2021529A1 CA2021529A1 (en) | 1991-01-21 |
| CA2021529C true CA2021529C (en) | 1997-12-30 |
Family
ID=6385494
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002021529A Expired - Fee Related CA2021529C (en) | 1989-07-20 | 1990-07-19 | N,n'-bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamides, preparation and their use |
Country Status (26)
| Country | Link |
|---|---|
| EP (1) | EP0409119B1 (en) |
| JP (1) | JPH0776213B2 (en) |
| KR (1) | KR0181945B1 (en) |
| AT (1) | ATE104280T1 (en) |
| AU (1) | AU624978B2 (en) |
| CA (1) | CA2021529C (en) |
| CY (1) | CY1997A (en) |
| CZ (1) | CZ280129B6 (en) |
| DD (1) | DD300429A5 (en) |
| DE (2) | DE3924093A1 (en) |
| DK (1) | DK0409119T3 (en) |
| ES (1) | ES2052112T3 (en) |
| FI (1) | FI94630C (en) |
| HU (1) | HU218274B (en) |
| IE (1) | IE64438B1 (en) |
| IL (1) | IL95121A (en) |
| LT (1) | LT3798B (en) |
| LV (1) | LV10430B (en) |
| NO (1) | NO177187C (en) |
| NZ (1) | NZ234563A (en) |
| PL (1) | PL166307B1 (en) |
| PT (1) | PT94779B (en) |
| RU (1) | RU1836350C (en) |
| SK (1) | SK279199B6 (en) |
| UA (1) | UA19056A (en) |
| ZA (1) | ZA905680B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| DE58908519D1 (en) * | 1988-08-04 | 1994-11-24 | Hoechst Ag | Improved process for the preparation of N, N-bis (alkoxyalkyl) pyridine -2,4-dicarboxylic acid diamides. |
| DE4020570A1 (en) | 1990-06-28 | 1992-01-02 | Hoechst Ag | 2,4- AND 2,5-SUBSTITUTED PYRIDINE-N-OXIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| DE4030999A1 (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 | |
| 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 |
| TW222585B (en) * | 1992-09-11 | 1994-04-21 | Hoechst Ag | |
| DOP2002000332A (en) | 2001-02-14 | 2002-08-30 | Warner Lambert Co | MATRIX METALOPROTEINAS PYRIDINE INHIBITORS |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3432094A1 (en) | 1984-08-31 | 1986-03-06 | Hoechst Ag, 6230 Frankfurt | ESTER OF PYRIDINE-2,4- AND -2,5-DICARBONIC ACID AS A MEDICINAL PRODUCT FOR INHIBITING PROLIN AND LYSINE HYDROXYLASE |
| 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 |
| 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 |
| 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 |
| DE3826471A1 (en) | 1988-08-04 | 1990-02-22 | Hoechst Ag | Improved process for the preparation of N,N'-bis(alkoxyalkyl)pyridine-2,4-dicarboximides |
| DE3828140A1 (en) | 1988-08-19 | 1990-03-01 | Hoechst Ag | 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 |
| DE58908519D1 (en) * | 1988-08-04 | 1994-11-24 | Hoechst Ag | Improved process for the preparation of N, N-bis (alkoxyalkyl) pyridine -2,4-dicarboxylic acid diamides. |
-
1989
- 1989-07-20 DE DE3924093A patent/DE3924093A1/en not_active Withdrawn
-
1990
- 1990-07-14 AT AT90113528T patent/ATE104280T1/en not_active IP Right Cessation
- 1990-07-14 DK DK90113528.5T patent/DK0409119T3/en active
- 1990-07-14 DE DE59005328T patent/DE59005328D1/en not_active Expired - Fee Related
- 1990-07-14 ES ES90113528T patent/ES2052112T3/en not_active Expired - Lifetime
- 1990-07-14 EP EP90113528A patent/EP0409119B1/en not_active Expired - Lifetime
- 1990-07-18 CZ CS903576A patent/CZ280129B6/en not_active IP Right Cessation
- 1990-07-18 IL IL9512190A patent/IL95121A/en not_active IP Right Cessation
- 1990-07-18 FI FI903624A patent/FI94630C/en not_active IP Right Cessation
- 1990-07-18 DD DD342874A patent/DD300429A5/en not_active IP Right Cessation
- 1990-07-18 NZ NZ234563A patent/NZ234563A/en unknown
- 1990-07-18 SK SK3576-90A patent/SK279199B6/en unknown
- 1990-07-19 ZA ZA905680A patent/ZA905680B/en unknown
- 1990-07-19 KR KR1019900010938A patent/KR0181945B1/en not_active IP Right Cessation
- 1990-07-19 IE IE264290A patent/IE64438B1/en not_active IP Right Cessation
- 1990-07-19 PL PL90286132A patent/PL166307B1/en unknown
- 1990-07-19 AU AU59144/90A patent/AU624978B2/en not_active Ceased
- 1990-07-19 CA CA002021529A patent/CA2021529C/en not_active Expired - Fee Related
- 1990-07-19 UA UA4830947A patent/UA19056A/en unknown
- 1990-07-19 HU HU549/90A patent/HU218274B/en not_active IP Right Cessation
- 1990-07-19 NO NO903235A patent/NO177187C/en not_active IP Right Cessation
- 1990-07-19 JP JP2189620A patent/JPH0776213B2/en not_active Expired - Lifetime
- 1990-07-19 RU SU904830947A patent/RU1836350C/en active
- 1990-07-20 PT PT94779A patent/PT94779B/en not_active IP Right Cessation
-
1993
- 1993-05-07 LV LVP-93-301A patent/LV10430B/en unknown
- 1993-11-12 LT LTIP1462A patent/LT3798B/en not_active IP Right Cessation
-
1997
- 1997-09-05 CY CY199797A patent/CY1997A/en unknown
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