CA2034206A1 - Di(nitroxyalkyl)amides of pyridine-2,4- and -2,5-dicarboxylic acids, a process for the preparation thereof, and the use thereof - Google Patents

Di(nitroxyalkyl)amides of pyridine-2,4- and -2,5-dicarboxylic acids, a process for the preparation thereof, and the use thereof

Info

Publication number
CA2034206A1
CA2034206A1 CA002034206A CA2034206A CA2034206A1 CA 2034206 A1 CA2034206 A1 CA 2034206A1 CA 002034206 A CA002034206 A CA 002034206A CA 2034206 A CA2034206 A CA 2034206A CA 2034206 A1 CA2034206 A1 CA 2034206A1
Authority
CA
Canada
Prior art keywords
formula
compound
collagen
salts
pyridine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002034206A
Other languages
French (fr)
Inventor
Ekkehard Baader
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hoechst AG
Original Assignee
Hoechst AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoechst AG filed Critical Hoechst AG
Publication of CA2034206A1 publication Critical patent/CA2034206A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • C07D213/26—Radicals substituted by halogen atoms or nitro radicals
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • 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

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Transplantation (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE:

The invention relates to di(nitroxyalkyl)amides of pyridine-2,4- and -2,5-dicarboxylic acids, of the formula I

Description

HOECHST AXTIENGESEhLSCHAET HOE 90/F 010 Dr. SW/PP
De~cription 20~20B

Di(nitroxyalkyl)amides of pyridine-2,4- and ~2,5-dicarboxyli~ acids, a process for ~he preparation there-of, and the use thereof Compounds which inhibit the enzymes pxol~ne hydroxyla~e and lysine hydroxylase bring about ~ very ~elective inhibition of collagen biosynthesi~ by influencing the collagen-~pecific hydroxylation reaction~. In the cour~e thereof, prote~n-bound proline or lysine i8 hydroxylated by the enzymes proline hydroxylase or lysina hydroxyla5e.
If this reaction i~ suppressed by inhibitor6, the re~ult is an insufficiently hydroxylated colla~en molecule which is unable to function and can be released by the cells into the extracellular ~pace only in a ~mall ~mount.
~oreover, the in~ufficiently hy~roxylated collaqen cannot be incorporated in the ~ollagen matrix and very readily undergoes proteolytic degradation. The consequence of these effects i~ an overall reduction in the amount of collagen deposited outside the cell~.

It is knvwn that the inhibition of proline hydroxylase by known inhibitors ~uch as ~ dipyridyl results in inhibition of Clq biosynthesi~ by macrophages (W. Muller et al., FE3S Lett7 90 (1978), 218; Immunobiology 155 (1978), 47). Thi~ lead to the classical pathway of complement activation becoming inoperative. ~hus, inhibi-tors of proline h~droxylase also act a~ immunosuppre~-~ants, for example in immune complex diEeases.

It is ~nown that the enzyme proline hydroxylase i8 e~ficien~}y inhibited by pyridine-2,4- and -2,5-dicarb-oxylic acids (X. Ma~amaa et al., Eur. J. Biochem. 138 (1984) ~39-245). The~e compounds are, however, effective inhibitors in cell culture only in very high concentra-tions ~Tschank, G. et al., Biochem. J. 238 (1987~ 625-633).
- 2 ~ 20~20~
DE-A 34 32 094 ~3i.ve~ a d~cription of die~tQrs of pyri-dine-2, 4- and -2, 5-dicarbo~rlic aclds with 1-6 carbon atom~ in the efiter alkyl moiety as pharma~ceuticals ~c~r inhibiting proline hydro~ se ~n~ ly~ine hy~roxyla~e.

These lower nlkyl diesters ha re ~he diRadvantage, how-ever~ th~t ill ~he body they are too rapidly clea~red to the acids and do not reach ~heir ~te of ~ctioTl ~ n the Cl311 in ~ufficiently high concentration and thu~ nre poorly suited :Eor po6sible ~*ministration a8 phann~:eu~i-cal~.

DE-A 37 03 959, D~:-A 37 03 962 and DE-A 37 03 963 de~-criba in a ~eneral ~Eorm mixed ester/amide~, higher all~l diesters and diamide~ of p~ridine-2, 4- ~nd -2, 5-dicar-boa~lic acid~, which are effec~ive inhibitors of collagen biosynthe~ ani~al model~.

~hus, DE-A 37 03 959 de~cribes, inker alia, the ~ynthe~i~
OI N,N'-bi8(2-methoxyethyl)pyridine-2,4-dic~rboxamideand N,N'-bls(3-isopropoxypropyl)pyridine-2,4-dicarboxamide.

German Patent Applications P 38 26 4~1.4 and P 38 28 140.6 propose ~n improved proce~ for the preparation of N,N'~bis(2-methoxyethyl)pyridine-2,4-di~arboxamide.
~erman Patent Application P 3924093.2 propo~e~ n~w N,~'-bi~(alkoxyalkyl)pyridine-2,4-dicarboxamides.

Both pyridine-2,4- ~nd -2,5-dicarbox2mides (Hirakata et al., J. pharm. So~. Japan 77 (19S7) 219 and H~rincJ et elv. 37 ~1954) 147, 153) ~nd pyridinel~2,4- and ~2,5-dicarbohydrazides (Itai et al ., Bl . nation . hyg .
~abor. ~okyo, ?4 (1956) 115, 117 and Shinohara st ~1., Chem. High Polymer~ Japan, 15 (1958) 839) have already been di6closed a8 agent~ for tuberc~losi~.

JP 53/28175 ~78/28175) describes N,~'-bis(2-nitroxy-ethyl)pyridine-2,4- and -2,5-dicarboxamides as substancQs with a vasodilator action.

~3~2~
_ 3 _ It has now ~een ~ound, ~nrpri~i~gly, th~t di~nitroxy-~lkyl)amides ~f pyridine-2,4- and -2,5-dic~rboxylic aci~s, of the fo~mula I

02NO~ NOC~,~

~ ~a~~ C:ONH-~.- ON02 in which R is C1-Cj-alk~n~diyl, and ~he phy~iol~gically tolera~ed ~allts, effactiv~ly inhibit lys~na hydroxyl~e and proline hydroxylas~ in animal ~odels.

Accordingly, the invention relate~ ~o a~ ~he u~e of compounds of ~he for~ula I

02NO-R-HNoC_ ~ ~ (I) N C4NH-R-~N02 ~-.

~n whi~h R is Cl C4-alkaned~yl, and the physiologically tolerated 8alt~, for the prepar-ation of a pharmaceutical which inhibit~ proline hy-droxylase and ly~ine hydroxylase.

Tha inven~ion additionally rela~e~ to b) the co~pound3 of~he formula I
in w~ich R is methylene, propylen~ or butylene, and the phy~iologically tolerated ~alt~, for use a~
pharmaceuticals.

" 2~3420~

The i~ven~ion ~dditionally rel~tes ~o c) the compound~ of the formul~ I
in which R is methylene, propylene or butylene, 5 and the physiolog~cally tolerated salts th~reof.

The invention particularly r~late~ to ~he c~mpound~ o~
the formula I def~ned ~n a~, b) ~nd c) for u~e a~ fibro-~uppres~ant~ and immuno~uppres~ants and for the ~nhi-bi~ion of proline hydroxyla~e and ly~ine h~droxyla~e and for influencing ~he metaboli~m of ~ollagen ~nd coll~gen~
like ~ubstances ~nd the biosynthesi~ of ~

All the ~aid alkyl radic~ls with more than 2 carbon atoms can be both straight-chain and branched.

~he in~ention additionally relat28 to ~ proces~ for ghe preparation of cGmpou~d~ of the formula I, which com- --pri~es r~actin~ a csmpound of the formula I~

Y-C -r~
N ~Y

with a co~pound of the formula III

~2N-R-ONO~ (I$~) where R has the ~eaning ~peci ied for for~ula I, ~nd ~ i8 halogen, hydroxyl or Cl--C~-alkoxy, or form~ toge~h2r with the carbon~l group an active e3ter or a mixed anhydrida, or compriEes nitrating ~ compound o~ tho formula IV

~3~2~6 H0- R- ~NOC f ~, g IV) ~ N~~ t:O~ OH

in which R ~ ~ as dafined above, ~d sub~equently con~ertirlg the reaction product~ whare appropri~te .~ n~o their phy~io-logi cally tolerated l~alt8 .

S The pr~par~tion of compounds of the formula I ~nd the preparation of tho~e ~ar~ing sub~tances re~ir~d for th~ which canno~ be bought i~ da~cribed in detai 1 hereinafter .

The compound~ according ~o the ~ nvention are prepzred 10 ~no~t ~traightforwardly by ~he two component~, ~he pyr~-dine derivative of t~e formula ( II ) and the amine of 1the formula (III), baing ~ixed in equimolar amoun~ or with ~n up to about 5-fold exces~ of III and reacted at temperatures between -30 and 150C, prefer~bly at 20 to 15 100C, urltil the reaction i6 c:omple~e. ~he completion of the reaction can be deter~ined, for esample, by thin-layer ~hromatograp~y. One vari~nt of thi~ process ~o~-pri~e~ u~ing ~ ~uitable 801vent ~uch as die~hyl ether or dime~hoxyethane or ~etrahydrofuran, chlorinated hydro-carbon~ such a~ methylene chloride, chloroform, tri- or tetrachloroethyl~ne, benzene, toluene or else polar solvent~ ~uch ~ dimethyl~or~amide, acetone, al~ohols su~h a~ methanol or ethanol or dimethyl sulfo~ide. It ~a al80 po~sible in this ca~e to u~e an exce88 of amine of the formula (III), which c~n be up ~o about 5-fold amount~. ~he t~mperatures for this reaction ar0 betwaen room temperature ~nd the boilin~ point of the ~ol~ent, with temperatures in the range ~rom room temperature to 130C being partlcularly preferred.

The reaction can likewise be carried out via a ~i~ed - 6 - 2~2~
anhydride such a~ athyl ~hloroformate or ~ia an activated e~ter ~uch as p~ranitrophenyl e~ter ~g= ClCH2-COO or ~O2-C~H~-O). Appropri~te methods ~re de~cxibed in the literature.

It i~ al~o pos~ible, where appropriate, for the r~action to be carxied out in the presence of b~e~. ~x~ple3 of suitabl~ additional ba~es are carbonate~ or bicarbonat~
~uch a~ ~odium or potas~ium car~onate or ~odium or potasfiium bicarbona~e, or ter~iary amines ~uch a~ tri-e~hylamine, tributyl~ine, ethyldii~opropylamine or hetQrocyclic amine~ ~uch a~ ~al~y~orpholin~, pyridlne, quinoline or dialkylanilines.

Ome variant for the prQparation of the comp~unds o$ the fonmula I comprises nitration of the correspondiny hydroxyalkyldia~ides of pyridine-2,4- or -2,5 di-carboxylic acid ~ IV) . Thi8 entail~ adding concentrat~d nitric acid to the coxre~ponding hydroxyalkyldiamide~ at reaction ~emperature~ ~rom -20C to +10C~ preferably at -10C to 5C. The reaction t~me in thi~ ca~e i~
10-240 min, pr~ferably 20-90 min. The reaction product iB
sub~eguently neutralized where appropriate.

Where appropriate the produc~ can be worked up, for example, by extraction or by chromatography, for example on silica gel. The i~olated product can ba racry~tallized and, where appropriat2, reacted with a auitsble acid ~o gi~e a physLolo~ically toler2ted salt. ~ample~ of ~uitable acids are:

mineral acid~ such a~ hydrochloric and hydrobromic ~cid, ~nd ~ulfuric, phosphoric, nitric or perchloric acid or organic acid~ such as formic, ~cetic, propionic, ~uc-cLnic, glycolic, lactic, malic, ~artaric, citric, maleic, fumaric, phenylacetic, benzoic, methanesulfonic, toluene-~ulfonic, oxalic, 4-uminobenzoic, naphthalen3-lt5-disulf-onic or a~corbic ~cid.

Those starting compounds of the formul~ (III) which cannot ba bought can b~ ~ynthe~ized by proce~se~ known from the liter~ture.

The 3tarting ~ompounds of ~he for~la (II) ~re obtained, S for example, by conv~rt~ng pyridine-2,4- or -2,5-dicarb-oxylic acid ~nto the corre~pondi~g p~ridine~2 t 4- or ~2,5-dic~r~o~yl halide, praferably ~hloride (~y proce~e~
known fro~ the literature), preferably in tha pr~ence of a catalyst such AS dimethylform~mide. Thi~ acid halide 10 can then be reacted, ~or ex~mplQ, either wLth ~ suitable alcohol, for example par~nitrobanzyl alcohol, to giva ~he co~re~ponding active ester, or else with lower alcohol~
~uch a~ ~ethanol or ethanol ~o give the corre~po~ding esters. It i~ likewi~e a180 pos~ible for the pyridine-2,4- or 2,5-dicarbo~ylic acid ini~ially ~o be conYerted by addition of a 6uitab1e carboxylic acid vr of a carb-oxylic es~er such as ethyl chlorovrmate into a ~ixed anhydride which i~ then reacted with ~he amine~ ~III) to give the products accord~ng to the invention. An approp-riate method i~ likewi~e de~cribed in the literature.

~he starting compounds o~ the formula (IV) are obtained,for example, by reacting corre~ponding ~,N'-bis(alkoxy-alkyl)pyridi~e-2~4- or -2,5-dicarboxamide~, preferably the bis(methoxyalkyl)diamide by proce~se~ known fro~ the literature, for ex2mple wi~h boron tribromide. The preparation of the bi~(alkoxyalkyl)diamide~ i~ knowm and de~cribed, or e~ample, in DE-A 3,703,~59. Thi~ entail~
reactin~ a reac~ive pyridinedicarboxylic acid derivativa, for exsmple the pyIidinedicarbon~l ~hloride, with an alkoxyalkylamine.

The compound~ o~ th2 formula I according to the in~ontion have valuable pharmacological properties and di~pl~y, in particular~ activity aE inhibitors of proline hydroxyla3e and lysine hydro~ylase, as fibrosuppres~ant and immuno-3s ~uppres~ant.

2~3~2~6 secause of the~ pharmacological propertie~ the co~-pounds according to the invention are suitable for the treatment of di~turbance~ of ~he metaboli~m of ~ollag~n and collagen-like ~ub~tance~ an~ ~or the treatment of S disturbances of the bio~ynthe~i3 of Clq.

Hence the i~ention furthermore rel~te~ to the u8e of the ~ompounds of the formula I ~ccording to ~he invention ~nd of the phy3iologically tolerated ~altls thereof for the tx~atment of the abovementioned metabo.lic dieorder~.

14 The compounds can be used as pharmaceuticals eithe~ ~lone or mi~ed ~ith physlologically tslarated ~uxiliari~ or excipient~. They can be ~dm$nistered or this purpo~e orally in do~es of O.Ol - 25.Q mg/kg/day, pxefer~bly O.Ol - 5.4 mg/kg~day or parenterally in dose~ of O.OOl - 5 ~/
kg/day, preferably 0~401 - 2.5 mg/kg~day, in particular 0.005 - 1.0 mg~kg/day. ~he do~e can al90 be increas~d in aavere ca3es. How~vsr~ in many ca~es, low~r dose~ are al~o sufficient. ~hese data rel~e to ~dul~s weighing about 75 kg.

The invention ~dditionally e~braces the use of ~h~
compound~ according to the inv~ntion for the preparation of pha~maceutical3 which are ~ployed ~or the ~reatment and prophylaxi3 o~ the abovemen~ione~ me~abol~c dia-order~.

The invent~on furthermore relates to pharmaceutical~
which contain ona or ~ore compound~ o~ the formllla.I
according to the inven~ion ~nd/or the phy~iologically tolerated salts thereof.

The pharmaceuticals are prepared by proce~fies which are known per se ~nd ~amiliar to tho~e skilled in the ~rt.
The pharmacologically active compounds (~ ~cti~e ~ub-s~ance~ according to the invention are ffmployed a~
pharmaceutical~ either ax ~uch or, pre~erably, in com-bination with ~uitable pharmaceutical ~uxiliaries or - 9 - 2~206 excipients in the form of tablsts, coatsd tablet~, cap~ules ~ ~UppoE~itorie~ ~ ~mulsions ~ su3pension~ or solutions, in whi~h the content o~ ac~ive ~ aIIce~ i~ up to abollt 9596, advantag20usly between 10 and 759~.

S ~:xample~ of suitablQ æuxill~Lrie~; or Q~ccipient~ for the desired pharmaceutical formulation are, be~ides ~olvent~, gel-formers, suppository ba~a~, t~blet auxiliarie~ ~nd other act~ve E3ubstanae ~ehicle~, al~o ant~o~idan~, dispersing agent~, 0mul~ifierE~, anti~oam z~5~ents" flavor correctlves, pre~ervative~, ~olubilizers ~nd color~nt~.

The acti~e substance6 c:an be admini6tered sr~lly, paren-ter~lly or rec~ally.

The a~tive compound3 are mixed with the additives ~uit-able for this purpo~e, ~uch a8 excipients, Etabili~ers or inert diluent~, ~nd conYerted by cu~tomary methods into ~uitab~e dosage forms ~uch a~ tablets, coated tablets, hard gelatin cap~ules, aqueou~ alcoholic or oily suspen-~ion~ or aqueou~ or oily ~olution~.

~ xamples of inert excipients which can be u~ed are gum arabic, magnesia, ma~nesium ~arbona~e, potassium phos-phate, lacto~e, gluco~e or starch, especially corn starch. This preparation can be carried out both ~ dry and as w~t ~ranules. Examples of ~uitable oily excipients or ~ol~ent3 are qegetabla or animal 0~18 r BU~h a~ sun-flower oil or fish liver oil.

For subcutaneous or intravenous administration, ~heactive compounds are converted in~o ~olution, su~pen~ion or emulsion, if de~ired with the sub3tances suitable for thi~ purpose, ~uch as ~olubilizers, emulsifier~ or other auxiliaries. ~xamples of suitable ~olvents are phy~io-logical saline or alcohols, for ex~mple ethanol, propan-ol, glycerol~ a~ well as sugar solution~ ~uch as glucoQe or mannitol solutions, or el~e a mi~ture of the various solvent~ men~ioned.

lo- ~3~6 The invention 1~ explain2d in detail hereinaf~er by means of axamples.

lr80r 1 S

bis-N,N~-(Metho~yathyl)amideofpyridine 2,4-dicarbosylic aci~

~ON~ 2-C~2-~H3 N CffN~-CH2~C~2-OC~3 3 g of pyridine-2,4-dicarboxylic acid are introduced into 50 ~1 of toluene and 1 ml of D~F, ~nd 2.7 ~1 o ~hinnyl chloride are added dropwi~e to the ~olut~o~. ~he ~ixt~re i8 heated un~il no further evolutio~ of g~ i8 evid2nt (about 2.5 h). The mixture i8 cooled, 5 ml of toluene are di~illed out, and 4.6 ml of 2-methoxyethylamine and 5 ml o~ trieth~lamine are added dropwi~e to the solution. ~he ~olution i~ ~t~rred ~t room temperature ~or 4 h and ~hQn evaporated, the rQsidu2 i~ taken up in water and QX-tracted 4 x with ~ethylene chlorlde. ~he ~o~bined orga~ic pha~es are dried over m~gne3ium eulfate ~nd e~aporated.
The cruda produ~t i~ ~hromatographed on ~ilica gel (solven~ ethyl acetate).

Nelting point: 42 44C
lH-~MR tCDCl3)s 6 = 1.2 (3H, tr); 3.3-3.8 (12H, gu. and m); 7.9 (lH, m); 8.4-8.5 (1~, m3;
8.7-808 (1~, m);

U3~206 Precur30r 2 ~

bi~ -~, N ' ~ ydrc)xysthyl ) amld~e o f pyridi~e~2, 4 -dicarboxylic acid ~:ONH- C~H2- ~2- ~
~ i ~:02~ 2- ~2- ~

0.5 g of bi~ ,N'-(2-methoxyethyl)am~de o~ pyridim3-2,4-dicarboxylic ~cid (precur~or 1) i8 diB81:)1Ved ~n 10 ml of dichlorome~hane and, at -78~C, boron tribromide ~11 ~1, 1 molar ~olution in dichlorometh~ne) ~3 added drop~ e.
After addition i~ co~plote, ~llow to reach room teDlper-ature and then stir ~or 3 hour~. Pour in~o 100 ml of 10 ~atura~ed bicarbonate ~olution and ~actrwt 3 ae wi~h ~thyl ~cetate. The combined or~lanic 801~ent~ re dried with magnesium sulfate ~nd e~aporated. The c:~ude produc~t i~
chromatographed on silica gel.

lY-~5R (CDCl3)s o ~ 1.5-2.2 (4LH, m); 3.4 (4H, m)7 3.6 (4H, m), 7.9-8.0 (lH, ~); 8.4-8.5 (lH, ~; 8.7-8.8 (lH, m) ~ca~pl~ 1 N,N'-Di(2-nitroxyethyl)amideofpyridine-2,4-dicarbo~ylic ci~
.
CON~-CH2-CH2-`ON02 ,. ~
N OONH-eX2-~H2~0NO~

1 g of di(2-hydroxyethyl)amide of pyridine-2,4-di-carboxylic acid (precursor 2) i8 added at -10C to -5C

- 12 - 2~3~20~
to5ml of concentrated nitric acid. ~he mixture i8 al-lowed to warm to 2C and then ~tirrad for 40 minutes. It is pouxed into ice~w~ter and ~eutralized with sodium carbonate. The ~olution $~ ex~racted three ~imes with dichloromethane, and the organic pha~es are dried over magnesium sulfata and evaporat~d. The rasidu~ cry~tal-lizes from ether.

Yield: 750 mg Melting points 85 - 88C

Claims (13)

1. The use of di(nitroxyalkyl)amides of pyridine-2,4- and -2,5-dicarboxylic acids, of the formula I

(I) in which R is linear or branched C1-C4-alkanediyl, and the physiologically tolerated salts, for the prepar-ation of pharmaceuticals which inhibit proline hydroxyl-ase and lysine hydroxylase.
2. The use as claimed in claim 1, wherein R is ethylene or propylene.
3. A compound of the formula I

(I) in which R is methylene, propylene or butylene, and the physiologically tolerated salts.
4. A compound of the formula I as claimed in claim 3, wherein R is methylene or n-propylene.
5. A compound as claimed in claim 3 or 4, for use as pharmaceutical.
6. A process for the preparation of compounds of the formula I as claimed in claim 3, which comprises reacting a compound of the formula II

(II) with a compound of the formula H2N-R-ONO2 (III) where R has the meanings specified in claim 3, and Y is halogen, hydroxyl or C1-C4-alkoxy, or forms together with the carbonyl group an active ester or a mixed anhydride, or comprises nitrating a compound of the formula IV
IV

in which R is as defined in claim 3, and subsequently converting the reaction products where appropriate into their physiologically tolerated salts.
7. A compound as claimed in claim 3 or 4 for inhibiting proline hydroxylase and lysine hydroxylase.
8. A compound as claimed in one or more of claims 1 to 4 for use as fibrosuppressants and immunosuppressants.
9. A pharmaceutical containing a compound of the formula I
as claimed in claim 3 or 4 with tolerated pharmaceutical vehicles.
10. The use of compounds of the formula I or the salts thereof as claimed in one or more of claims 1 to 4 for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of Clq.
11. The use of compounds of the formula I or the salts thereof as claimed in one or more of claim 1 to 4 for the treatment of disturbances of the metabolism of collagen and collagen-like substances and of the bio-synthesis of Clq.
12. A process for the preparation of pharmaceuticals for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of Clq, which comprises adding a compound of the formula I or the salts thereof a claimed in one or more of claims 1 to 4 to the pharmaceutical.
13. The use of the compound as claimed in claim 1 and substantially as described herein.
CA002034206A 1990-01-16 1991-01-15 Di(nitroxyalkyl)amides of pyridine-2,4- and -2,5-dicarboxylic acids, a process for the preparation thereof, and the use thereof Abandoned CA2034206A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4001002.3 1990-01-16
DE4001002A DE4001002A1 (en) 1990-01-16 1990-01-16 PYRIDINE-2,4-AND 2,5-DICARBONSAEUREDI (NITROXYALKYL) AMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF

Publications (1)

Publication Number Publication Date
CA2034206A1 true CA2034206A1 (en) 1991-07-17

Family

ID=6398117

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002034206A Abandoned CA2034206A1 (en) 1990-01-16 1991-01-15 Di(nitroxyalkyl)amides of pyridine-2,4- and -2,5-dicarboxylic acids, a process for the preparation thereof, and the use thereof

Country Status (19)

Country Link
EP (1) EP0438795A1 (en)
JP (1) JPH04330060A (en)
KR (1) KR910014352A (en)
CN (1) CN1053606A (en)
AU (1) AU631285B2 (en)
BR (1) BR9100159A (en)
CA (1) CA2034206A1 (en)
CS (1) CS7591A2 (en)
DE (1) DE4001002A1 (en)
FI (1) FI910177L (en)
HU (1) HUT59102A (en)
IE (1) IE910126A1 (en)
IL (1) IL96941A0 (en)
MA (1) MA22041A1 (en)
MX (1) MX24143A (en)
NO (1) NO910163L (en)
NZ (1) NZ236766A (en)
PT (1) PT96493A (en)
ZA (1) ZA91291B (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
YU9492A (en) * 1991-02-05 1995-03-27 Hoechst Ag. 2,4- and 2,5-BIS-TETRAZOLYL pyridines and the process for their preparation
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
RU2147301C1 (en) * 1998-10-28 2000-04-10 Институт проблем химической физики РАН Amidoalkanolnitrates and method of preparation thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK145608C (en) * 1976-04-02 1983-07-11 Chugai Pharmaceutical Co Ltd ANALOGY PROCEDURE FOR PREPARING THE NICKETIC ACID ESTER OF N- (2-HYDROXYETHYL) NICOTINAMIDE
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
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

Also Published As

Publication number Publication date
FI910177A0 (en) 1991-01-14
PT96493A (en) 1991-10-15
KR910014352A (en) 1991-08-31
BR9100159A (en) 1991-10-22
AU6936691A (en) 1991-07-18
JPH04330060A (en) 1992-11-18
MX24143A (en) 1993-05-01
MA22041A1 (en) 1991-10-01
HU910109D0 (en) 1991-08-28
EP0438795A1 (en) 1991-07-31
CS7591A2 (en) 1991-09-15
NO910163D0 (en) 1991-01-15
DE4001002A1 (en) 1991-07-18
FI910177A7 (en) 1991-07-17
CN1053606A (en) 1991-08-07
AU631285B2 (en) 1992-11-19
FI910177L (en) 1991-07-17
IL96941A0 (en) 1992-03-29
ZA91291B (en) 1991-09-25
IE910126A1 (en) 1991-07-17
NO910163L (en) 1991-07-17
HUT59102A (en) 1992-04-28
NZ236766A (en) 1993-08-26

Similar Documents

Publication Publication Date Title
IT8922768A1 (en) ACTIVE COMPOUNDS AS HMG-COA REDUCTASE INHIBITORS
FR2673427A1 (en) HETEROCYCLIC DIAZOTES N - SUBSTITUTED BY BIPHENYLMETHYL GROUP, PREPARATION THEREOF, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME.
FR2678618A1 (en) NOVEL TRIAZOLO PYRIMIDINE DERIVATIVES ANTAGONISTS OF ANGIOTENSIN II RECEPTORS; PROCESSES FOR PREPARING THEM, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
CA2690349A1 (en) Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics
CA2034206A1 (en) Di(nitroxyalkyl)amides of pyridine-2,4- and -2,5-dicarboxylic acids, a process for the preparation thereof, and the use thereof
US4952698A (en) Imidazole derivatives
FR2501209A1 (en) NOVEL DERIVATIVES OF CEPHALOSPORINS AND ANTIBIOTIC DRUGS CONTAINING SAID DERIVATIVES
FR2567887A1 (en) NEW SUBSTITUTED AMIDES, THEIR PREPARATION AND THE MEDICINES THAT CONTAIN THEM
IL116384A (en) Ylidene compounds and their preparation
HU195957B (en) Process for preparing betq-hydroxy-butyric acid ester derivatives
US4088668A (en) Acetylene derivatives
Paternotte et al. Syntheses and hydrolysis of basic and dibasic ampicillin esters tailored for intracellular accumulation
FR2927331A1 (en) NOVEL ANTI-INFECTIOUS DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE IN THERAPEUTICS
CA1135697A (en) 1-phthalazone derivatives, process for preparation thereof, and use thereof
Phelan et al. Improved delivery through biological membranes. XXXVII. Synthesis and stability of novel redox derivatives of naproxen and indomethacin
US6143900A (en) Stereoselective synthesis of oxazoline derivative
US6046201A (en) Pyridinecarboxamide derivatives
AU637848B2 (en) Pyridine-2,4- and 2,5-dicarboxamides, a process for the preparation thereof, and the use thereof
US3983127A (en) Pyrrolo[3,4-b]pyridines
CH620678A5 (en) Process for the preparation of a derivative of piperidine
EP1140874A1 (en) Stereoselective synthesis of oxazoline derivative
CH671762A5 (en)
US4156728A (en) 3-Substituted-2(1H)pyridone-6-carboxylic acids
JP3332171B2 (en) Method for producing thieno [3,2-b] pyridine derivative
FR2597869A1 (en) NOVEL ERGOLENE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME, AND PROCESS FOR THEIR PREPARATION

Legal Events

Date Code Title Description
FZDE Discontinued