CA1331986C - Polysulfuric acid esters of bis-aldonamides and their derivatives, process for their preparation and medicaments - Google Patents

Abstract

ABSTRACT
The invention relates to polysulfuric acid esters of bis-aldonamides in which the underlying aldonic acids can be linked glycosidically with a galactopyranosyl, mannopyranosyl, glucopyranosyl or oligopyranosyl radical in the 3-, 4- or 6-position. They are therapeutically active compounds, possessing antithrombotic and antiinflammatory properties. Their preparation and pharmaceutical compositions containing them are likewise des-cribed. The invention also relates to novel intermediates useful in preparation of the therapeutically active polysulfuric acid esters of bis-aldonamides.

Description

~ 3 3 ~ 9 8 ~

POLYSULFURIC ACID ESTERS OF BIS-ALDONAMIDES AND THEIR :
DERIVATIVES, PROCESS FOR THEIR PREPARATION
AND MEDICAMENTS : -:
Descrl~t:lon The lnvention re~lates to~polysulfurlc acld esters of ;~
bls-aldonamldes and thelr~derivatlves of the general formula I, lo -CH~:- CH(OX)- CH~ORZ~- CH~oR3)--cu~ox~- O -N~R4~3 A

~10 ~ ln~whlch~eleher~
all radicals R1, R2 and R3 independently;of one another stand for :~:
X, or :~
two of the radicals Rl, R2 and R3 a~tand for X,~and the thlrd ~ stands for a radical of the formulae II-VII, :~
,., -H OX

H OX

~ 2 1 33 ~ 22237-378 .

H /~
H \ (IV) :.
~ OX OX~
OX ~__~ H ~ ~ :
H H~
,, ~ -CH2ox ~~ -0~0-~ ~

m ~0 ~ `'; ~ ' : ~'" `; ~'~ '';
CH20X: H~H: ~ - ~VII) ;~
H~ \~ ~ ~ ~
OX H ~¦ H OX ~ : ~ :
OX~ H : ~ m H ' ` OX

X~ln~t~e formu~la- I to~VlI slmultaneou~ly or ln~ep-ndently of one~
another~;denotes a hydrogen atom or the~group -S03H, where at least one~X~st:ands ~or the group -S03H, ~ ~ ~
m stands~or 0, 1, 2, 3, 4, 5 or 6, : ~ :
A in formula I stands for a stralght-chain or branched, :: ~ ~-X ' ;' ~`" 1331q86 22237-378 saturated alkylene radical having 2 to 22 carbon atoms which is optionally substituted by one or more radicals -C02R5, and this -alkylene radical is optionally interrupted by up to 5 -O-, -S-, fi :~--S-S-, ~S()n~, -C-NH- or/and -NR -groups or c5-C8-cycloalkylene ~-or C6-C14-arylene radicals, or A stands for a single bond or ~-the radical CH

n is 1 or 2j R4, R and R simultaneously or independently of one another denote a hydrogen atom or a Cl-C6-alkyl radical, ~;
and their salts with inorganic or organic bases. ;~
The compounds according to the invention represent active compounds having useful pharmacological properties, as ~;``
is shown below.
The following comments apply to the various : :
substituents or radicals (in the various formulae indicated) mentioned in connection with the present invention:
The aldonic acids underlying the present polysulfuric acid esters possess the general formula VIII ~ ~:~
R1O-CH2-CH(OH)-CH(OR )-CH(OR )-CH(OH)-CO2H (VIII) ~
in which R , R and R3 possess the meaning indicated. These ~ --aldonic acids cah be presènt in the D-form, the L-form or in`;
~; the form of their racemates, preferably in their naturally predominant form.
Examples of these aldonic acids comprise the hexonic `
acids allonic acid, altronic acid, galactonic acid, gluconic acid, gulonic acid, idonic acid, mannonic -;

- 4 - ~ ~ 3 3 9 ~ ~2237-378 acid and talonic acid, preferably galactonic acid, glu-conic acid, gulonic acid and mannonic acid. Further examples are derivatives of these hexonic acids which are connected glycosidically on the oxygen atoms in the 3-, 4-, or 6-position with a radical R3 or R2 or R~ of the formulae II to VII, in which X stands for hydrogen. The bond here can be ~- or ~-glycosidic. The radicals II to ~ -V a~e galactopyranosyl and mannopyranosyl radicals. The radicals VI and VII are glucopyranosyl radicals ~in the case where~m = 0) and ~ 4) or ~ 4)-linked oligo~
glucopyranosyl radicals (~hen m = 1 to 6). The index m in the formulae VI and VII preferably stands for 0 or 1.
The saccharide un;ts linked with the aldonic acid are ~-normally present in the D form. Examples of hexonic acids of the general formula VIII which are subst;tuted with radicals of the formulae II to VII are glucopyranosyl-gluconic acids, glucopyranosylmannonic acids, glucQpyrano-sylgalacton;c ac;ds, galactopyranosylglucon;c acids, mannopyranosylgluconic acids, mannopyranosylmannonic acids and oligoglucopyranosylgluconic acids. Lacto-bionic acid t4-0-B-D-galactopyranosylgluconic acid), ~,:
gentiobionic acid, mel;b;onic acid (6-O-c~-D-galactoPyrano-sylgluconic acid), mannob;on;c acid, cellob;on;c acid ~;
~ 4-0-~-D-glucopyranosylglucon;c acid) and maltobionic ~`
;~ 25 acid (4-0-ct-D-glucopyranosylgluconic acid) and also mal- ~k ; ~ totr;onic ac;d and cellotrionic ac;d are preferred here.
Examples of salt-form;ng bases are trialkylamines having 1 to 6 carbon atoms in the alkyl moietY, such as ~ ;
~: .
~ trimethylam;ne, triethylam;ne, tripropylamine, tributylamine, ~ ~

:~ ' .'' .

~ 5 _ ~ 33~ 9~ 22237~378 ~:
tripentylamine and trihexylamine. Trimethylamine, tri-ethylamine and tributylamine are preferred.
Examples of physiologically tolerable inorganic and organic salts are the ammonium, lithium, sodium, potassium, magnesium, calcium and aluminum salts and the salts with ethanolamine, triethanolamine, morpholine, - ;
pyridine and piperidine. The sodium, potassium, calcium, aluminum and ethanolamine salts are preferred.
Examples of the straight-chain or branched, ;- ~
10 saturated alkylene radicals having 2 to 22 carbon atoms -representing the group A are ethylene, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, ~ ;;
dodeca-, tetradeca-, hexadeca-, octadeca-, icosa- and docosamethylene and also methylethylene, methylpropylene, 15 methylbutylene, methylpentylene and dimethy(ethylene. ~-~
Ethylene, tri-, tetra-, hexa-, nona-, dodeca- and docosa-methylene and also methylethylene and methylpentylene are ~ ~
preferred. ~ ~ ;
Examples of arylene rad;cals by wh;ch the alkyl- ~ ; `
ene radical of the group A can be ;nterrupted are phen-yLene, naphthylene, anthrylene, phenanthrylenes and ;
fluorenylenes. In th;s connection, ortho-, meta- and para-phenylene radicals are preferred. -Examples of cycloalkylene rad;cals by which the Z5 alkylene radical of the group A can be interrupted are cyclopentylene, cyclohexylene, cyclohep~ylene and CyC(D~
octy(ene, 1,3- and 1,4-cyclohexylene being preferred here.
~-~ The straight-chain or ~ranched, saturated ~ ~ ~
: ~ : ' ~ ,; :'' '"~

~ 6 - ~ 3 3 ~ 22237-378 lene radical of the group A preferab~y possesses 2 to 1Z
carbon atoms. If the straight-chain or branched, satur-ated alky~ene rad;cal of the group A is interrupted by one of the radicals or groups mentioned, it is preferably 1 or 2 of those radicals or groups.
Specific examples of alkylene radicals repre-senting group A according to the definition arè groups derived from the follo~ing ,~-diamines~

HN - (CH2)2 - NH -5'H . CH m:~

~ Co2R5 : H2N -CH ( 2)~-NH2 -~
Enantiomers of lysine (R~ = H) and its esters (R5 = C
H C 6 - a L k y l ) ~: 15 containing S atoms~

:~ R5o2c-HctNH2)-cH2s-cH2-(NH2)cH-co2R5 ~ ~.. ;',~, Diastereomers of lanth;on;ne ~R5 = H) :` and esters ~R5 = C1-C6-alkyl) ;

2 HCtNH2) (CH2)x-s-s-~cH2)x -(NH2)CH~c2R5 `~
D;astereomers of cystine ~x = 1, R = H) and esters ~R = C1-C6-alkyl) Diastereomers of homocystine ~x = 2, R5 = H) :~ and esters ~RS = C1-C6-alkyl) ~ .;
li , Ho2c-cH(NH2)-(cH2)2-5-cH2-cH(NH2)-co2H

: :.
~ 25 D;astereomers of cystathionine ~ ~
:
containing NH groups: :

H2N(-CH2-CH2-NH)x-CH2-CH2-NH2 x = 1 diethylenetriamine : x = 2 tr;ethylenetetramine x = 3 tetraethYlenePentamine ~ .

~ 3 3 ~

2 2 2)3 NH-(cH2)2-NH2 1~9-diamino-3 7-diaza 2 3 ( 2)2-NH-(CH2)3-~H2 1~1o-diamino-4~7-diazadeca:: -li2N-(cH2)6-NH-(cH2)6-NH2 bis-(6-aminohexyl)amine ~ ~:
H2~-(cH2)3-NH-(cH2)4-NH-(cH3)3-NH2 5 H2N-(CH2)4-NH-(cH2)3 ~H2 spermidine : 2 ( H2)3 NH-(CH2j3-NH-(CH2)3-NH2 1r11-diamino-4~8-diazaundecane ::: containing O atoms~
. . ~ . -HzN-(cH2)2-o-(cH2)z-NH2 bis-(2-aminoethyl) ether -The group A can preferably stand for the follow-10 ing radicals: .. , ;~

~_~}C ~ C~

2 ~
C~'2-- ~ '''~`"''`;'' - CH - C~ 2 - CH 2 - CH 2 - ` : `' ' C02R~
: hav;ng p = 1 or 2 -CH-CH2-Sp-CH2-CH-;~: , C02RS ~ Co2R5 ~ ~ . . ` ;' ~;

-tcH2)2-s-s-(cH2)2 ~ ~ ;

i , -tCH2)3-O-(CH2)4-O-(CH2)3 ~ 25 -(CH2)3-NH-(CH2)3-~ ~ ~ tCH2)6 NH-~-(c~2)3-~NH-(cH2)6-~ ~ ; Examples of C1-C6-alkyl radicals of the groups ~3~8~ :

R4l R5 and R6 are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n- ;~
`~ hexyl, lsopropyl, lsobutyl, tert.-butyl, neo-pentyl, whereby methyl, ethyl, n-propyl, lsopropyl, tert.-butyl and n-butyl are -preferred.
The inventlon also relates to a process for the prepara-tlon of polysulfuric acld esters of bls-aldonamldes of the general formula I, which comprlses reactlng bis-aldonamldes of the general formula IX

Elo -CHz- CH(~OH)- CH(OR2)- CH(oR3)- CH(OH)- O -N(R4) ~ A
2 (IX) ln whlch R1, R2, R3, R4 and A havlng the meanings lndlcated, `
where, however, X in the formulae II to VII stands for hydrogen, wlth a sulfating agent ln an aprotic solvent and converting the products thUs obtained into the correspondlng salts using an in-organic or organic base. The compounds of the general ~ormula IX
are obtained in analogy to processes known from the llterature (for example, F. Scholnick, P.E. Pfeffer, J. Dairy Sci. 63 (3), 471 (1980)~ W.N. Emmerllng, B. Pfannem~ller, Starch 33 (6), 202 ` ~ 20 (1981)). To prepare the bls-aldonamides of the general formula IX, lactones of;the;aldonic aclds of the general formula VIII are ~;~
allowed to react ln a solvent With a diamino compound R4HN-A-NHR4.
The lactones can be employed both in the 1,4-lactone form of the ~ general formula X and also ln the 1,5~1actone form of the general ;~ formula XI.

~;J

~ :` 133~
9 22237-378 . ~.
O ~ .^ ;, ~:

~ ~R10- CH2- CH~OH ~ CH CH~OH)~
: ~ ~ \ CH(oR3 O--C . ~.. . i ;(R OCH2)CH ~ f H(OH) ~ (XI) ( R O CH--CH ( OR~

The~compounds of the general formulae X and~XI~are ob~
talned by ellmlnatlon of water from the aldonlc aclds VIII. The~ ~ .~... ...
~: . aldonlc acids~can be obta~lned by processes knowni~;e`rom~the lltera~
::~ ture~(for example W.N.: Emmerling, B. Pfannem~ ler,~Starch 33 (6 202 (1981), R. Schaffer,~ H.S. Isbell, J. Am.~Chem. Soc.~ 81, 2178 (l959), H.W. Dlehl et al.,~Carbohydrate~Research 38, 364 (1974)) by electrochemlcal or hypohalite oxldatlon of the correspondin~
aldoses. To prepare the bis-aldonamides of~the general formula~
~ ~ , IX, 2 moles of aldonolactone are employed per mole of diamino compound. Sultable solvents for the reactlon~are methanol, ethanol, ethylene glycol, dlmethyl sulfoxlde, dl~methylformamlde~o~r : N-methylpyrrolldone. Dimethyl~ormamlde ls preferred. The~re-::
actlon tlmes are several hours to days, preferably between~5~and 8 ` .
; ~ h. ~The reactlon temperatures~are bet~ween room~temperature and the~
boiling temperatures of the respectlve~:~solvents, preferably be~
tween ~OoC and~aOC. The aldonic acld~amldes~either crystalllze out of the reaction solutlon or can be preclpltated by additlon of:
ZO an organlc solvent. Sultable for thls are methanol, ethanol, lso- . ;
propanoI or acetone, preferably:lsopropanol.

. t~

:~ `
133~

;: In another aspect, the lnventlon relates to bls-~ aldonamides of the general ~ormula IX
:, ;.

[R10- CH2- CH(OH)- CH(OR2)- CH(oR3)- CH(OH- O- M~R9) ~ A (IX) : ln whlch either all radicals Rl~, RZ and R3 stand for a hydrogen atom, or two of :~ the radlcals Rl, R2 and R3 stand;for a hydrogen atom and the thIrd ,:
; stands~for a radical of the formulae II' to VII', ~ . ..
:: . ~-~i~ CH20H : ::-(II') :~ HK~H
H OH . ~

CH20H ~ :`
OH~ \~H
H~ ~ ( III') ~ " , , , .: ~

11 1 3 3 ~ 9 8 ~ 22237-378 ~ ~, , ,'' '., ~.

CH20~
` ~ H~ (V' I

CH20H : ~ CH20H ~ ~ ~

( VI ' ) H OH H OH :~
; ~ m CH20H ~ :
CH20H H~ O~
H~O~ o J~/;~ : ~ ~ : ( VII ' ) O~H ~ H: ~ OH; m ~ ~ H: OH

:~ m stànds ~or 0, 1, 2, 3, 4, 5 or 6, ;: :~
:: A : ln formula:IX stands ~or a 5tralght~-cha~ln~or~b~ranched,~:satu~
rated alkylene radical~havlng 2 to~22~:carbon~atoms~whlch ;is opt lonally subst ltuted by one or~more~radlcals~-C02R5,~ and ~ ~
this alkylene radical ls~optlonally lnterrupted ~y~ up~to S ; .``~.
; ~0- 1 ~ S~ I ~ S~ S~ I ~ S ~ O ) n- ~

~, - 12 - ~ 33~ 22237-378 O
~l 6 ~ ~ --C-NH- or/and -NR - groups or C5-C8-cycloalkylene or C6-C14- -arylene radicals, or A stands for a single bond or the radical ~ `

~ CH2 ~ - --n is 1 or 2, R , R and R simultaneously or independently of one another denote a hydrogen atom or a Cl-C6-alkyl radical, and their salts with inorganic or organic bases, with the proviso that in the case of bis-gluconic acid amides a) Rl, R2, R3 and i ; -R4 do not simultaneously denote hydrogen atoms and that b) when R is a radical of the formula II', and Rl, R3 and R4 are ' simultaneously hydrogen atoms, A is not -(CH2)2- in this case and that c) when R2 is a radical of the formula VI', in which m = 0, 1, 2, 3 or 5, and Rl, R3 and R4 are simultaneously hydrogen atoms and A is an unsubstituted, straight-chain alkylene radical, in this case the number o chain members i9 an uneven number. ~ `
The aompounds o ormula IX according to the invention `;
are useul intermediates. Highly valuable active compounds having surprising pharmacological properties are obtained from them by reaction with sulfating agents. Some bis-aldonamides ~ 20 are already known and for this reference is made to the follow- '``'''r'"' "
;~ I ing literature sources: F. Scholnick, P. E. Pfeffer, J. Dairy Sci. 63 (3), 471 (1980); W. N. Emmerling, B. Pfannemuller, Starch 33 (6), 202 (1981); G. Ziegast, B. Pfannemuller, Makromol. ~
Chem. ``

~ ~. .. . .. :

~ " '.. '. ' "' ~ - 13 ~ 3~9~3~ 22237-378 ~ ~
185, 1855 (1984); J. Masse et al., C. R. Acad. Sci., Ser.

3, 301 (1), 27 (1985); K. Dill et al., Inorg. Chim. Acta, 106 (4), 203 (1985). However, the kno~n compounds are in no case described as intermediates for the preparation of -S the abovementioned active compounds. Emmerling and Pfannemuller used them in enzymatic syntheses of amylose ~ . .
chains using potato phosphorylase~ Scholnick and Pfeffer and also K. Dill et al. studied their chelating proper-ties and J. Masse et al. studied their influence on growth and chlorophyll content of cereals.
-~ The following comments apply to the various sub~
stltuents or radicals (in the various formulae indicated) mentioned in connection with the present ;nvention~
The aldonic acids underlying the present bis- ; ; -15 aldonamides possess the general Tormula VIII. , ~`~
R10--CH2--CH(OH)--CH(OR2)--CH(oR3)--CH~OH~--CO2H (VIII) :
in which R1, R2 and R3 possess the meaning indicated. ~
These aldonic acids can be present in the D-form, the L- ~ ;
. . .
- form or ;n the form of their racemates, preferably in their naturally predominant form~
Examples of these aldonic ac;ds of the formula VIII
comprise the hexonic acids allonic acid, altronic acid, .
galacton;c acid, gluconic ac;d, gulonic acid, idon;c acid, mannon;c acid and taLonic acid, preferably galac-ton;c acid, gluconic acid, gulonic acid and mannonic acid. Further examples are derivatives of these hexonic ac;ds which are connected glycosid;cally on the oxygen ;-atoms in the 3-, 4- or 6-position with a radical of the ~ormulae III.to VII~ . The bond here can be ~ or ~

~ ~ 3 ~ ~ ~J ~ V ; ~ ::

glycosidic. The radicals I1' to V' are galactopyranosyl and mannoPyranosyl radicals The radicals Vl ~and VIII are glucopyranosyl radicals (in the case where m = 0) and c~ >4)- or B(1->4)-linked oligoglucopyranosyl radicals (when m = 1 to 6). Preferably, the index m in the formu-lae VI~ and VIII stands for 0 to 1. The saccharide units linked with the aldonic acid are normally present in the D-form. Examples of hexonic acids of the general formula VIII ~hich are s~-h~tituted bv r~icals of the fornulae II~
~to Vl-l'are glucopy~ranosylgluconic ac;ds, glucopyranosyl-mannonic acids, glucopyranosylgalacton1c acids, galacto~
pyranosylgluconic acids, mannopyranosylgluconic acids, .: ., mannopyranosylmannonic acids and o~igoglucopyranasyl-gl~uc<nic ac;ds. Lactobionic acid (4-0-~-D-galactopyrano~
sylgluconic acid), gentiobionic acid, melibionic acid (6-0--D-galactopyranosylgluconic acid), mannobionic acid, ' cellobionic acid ~4-0-B-D-glucopyr~anosYlgluconic a~cid) and maltobionic acid ~4-0-c~-D-glucopyranosylglucqnic ; acid~ and also maltotrionic acid and cellotrionic acid are preferred here.
Examples o~ inorganic and organic salts arei the ~ ;
ammon;um, lith1um, sodium, potassium, magnesium, calcium and aluminum salts and the salts with et;hanolamine, tri-ethanolamine~, morpholin;c, pyridine ahd piperidlne. ,he ~-sod;um, potassium, calclum, aluminum and e~ehanolamine salts are pre~erred~
xamples of the straight-chain~or;branchedr saturated alkylene radicals having~2~to Z2 carbon atoms representing the group A are ethylene, tri-, tetra~

~:';: . .

~ 3 3 ~

penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca~
tetradeca-, hexadeca-, octadeca-, lcosa- and docosamethylene and also methylethylene, methylpropylene, methylbutylene, methylpenty-lene and dlmethylethylene. Ethylene, trl-, tetra-, hexa-, nona-, dodeca- and docosa- methylene and also methylethylene and methyl-pentylene are preferred. ~ ;
~ Examples of arylene radlcals by whlch the alkylene radl-:~ cal of the group A can be interrupted are phenylene, naphthylene, -anthrylene, phenanthrylene and fluorenylene. In thls connectlon, ortho-, meta- and para-phenylene radlcals are preferred. ~ n Examples of cycloalkylene radicals by whlch the alkylene . ~ . ,: . ~ , radical of the group A can be interrupt0d are cyclopentylene, cyclohexylene, cycloheptylene and cyclooctylene, 1,3- and 1,4-cyclohexylene being preerred here. ;
..~ ... .
The straight-chain or branched, saturated alkylene radi-cal o~ the group A preferably posse~ses 2 to 12 carbon atoms. I~
the stralght-ch~in or branched, saturated alkylene radical of the group A is interrupted by one o~ the radlcals or groups mentloned, it 1~ preferably 1 or 2 of tho~e ra~icals or groups. ~ ;
Speclflc e~amples accordlng to ~he deflnltion which are alkylene radicals repre~enting group A are groups derived from the , ~ , followlng ~ diamines, i~
HIN'-(CH2)2 -NH

. .~ . , , ;` Co2R5 ` '':.`
~; H2N- CH - lCH2)4- NH2 ~ `

: ., Enantlomers of Lysine (R5 = H) and its esters (R5 = Cl-C6-alkyl) containinq S atoms R5O2C-HC(NH2)-CH2S-CH2-(NH2)CH-Co2R5 :
Dlastereomers o~ lanthionlne (R5 - H) and esters (R5 = Cl-C~-alkyl) .

R O2C Hc(NH2)-(cH2)x-s-s-(cH2)(x-(NH2)cH-co2R5 Dlastereomers of cystlne (x = 1,~ R5 ~ H) `
~: and esters (R5 = Cl-C6-alkyl) .. ::~
Dlastereomers of homocystlne (x = 2, R5 ~ H) and esters (R5 = Cl-C6-alkyl) .: .

Ho2c-cH(NH2)-(cH2)2-s-cH2-cH(NH2)-co2H
Dlastereomers of cystathlonine `.
containln~ NH qrou~s, .
H2N~-CH2-CH2-NH~x-cH2-cH2-HN2 x = 1 diethylenetriamine l`;`
x ~ 2 trlethylenqtetramine .~ .i, .
x ~ 3 tetraethylenepentamine 2N (CH2)2 MH-(CH2)3-NH-(CH2)2-NH2 1~9-dlamino-3~7-diazanonane ` `

H2N-~CH2)3-NH-(CH2)2-NH-~CH2)3-NH2 1~lO-diamino-4~7-diazadecane .-.
H2N-~CH2)6-NH-~CH2)6-NH2 bis-~6-aminohexyl)amine H2N ~CH2)3-NH-~cH2)4-NH-~cH3)3-NH2 spermine ` `
H2N-~CH2)4-NH-~CH2)3-NH2 spermidlne .
H2N-~CH2)3-NH-~CH2)3-NH-~CH2)3-NH2 1,11-diamino-4,8-diazaundecane contalnin~ 0 atoms:
H2N-~CH2)2-O-~CH2)2-NH2 bls-~2-amlnoethyl) ether The group A can preferably stand for the following ;~
radicals~ ~ :
.' ..'.''~`. ';: '~
.. .

17 1 3 3 i ~ ~ ~ 22237-378 - -H2 , . .
. ., ~ CH2 - ;

-CH~ }CH

.: ` . ' -CH-CH2-CH2-cH2-Co2R5 ~'` `'.,~`` ~:'. ."' -CH~CH2-Sp-CH2-CH- having p ~ 1 or 2 `- -~
Co2R5 Co2R5 .'' ,. -".', -~CH2)2-S-s-(cH2)2--~CH2)3-0-~CH2)~-O-~cH2)3 `
- ~ CH2 ) 3-NH- ~ CH2 ) 3 -(CH2)6-NH-c-~cH2)3-cNH-~cH2)6- ~ ;
O O : ' ~ `

~xamples of Cl-C6-alkyl radicals of the groups R4, R5 and R6 are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, tert.-butyl, neo-pentyl, methyl, ethyl, n~
propyl, isopropyl, tert.-butyl and n-butyl being preferred.

18 ~ 3 3 ~ 9 ~ ~ 22237-378 The invention also relates to a process for the pre-paratlon of the bis-aldonamides of the general formula IX. In thls connectlon, the lactones of the aldonlcs acids VIII are allowed to react in a solvent wlth a diamino compound of the -;
general formula R4HN-A-NHR4, in whIch R4 posse~ses the lndlcated '~
meanlng, ln analogy to processes known from the literature (see precedlng literature sources). The lactones can be employed both ln the 1,5-lactone form of the general formula XI and also in the . . .
~ 1,4-lactone form of the general formula o--c D

tRlOCH2)C~ CH(OH) tXI) t R20~- CH t oR3 ) `
0` : .':,,.'~"'.',','``''' .

E. O-CH2 CH(OH cf I (X) \ CHtOH) ~H ~ 3) ; . , .
"' ' ' They are obtained by eliminatlon of water from the ~ ~
, , i .... : ~ ~
aldonic acids VIII. The aldonic acids can be obtained by pro- ~
cessea known from the llterature tfor example: W.N. Emmerllng, B. ~ ;
Pfannem~ller, Starch 33 (6), 202 (1981); R. Schaffer, H.S. Isbell, J. Am. Chem. Soc. 81, 2178 (1959~, H.W. Diehl et al., Carbohydrate Research 38, 369 (1974)) by electrochemlcal or hypohaIite oxida-tion of ~he corresponding aldoses. .

X
::

133~ ~5 18a 22237-378 To prepare the present bls-aldonamides, 2 moles of aldonolactone are employed per mole of dlamlno compound. -Suitable solvents for the reaction are methanol, ethanol, ethylene glycol, dimethyl sulfoxlde, dimethylformamlde or ; N-methylpyrrolldone. Dimethylformamide is preferred.
The reactlon tlmes are several hours to days, preferably ~ , ... .....
between 5 and 8 hours.
'':`.,.,', '' ,,'.'`"' '' ' '`.';,;,`'':',"``
.."",-......

'.' '~, ~'' '' ',.

; ' ~'' "'; ' ~"
,.,.. ~:

; ~
;','' ."""'"'`

~: . ' ' :

' ' '~ ., .

^ - 19 - ~ 3 3 ~ ~2~37-378 Tne reaction temperatures are Detween room tem- ;~
perature and the boiling temperatures of the resoective solvent, preferably between 40C and 80C.
The aldonamides either crystallize out from the reaction soLution or can be precipitated by addition of an organic solvent. Suitable for this are , ,. " ~
~; methanol, ethanol, isopropanol or acetone, preferably isopropanol. ~`
In a preferred embodiment of the process accord- -ing to thF invention, the compounds of the formula I are produced from the aldonic acids of the formula VIII without :~ ~
isolation of the lactones. ~ -In this connection, an aclueous solution of the free aldonic acids VIII is prepared by means o~ a cation 15 exchanger from alkali metal salts or alkaline earth metal ``
salts of the aldonic ac;ds VIII which can be purcha~ed or ... ;
synthesized by processes known from the literature tsee above) and this is concentrated substantially. The lactones corresponding to the aldonic ac;dsVIII are then . h 2û produced without isolation by elimination of water~ For ~ ~`
this purpose, the residue, which represents a water- ~
:: : - ~
containing mixture of aldonic acid and lactone, is ~`
dissolved in a high-boiling solvent. Examples of high-boiling solvents are dimethyl sulfoxide, dimethylforma- -~
mide, N-methylPyrrolidone, dimethoxymethyl ether etc., : : ~
dimethylformamide being preferred. A second, low-boiling solvent which can form an azeotrope with water is then added. Suitable solvents are, for example, n-pentane, n-hexane, cyclohsxane, benzene etc., n-hexane being :~ ' ` "~';' ''~ ' . . , 3 ~

~ - 20 - 22237-378 preferred. Water is then eliminated quantitatively from the ~ ;
aldonic acids in a water separator. The low-boiling solvent is then distilled off and the lactone situated in the remaining, -~
high-boiling solvent is reacted, without isolation of same, with the diamino compound. The reaction temperatures are between 20C -and 120C, preferably between 50C and 80C. The reaction products are obtained by precipitating with an organic solvent.
Suitable solvents are, for example, diethyl ether and other .: ~ -: .
ethers, methanol, ethanol, isopropanol, carboxylic acid esters and acetone. Isopropanol and acetone are preferred. If necessary, the compounds can be freed from unreacted starting compounds by treating with acid and basic ion exchangers.

;'~..'".~:';

;:.

: ..
', ~ ' ' . .
~ 3 3 ~
- 21 - 22237-378 .,:

: . , To prePare the present compounds of the general formula I, the aldonamide(s) of the formuLa IX are dis- ~-:.. :-....:, solved or susPended in an aprotic solvent. Pyridine, dimethylformamider dimethylacetamide, N-methyl-pyrrOl-~; idone etc. are suitable, dimethylformamide being pre-ferred.
The mixture is heated to temperatures between 2ûC and 100C, preferably between 30C and 70C, and a sulfating agent is added. Examples of this are chloro-sulfonic acids, sulfur triox;de, oleum, or ether- or amine-sulfur trioxide complexes. Sulfur trioxide com-;~ .,.~
plexes w;th trimethylamine, triethylamine and pyridine ~
are preferably employed. ~ ~ ;
In order to obtain polysulfuric acid esters of bis-aldonamides of the general formula I, in which each X
stands for the group -S03H, 1 to 2 equivalents of sulfat~
;ng agent, preferably 1.4-1.7 equivalents, are employed for each hydroxyl group capable of esterification. Com-pounds in which some X are hydrogen atoms and the others are the group~
S03H are obtained when the sulfating agent is employed in subequivalent amounts. The amount of sulfating agent is chosen depend- :
ing on how high the sulfur content of the product should be. Amounts between 0.5 and 1 equivalent of sulfating~;~
agent per hydroxyl group capable of esterification are preferred. The reaction mixture is stirred for 1 to ~: , , . ~. - . ~
: . ~,.
. . ~
.

22 - ~ 3 3 ~- ~ g j2237-378 Z4 h at temperatures between 20C and 100C. ;rom the poly~
sulfate compounds of the general formula I thus obtained, ~; ;
in which X stands for -503H, which can also be present as the salt of the amine of the amine-sulfur trioxide com~
plex employed, the corresponding salts of inorganic bases are obtained by addition of these bases or their inorganic ; salts. The hydroxides and acetates of the alkali metals and alkaline earth metals are preferably employed here. -Salts of physiologicdlly acceptable organic bases are -~
obtained either by using a sulfur trioxide complex of ~-these bases in the sulfation reaction or by treating the -~
alkaline earth metal salt or alkali metal salt with a ~ -~
cation exchanger in the acidic form and subsequently neutral;zing the acidic sulfuric acid hemiester with the organic base. The isolation of the compounds according to the invent;on in general takes place by precipitating from the reaction solutions or from aqueous solutions using organic solvents. Suitable organic solvents are methanol, ethanol, isopropanol or acetone, preferably methanol.
The compounds can be purified by repeated pre-: :
; cipitation from aqueous solutions using the abovementioned ~ ;
solvents and by treat;ng w;th activated charcoal or hydro~
gen peroxide. In general, the products thus obtained ;~
are mixtures with a more or less high content of compounds, ;~ all the hydroxyl groups of which are esterif;ed with sul-fate radicals and of compounds whose hydroxyl groups are only partially sulfated, depend;ng on the amount of sul-`~ fating agent employed. The mixtures obtained can `

~ , :

"~

~ 33~ ~$ :: ~
23 22237-378 ;
optlonally be separated lnto products havlng a unlform content of sulfate radlcals hy varlous separatlon processes. The separatlon -~
may take place by varlous physlcal separation processes, such as, for example, fractlonal preclpltatlon, gel chromatography, lon ~;
exchange chromatography or affinlty chromatography, HPLC or elec-:
trophoretlc processes. Fractlonal preclpltation ls preferred.
For example, an aqueous solution of the product mixtUre ls pre- -pared and one to four tlmes the amount of an organlc solvent ls . , added. Water-mlsclble solvents such as methanol, ethanol, lso-propanol, acetone or tetrahydrofuran are sultable, methanol belng preferred. The preclpltate thus obtalned ls allowed to settle. ;~
In general, the compounds havlng a hlgher sulfate content are then concentrated ln the preclpltate, and those havlng a lower sulfate ~-content in the supernatant solutlon. Compounds havlng a deflned number of sul~ate groups are obtalned by repeated fractional pre- `~
cipitatlon of the preclpltates or supernatants.
:, - :. ~:
In a preferred embodlment of the process according to the inventlon, the compounds of the formula I are producèd Erom i~
the aldonlc aclds of the formula VIII without isolatlon of the neaessary intermediate. '''!
In thls connection, an aqueous solutlon of the free aldonlc aclds VIII ls prepared by means of a catlon exchanger from the alkall metal salts or alkallne earth metal salts of the aldon-lc aclds VIII syntheslzed commerclally or by processes known from '~
the llterature (for example W.N. Emmerllng, ~. Pfannem~ller, - ~`

Starch 33 (6), 202 (1981)~ R. Schaffer, H.S. Isbell, ~. Am. Chem. ~ ~
' ,',~ ~: . ' .:.
Soc . , ., ~, . ,-`',':',""
. . ~ .:
:.,~;,.
-. .~.. :

- 24 - ~ 3'~ 237-378 ;
81, 2178 (1959), H.W. Diehl et a~., Car~onydrats 2esearch 38, 364 (1974)) and this is concentrated substantially.
The lactones corresponding to the aldonic acids VIII are ~
then produced in situ ~ithout isolation by elimination of ~-water. For this purpose, the residue, which in general represents a water-containing mixture of aldonic acid and lactone, is dissolved in a high-boiling solvent. Examples of high-boiling solvents are dimethyl sulfoxide, dimethyl-:
formamide, N-methylpyrrolidone, dimethoxymethyl ether etc., dimethylformamide being preferred. A second, low~
boiling solvent ~hich can form an azeotrope with ~ater is then added. Suitable solvents are, for example, n-pen- `~
tane, n-hexane, cycLohexane, benzene, etc., n-hexane be- `;~
ing preferred. Water is then eliminated quantitatively from the aldonic acids in a water separator. The low-boiling extraining agent ;s then distilled off and the lactone s;tuated in the rema;n;ng, h;gh-boil;ng solvent is reacted, without isolation of same, with the diamino com-pound. The reaction temperatures here are between 20C ~
and 120C, preferably between 50C and 80C. The mixture ~ ~;
is stirred over t;me spans of 3 to 24 hours, preferably 3 to 8 hours. Without isolation of the resulting bis-aldona- ;~
;~ mides , this is brought to reaction with a sulfating ~j agent in the same reaction vessel. React;on conditions ~
; 25 and ;solat;on and purification of the products are des- ~-;~ cr;bed ;n the prev;ously mentioned process.
` ~ The compounds of the general formula I are pharma-cologically useful substances. They possess antithrom-; bot;c and ant;-inflammatory propert;es. The compounds ~

' ' :~ .:.: ~,., ~33~ 98~ : `

according to the lnventlon are therefore sultable for the treat-ment of the whole clrcle of rheumatlc diseases and for the prophylaxls and therapy of venous and arterial thrombosls. The invention therefore also relates to a medlcament for human and veterinary use. Human use ls preferred.
The antlthrombotlc actlvlty of the compounds accordlng to the lnvention ls partlcularly surprislng.
Up to now, heparln ha~ prlmarlly been used for prophyl-axls of thrombosis. Heparin is a mucopolysaccharlde whlch ls lsolated from anlmal tlssue, in partlcular plg lleum (Thomas, D.P.
~1981) ln Cllnlcs ln Haematology, Vol. 10, p. 443-458, Saunders Comp. Ltd., 1981). In addltion to heparin, other naturally occur- ~-rlng mucopolysaccharldes, such as dermatan sulfate or heparan ~ -sulfate, also possess antlthrombotlc properties (Rosenberg, R.D., Rosenberg, J.S. (1984), J. Clln. Invest. 74, 1-6~ Sle, P., Ofosu, F., Fernandez, F., Buchanan, M.R., Petltou, M., Boneu, B. (1986) . .
Br. J. Haematol. 64, 707-714). A seml-synthetic chondroltln ~ ~`
polysulfate 18 also known, for example from D~-PS 3,118,588, - "
whlch, lnter alla, has antlthrombotlc propertles. However, only heparin i8 therapeutlcally used. More recently, several low .,:
molecular welght heparlns have been developed for clinlcal use.
.... , ,~ ...
In this case, they are substances which can be obtalned from ~:`
heparln by various chemical or enzymatlc depolymerization pro-cesses (Thomas, D.P., Merton, R.~. (1982) Thrombos. Res. 28, 343 350~ Walenga, J.M., ~areed, J., Petltou, M., Samana, M., Lormeau, . . ,,: .~
-~ J.C., :. ..:.. :,:

. .

~ - 26 - :L 3 3 ~- 9 ~ ~22~37-378 Choay, J. (1986) Thrombos. Res. 43, 243-Z48; Koller, ~., Schoh, U., Buchmann, P., Largiadèr, F., von Felten, A., '` Frick, P.G. (1986) Thrombos. Haemostas. 56, 243-246).
A disadvantage of the heparins and low molecular S weight heparins is that they are of natural origin (for -- example derived from animals). There are therefore small --amounts of antigen present derived from the animal tissue, which can lead to anaphylactic reactions such as a decrease in the number of thrombocytes, thrombosis and embolism.
These side-effects are, of course, relatively rare, but can be serious and clinically difficult to control.
In contrast, the compounds according to the -invention are wholly synthetic and therefore free of animal antigen.
Another substantially more frequent complication in the prophylaxis of thrombosis with heparin and low molecular weight hepar;n is the appearance~of hemorrhages.
Substances which cause less hemorrhages in combination with equivalent antithrombot;c action can therefore represent a substantial therapeut;c advance.
Several pharmacolog;cal tests were used to test the compounds accord;ng to the ;nvent;on for ant;throm-bot;c act;v;ty and ant;-;nflammatc,ry act;vity.
1. Accelerat;on of ~;br;nolysis The formation of a clinically man;fest trela-tively large) thrombus can be prevented in various ways.
~ For one, the factors which are involved in the formation ;
'~ of the primary thrombus, such as blood platelet aggre-;~ gation or the blood clotting system, can be el;minated.
.~ ` Y~

l . ~
i ,-: :

- 27_ 1 33~ 22237-378 On the otner hand, thejdissolution of the Drimary throm- -bus can be accelerated by potentiating endogeneous fibrinolysis. A Dotentiation of endogeneous fibrinolysis can also serve to dissolve already clinically manifest - -thrombi again. The fibrinolytic action of a substance ;;
is thus of great significance in the prophylaxis and therapy of thrombosis. The fibrinolytic action of the substances according to the invention was determined in ~-~ the tes~t below. The test is a slight modif~cation of a ;;~
method known from the literature for the determination of fibrinolyti~c action (Kluft, C. (1979) Thromb. Haemostas.
41, 365-383 ) .
Fibrinolysis test Fibrinolysis was determined by means~of plasmino-gen-containing fibrin plates.
: , ~
Petr; dishes, dia. 9 cm, were prewarmed to 40C. -3 ml of a 2% solution of fibrinogen ~8ehringwerke, ~
Marburg) in water, 1 ml of a plasminogen solution, 2 CTA/ `
ml t~ehringwerker Marburg), 3 ml of a l~ agarose solution ~ `
~Serva, Heidelberg) in 50 mM TRlS/HCl, p~l 7.8 and l ml of a solut;on of 15 U/ml of thromb;n ~8ehr;ngwerke, Marburg) in water were p;petted into the d;shes w;th swirling.
After cool;ng the Dlates~ well~s of 5 mm diameter were punched out. ~ ~
0.1 ml of plasma (human standard plasma, ~ ~ -ehringwerke, Marburg), 0.8 ml of water and 0.1 ml of ~-solution of the test substance in various concentrations were incubated for 10 minutes at 37C. After addlcion of ; 0.9 ml of 0.025% acetic acid, the mixture was incubated ;~

,' :
:' :

28 ~ 9 8 ~2237-378 for 5 minutes at 4C and subsequently centrifuged for ¦ 5 minutes at 2,000 9. The precipitate was taken up in 0.1 ml of buffer (20 mM TRIS/HCl, 100 mM NaCl, 2.7 mM
¦ EDTA, pH 7.8).
0.02 ml of this solution and O.OOS ml of 14.3 mM - ~
1~ ' - ---, flufenamic acid solution tSigma, Taufkirchen) in buffer ;~
- are pipetted Into the apDlication wells of the fibrin -plates. After 24 hours at 37C, the lysis haloes were ;~
planimetered. The areas of the lysis haloes less the ~;
lysislareas w~ithout addition of substance serve as a measurelfor the f~Ibrlnolys~is-lncreasing a~ct;vity. ~`
Result: The result is represented in the table ~ -below.
1, , .,, . ~
15 ~ Substance from Fibrlnolysis at 2 ~ig/ml (mm2) -Example ! ~ ~ ~ : ; ..
~ ~ 23 ~ 21.6 `~ 20 19.2 24 17.8 ;" ,~ ~ .,_, ,,_ ,,._ :",.
HeparIn 14.8 : : -: :: .
2. Inhibition of blood clottIng ~} ~ ~ 25 The inhibition of blood clotting can be measured in a s;mple manner by means of the act~iva~ed partial thromboplastin ;time aPTT. It gives information about ~ ~;
the~general inhibition of the act;vated clotting system.
In order to decrease the inc;dence of nemorrhages, as low !'` ~. ~ : : ~ : .

I'i~: : : , 3 3 ~
: - 29 - 22237-378 as Possible an inhibition of blood clotting is desired here. ~-Clotting test, aPTT
0 1 ml of plasma and 0.1 ml of PathromtinR `
~: ;, :. ,, ~ :
(Behringwerke, Marburg) are incubated at 37C for 2 min-utes and 3.1 ml of ZS mM CaClz solution is added. The cLotting time is measured in a Schnitger & Gross coagu~
lometer. The~agent is made up for 5 individual deter-minations per concentrat~ion. A heparin containing 175 U/ - -mg from~t~he firm Pharmindustrie ls used as a standard.
The prolongation ~of the clotting ti~me is~converted ~
into heparin units by means of a calibration curve. Since -the calibration curves are not parallel, the Drolongation ~ `~
of lS0 % of the blank value is chosen as the~reference 1 5 P o i n t .
Result: The fol~lo~ing table sho~s the heParin units of compounds according to the invention.

Substancm from Example U/mg~

_ -23 ~ 30.9 ; ;~

s . a s ~ 20 42.1 :
Hepar1n ~ 175 Fragmin~ 64.5 (low mol. ~t._heDarin_) _ . , , .li; . .; , , ~3 ~ 33~ ~8~
` - - 30 - 22237-378 ! 3. Influence on the ~leeding time A piece of tail about 2 mm long uas cut from -rats. The time until bleeding had stopped was measured.
The test substance in various concentrations or physio-logical saline solution (control) uas administered to the animals 5 minutes before causing the bleeding. Groups ;~
of 20 animals were treated. The prolongation of the bleeding time compared to the control uas exPressed in percent.
"~ ~O
:~ ~ , . _ Substance from Lengthening of the bleeding time Example (,0) Dose (mg/kg) ~;`

; 15 0.25 0.5 Z ~ -. ~. ... . ~ . _ . --- 5.1 3S.1 ;~ Heparin 55.4 120 4. Anti-inflammatory action ~4`!.

` ln ~nflammatory processes, large amounts of re~
.
active oxygen species, among them superoxide radicals and hydroxyl radicals, are released from the phagocytes polymorphonuclear leucocytes and macroPhages).~ These ~;' i radicals are involved in tissue destruction. Substances : ~
uhich inhibit the radical formation in leucocytçs are therefore of great therapeutic interest in the control~;
1;~, . , - of inflammations (Flohé, L., Giertz, H., Beckmann, R.

(1985) in The Pharmacology of inflammation, ~ol. 5 (90nta, I
I. et al. eds.) p. 255-281, Elsevier, Amsterdam-New York)~

~,,; ." '.. .. : ' - ~ 3 3 ~
- 31 ~- 22237-378 The radical formation by leucocytes can be mea- j sured by measuring the luminol-potentiated chemilu-minescence in whole blood (Peter, M. et al. (1985) in Chi. Forum 85 tStelzner, F., eds), p. 81-84, Springer ~-~ 5 Verlag~ Berlin).
Test on anti-inflammatory action - Test substances are dissolved in PBS and serial dilutions are prepared in PBS. 600 ~l of PBS, 100 ~
of solution of the test substance, 100 ~l of zymosan sus-pension t100 mg/ml) and 100 ~l of citrated rabbit blood --are pipetted into cuvettes which are suitable for a 1251 luminometer from LKB. The measurement is started by ~
additic,n of 100 ~l of 10 3 M luminol solution. The -- -~; chemilum;nescence is measured every 5 minutes over 90 - -~
minutes in each sample The max;mum chem;lum;nescence is determined. A sample without test substance ;s used as a j~ reference value. A sample w;thout the add;t;on of zymosan -;s used as a blank value. Three ;ndependent determina-t;ons are carr;ed out per substance. The calculat;on of ; ~ Z0 the res;dual chem;luminescence Is performed according to 3 ~ the formula:
CLmaX (subst) - CLmaX (blank) '~
- -- ~ x 1 0 0 ~ i ! ' . , ' CLmaX (ref) - CLmaX tblank) Concentrations for SOX CL ;nh;bition tICso values) ~ -result from a semilogarithm;c plot of res;dual chem;-lum;nescence against log concentration.
Result:
,: ;~ - - , 3~fi~ The ;nhibition of the luminol-potentiated CL by , ` - 32 - 22237-378 d ' compounds according to the invention is sho~n in ~e table belo~.
~ ,:
~ 5 substance from IC50 (~g/ml) 133~ 98~ ~
~-~ Exa~ple I

~ ~ZO
10 ~ ~24 Z20 ~31 170 il ~ . . .:__ indomethacin 240 . --15 ~ Th p~resent invention also relates t~o pharmaceu~
` tical preparat;ons wh;ch contain one or~more active com~
pound accord;ng to the invention or which consist of one or more active compound according to the invention in ;;~
addition to non-toxic, inert, pharmaceutically~suitable excipients.
Non-tox;c, ;nert, pharmaceut;cally su;table excipients are taken to memn solid,~semi-sol;d or liqu;d ~ ~ ;
d;luents, fillers or formulat;on a~uxil;ar;es of any type.
Preferred pharmaceut;cal preparat;ons which may be mentioned are tablets, dragees, capsules, pills, ; ~ granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders~, sprays~and aerosols.
blets, ar~gees, caD ules, piLls and granu~as e~ ";~

L ~ 3 ~

may contain the activeicompound(s) in addition ~o the . ..
customary eXCiPients, such as (a) fillers and extenders, for example starches, lactose, sucrose, glucose, mannitol and silica, (b~ binders, for example carboxymethylcellu- -5 lose, alginates, gelatin, polyvinylpyrrolidone, (c) -humectants, for example glycerol, (d) disintegrants, for ~-example agar-agar, calcium carbonate and sodium b;carbon-;
~ ate, (e) solution retardants, for example paraffin and ~-~
¦- (f) absorption accelerators, (g) wetting agents, for --10 examp~e~cetyl alcohol, glycerol monostearate, (h) adsorption agents, for example kaolin and bentonite n ! and (i) lubricants, for example talc, calcium stear-ate and magnesium stearate and solid polyethylene ~-~
glycols or mixtures of the substances mentioned under 15 (a) to (i). - ;
¦ The tablets, dragees, capsules, p;lls and gran-ules may be provided with the customary coatings con-taining, if appropr;ate, opac;fy;ng agents, for example `~ ~
; sugar, coat;ng laquer, and can also be so composed thati ;;
20 they release the active compoundts), if approprlate with a delay, only or preferably in a certain part of the ~ intestinal tract, in which case, for examPle, polymeric ¦~ substances and waxes can be used as embedding mater;als.
, If appropriate, the act;ve compound(s) may also 25 - be present in m;croencapsulated form with one or more ~ of the abovementioned excipients.
`~` In addit;ion to .he active compound(s), SUDpOSi- ~`' tories may contain the customary water-soluble or water- ; ;;
insoluble excipients, for~examDle polyethylene glycols, ~ j ~

-~ 3 ~

fats, for example cocoa fat and higher esters (~or ¦~ example C14-alcohol with C16-fatty acid or mixtures ¦ of these substances).
Ointments, pastes, creams and gels may contain ~
5 the customary excipients in addition to the act;ve com- -pound(s), for example animal and vegetable fats and their derivatives, waxes, paraffins, emulsifiers, starch, tragacanth, cellulose derivatives, polyacrylates, poly-ethylene glycols, silicones, bentonites, talc, silica ,~
and zinc oxide or mixtures of these substances.
Sprays and powders may contain the customary excipients in addition to the active compound(s), for example lactose, talc, silica, aLuminum hydroxide, `
calcium silicate and polyamide po~der or mixtures of these substances. Sprays may addit;onally contain the customary propellants, for example chlorofluorohydro- ~ ;
carbons~ .
Solutions and emuls;ons may contain the cust-omary exc;p;ents, such as solvents, solubilizers and emul-sifieis, for example water, ethyl alcohol, ;sopropyl ¦~ alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, ~
benzyl benzoate, propylene glycol, 1,3-butylene glycol, ` ~;
o;ls, in particular cottonseed oil, groundnut oil, ~ ;
cashew nut oil, maize germ oil, olive oil, castor oil ~ `
25 and sesa-e oil, glycerol, glycerol formal, polyethylene : ;
glycols and fatty acid esters of sorbitan or mixtures of ;
these substances ln addition to the act;ve compound(s). ~ ``
For parenteral admlnistration, the solut;ons and emulsions may also be present in sterile and blood-isotonic ''' ''''' ' ~ 3 3 ~

form.
Suspensions may contain the customary excipients, -such as liquid diluents, for eXamPle, ethyl alcohol, propylene glycol, suspending agents, for example ethoxyla-, ,:
~ S ted isostearyl alcohols, po~yoxyethylene sorbitol and ~ ~
~ , , sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar or tragacanth or ~ - :
;~ mixtures of these substances in addition to the active compound(s). ;
The said formulation forms may also contain ` '' : ' :, colorants, preservatives and also odour-improving and flavour-improving addit~ives, for example peppermint oil and eucalyptus oil and~sweeteners, for example saccharin~
The therapeutically active compounds shculd ;~
preferably be present in the abovementioned pharmaceuti-cal preparations in a concentration of about 0.1 to 99.5, preferably 0.5 to 95X by weight, of the total mixture.
The abovementioned pharmaceutical preparations ~; may also contain further pharmaceutical active compownds in addition to the active compounds according to the invention.
. ~ .
The preparat;on of the abovementioned pharma- ;
ceutical preparat;ons takes place in a customary manner ;
by known methods, for example by m~xing the active com-pound w;th the excip;ents. ~`
~ ~ .,: ~. ...
- 25 The present invention also includes the use of the active compounds according to the invention, and also :.: . . .
of pharmaceutical preparations which contain one or more ;~
~; active compound, in human and veterinary medicine for the `

prophylaxls, amelloration and/or cure of the abovemeneioned ~ 36 - ~3~

,~" ,,.
diseases.
¦ The active compounds or the pharmaceutical preparations may be administered locally, orally, parenterally, rectally and/or as an aerosol, preferably parenterally.
¦ In general , it has proved advantageous to administer ¦~ the active compound(s) in total amounts of about 0.1 to about 100, preferably 0.5 to 50 mg/kg of body welght every 24 hours, if appropriate in the form of several individual doses, to attain the desired results.
However, it may be necessary to depart from the dosages mentioned, depending on the type and the body weight of the subject to be treated, the nature and severity of the disease, the type of preparation and the administration of the medicament and also the time period or interval within which the administra~
tion takes place. Thus in some cases it may be suficient to manage with less than the above-mentioned amo~mt of active ~
compound, whereas ln other cases the above-mentioned amount of ;~; ;
active compound must be exceeded. ~ ;
The invention also extends to a commercial package `` ``~`
containing, as active pharmaceutical ingredient, a compound of i`
the invention, together with instructions for its use for the prophylaxis and therapy of rheumatic diseases and venous and `
¦ arterial thrombosis. ` `-The following examples further illustrate the -invention, but in no way limit its scope. ;

'~

~ "'.,. "', ,.

_ ~ 3~ 2237_378 xample 1 -,N'-1,3-~ropanediylb~s-D-gluconamide 7.13 g of D(+)-glucono-1,5-lactone are dissolved in 40 ml of amine-free dimethylformamide and 1.67 ml of 1,3-diaminopropane are added. The mixture is then warmed to 60C and stirred for 5 hours. The resulting pre-~ cipitate is filtered off, washed with methanol and dried.

;~ 7.96 9 of a white powder are obtained.

Melting point: 165-173C

IR (KElr): v = 3540, 2960, 2915, 2890, 1660, 1537, 1100, 1040 cm 1 H-NMR (D20): 6 1.76 (d, 2H-, 6.5 Hz); 3.30 tt, 4H, 6.5H2); 3.4-4.0 (m, 8H); 4.09 ~m, 2H); -~

4.30 (d, 2H, 3Hz); 4.70 (H20, int. std.) , -~, ~ Example 2 ~ ~

L . N!N~-1,12-dodecanediylbls-D-9lUCOnam;de ~'~.. ' 7.1 9 of D-glucono-1,5-lactone are suspended in 9û ml of d;methylformam;de, 4.0 9 of 1,12-diam;nododecane , ~ are added and the mixture ;s st;rred for S hours at 60C.

After cool;ng, the m;xture is st;rred ;nto 0.3 l;;ters of methanol, and the sol;d is collected and washed with meth-anol. The solid is then suspended ;n 1 N HCl, stirred for 1 hour at room temperature, and the solid ;s collected again and washed w;th water, acetone and finally with -~
diethyl ether. 9.9 g of a white powder are obtained.
;~ ~ Melting point: 19Z-195C
-~;~ IR (K~r): v - 2920, 2850, 1630, 1550, 1085, 1027 cm ~ H-NMR (DMSO-d6): ~ 0.7-1.8 (m, 20H); 3.06 (m, 4H); ; ~;

t~ 3.25-3.75 ~m, 8H); 3.75 - 4.2 (m, 4H), ~
; . ::,. ~ :,:

~33~

4.40 (S, 10H); 7.51 ~t, 2H, S.SHZ);

int. std.: tetramethyl~ilane , : ,' ExamDle 3 ;
N,N'-1,3-propaned;ylbis-~4-0-B-D-galactopyranosyl-D-gluconamide~
5395.4 9 of calcium lactobionate are dissolved in ~ 1.Z liters of water and the solution is treated for 1 ~
-; ;~ hour with 0.7 liter of Lewatit S 100 (Hi form) in a ~ -batch process. The mixture is filtered with suction and -t~he exchanger is ~ashed with 2 x 1 liter of water. The comblned eluates are concentrated substantially in vacuo.
The glass-like residue is then dissolved in 800 ml of I~ ;
amine-free dimethylformamide, 800 ml of n-hexane are ~-~
added and the mixture ;s heated to bo;ling~in a water separator with v;gorous stirring. After water separation 15 is complete, the n-hexane is distilled off, 43 ml of 1,3- ~ -diam;nopropane are added and the m;xture is stirred for 7 ~-hours at 63C. The mixture is then stirred into 5 `l liters of isopropanol, and the solid is collected and washed w;th 1 liter of ;sopropanol. After drying, 350 9 of a white solid are obtained~ For purification, this is dissolved in 2 liters of water~ The solution is treated for 1 hour with 100 ml of Lewatit S 10û (H form), then with 100 ml of Amberlyst A 21 (OH form). After freeze- ~ ~;
drying, the title compound is obtained in pure form.
Melting poir,t: 125-132C .-IR (K8r): v = 2930, 1645, 1550, 1080 cm 1 1H-NMR (D20): ~ 1.75 (dt,2H, 6HZ); 3.27 (t, 4H, ~j ~; 6Hz); 3.4-4.1 (m, 2ûH); 4.15 (t, 2H, !' ;'' '~
~ ~ ' ;',~.' i.~.`' ~ ` ; ' ~ ' ~ 2 r ~ A .Q"~

~ ~ 3 ~3 ~

3Hz); 4.39 td, 2H, 3Hz)~ 4.54 (d, 2H, 7Hz);
4.70 (H20, lnt. std.) 3C-NMR (D20): 6 30.79s 38.99; 63.73~ 64.65; 71.30; 73.12;
73.74; 74.14; 74.50; 75.06; 75.18; 77.99;
83.71; 106.10; 176.84 int. std.5 CH30H 6 51.56 xample_4 N,N'-1,6-hex~nedlvlbls-[4-0-~-D-qalactoPyranosyl-D-sluconamldel 17.0 g of lactoblono-1,5-lactone are suspended in 100 ml of amlne-free dimethylformamlde, 2.9 g of 1,6-dlamlnohexane are added and the mixture ls stlrred for 6 hours at 80C. After cool- ;
lng, the m~xture is ~lltered and the flltrate ls stlrred lnto 1 ;
liter of dlethyl ether. The partly oily precipitate ls dissolved ln 50 ml o~ water and treated with 80 ml o~ ion exchanger (Merck 4765, H~ form). The mixture is flltered and, after lyophiliza-tion, 19.5 g of colorless powder whlch decomposes from 175C wlth ,: - , . ~.
brown coloration are obtained.

IRI v ~ 2930, 2860, 1645, 1548, 1080 cm~l lH-NMR (D20)~ ~ 1.0-1.8 (m, 8H)~ 3.25 (t, 4H, 5.5Hz); 3.3- ~ `;

4.1 (m, 20H)~ 4.15 (t, 2H, 3Hz); 4.38 (d, 2H, ;`~

3Hz); 4.55 (d, 2H, 7Hz); 4.70 (H20) ; ;

lnt. std.~ 3-trlmethylsilylpropane-sulfonic acid Na salt 3C-NMR (D20)~ ~ 28.19; 30.89; 41.63; 63.68; 64.64; 71.25;

73.06; 73.72; 74.12; 74.96; 75.18~ 77.97 83.61~ 106.08; 176.42 int. std.~ CH30N ~ ~

51.54 ~ ;

40 - ~ 3 3 ~ 9 ~ ~2237-378 ExamDle 5 N,N'-1,1Z-Dodecaned _lbis-t4-0-B-D-galactopyranosyl-D-gluconamide]
40.8 9 of lactobiono-1,5-lactone are suspended in 150 ml of anine-free dimethylformamide, 12.0 g of 1,1Z-di-aminododecane are added and the mixture is stirred for 6 hours at 60C. The mixture is added dropwise with stirring to 1.5 liters of isopropanol. The precipitate is washed with isopropanol and dissolved in 250 ml of water. The solution is treated first with 20 ml of an acid ion exchanger (Lewatit 5 100), then with a basic ion exchanger (Merck 4767). After ~-lyophilization, 35.0 g of a colorless powder are obtained. `~i Melting point: 79-81C
IR: v = Z920, 2850, 1645, 1550,~1080 cm 1 1H-NMR (D2U) ~ 0.8-1.9 (m, 20H); 3.24 (t, 4H, ``
5.5Hz); 3.4-4.1 (m, 20H); 4.17 (t, 2H, - ~ `
3Hz); 4.38 ~d, 2H, 3Hz); 4.55 (d, 2H, 7Hz); 4.68 (H20, ;nt. std.) C-NMR ~D20): ~ 29.û2; 31.36; 31.70; 41.86; 63.64;
~ 64.69; 71.20; 73.08; 73.72; 74.17; 75.03;
75,20; 77~97; 83.72; 106.12; 176.24; int.
s t d . CH30H ~ 51.56 ;~
Example 6 ` ~
N,N'-1,9-Nonanediylbis- ~;
4-0-~-D-galactopyranosyl-D-gluconamide] -~
Preparation and purification are analogous to ;;;;~
Example 5. 15.0 9 of the title compound are obtained from 15.0 g of lac~obiono-1,5-lactone and 3.47 9 of 1,9-diaminononane.

:

- ~ 3 3 ~
,~ , , -IR: v = 2930, 2860, 1660, 1545, 1080 cm 1 H-NMR (D20): ~ 0.9-1.8 (m, 14H); 3.20 (t, 4H, 5.5Hz);
3.3-4.1 (m, 20H~; 4.15 (t, 2H, 3Hz);
4.38 (d, 2H, 3Hz); 4.55 (d, 7Hz); 4.68 ;
(H20, int. std.) Example 7 -N,N'-1,1Z-Dodecanediylbis- ', (4-C-B-D-glucoDyranosyl-D-gluconam;de) ,...... ' 2.04 g of cellobiono-1,5-lactone (H.W. Diehl et ~-10al., Carbohydr. Res. 38~j 364 (1974)) are reacted ~ith ~; -0.60 g of 1,1~2-diaminododecane analogously to ExamPle 5 and 0.60 g of the title compound are obtained.
IR: v = 2925, 2850, 1645, 1545, 1075, 1040 cm 1 1H-NMR (D20): ~ 0.7-1.9 (m, 20H~; 3.0-4.6 (m~ 30H); - ;
4.68 (H20 ;nt. std.) Example 8 N,N'-1,12-Dodecanediylb;s- ` `
(4-0-~-D-glucopyranosyl-D-aluconamide) . ... ''; ':
20.0 9 of calcium maltobionate tW.N. Emmerling, 3. Pfannemuller, Starch 33, 202, (1981)) are reacted with 1,12-diaminododecane~analogously to ExamPle 3 and 17.8 g of product are obta;ned.~
, :. :. . :
IR: v = 2925, 2850, 1650, 1545, 1145, 1075, 1030 cm~1 H-NMR (DzO): ~ 0.7-1.9 (m, 20H); 3.20 (t, 4H, 5.5Hz); 3.3-4.4 (m, 24H); 5.15 (d, 2H, 3Hz); 4.68 (H2O, ;nt. std) : :,, ,~ , : "'' ~ 3 ~
- 4~! - 22237-378 Example 9 N,N'-1,12-Dodecanediylbis-(6-0-~-D-galactoDyranosyl)-D-gluconam_de 3.96 g of potassium melibionate (Sigma Chemie) are reacted with 1.ûO g of 1,1Z-diaminododecane analo- --gously to Example 3 and 3.3 g of the title compound are obtained.
Melting point: 114-123C
IR (KElr~: v = 2925, 1855, 1645, 1550, 1150, 1080, 1030, 980 cm 1 H-NMR tD2û): ~ 0.8-1.8 (m, 20H); 3.20 tm, 4H);
3.4-4.2 (m, 22H~, 4.29 (d, 2H, 3Hz); - ,-~
4.95 (s, 2H); 4.68 (H20, int. std.) , --Example 10 ` ~``
N,N'-1,3-ProDanediylbis- ~
t6-0-~-D-galactopyranosyl-D-gluconamide) ~ ~-Preparation is analogous to ExamPle 9. 3.0 9 of product are obtained from 3.96 9 of potassium melibionate .
and 0.37 9 of 1,3-d;aminopropane.
Z0 Melting po;nt: 90-96C
IR tKBr): v = 2925, 1645, 1550, 1152, 1080, -~
1 1030, 975 cm 1 H-NMR (D20): ~ 1.76 (dt,2H, 6.5Hz); 3.3û (t, 4H, 6.5 Hz); 3.4-4.2 tm, 22H); 4.33 td, ; ~
2H, 3Hz); 4.96 (s, 2H); 4.70 (H20~ int. ~-std.) 3C-NMR (D20): ~ 3û.73; 38.96; 63.75; 70.94; 74~13;
71.90; 72.12; 73.06; 73.52; 74.52; 75.97;
100.99; 176.91 , ~ ~
~ " ''..~ '~ ' '~ ~.,' ,..:
~, . .~, _ 43_ ~ 33~ 22237-378 j Examole 11 N,N'-~,rl'-m-XyLened;ylbis-~4-0-~-D-gaLactopyranosyL-D-oluconamide~
If 17.0 9 of lactobiono-1,5-lactone and 3.3 ml S of 3-(aminomethyl)benzylamine are used in a process according to Example S, then 12.2 9 of the title compound are obtalned in the same ~ay;as colorless powder. '~''`
IR: v =~2920, 1665, 1545, 1080 cm 1 ' '' ~; H-NMR (D'zO): ~ 3.3-4.6 (m, 30H); 4.68 (H20); '''' ~ 7.24 (m, 4H) ' ExamDle 12 N,N'-4,4'-Dicyclohexylmethanediylbis-'~ ` . '.
C4-0-3-D-aalactopyranosyl-D-aluconamjde]
Preparation and purification from 17.0 9 of lacto~
biono-1,5-lactone and 5.~ 9 of 4,4'-diam;nodicyclohexyl-methane are analogous to Example 5.
Yield: 21.3 g.
iR: v = 2~30, 2850, 1645, 1545, 1080 cm 1 '~
H-NMR ~D20): C 0.6-2.Z ~m, 20H); 3.2-4.6 (m, 28H) 4.68 ~H20) ; ;
Example 13 . .
' N,N'-1,6-~3,4-D;thiahexanediylbis)-, 4-0-B-D-galactopyranosyl-D-gluconam;de ,~
! I 6.9 ml of tr;ethylam;ne ar'e added at room tempera-ture to 17.0 9 of lactob;ono-1,5-lact'one and 5.63 9 of '~
cyst~am;ne d~hydrochlor;de ;n 50 ml of am;ne-free DMF and the m;xture ;s subsequently st;rred for 6 hours at 60C.
It is then precipitated using 500 ml of ethanol and the ' ~' ~' precipitate ;s further treated as~ in ExamPle 5. 13.2 9 - 44 - ~ 3 3 3 ~ ~ ~22237-378 - --. . - .:
of ~hite powder are obtained.
IR: v = 2925, 1650, 1545, 1080 cm 1 ,~-H-NMR (D20): ~ 2.90 tt, 4H, 6Hz); 3.2~4.1 (m, 24H);
4.16 (t, 2H, 3Hz); 4.38 (d, 2H, 3Hz); . :~-:
S 4.55 (d~ 2H, 7Hz); 4.68 ~H20, int.
std.) `
Exam~ple 14 -N,N'-1,7-(4~Azaheptanediylbis)~
4-0- -galactopyranosyl~D~gluconamide 17.~0 9 of Lactob;;ono-1,5-lactone are suspended ;i ,~
in 100 ml of am~ine~free dimethylformamide, Z.28~ml of `~ ~`
bis-(3-aminopropyl)amine are added~at room temperature and the mixture is stirred for 10 hours. It is then stirred for 4 hours at 40C and filtered. The filtrate is stirred into 900 ml of acetone and 23.0 9 of white ; ~
crystals are obtained~after washing with acetone and drying. These are dissolved in 80 ml of water and pre~
cipitated using 900 ml of acetone. The partly oily pre-cip;tate is dissolved ;n 150 ml of water, f;ltered and 20 lyophilized. Yield: 16.5 9.
IR: v = 29Z0, 1650, 1545, 1080 cm 1 H-NMR ~DzO): ~ 1.8Z (dt,4H, 6Hz);~Z.91 (t, 4H, 6Hz); 3.30 (t, 4H, 6Hz); 3.45-4.6 (m, 26H); 4.68 (H20) ~ Example 15 N,N'-1,12-(4,9-Dioxadodecanediylbis)~
- :- :.:: :. :
4-0-~-D-galactooyranosyl-D-gluconamide Preparation and Purification are analogous to Example S. 18.9 g of the title compound are obtained , ~ " :

~ 3 3 ~
- ~ 5 - 2 2 2 3 7- 3 7 8 from 17.0 9 ~f lactobiono-1,5-lactone and 5.1 9 of 1,12- ~ ;-diamino-4,C~-d;oxadodecane. '~
H-NMR (D20): ~ 1.4 2.0 (m, 8H); 3.1-4.1 (m, 32H); - --4.6 (t, 2H, 3Hz); 4.38 td, 2H, 3Hz);
4.55 (d, 2H, 7Hz) ;~
Example 16 N,N'-Dimethyl-N,N'-1,2-ethanediylbis- '-,','-t4-0-B-D-galactopyranosyl-D-gluconamide?
Preparation and purification are analogous to Example 5. 3.0 g of the title compound are obtained from ~-~
. }. .:
3.40 9 of lactobiono-1,5-lactone and 0.44 9 of N,N'-dime thylethylenediamine.
Melting point: 125-133C
IR (K~r): v = 2930, 1640, 1400, 1075 cm 1 1H-NMR (D2O): ~ 2.99, 3.16 (2S, 6H); 3.3-4.3 (m, 28H); ;
4.49 (d, 2H, 7Hz); 4.68 (H2O, int. ~;;
std.) ~:~
Example 17 ~; -N,N'-1,5-~1-Ethoxycarbonyl)pentanediylbis-~4-0-3-D-galactopyranosyl-D-gluconamide) ~
2.47 9 of lysine ethyl ester dihydrochloride are suspended in 40 ml of amine-free dimethylformamide, 3.0 ml of triethylamine are added and the m;xture is stirred for 15 minutes. 6.8 9 of lactobiono-1,5-lactone are then added, and the mixture is heated to 60C and st~irred for 1 day. It is then filtered and the filtrate is stirred inta 400 ml of isopropanol. The prec;pitate is collected, dissolved in 60 ml of dimethylformamide and precipitated again using ;00 m~ of isoprooanol. The precipitation ;, `~

:
"

~ 3 3 ~
i~ - 46 - 22237-378 repeated, the precipitate is washed witn isopropanol anc die~hyl ether and 4.05 9 of a white powder are thus obtained.
Melting point: 106C
S IR: v = 2930, 1735, 1655, 1550, 1075 cm 1 H-NMR tD20): ~ 1.25 (t, 3H, 7Hz); 1.2-2.Z (m, 6H); -3.25 (t, 2H, 5.5Hz)l 3.4-4.6 (m, 29H);
; 4.b8 (H20, int. std.) ExamPle 18 ,'.
Dec~asodium N,N'-1,3-Propanediylbis-. :-(2,3,4,5,6-penta-0-sulfo-D-gluconamide) .

4.30 9 of N,N'~1,3-propanediylbis-D-gluconamide -.: :~' ::-.':
are suspended in 50 ml of dry dimethylformamide and heated to 40C, and 23.9 g of pyridine-sulfur trioxide complex are added with stirring. After a few minutes, the product precipitates out in the form of the pyridinium salt as an ` ;~
oil. After 1 hour, the m;xture is allowed to cool and the supernatant solution ;s decanted off. The o;l is d;ssolved ;n 50 ml of water and brought to pH = 1û U5 ing ; ~;~
6 N sod;um hydrox;de solution. The solution ;s made up to 90 ml using water and stirred into 350 ml of a 1X
strength sod;um acetate solution. The precip;tate ;s ;~
washed with methanol and dr;ed. 18.6 9 of a colorless powder are obta;ned. This is dissolved ;n 186 ml of water~
227 ml of methanol are stirred 1nto the solution and it is allowed to stand for 15 hours. The supernatant is decanted from the deposited oil and the latter is tri-turated with methanol. The preciPitation is repeated until the title compound is pure. `

~ :" : ~ .

Decomposition from 190c with brown coloraeion.
IR (KBr): v = 2960, 1670, 1555, 1250, 1073, 1045, 1019, 770 cm 1 1H-NMR (D20): ~ 1.87 (dt,2H, 7Hz); 3.36 (dt,4H, 7Hz); 3.9-4.6 (m, 4H); 4.8-5.4 (m, 8H);
4.68 (H20, int. std.) []D = +26.2 (c = 5 in H20) Elemental analysis: - -. .
calc.: N 22.10% S 1.93% ~
found: N 22.29% S 1.83%
,:
3C-NMR (D20): ~ 29.97; 39.69; 69.06; 77.68; 78.10;
78.39; 79.65; 171.33; int. std.:
CH30H ~ 51.56 ~ .
Examp~e 19 Decasod;um N,N'-1,12-dodecanediylbis~
t2,3,4,5,6-penta-D-sulfo-D-gluconamide) 5.60 9 of N,N'-1,12-dodecanediylbis-D-gluconamide are reacted with 25.5 9 of pyr;dine-sulfur tr;ox;de com- -plex analogously to Example 18 and 20.5 9 of crude product -~
are obtained. The pure product is obtained by gel chro~
matography of an aqueous solut;on on a Sephadex G 25 column. After freeze-dryin~, a colorless powder wh;ch decomposes between 175C and 189C w;th brown colorat;on is obtained.
IR ~KBr): v = 2930, 2855, 1665, 1555, 1250, 1072, 1042, 1010 cm 1 ~; 1 ': ':' ::' :' `::
H-NMR (D20): ~ 1.0-1.9 tm, 20H); 3.32 (m, 4H); ~ ~
. :.
4.2-4.6 (m, 4H); 4.9-5.3 (m, 8H); 4.68 (H20, I n t ~ std.) ~k rr~ k - 48 ~ 3 ~ ~ ~ 8 ~22237-378 `: ~ ~
3C-NMR ~2~: ~ 2;8.72; 30.52; 31 02; 42.30; 69.22;
77.67; 78.34; 78.65; 79.91; 171.09;
int. std. CH30H ~ 51.56 Example 20 Hexadecasodium N,N -1,3-proDanediylbis-t2,3,5,6-tetra-0-sulfo-4-0-(2,3,4,6-tetra-0-sulfo-3-D-galactoDyranosyl)-D-gluconamide]
79.~1 9 of calcium lactobionate are dissolved in 240 ml of water~and the solution is treated with 240 ml ;-of Lewatit S 100~(H+ form). The ion exchanger is washed us~lng 3 x~200 ml of water and the combined solutions are concentrated as far as possible. The glass-like residue is dissolved in 700 ml of amine-free dimethylformamide an~d heated to boiling with 600 ml of n-hexane ;n a water separ-ator. After water separation is complete, the n-hexane is ~-~
evaporated off and 7.7 9 of 1,3-diaminopropane in 50 ml of dimethylformamide are added to the solution at room temPer ature. After stirring for 5 hours at 60C, the mixture ;s `
allowed to cool to atout 30C and d;luted with 450 ml of dimethylformam;de, and 400 9 of pyr;d;ne-sulfur tr;ox1de ~`
complex are added rap;dly ;n portions w;th stirr;ng. The mixture ;s st;rred for 1 hour between 40 and~45C and allowed to cool. The supernatant ;s decanted off from the , depos;ted o~;l, and this is d;ssolved in 500 ml of water and the solut;on ;s adjusted to pH = 10 us;ng 30;% strength ~ `
sod;um hydroxide solution. The solution ~s made up with water to a volume of 1.5 liters and stirred into 4.5 liters `
of a 1% strength methanolic sodium ace~ate solution. The preclpita~e is stirred with 1 liters of methanol, filtered ~ ; ;
~ T~
; , ....;,.

3 3 3 9 ~

off ~ith suction and dried. 250 9 of a yellowish powaer are obtained. This is dissolved in 2 liters of water, 250 ml of 30% strength hydrogen peroxide are added and the mix- ~i ture is stirred for 1 hour at 45C. After cooling, it is S neutralized and made up to 2.5 liters using water. The solu- ~ -tion is stirred into 3.06 liters of methanol and allowed to stand for 15 hours. The supernatant is decanted off from deposited oil and the latter is triturated with methanol. -After drying, 188.5 9 of colorless powder are obtained.
:
The precipitation procedure is repeated four times~ and about 50 9 of the pure title compound are finally ob~
tained as a colorless powder ~h;ch turns brown from 172C
with decomposition and does not melt under 250C.
IR (KBr): v = 2965, 1665, 1552, 1250, 1055, 1020, 927, 820 cm ~
H-NMR ~D20)~ Z (t, 2H, 6.5Hz); 3.35 tt, 4H, 6.5Hz); 3.9-4.4 (m, 8H); 4.4-4.8 (m, ~H20 signal at 4.68 as int. std.);
4.8-5.4 tm, 10H) 2û13C-NMR tDzo): ~ 30.31; 39.77; 68.36; 68.92; 74.22;
77.49; 77.79; 78.39, 78.76; 80.15;
103.55; 171.76; int. std.: CH30H

51.56 ~ ~ ;
[~]D = +13.3 (c - 5 in H20) Elemental analysis:
calc.: N: 1.17% S: 21.49%

- : . .: ~
found: N: 1.16% S: 21.61% ;

,:

~ ~33~ ~$~

E~ample 21 Pentadecasodium pentadeca-O-sulfo-N,N'-1 3-~ . .
propaned;ylbis(4-o-B-D-aalacto~yranosyl-D-gluconamide) 3.77 g of N~N~ 3-propanediylbis(4-o-B-D-galacto- -pyranosyl-D-gluconamide) are dissolved in 60 ml of dry dimethylformamlde and 13.5 9 of pyridine-sulfur trioxide complex are added in portions at 40C with stirring~
After 1 hour, the mixture is worked up as in Example 18 ~~
and 10.3 9 of yellowish, sulfate-containing crude product are obtained. This is dissolved in 90 ml of water, 10 ml ~
ùf 30% strength hydrogen peroxide are added and the mix- -ture is stirred for 1 hour at 45C. After cooling, 230 ml --~
of methanol are stirred in and the mixture is allowed to : ~
stand for 15 hours. The supernatant is decanted off from - -the deposited oil, the latter is triturated using methanol and 6.72 9 of sulfate-free product (hav;ng a sulfur content of 20.6X) are obtained. This is dissolved in 67 ml of water, 82 ml of methanol are stirred ln and ~1 `
the mixture ;s allowed to stand for 15 hours. The super-.: ~:
natan~t is decanted off from the deposited oil and a further 74 ml of methanol are stirred in. After 15 hours, the oil ;s isolated and the fractlonal crystallization is ~ ~',''',~",'~'i,~i,J~
repeated ~ith it several times as above until the title compound is pure. 0.53 9 of colorless powder which decomposes frr,m 180C with brown coloration are obtained.
IR~(K~r): v = 2960, 1660, 1550, 1250, 1055, 10Z0, 930, 820 cm 1 H-NMR (D20): ~ 1.87 (t, 2H, 6Hz); 3~42 (t, 4H, 6Hz); 3.9-4.5 (m, 8H); 4.5-4.85 ;m ~ ~
~ ~.':; .
, ' " '; ' :~' ,~ 133~
:` - 51 - 22237-378 H2C signal at 4.68 as int. std.);
4.85-5.3 (m, 10H) 1 C-NMR (DzO): ~ 30.53; 39.79; 68.46; 69.11; 72.28;
74.36; 74.56; 77.43; 77.88; 78.14;
78.49; 79.03; 79.61; 79.84; 80.43;~;
103.45; 171.82; 172.61; int. std.:

ELemental analysis: calc.: N 1.23% S 21.04Z
found: N 1.21% S 20.91%
Example 22 -~
:: - HexadecamorDholinium N,N'-1,3-DroPaned;ylbis-r2j3,5,6-tetra-O-sulfo-4-0-(2,3,4,6-tetra-0-. ~
sulfo-B-D-9aLactopyranosyl)-D-9luconamide]
A solution of 1.76 9 of the sod;um salt from Example 20 is treated for 15 minutes with 16 ml of Lewatit S-100 ~H~ form), the ion exchanger is filtered off and 1.03 9 of morpholine are ~added to the filtrate. After : ~, lyophilization, 2.40 9 of yellowish powder are obtained.
; Decomposition from 120C; and black coloration at 210C
IR ~K~r): v = 2950, 2780, 1665, 1563,~ 1450, 1426, 1250, 1097, 1015, 925, 893, 868, 810 cm 1 H-NMR ~D20): ~ 1.82 ~dt,2H; 6.5Hz); 3.15 (m, 64H);
, 3.35 (m, 4H); 3.90 (m, 64H); 4.0-4.4 -;
~m, 8H); 4.4-4.8 (m, ~H20 signal at ~-4.70 as int. std.); 4.8-5.4 tm, 10H); ~ ;

~: :
.:

,: .: . ~ :~ :

~ 3 ~
- ~z - 22237-378 Examole 23 Hexadecasod;um N,N'-1,6-hexanediylbis~2,3,5,6-tetra-O-sulfo-4-0-(2,3,4,6-tetra-0-sulfo-~-D-galacto- ,,~' pyranosyl)-D-gluconamide] -16.3 9 of N~Nl-1~6-hexanediylbis(4-o-B-D-galacto-., pyranosyl-D-gluconamide) are reacted with 75.0 9 of pyri-dine-sulfur trioxide complex analogously to Example 18. - -After the first prec1Pitation, 56.9 9 of a yellowish pow~
der are obtained which is purified as in Example 20.
About 15 9 of the pure title compound are finally obtained in the form of a colorless po~der which sinters from , -120C. , , ~; -Decomposit;on from 170C with brown coloration. ~ `
IR ~KElr): v = 2930, Z860, 1655, 1550, 1250, -1055, 10Z0, 9Z8, 810 cm 1 -~
H-NMR (D20): ~ 1.1-1.9 (m, 8H); 3.37 (m, 4H?J 3.9-4.5 ~m, 8H); 4.5-4.85 (m ~ H20 ~ !n ;,~.'-'~.
signal at 4.68 as int. std.); 4.85-5.3 tm, 10H) ~
20 13C-NMR ~D20): ~ 28.42; 30.74; 42.17~ 68.56; 69.01;
74.39; 77.Z0; 77.80; 78.37; 78.94;
80.47; 103.21; 171.27; int. std.
CH30H ~ 51.56 Cc~]D = +9.9 ~c = 5 in H20) ~ Example 24 Hexadecasodium N,N'-1,9-nonanediylbis~Z,3,5,6-tetra-0-s~ulfo-4-0-(2,3,4,6-tetra-0~-sulfo-~-D~galactoDYranos~tl)-D-gluconamide]
~ : , ~ - ~ . ,:
~ ~ Preparation and purif;cation are analogous to ~;

~ , ~:; ';.'~' 3 3 ~

Example 23. 45.0 9 of crude product are obtained 'rom 15.0 9 of N,N'-1,9-nonanediylbis(4-0-B-D-galactoPyrano-syl-D-gluconamide) and 63.0 9 of pyridine-sulfur tri-oxide complex. After purification: 10.5 9 of colorless '~
powder.
Decomposition between 192-210C with brown coloration IR (K8r): v = 2935, 2860, 1665, 1555, 1250, 1057, 1020, 925, 815 cm ~
H-NMR (D20): ~ 0.9-1~9 (m, 14H); 3.29 (t, 4H, ~' 6.5Hz); 3.8-4.45 (m, 8H); 4.45-4.8 : .
(m + H2O signal at 4.68 as int.
std.); 4.8-5.4 (m, 10H) ~'~
3C-NMR (DzO): ~ 28.?7; 30.83; 31.09; 31.32; 42.19;
68.69; 68.99; 74.46; 77.12; 77.79;
78.33; 78.93; 80.51; 103.11; 1Z1.21 ;~
int. std.; CH30H, ~ 51.56 Examole 25 Hexadecasodium N,N'-1,12-dodecanediylbis~2,3,5,6-tetra~
O-sulfo-4-0-(2,3,4,6-tetra-0-sulfo-B-D-galacto-~ ,;',.. ',., Pyranosyl)-D-gluconam;de] ~ ; ' Preparation and purif;cat;on are anaLogous to Example 23. 13.30 9 of crude product are obta;ned from 4.23 9 of N,N'-1,12-dodecaned;ylb;s (4-0-~-D-galacto-pyranosyl-D-'gluconam;de); and 19.1 9 of pyrid;ne-sulfur tr;ox;de complex. After purif;cat;on: 3.5 g of pure title compound are obtained as colorless powder.
Decomposition between 188-198C with brown coloration : , .
lR (K3r): v = Z940, 2880, 1665, 1555, l250, 1055, 1020, 930, 820 cm 1 .:

~ ~ 3 ~
- 54 - 22237-378 ~:
H-NMR tD20): ~ 0.9-1.9 (m, 20H); 3.35 (t, 4H, 6.5Hz); 3.9-4.5 (m, 8H); 4.5-4.8 (m, +H20 signal at 4.70 as int. std.);
4.8-5.4 (m, 10H) S 13C-NMR (D2O): ~ 28.74; 30.80; 31.09; 31.44; 42.18;
68.76; 6a.96; 74.50; 77.08; 77.80;
78.29; 78.94; 80.51; 103.07; 171.19 ;~ - ;
int. std.: CH30H ~ 51.56 ExamDle 26 --Hexadecasodium~N,N'-1,1~2-dodecanediyl~bis[2,3,5,6-tetra-0-sulfo-4-0-~2,3,4,6-tetra-O-sulfo-B-D-glucopyranosyl)-D-gluconamide]
0.68 9 of crude or 0.10 9 of pure product are .
obtained from 0.34 9 of N~N~ 12-dodecanediylbis(4-o-B
D-glucopyranosyl-D-gluconamide) and 1.12 g of pyridine- ~ -sulfur trioxide complex analogously to Example Z3.
Decomposition from 148C to 159C with bro~n coloration.
IR tK~r): v = 2930, 2855, 1670, 1560, 1250, ~- .
1070, 995, 935, 800 cm ~
1H-NMR ~D20): ~ 0.8-1.8 tm, 20H); 3.30 (m, 4H);
3.7-4.8 (m ~ HzO signal at 4.68 as ; -;~
;nt. std.); 4.8-5.3 (m, 10H) `~
3C-NMR ~DzO): ~ 2~.92~ 30.95; 31.32;~31.64; 42.34;
69.20; 70.12; 75.57; 77.44; 77.67;
77.85; 79.33; 79.41; ;79.97; 8~1.08;
102.53; 171.27; int. std.: CH30H
51.56 ; ~:

.;
. :

~ 3 3 3 ~

ExamDle 27 Hexadecasodium N,N'-1,12-dodecanediYlbis[Z,3,S,6-tetra-O-sulfo-4-0-(2,3,4,~-tetra-O-5ulfo-c~-D-alucoDyranosyl)- :~ -D-gluconamide]
S 47.5 9 of crude or 3.0 9 of pure product are obtained from 12.8 9 of N,N'-1,12-dodecanediylbis(4-O-D-glucopyranosyl-D-gluconamide) and 64.6 9 of pyridine-; sulfur trioxide complex anaLogously to Example 23.
Decomposit;on from 175C to 189C with brown coloration.
; 10 IR (K8r): v = 2930, 2860, 1660, 1560, 1Z50, 100û, 943, 805 cm~~
H-NMR tD20): C 1.0-1.9 (m, 20H); 3.27 tm, 4H);
~, ~,.....
4.0-4.82 (m -~ signal for H20 at 4.68 : -as int~ std.); 4.82-5.25 (m, 10H);

5.52 (d, 2H, 3Hz) 3C-NMR (D20): C 28.84; 30.69; 31.15; 31.47, 42.41;

68.51; 69.29; 71.95; 76.14; 76.82; ~ `

77.91; 78.30; 78.44; 79.98; 98.93; ;~

171.27 ~ `

ExamPle 28 ; ~
Hexadecasodium N,N'-1,12-dodecaned1ylb;s~2,3,4,5-tetra-0-sulfo-6-0-t2,3~4,6-tetra-O-sulfo-~-D-oalacto-pyranosyl)-D-gluconamide]
,,._ : ,: ~ :.. .
9.7 9 of crude or 3.4 9 of pure product, which s;nters at 57C, are obtained analogously to Example 23 from 3.30 9 of N,N'-1,12-dodecanediylbis(6-0-~-D-galacto-pyranosyl-D-gluconamide) and 14.9 9 o~f pyridine-sulfur trioxide complex.
Decomposition from 182C with brown coloration.

~ j ' ' ~',',' ' ;''.~ "' ''"., ;;'~':
:, ',: ,. ,.: ~' .., : :.:. .

~-- ~ 3 3 ~

IR (KBr): v = 2930, 2855, 1650, 1555, 1250, 1050, 1027, 830 cm~~
H-NMR ~D2O): 6 1.0-1.9 (m, 20H); 3.25 (m, 4H)s 3.9-4.4 (m, 8H); 4.4-4.8 (m + H20 signal at 4.68 as lnt.
std.)t 4.8-5.25 (m, lOH); 5.38 (d, 2H, 3Hz) .-~
3C-NMR (D2O): 6 28.72; 30.58; 31.03~ 31.34; 42.30; 69.14;
69.77; 70.66; 74.51; 74.92; 77.91; 78.21t ~
78.49; 78.93; 80.~75; 99.12; 171.26; int. std.s . ~-CH30H 6 51.56 .
ExamPl~ 29 Hexadecasodlum N,N'-1,3-ProPanedi~lbis r 2,3,4,5-tetra~-O-sulfo-6-0- L2~ 3,4,6-tetra-O-sul~o-a-D-qalactoPyran D-~luconamldel 0.96 g o~ crude or 0.50 g of pure product are obtained ` -~rom 0.34 g of M,N'-1,3-propanedlylbls(6-O-a-D-galactopyrano~yl-D-gluconamlde) and 2.0 g o~ pyridine-sul~ur trloxide complex analo- ;
gously to Example 23. Decompo3itlon ~rom 168C with brown colora- ;~
tlon IR ~K~r). v - 1640, 1550, 1250, 1050, 1025, 830 cm~
lH-NMR (D20)~ 6 1,85 (t, 2H, 6.5Hz)1 3.35 (t, 4H, 6.5HZ)1 3.9-4,4 (ml 8H)J 4.4-4.8 (m ~ H2O slgnal at 4.68 as int. std.)~ 4.8-5.2S (m, lOH); 5.36 ~d, 2H, 3Hz) ; 13C-NMR (D20) t 6 30.13~ 39.84~ 69.171 69.86~ 70.74~ 74 53 74.97~ 78.00~ 78.177 78.37~ 79.00~ 80.81 99.18~ 171.70~ lnt. std.. CH30H 6 51.57 ; ' . ',' :'' ' "
'~.: ~ ;. ` . :
''',''."'. ''",",'..'"''''.' '',':,"",",'"''' ` ~ ~33~

Examp~e 30 Hexadecasodium N,N'-~,c~'-m-xylenediylbis[2,3,5,6-tetra-O-sulfo-4-0-(2,3,4,6-tetra-0-sulfo-B-D-galacto- , pyranosyl)-D-gluconamide] ~-28.0 9 of crude or 5.3 9 of pure product are obtained from 12~0 9 of N~N~ m-xylenedilybis(4-o-B
D-galactopyranosyl-D-gluconamide) and 58.8 9 of pyrid;ne-sulfur trioxide complex analogously to Example 23.
Decomposition from 157C with brown coloration.
IR (KBr): v = 2960, 1660, 1550, 1250, 1055, 1020, 930, 815 cm 1 H-NMR (D20): ~ 3.9-4.85 (m ~ H20 signal at 4.68 as int. std.), 4.85-5.4 (m, 10H); 7.38 (s, 4H) 3C-NMR (D20): ~ 45.51; 68.63, 69.15; 74.42; 77.24;
77.67; 77.91; 78.49; 79.08; 80.70; ;~
103.29; 128.15; 128.86; 131.64; ;
140.80; 171.88; int. std. CH30H
51.56 i ;
Example 31 20Hexadecasodium N,N'-4!4~-d;cylcohexylmethaned;ylb;s- `~
C2~3~5r6-tetra-o-sulfo-4-o-(2~3~4~6-tetra-o-sulfo-B-D
galactopyranosyl)-D-gluconam;de~
70.7 9 of crude or 15.2 9 of pure product, which sinters from 120C, are obtained analogously to cxample ;, . . .
25Z3 from 25.7 9 of N,N'-4,4'-dicyclohexylmethanediylbis- ~ ~`

(4-O-B-D-galactoPyranosyl-D-gluconamide) and 114.7 9 of pyridine-sulfur trioxide complex.

Decomposit~on from laoc with brown coloration. ~ , . `

'.'.'' ,`'.~ ... ','',' '.`

9 ~ ~
5 8 - 2 2 2 3 7- 3 7 8 :

IR (KBr): v = 2930, 2860, 1660, 1550, 1250, 1055, 1020, 9Z8, 815 cm 1 - -H-NMR (D20): ~ 0.6-2.4 (m, 20H); 3.65 (m, 2H);
3.9-4.5 (m, 8H); 4.5-4.85 (m + H20 - ;~
signal at 4.68 as int. std.); 4.85-4.4 (m, 10H) C-NMR (DzO): ~ 30.18; 30.36; 30.75; 34.09, 44.40;
46.20; 49.45; 52.33 68.27; 68.75;
74.35; 77.80; 78.41; 78.68; 79.49; ~ ;
104.09; 170.61; int. std~ CH30H ~ 51.56 ~D = +10.0 (c = 5 in H20)~
Example 32 - -~
Hexadecasodium N,N'-1,6-~3,4-dithiahexanediylbis)-~2,3,5,6-tetra-0-sulfo-4-0-~2,3,4,6-tetra-0-sulfo-B-15D-galactopyranosyl)-D-g(uconamide]
38.0 9 of crude and 8.5 9 of pure product are obtained from 11.2 9 of N,N'-1,6-(3,4-dithiahexanediyl- `
bis)4-o-B-D-galactopyranosyl-D-gluconamide and 53.4 9 of pyr;dine-sulphur tr;ox;de complex analogously to Example 23.
Decomposition from 163C with brown coloration. ;
IR ~KHr): v - 2965, 1665, 1550~ 1250, 1055, 1015, 930, 810 cm 1 H-NMR (D20): ~ 2.96 (t, 4H, 6.5Hz) 3.69 (m, 4H); - ;
4.0-4.47 ( m, 8H); 4.45-4.8 ( m +
HzO signal at 4.68 as int. std.);
4.8-5~.3 ( m, 10H) 1 C-NMR (D20): ~38.72; 41.06; 68.68; 69.05; ~
74.~8; 77.40; 77.87; 78.46; 80.46; ;~ ;

~ , ,. ,~, .. .

~ 3 ~
~, - 59 _ 22237-378 lG3.48; 171.86; int. std. CH30H
51.56 ExamDle 33 -Hexadecasodium N,N'-1,7-(4-a~aheDtanediylbis)-., . j : :: .
5[Z,3,5,6-tetra-0-sulfo-4-O-t2,3,4,6-tetra-O-sul~o-B-D-galactoDyranosyl)-D-gluconamide] ~-~ 3 15.4 9 of crude and 2.Z g of pure product are obtained from 11.0 9 o~f N,N'-1,7-(4-azaheptanediylbis)- ~;
4-o-B-D-galactopyranosyl-D-gluconamide and 50.0 9 of pyrldine-sulfur trioxlde complex analogousLy to Example 23.
Decomposition ~rom 165C with brown coloration.
IR (KBr): v = 2960, 2925, 2855, 1650, 1SS0, 1250, 1055, 1020, 927, 820 cm 1 1H-NMR (D20): ~ 2.98 (m, 2H); 3.17 (t, 4H, 7Hz);
3.44 (t, 4H, 6Hz); 3.9-4.4 (m, 8H);
4.4-4.85 (m ~ H20 signal as int.
std. at 4.68); 4.85-5.3 (m, 10H) 13C-NMR (D20): ~ 28,11; 39.08; 48.12; 68.65;
` 69.24; 74.45; 76.94; 77.93; 78.46;
79.09; 80.71; 103.13; 172.06 , , ExamDLe 34 Hexadecasodium N,N'-1,12-(4,9-dioxadodecanediylbis~
[2,3,5,6-tetra-0-suLfo--4-0-(2,3,4,_-tetra-O-sulfo-B- ~}
25~ D-galactopyranosyl)-D-gluconamide]
; 37.l 9 of crude and 9.3 9 of pure product, which ~ '~
s~n~ers from 120C, are obtained from 18.2 9 of N,N'-1,12-(4,9-dioxadodecanediylbis)4-0-B-D-~alactopyran~osyl-. '', ''', D-g~uconamide and 59.û 9 of pyridine-su~fur trioxid~

,, ; :, ~. ,-,: ~:: ';,;:

~ ~ 3 3 3 ~

complex according to Example 23. -Decomposition from 170C with brown coloration.
IR (KEr): v = 2960, 2880, 1665, 1555, 1250, 1055, 1022, 928, 815 cm 1 1H-NMR (D20): ~ 1.64 (m, 4H); 1.88 (t, 4H, 6.5Hz); -~
3.0-3.9 (m, 12H), 3.9-4.45 (m, 8H); ~ `
4.45-4.8 (m + HzO signal at 4.68 as int. std.); 4.8-5.3 (m, 10H) 3C-NMR (D20): ~ ~ 27.82; 30.78, 39.02; 68.64;
~; 10 69.01; 70.54; 72.96; 74.44; 77.02;
~; 77.79; 78.33; 78.94; 80.52; 103.10;
~, 171.45; int. std.: CH30H ~ 51.56 ~r~] = +9.0 tc = 5 in H20) ;;
Example 35 -~
Hexadecasodium N,N ~dimethyl-N,N -1,2-ethanediylbis~
~2,3,5,6-tetra-0-sulfo-4-0-t2,3,4,6-tetra-0-sulfo-B- ~ ;~
D-galactopyranosyl~-D-gluconamide~

8.2 9 of crude and 1.2 9 of pure product are ; `~
.
obtained from ~.50 g of N,N -dimethyl-N,N -1,2-ethanqdiyl-bist4-0-B-D-galactopyranosyl-D-gluconamide) and 12.4 9 ; ~
of pyridine-sulfur trioxide complex analogously to ~ -Example 23. ~ / -Decomposition from 188-200C with brown coloration.
, IR tKElr): ; v = 2970, 1650, 1250, 1015, 930, ; 1H NMR (D20): ~ ~ 3 0-4.0 tm with 5 at 3.35; 10H);
4.0-4.7 (m, 14H); 4.70 (H20, int. ; ;
; std.); 4.9-5.4 (m, 10H); 5.54 (d, 2H, 4Hz) .~ .

:

~ 3 3 ~ 9 ~

3C-NMR (D20): ~ 38.96; 48.25; 68.36; 69.25;
: . ~r- ,~,~;.7 :~
74.17; 75.11; 77.26; 77.73; 78 00;

78.45; 78.76; 79.80; 103.35; 171.25;

int. std.: CH30H, ~ 51.56 S Example 36 Hexadecasodium N,N'-1,5-(1-ethoxycarbonyl)Pentane- ~ :
diylbis[2~3~si6-tetra-o-sulfo-4-o-(2r3~4r6-tetra-o- ., sulfo-B-D-galacto3yranosyl)-D-gluconamide]
8.7 g of crude and 1.2 g of pure product, which sinters from~60C, are obtained from 3.6 g of N,N'-1,5-.
(1-ethoxycarbonyl)pentanediylbis(4-0-~-D-galactoPyrano- , syl-D-gluconamide) and 15.8 g of pyridine-sulfur trioxide complex according to Example 23.
Decomposition from 161C with brown coloration.
IR (KE~r): v = 1730, 1650, 1550, 1250, 1055, 1020, 930, 810 cm 1 H-NMR (D20): ~ 1~0-2.2 ~m, 9H, ~ith t at 1.31, ~ - `
7Hz) 3.30 (m, 2H); 3.9-4~8 (m with ~, `" `
H20 s;gnal at 4.68 as int. std.);
4.8-5.3 ( m, 1 O H ) : .. ~
3C-NMR (D20): ~ 15.94; 29.68; 30.54; 33.17; ~ ~ i 41.87; 55.93; 65.19; 68.23; 68.53;
............................................ ............................ ~, . '., -' ',!'.
69.04; 74.36; 77.33; 79.81; 78.45; -~

78.80; 79.61; 80.47; 103.36;

103.99; 171.39; 171.65; 176.12 -`

ExamDle 37 ~ -~

N,N'-1,3-Propanediylbis-D-aulonamida ` ` ;

3.56 g of D-gulono-y-lactone and 0.84 ml of 1,3-; i diaminoororJane are dissolved in 40 ml of d;methylformamide ~':':; `''~. ' ' ~333 ~

and the mlxture is stlrred for 6 hours at 60C. The mlxture i9 then stirred into 200 ml of lsopropanol and the preclpltate i8 washed with lsopropanol and dlethyl ether. The solld ls dissolved ~
in 20 ml of dlmethylformamlde and preclpltatad again using 200 ml ~ ~-of lsopropanol. The preclpltate ls dlssolved ln water and freeze~
dried. 2.2. g of a colorless powder are obtalned.
Meltlng polnt, 49-54C wlth sinterlng, 168C wlth decomposi-~;~ - tion IR (KBr~, v = 2930, 2890, 1645, 1545, 1440, 1080 cm~l ~-lH-NMR (D20): o 1.74 (dt, 2H, 6.5Hz); 3.27 (t, 4H, 6.5Hz)~
3.45-4.05 (m, lOH); 4.23 (d, 2H, 6Hz); 4.68 `~
(H20, int. std.) 3C-NMR (D20)' 6 30.651 39.02~ 65.13~ 72.64~ 74.69~ 75.00~ ;
75.12t 176.78~ lnt. std. CH30H o 51.56 ` ~
~xam~le 38 ~ -N.N'-1.2-ProeanedlYlbis-D-qalactonamide ~;Z
4.1 ~ of the tltle compound as colorless powder are obtained analogoUsly to Example 37 from 7.12 g o~ D-galactono-~
lactone and 1.48 g of 1,2-diaminopropane. -Melting polnt~ 183-193C with decomposition and brown colora-tion ,.. ~`
IR (KBr): v = 2940, 1656, 1552, 1109, 1055, 1044, 1028, 865 cm-l ~`
' ~
-NMR (D2O)~ 6 1.18 (d, 3H, 6Hz), 3.1-4.6 (m, 15H)~ 4.68 `~;

(H20, lnt. std.) ;~
1, ,~ . . , . ~.
~C-NMR (D2O)~ o 19.64~ 19.77, 46.16~ 47.87~
: . , .: : ~

~ 3 3 ~

48.10; 65.90; 71.93; ~2.64; 77.49;
177.75; 178.42; 178.54 Example 39 N,N'-1,4-3utanediylbis-L-mannonamide 2.4 g of the title compound are obtained as - ' colorless powder analogously to ExamDle 18 from 3.56 9 of L-mannono-y-lactone and 0.90 9 of putrescine. ~
Decomposition from 181-188;C with brown coloration -~;
IR (K3r): v = 2955, 2925, 2855, 1643, 1555, : 1Z31 1098, 10 -3, 1031, 880, 740, H-NMR (D2O): 6 1.58 (m, 4H), 3.30 tm, 4H); 3.75 ~m, 8H); 4.02 (d, 2H, 7Hz); 4.26 (d, ZH, 7Hz); 4.68 (H20 int. std.) 'lS 3C-NMR (D20): ~ 28.42; 41.38; 65.67; 72.58; "~
72.76; 73, 43; 75.1i; 177.09, `~
Example 40 N,N'-D;lactobionoylhydrazine ~ `N
6.1 9 of crude product are obtained~analogously to E~xample 37 from 6,8 9 of lactobiono-1,5-lactone and ~'' ~; 0.5 ml of hydrazine hydrate. Column chromatography over ~`' ~ "i Fractogel TSK H~ 40S yields the pure product as a color~
less powder af$er freeze-drying.
' iExamDle 41 ~ ~ Decasodium N,NI-1,3-prooanediylbis(2,3,4,5,6-Penta~
0-sulfo-D-gulonamide) ;' 9.8 g of crude or~ 6.4 g of pure product as colorless powder are obtalned analogously to Example 18 from 2.2 g of N,N'-1,3-propanediylbis-D-gulonamide and ~. : .
:' ~
.' '. :

~ ~ 3 3 ~

12.3 9 of pyridine-sul~ur trioxide comPlex.
Gecomposition from 185C with brown coloration.
IR (KBr): v = 2960, 1675, 1555, 1250, 1070, 1010, 925, 805 cm 1 1H-NMR (D2O): ~ 1.85 (m, 2H); 3.34 (m, 4H); 4.52 (d, 4H, 3.5Hz); 5.07 (m, 6H); 5.34 ~(d, ZH, 3.5Hz); 4.68 (H2O, int. std.) C-NMR (D2O): ~ 30.05; 39.62; 68.78; 76.28;
. -..
76.41; 77.78; 80.14; 171.15; int. .
std. CH30H ~ 51.55 ~ Example 42 ~ -DecasDdium N,N'-1,Z-DroPanediylbis(2,3,4~,5,6- ~,,.'.,.,.. ,:
penta-0-sulfo-D-galactonamide) --13.0 9 of crude or 9.8 9 of pure Product as 15 colorless powder are obtained analogously to Example 18 -from 3.3 9 of N,N'-1,2-propaned;ylb;s-D-galactonamlde and :` :
19.5 9 of pyr;d;ne-sulfur trioxide complex.
Decomposit;on from 191C with brown colorat;on~ ~;
IR tK~r): v = 2970, 1665, 1550, 1250, 1û65, 1040, 1007, 900 cm 1 ;~
H-NMR tD20): 6 1.26 td, 3H, 6.5Hz); 2.9-4.3 (m, 3H); 4.3-4.6 tm, 4H); 4.68 (HzO, int. std.); 4.8-5.3 (m, 8H) C-NMR tD2): ~ 19.20; 45.94; 46.15; 47.61;
69.07; 78.4Z; 78.86; 79.90; 170.84;
171.03; 191.93 int. std. CH30H

'' ;' '"~''" :' ~

~33~a~ :

~xam3le 43 ~ecasodium N,N -1,4-butanediylbis(2,3,4,5,6-penta-0-sulfo-L-mannonamide) 10.5 9 of crude or 7.2 9 of pure product as ~ ~;
colorless powder are obtained analogously to ExamPle 18 from 2.5 9 of N,N -1,4-butanediylbis-L-mannonamide and 14.1 9 of pyridine-sulfur trlox;de complex.
Decomposition from 180C ~ith brown coloration IR (KBr): ~ v = 2960, 2930, 2850, 1670, 1555, ~1Z50, 1075, 1010, 925 cm ' H-NMR (D20): ~ 1.65 (m, 4H); 3.31 (m, 4H~; 4.43 ; . i- --(m, 4H); 4.8-5.û8 (m, 4H); 5.15 (m, 4H); 4.68 (H20, int. std.) 13C-NMR (D20): ~ 27.98; 41.62; 69.15; 78.81;
79.36; 79.75; 170.93; int. std. ` ~
CH30H ~ 51.55 -, ~ ;
~. , . , ., . ~ . ~
Example 44 ; l `
Hexadecasod;um N,N -b;s~2,3,5,6-tetra-0-sulfo-4-0 (2,3,4,6-tetra-0-sulfo-~-D-galactopyranosyl)-gluconoyl]hydrazine :~
17.5 9 of crude or 7.3 g of pure product are obtained analogously to Example 18 from 6.0 9 of N,N
dilactobionoylhydrazine and 33.7 9 of pyridine-sulfur ;~
trioxide complex.
Example 45 ~ ;
5.000 kg of hexadecasodium N,N -1,3-proPanediyl- ;
bis~2,3,5,6-tetra-o-sulfo-4-o-(2,3,4,6-tetra-o-sulfo-~
D-galactopyranosyl)-D-gluconamide~ as dry substance are dissolved ~ith s~irring in~40 liters of ~ater for injectlon.

3 3 3. ~

After adjusting the pH of the solution to 7.5 with dilute -~
sodium hydroxide solut;on, it is made up to 5û.00 liters of water for ;nject;on and filtered through a membrane -`
f;lter of pore s;ze 0.2 ~m. The solution is f;ltered off ~ `
S under asept;c condit;ons into ampoules of 1 ml and these ~ :
are sealed off.
,, .,,. ",,. .:",.... ...
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.: `'; ;'

Claims (28)

1. Polysulfuric acid esters of bis-aldonamides and their derivatives of the general formula I
(I) in which either all radicals R1, R2 and R3 independently of one another stand for X, or two of the radicals R1, R2 and R3 stand for X, and the third stands for a radical of the formulae II-VII, (II) (III) (IV) (V) (VI) (VII) X in the formula I to VII simultaneously or independently of one another denotes a hydrogen atom or the group -SO3H, where at least one X stands for the group -SO3H, m stands for 0, 1, 2, 3, 4, 5 or 6, A in formula I stands for a straight-chain or branched, saturated alkylene radical having 2 to 22 carbon atoms which is optionally substituted by one or more radicals -CO2R5, and this alkylene radical is optionally interrupted by up to 5 -O-, -S-, -S-S-, -S(O)n-, -?-NH- or/and -NR6- groups or C5-C8-cycloalkylene or C6-C14-arylene radicals, or A stands for a single bond or the radical n is 1 or 2, R4, R5 and R6 simultaneously or independently of one another denote a hydrogen atom or a C1-C6-alkyl radical, and their salts with inorganic or organic bases.

2. Compound as claimed in claim 1, wherein each X in the formulae I to VII stands for the group -SO3H.

3. Compound as claimed in claim 1, wherein in the formulae I to VII at least half the X groups present represent an -SO3H
group.

4. Compound as claimed in claim 1, wherein R2 and R3 stand for X.

5. Compound as claimed in claim 4, wherein R1 denotes the radical III or the radical VI having m = 0.

6. Compound as claimed in claim 1, wherein R1 and R3 stand for X.

7. Compound as claimed in claim 6, wherein R2 denotes the radical II or the radical VI having m - 0 or the radical VII
having m = 0.

8. Compound as claimed in any one of claims 1 to 7, wherein A in formula I denotes a polymethylene radical -(CH2)p-having p = 2 to 22.

9. Compounds as claimed in any one of claims 1 to 7, wherein A in formula I denotes a polymethylene radical -(CH2)p-having p - 2 to 12.

10. Compounds as claimed in any one of claims 1 to 7, wherein A in formula I represents a straight-chain alkylene radical having 2 to 22 carbon atoms, whole chain can be interrupted by the groups -O-, -S-, -S-S-, -S(O)n-, -?-NH- and/or -NR6, where n and R6 possess the meanings indicated in claim 1.

11. Compounds as claimed in any one of claims 1 to 7, wherein A in formula I is substituted by one, two or more radicals -CO2R5, where R5 has the meaning indicated in claim 1.

12. A process for the preparation of polysulfuric acid esters of bis-aldonamides and their derivatives of the formula I

as claimed in claim 1, wherein bis-aldonamides of the general formula IX, (IIX) in which R1, R2, R3, R4 and A have the meanings indicated in claim 1, where, however, X in the formulae II to VII stands for a hydrogen atom, are reacted with a sulfating agent in an aprotic solvent and the products thus obtained are optionally converted into the corresponding salts using an inorganic or organic base.

13. The process as claimed in claim 12, wherein in each case, without isolation of intermediates, aldonic acids of the general formula VIII, t VIII) in which R1, R2 and R3 have the meanings indicated in claim 1, where, however, X in the formulae II to VII stands for a hydrogen atom, are converted into the aldonamides of the general formula IX
and reacted to give their polysulfuric acid esters.

14. Medicaments, containing one or more compounds of the general formula I, as claimed in any one of claims 1 to 7, together with suitable excipients and auxiliaries.

15. Bis-aldonamides of the general formula IX
(IX) in which either all radicals R1, R2 and R3 stand for a hydrogen atom, or two of the radicals R1, R2 and R3 stand for a hydrogen atom and the third stands for a radical of the formulae II' to VII', (IV') (V') (VI') (VII') m stands for 0, 1, 2, 3, 4, 5 or 6, A in formula IX stands for a straight-chain or branched, saturated alkylene radical having 2 to 22 carbon atoms which is optionally substituted by one or more radicals -CO2R5, and this alkylene radical is optionally interrupted by up to 5 -O-, -S-, S-S-, -S(O)n'--?-NH- or/and -NR6- groups or C5-C8-cycloalkylene or C6-C14-arylene radicals, or A stands for a single bond or the radical n is 1 or 2, R4, R5 and R6 simultaneously or independently of one another denote a hydrogen atom or a C1-C6-alkyl radical, and their salts with inorganic or organic bases, with the proviso that in the case of bis-gluconic acid amides a) R1, R2, R3 and R4 do not simultaneously denote hydrogen atoms and that b) when R2 is a radical of the formula II', and R1, R3 and R4 are simultaneously hydrogen atoms, A is not -(CH2)2- in this case and that c) when R is a radical of the formula VI', in which m = 0, 1, 2, 3 or 5, and R1, R3 and R4 are simultaneously hydrogen atoms and A is an unsubstituted, straight-chain alkylene radical, in this case the number of chain members is an uneven number.

16. Compound as claimed in claim 15, wherein R2 and R3 stand for hydrogen atoms.

17. Compound as claimed in claim 16, wherein R1 denotes the radical III' or the radical VI' having m = 0.

18. Compound as claimed in claim 15, wherein R1 and R3 stand for hydrogen atoms.

19. Compound as claimed in claim 18, wherein R2 denotes the radical II' or the radical VI' having m = 0 or the radical VII' having m = 0.

20. Compound as claimed in any one of claims 15 to 19, wherein A in formula IX denotes a polymethylene radical -(CH2)p-having p = 2 to 22.

21. Compound as claimed in any one of claims 15 to 19, wherein A in formula IX denotes a polymethylene radical -(CH2)p-having p = 2 to 12.

22. Compound as claimed in any one of claims 15 to 19, wherein A in formula IX represents a straight-chain alkylene radical having 2 to 22 carbon atoms, whose chain can be interrupted by the groups -O-, -S-, -S-S-, -S(O)n-, -?-NH- and/or -NR6-, where n and R6 possess the meanings indicated in claim 15.

23. Compound as claimed in any one of claims 15 to 19, wherein A in formula IX is substituted by one, two or more radicals -CO2R5, where R5 has the meaning indicated in claim 15.

24. A process for the preparation of bis-aldonamides of the general formula IX as claimed in claim 15, wherein an aldonolactone of the general formula XI or X
(XI) (X) is reacted with a diamino compound of the general formula R4HN-A-NHR4, in which R4 and A possess the meaning indicated in claim 15.

25. The process as claimed in claim 24, wherein the aldonolactones of the general formulae XI and X are prepared in situ by water elimination from the corresponding aldonic acids of the general formula VIII
R1O-CH2-CH(OH)-CH(OR2)-CH(OR3)-CH(OH)-CO2H (VIII) and are brought to reaction with the diamino compound without isolation.

26. A process for preparing a medicament for the use in the prophylaxis and therapy of rheumatic diseases and venous and arterial thrombosis which process comprises admixing a compound of the general formula I according to any one of claims 1 to 7 with a suitable diluent or carrier.

27. Use of a compound of the general formula I according to any one of claims 1 to 7 for the prophylaxis and therapy of rheumatic diseases and venous and arterial thrombosis.

28. A commercial package containing, as active pharma-ceutical ingredient, a compound of the general formula I
according to any one of claims 1 to 7, together with instructions for its use for the prophylaxis and therapy of rheumatic diseases and venous and arterial thrombosis.