Derivatives of carbohydrates and compositions containing them

Details Derivatives of carbohydrates and compositions containing them Derivatives of carbohydrates and compositions containing them

1998-11-20

2001-10-30

Fonda, Kathleen Kahler (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S025000, C536S004100, C536S017100, C536S018500, C536S018600, C536S117000, C536S120000

Reexamination Certificate

active

06310042

ABSTRACT:

The present invention relates to derivatives of phosphorylated carbohydrates and pharmaceutical compositions comprising as a pharmaceutically active ingredient at least one of these compounds.
Some phosphorylated carbohydrates exist in mammals and are considered to have specific biological properties. Lyscsomes contain a large amount of degradative enzymes which play a role in the entry of cells such as leukocytes into inflammatory areas. These enzymes undergo glycosylation and phosphorylation resulting in residues containing mannose-monophosphates. Thus it has been shown that the administration of mannose-6-phosphate to animals suffering from adjuvant arthritis reduces the inflammatory expression (PCT Patent Application publication WO 90/01938) to some extent.
Furthermore it has been shown that mannose-6-phosphate might promote wound healing when given to animals (PCT Patent Application publication WO 93/18777).
Other monophosphorylated carbohydrates also occur in a living organism. An example is the formation of glucose-1-phosphnate and glucose-6-phosphate after the cleavage of glycogen rendering an energy-rich structure.
The utilization of phosphorylated carbohydrates for preparing pharmaceutical compositions has been very limited for many reasons. Monophosphorylated carbohydrates exhibit low potency when applied in animal models which results in the need of fairly large amounts administered which would not be beneficial in a patient situation. Furthermore high dosages expose the risk of side effects and lack of selectivity regarding the therapeutic effect. These type of compounds also have a very short half life due to the fast enzymatic degradation by for example alkaline phosphatases.
According to the present invention it has quite unexpectedly been possible to produce novel derivatives of phosphorylated carbohydrates in substantially pure form.
The invention relates to compounds of formula (I)
where three of R
11
/R
12
, R
21
/R
22
, R
31
/R
32
, R
41
/R
42
and R
61
/R
62
/R
63
are
where Y is
(1) oxygen
(2) (CH
2
)
n
, where n is 1-4
(3) (—CH
2
—)
n
O where n is 1-4
and where R
7
and R
8
independently are
(1) hydrogen
(2) a cation selected from the group of sodium, potassium, calcium, magnesium and zinc
(3) an alkyl or substituted alkyl selected from the group of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl or pentadecyl
(4) an aryl or substituted aryl selected from the group of phenyl, biphenyl, terphenyl or naphcyl or
(5) an acyl or substituted acyl selected from the group of formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, myristoyl, palmitoyl, stearoyl, oxalyl, malonyl, succinyl, glutaryl, glyceryl, benzoyl, cinnamoyl and nico inyl
where four of R
11
/R
12
, R
21
/R
22
, R
31
/
32
and R
41
/R
42
are hydrogen and where the remaining of R
11
, R
12
, R
21
, R
22
, R
31
, R
32
, R
41
, R42, R
61
, R
62
and R
63
are
(1) hydrogen
(2) —OR
9
where R
9
is
(a) straight or branched alkyl with 1 to 24 carbon atoms
(b) cycloalkyl with 3 to 16 carbon atoms
(c) alkenyl with 2 to 24 carbon atoms
(d) cycloalkenyly with 4 to 16 carbon atoms
(e) aryl with 6 to 24 carbon atoms
(f) aralkyl
(g) alkaryl
(h) aralkenyl
(i) alkenylaryl
(j) a heterocyclic group with at least one carbon of oxygen, nitrogen or sulfur
(k) a glycosyl residue
(l) a glycopeptide
(m) a glycoprotein
(n) a glycolipid
(o) carboxy, sulfonyl or phosphonyl
(p) silyl or substituted silyl
(q) hydrogen
 the above groups (a) to (n) are unsubstituted or substituted with hydroxy, oxo, alkoxy, aryloxy, halo, cyano, isocyanato, carboxy, esterified carboxy, amino, substituted amino, formyl, acyl, acyloxy, acylamino, sulfinyl, sulfonyl, phosphino, phosphinyl, phosphonyl, mercapto, alkylthio, arylthio, silyl, silyloxy, silylthio, nitro or azido
 where R
10
is
(a) straight or branched alkyl with 1 to 24 carbon atoms
(b) cycloalkyl with 3 to 16 carbon atoms
(c) alkenyl with 2 to 24 carbon atoms
(d) cycloalkenyl with 4 to 16 carbon atoms
(e) aryl with 6 to 24 carbon atoms
(f) aralkyl
(g) alkaryl
(h) aralkenyl
(i) alkenylaryl
(j) a heterocyclic group with at least one carbon of oxygen, nitrogen or sulfur
(k) carboxy or esterified carboxy
(l) amino or substituted amino or
(m) hydrogen
 the above groups (a) to (i) are unsubstituted or substituted with hydroxy, oxo, alkoxy, aryloxy, halo, cyano, isocyanato, carboxy, esterified carboxy, amino, substituted amino, formyl, acyl, acyloxy, acylamino, sulfinyl, sulfonyl, phosphino, phosphinyl, phosphonyl, mercapto, alkylthio, arylthio, silyl, silyloxy, silylthio, nitro or azido or
(4) —NR
13
R
14
where R
13
and R
14
independently are
(a) hydrogen
(b) hydroxyl
(c) acyl or substituted acyl selected from the group of formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, myristoyl, palmitoyl, stearoyl, oxalyl, malonyl, succinyl, glutaryl, benzoyl, cinnamoyl or nicotinoyl
(d) alkyl or substituted alkyl selected from the group of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl or pentadecyl or
(e) aryl or substituted aryl selected from the group of phenyl, biphenyl, terphenyl or naphtyl
The expression R
11
/R
12
etc above or generally (R
n
/R
n+1
) means that only one of Rn and R
n+1
could be the radical described i.e. if R
n
is
R
n+1
could not be the same in one specific compound.
According to the invention three of R
11
/R
12
, R
21
/R
22
, R
31
/R
32
, R
41
/R
42
and R
61
/R
62
/R
63
are
where Y is oxygen or (CH
2
—)
n
or (—CH
2
—)
n
O; n=1-4.
In one preferred form Y is oxygen which means that three of R
11
/R
12
, R21/R22, R
31
/R
32
, R
41
/R
42
and R
61
/R
62
/R
63
are
R
7
and R
8
can independently be hydrogen, a cation, alkyl or substituted alkyl, aryl or substituted aryl or acyl or substituted acyl. Preferably R
7
and R
8
are hydrogen, a cation or a lower alkyl such as methyl, ethyl, propyl, butyl or pentyl.
The radicals R
9
and R
10
above can be an alkyl with 1 to 24 carbon atoms, for example, lower alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tributyl, sec.-butyl or tert.-butyl, also n-pentyl, neo-pentyl, n-hexyl or n-heptyl or higher alkyl such as straight-chain or branched octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, docosyl and n-tetracosyl;
Cycloalkyl with 3 to 16 carbon atoms is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and adamantyl;
Alkenyl with 2 to 24 carbon atoms is, for example, lower alkenyl such as vinyl, allyl, propenyl, butenyl, pentenyl and hexenyl or higher alkenyl such as oczadienyl, octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, octadecenyl, octadecadienyl, octadecatrienyl, nonadecenyl and arachidonyl;
Cycloalkenyl with 4 to 16 carbon atoms is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclooctadienyl and cyclooctatrienyl;
Aryl with 6 to 24 carbon atoms is, for example, phenyl, biphenyl, terphenyl, naphtyl, anthracenyl, phenanthrenyl;
The radicals R
9
and R
10
an also be a heterocyclic group containing at least one atom selected from the group of oxygen, nitrogen and sulphur and is for example pyridylt pyrrolyl, pyrrolidinyl, piperidinyl, indolyl, imidazolyl, furyl, dioxolanyl, cxiranyl, thiiranyl, thiopyranyl, oxazolyl and thiazoiyl.
R
9
can also be an etherified hydroxyl with a carbon radical which is a glycosyl residue. The glycosyl residue is derived for example from a monosaccharide such as erythrose, ribose, arabinose, allose, altrose, glucose, mannose, threose, xylose, lyxose, gulose, idose, galactose, talose, fructose or from a polysaccharide such as maltosed lactose, cellobiose or sucrose or nonhydrolyzed or partially hydrolyzed cellulose, amylose or amylopectin.
Preferably the glycosyl residue is derived from glucose, fructose, mannose or lactose.
The glycosyl residue

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