DERIVATIVES OF CARBOHYDRATES AND COMPOSITIONS CONTAINING THEM

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.

Description: Derivatives of carbohydrates and compositions containing them The present invention relates to derivatives of phos¬ phorylated 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. Lysosomes contain a large amount of degradative enzymes which play a role in the entry of cells such as leuko¬ cytes 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- phosphate and glucose-6-phosphate after the cleavage of glycogen rendering an energy-rich structure. The utilization of phosphorylated carbohydrates for pre¬ paring 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. Further¬ more 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 unex¬ pectedly 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^/R^, R 21 /R 22 . R 3 1 R 32' R 41 R 42 and R 61 R 62 R 63 0 II are -Y-P-OR, 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„ and R_ 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 naphtyl 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, alonyl, succinyl, glutaryl, glyceryl, benzoyl, cinnamoyl and nicotinyl where four of R^/R^, 21 /R 22 . R 3 1 R 32 and R 41 R 42 are hydrogen and where the remaining of R , R, p , R-, , R ?? R 31' R 32' R 41' R 42' R 61' R 62 and R 63 are (1) hydrogen (2) -OR 9 where Ry 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) a glycosyl residue (1) 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 sub¬ stituted with hydroxy, oxo, alkoxy, aryloxy, halo, cyano, isocyanato, carboxy, esterified carboxy, amino, substi¬ tuted amino, formyl, acyl, acyloxy, acylamino, sulfinyl, sulfonyl, phosphino, phosphinyl, phosphonyl, mercapto, alkylthio, arylthio, silyl, silyloxy, silylthio, nitro or azido 0 II (3) -OCR 10 where R 1Q 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 (1) amino or substituted amino or (m) hydrogen the above groups (a) to (i) are unsubstituted or sub¬ stituted with hydroxy, oxo, alkoxy, aryloxy, halo, cyano, isocyanato, carboxy, esterified carboxy, amino, substi¬ tuted amino, formyl, acyl, acyloxy, acylamino, sulfinyl, sulfonyl, phosphino, phosphinyl, phosphonyl, mercapto, alkylthio, arylthio, silyl, silyloxy, silylthio, nitro or azido or (4) -NR R where R and R 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, cinna oyl 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_ 1_1/R1_2_ etc above or generally (Rn/Rn+,i,)' means that only one of Rn and Rn+, ,l could be the radical described i.e. if Rn is O II Y - P I - OR_7 Rn+,l_ could not be the same in one sp ~ ecific 0R 8 compound. According to the invention three of R /R , R /R , R 31 R 32' R 4l/ R 42 and R 61 R 62 R 63 are O Y - P I - OR_7 where Y is oxy ■ *gen or (CH2-)n 0R 8 or (-CH 2 -) n O; n = 1-4. In one preferred form Y is oxygen which means that three of R χι /R 12 , R 21 /R 22 . R 3 1 R 32' R 41 R 42 and R 6l/ R 62 R 63 are O If -O - P - OR_ I 7 0R 8 R_ / and Ro_ can independently be hydrogen, a cation, alkyl or substituted alkyl, aryl or substituted aryl or acyl or substituted acyl. Preferably R and R are hydrogen, a cation or a lower alkyl such as methyl, ethyl, propyl, butyl or pentyl. The radicals R and R Q 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, cyclo- heptyl, cyclooctyl, cyclononyl and adamantyl; Alkenyl with 2 to 24 carbon atoms is, for example, lower alkenyl such as vinyl, al yl, propenyl, butenyl, pentenyl and hexenyl or high alkenyl such as octadienyl, octenyl, decenyl, dodecenyl, -..etradecenyl, hexadecenyl, octadecenyl, octadecadienyl, octadecatrienyl, nonadecenyl and ara- chidonyl; Cycloalkenyl with 4 to 16 carbon atoms is, for example, cyclobutenyl, cyclopentenyl, cy lohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, c__ clooctadienyl and cyclo- octatrienyl; Aryl with 6 to 24 carbon atoms is, for example, phenyl, biphenyl, terphenyl, naphtyl, anthracenyl, phenanthrenyl; The radicals R Q y and Rlu an also be a heterocyclic group containing at least one atom selected from the group of oxygen, nitrogen and sulphur and is for example pyridyl, pyrrolyl, pyrrolidinyl, piperidinyl, indolyl, imidazolyl, furyl, dioxolanyl, oxiranyl, thiiranyl, thiopyranyl, oxazolyl and thiazolyl. R Q y can also be an etherified hydro- 1 with a carbon radical which is a glycosyl residue. The glycosyl residue is derived for example from a monosaccharide such as ery- throse, ribose, arabinose, allose, altrose, glucose, mannose, threose, xylose, lyxose, gulose, idose, galactose, talose, fructose or from a polysaccharide such as maltose, 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 could also be substituted with for example carboxyl, amino- or phosphonyl groups such as glucoseamine or galactoseamine or glucosephosphate or glucopyranosyl phosphate or sialic acid. R- can also be an etherified hydroxyl with a carbon radical which is a glycopeptide. This radical is derived for example from one or more sugar residues which are attached primarily to serine, threonine or aspargine side chains of the peptide, where the peptide is formed by different combinations of amino acids up to a molecular weight of 10.000. Prefered radicals are those which include glucoseamine or galactoseamine attached to especially di- and tripeptides. R can also be an etherified hydroxyl with a carbon radical which is a glycoprotein. This radical is derived for example from one or more sugar residues which are attached primarily to serine, threonine or aspargine side chains of the proteins, especially alkaline phosphatase, acetylcholinesterase, 5-nucleotidase. Thy-1, Th B and Heparan sulphate proteoglycan. Preferred radicals are those which include glucoseamine and galactoseamine attached to the protein. Especially preferred radicals are lectins such as concanavalin A, wheat germ agglu- tinin, peanutagglutinin and sero ucoid and orosomucoid. Ry. can also be an etherified hydroxyl with a carbon radical which is glycolipid. This radical is derived for example from one or more sugar residues which are attached to a lipid. Preferred radicals are those which include glucose or galactose. Further preferred radicals are cerebroside and ganglioside. Ry can also be a functional group such as carboxyl, phos- phonyl or sulfonyl. R Q y can also be a silyl or substituted silyl such alkyl silyl or arylsilyl. The above mentioned radicals on R Q y and Rl_u are unsub- stituted or substituted. The substitution could consist of free functional groups such as hydroxyl, carbonyl, carboxyl, mercapto or amino or these groups could be present in protected form. Thus, carboxyl groups are usually protected in esterified form and contain as esterifying groups especially lower alkyl groups, which could be branched in the 1-position or suitably substituted in the 1- or 2-position. Preferred carboxyl groups protec d in esterified forrr re for example methoxycarbonyl, butoxycarbonyl, tert. alkox> arbonyl such as tert. butoxycarbonyl or arylmethoxycarbonyl having one or two aryl radicals. These aryl radicals preferably consist of phenyl radicals optionally substituted for example by lower alkyl, lower alkoxy, hydroxy, halogen and/or nitro, such as benzyloxycarbonyl, methoxybenzyloxycarbonyl, di- phenylmethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodo- ethoxycarbonyl. Other preferred protected carboxyl groups in esterified form are silyloxycarbonyl groups, especially organic silyloxycarbonyl groups. In these the silicon atom preferably contains as substituent a lower alkyl, especially methyl, or alkoxy, especially methoxy and/or halogen, for example chlorine. Suitable silyl-protecting groups are for example trimethylsilyl and dimethyl-tert. -butylsilyl. A protected amino group may be present for example, in the form of an acylaminogroup or in the form of arylalkyl- amino group or azido group or sulphonated amino group. In a corresponding acylamino group the acyl is for example the acyl radical of an organic carboxylic acid having for example up to 18 carbon atoms, especially the acyl radical of an alkanecarboxylic acid which is preferably substituted with halogen or aryl or of a carboxylic acid semiester. Such acyl groups are for example lower alkanoyl such as formyl or acetyl; halo-lower alkanoyl such as 2-chloro- and 2-bromoacetyl or lower alkoxycarbony1 straight or branched in the 1-position of the lower alkyl radical or suitably substituted in the 1- or 2-position, for example tert. butyl carbonyl; arylmethoxycarbonyl having one or two aryl radicals which are unsubstituted or, in the case of phenyl, may be substituted for example with lower alkyl, especially tert. lower alkyl, lower alkoxy, hydroxy, halogen and/or nitro; such as unsubstituted or substituted aryloxycarbonyl, for example benzyloxycarbonyl or 4-nitro- benzyloxycarbonyl or diphenylmethoxyctirbonyl, r example benzhydroxycarbonyl or di-(4-methoxyphenyl) -methoxycarbo¬ nyl; aroylmethoxycarbonyl for example phenacyloxycarbonyl in which the aroyl group is benzoyl which is unsubstituted or substituted for example with halogen; halo-lower alkoxy- carbonyl, for example 2-bromo- or 2-iodoethoxycarbonyl; or 2-(trisubstituted silyl)-ethoxycarbonyl such as for example 2-trimethylsilylethoxycarbonyl or 2-triphenylsilyl- ethoxycarbonyl. An arylalkylamino group is a mono-, di- or especially a triarylalkylamino group in which the aryl radicals are especially unsubstituted or substituted phenyl radicals. Such groups are for example benzylamino, diphenylmethyl- amino or tritylamino. Amino groups may also contain organic silyl groups as protecting groups. Suitable silylprotecting groups are especially tri-lower alkyls.__yl, such as trimethylsilyl and dimethyl-tert.-butylsil ... Preferred a inoprotecting groups are acyl radicals of carbonic acid semiesters especially tert.-butoxycarbonyl or aryloxycarbonyl that is unsubstituted or substituted for example benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl or 2.2.2-trichloroethoxycarbonyl. Other protected amino groups are sulphonated amino groups such as lower alkyl sul honamides especially N-methyl sulphonamic * and N-but sulphona de. Hydroxy- and mercapto-protectinc .roups a__e for example acyl radicals such as lower alkanoyl which is unsubstituted or substituted for example with halogen, such as 2.2-di- chloroacetyl or especially the acyl radicals or carboxylic acid semiesters mentioned in connection with the amino- protecting groups and also etherifying groups such as tert.-butyl or 2-oxa- or 2-thia-aliphatic hydrocarbon radicals, for example 1-methoxyethyl, 1-methyl-thiomethyl or 2-oxa- or 2-thia-cycloaliphatic hydrocarbon radicals, for example 2-tetrahydrofuryl or 2-tetrahydropyranyl or corresponding thia analogues and unsubstituted or substi¬ tuted benzyl and diphenylmethyl. The phenyl radicals, can be substituted with halogen, lower alkoxy and/or nitro for example. Hydroxy and mercapto groups may also be protected in the form of corresponding organic silyloxy or silylthio groups. Suitable silyl protecting groups are especially lower alkylsilyl such as trimethylsilyl or dimethyl-tert.- butylsilyl. Two free functional groups may also be substituted by a common protecting group. Thus, for example hydroxy groups may be substituted by a methylene radical which is un¬ substituted or preferably substituted for example with lower alkyl, such as methyl or aryl, such as phenyl or alkenyl such as methylene, isopropylidene, propylidene or benzylidene. The substitutions on the radicals could also consist of a halogen especially fluorine, chlorine and iodine and further by a cyano group. The radicals could also be substituted with phosphorus containing radicals, such as phosphine, phosphinyl and phosphonyl and with nitrogen containing radicals such as nitro or azido. R and R are hydrogen, hydroxyl, acyl or substituted acyl, alkyl or substituted alkyl, aryl or substituted alkyl. The substitution on the substituted acyl, alkyl or aryl on the radical R and R . can be 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. In one preferred embodiment of the invention R , R and R 42 are O // -O - P - OR,, 0R 8 where R_ / and Ro Q are as defined above R 22' R 32' R 41' R 61 and R 62 are n dro 9 en ' ' Rii and R 12 are different and are hy J drog -en, -OR9_, or -NR1, _3,R,14_ where R„9, R_13_ and R1,4. a c- as defined above and is -OR9., O 1/ -OCR 1Q or - R 13 R 14 where R g , R 1Q , R 13 and R 14 are as defined above. Preferably R Q y and R. u are (1) alkyl or substituted alkyl *~uch as methyl, ethyl, propyl, butyl, isobutyl, j yl or hexyl or (2) aryl or substituted aryl s.. n as phenyl or biphenyl and R and R . are (1) hydrogen (2) lower alkyl or substituted alkyl such as methyl ethyl, propyl, butyl, isobutyl, pentyl or hexyl or (3) lower acyl or substituted acyl such as acetyl or hydroxylated acetyl. In one most preferred embodiment of this type of the in¬ vention R2_1_ ,' R3_1_. and R4.2_ are - 0 - P - OR where R and R are hydrogen or a cation; R 22. R 3?» R 41 . Ro,,1. and R,_ are hydrogen; R, _1 and R_1___ are different and are hydrogen or -OR g where R g is lower alkyl such as methyl, ethyl, propyl or butyl and R t _ is (1) -OR Q y where R_ is alkyl or substituted alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl, silyl or substituted silyl or 0 (2) -OC where R is alkyl or substituted alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl, aryl or substituted aryl such as phenyl. In another preferred embodiment of the invention R ?2 , R 1 O II -O - P - OR„ I 7 0R 8 where R_/ and Ro_ are as defined above R 21' R 32' R 41' R 61' R 62 are h y dro 9 en ' * R n and R 12 are different and are hydrogen, -O or -NR _R where R q R1,3_, and R1,4„ are as defined above and R6,3_ is -OR n 9 , O -OCR 10 or ~ N R 13 R 14 where R g , R 1Q , R 13 and R χ4 are as defined above. Preferably Ry_ and R_l n u are (1) alkyl or substituted alkyl such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl or (2) aryl or substituted aryl such as phenyl or biphenyl, (1) hydrogen (2) lower alkyl or substituted alkyl such as methyl ethyl, propyl, butyl, isobutyl, pentyl, hexyl or (3) lower acyl or substituted acyl such as acetyl or hydroxylated acetyl. In still another preferred embodiment of the invention R 22 , R 31 and R 41 are O 1/ -O - P - OR,, . 7 0R 8 R 21 , R 32 , R 42 , R 61 , R 62 are hydrogen; R 1 and R 12 are different and are hydrogen, -OR q or -NR _R . where R , R-1_3 and R1_4. are as defined above and R6_3 is -0R o 9,' O li -OCR.1,0_ or -NR1_-3.R_14. where R9_ , R_10. , R_1_3 and R_14. are as defined above. Preferably R g and R are (1) alkyl or substituted alkyl such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl or (2) aryl or substituted aryl such as phenyl or biphenyl and R and R are (1) hydrogen (2) lower alkyl or substituted alkyl such as methyl ethyl, propyl, butyl, isobutyl, pentyl, hexyl or (3) lower acyl or substituted acyl such as acetyl or hydroxylated acetyl. Other preferred embodiments of this invention are where R 21 , R 32 and R 42 are o /; -o - P - OR_ i 7 0R 8 where R_ / and Ro are as defined above R 22' R 31' R 41' R 61 and R 62 are h Y άro( 3 en ' R n an R 12 are different and are hydrogen, -OR or -NR R where R , R1,3_ and R1,4. are as defined above, and R6,_3_ is -3R9_, O l( OCR1.0_ or -NR1_,_3.R1_4. where R9_,, R1_0_ , R1_ _3 and R1.4. are as defined above. Preferably Ry_ and R_ u are (1) alkyl or substituted alkyl such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl or (2) aryl or substituted aryl such as phenyl or biphenyl (1) hydrogen (2) lower alkyl or substituted alkyl such as methyl ethyl, propyl, butyl, isobutyl, pentyl, hexyl or (3) lower acyl or substituted acyl such as acetyl or hydroxylated acetyl. In another preferred embodiment of this invention R_ , -O - P - OR ~ where R_ / and R_S are as defined above R 22' R 31' R 42' R 61 and R 62 3re h Y dro<~en ! R u d R 12 a - * - "e different and are hydrogen, -OR g or -NR R and R is -OR , or ~ NR 13 R 14 where R g , R 10 , R 13 and are as defined above. Preferably R g and R are (1) alkyl or substituted alkyl such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl or (2) aryl or substituted aryl such as phenyl or biphenyl (1) hydrogen (2) lower alkyl or substituted alkyl such as methyl ethyl, propyl, butyl, isobutyl, pentyl, hexyl or (3) lower acyl or substituted acyl such as acetyl or hydroxylated acetyl. In still another preferred embodiment of this invention R2_1_ , R_31_ and R4. _1 are where R and R 0 are as defined above R 22' R 32' R 42' R 61 an R 62 arθ h y dro 9 en * : R nd R 12 are different and are hydrogen, -OR 9., or -NR,1_3,R1,4. and R6 . .3., O It is -OR g , "OCR 10 or "NR 13 R 14 where R g , R 1Q , R χ3 and R 14 are as defined above. Preferably Ry. and R_ u are (1) alkyl or substituted alkyl such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl or (2) aryl or substituted aryl such as phenyl or biphenyl (1) hydrogen (2) lower alkyl or substituted alkyl such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl or (3) lower acyl or substituted acyl such as acetyl or hydroxylated acetyl. In one other preferred embodiment of this invention R , 42 and R 63 are o II -0 - P - OR_ I 0R 8 where R_ and R_ are as defined above R 32 , R 41 , R 61 , R 62 are hydrogen; R^/R^. R 2 ι/ R 22 are hy J drog ~ en, -OR9_ or -NR1,3_R1_4. where R n 9,' R1.3_ and R1_4. are as defined above. Preferably R Q is (1) alkyl or substituted alkyl such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl or (2) aryl or substituted aryl such as phenyl or biphenyl (1) hydrogen (2) lower alkyl or substituted alkyl such as methyl ethyl, propyl, butyl, isobutyl, pentyl, hexyl or (3) lower acyl or substituted acyl such as acetyl or hydroxylated acetyl. The different compounds according to this invention can be isolated in substantially pure form. Thus the different compounds can have a purity of 80-100 %, such as 82-100 % or 85-100 %, preferable 90-100 %. The invention also relates to a pharmaceutical composition comprising as a pharmaceutically active ingredient one or more compounds of Formula (I) . The pharmaceutical composition can consist of a compound of Formula (I) solely or together with an additive, excipient or carrier. It is suitable that the composition exists in unit dosage forms. The administration forms could be parenteral such as subcutaneous, intramuscular or intravenous or non- parenteral such as tablets, granules or capsules. For administration to human patients appropriate dosages can routinely be determined by those, skilled in the art by extension of results obtained in animals. The preferred dosage for humans falls in within the range of 0.1 to 25 mg compound/day/kg body weight. The composition usually contains 0.01-1.5 g, such as 0.05-1.3 g or preferably 0.1-1.0 g of a compound of Formula (I) . The compound of Formula (I) may be the only pharmaceuti¬ cally active ingredient in the composition. However, also other pharmaceutically active ingredients can be present therein. The amount of the compound of Formula (I) should then constitute 5-95 % or 15-80 % such as 25-60 % by weight of said active ingredients. The following embodiment examples illustrate the inven¬ tion however without limiting it thereto. Examples 1 to 3 illustrate the formation of the sodium salt of 1-O-methyl- -6-0- (dimethyl-(1,1,2-trimethylpropyl) silyl) -α-D-manno- pyranoside-2,3,4-trisphosphate. Example 4 shows the stability of the sodium salt of l-O-methyl-6-O-butyl-α- D-mannopyranoside-2,3 ,4-trisphosphate against degradation compared to 1, 5-anhydro-D-arabinitol-2, 3 ,4-trisphosphate while example 5 demonstrates the manufacturing of a pharma¬ ceutical composition for intravenous administration. Example l Dimethyl-(1, l,2-trimethylolpropyl)chlorosilane (11.2 ml) was added to a solution of 10.0 g methyl α-D-mannopyrano- side in 51.5 ml pyridine in an ice bath. When the addition was completed, the ice bath was removed and the reaction mixture was left for 16 hours at room temperature. Methanol was added and the solvent was removed by evaporation. The residue was dissolved in ethyl acetate (200 ml) , washed with a mixture of 10 % hydrochloric acid and 10 % aqueous ammonium sulfate (2 x 50 ml, 1:2), and saturated aqueous sodium hydrogen carbonate (40 ml) . Drying with Na SO was followed by removal of solvents and chromatography on a SiO -column with ethylacetate as an eluent, which gave l-O-methyl-6-O- (dimethyl-(1,1,2-trimethylpropyl) silyl) -α-D- mannopyranoside. Example 2 l-O-Methyl-6-O-(dimethyl-(1, 1,2-trimethylpropyl) silyl) -α-D-mannopyranoside (500 mg) was heated with bis(benzyloxy)diisopropylaminophosphine for 4 hrs at 60°C. TLC indicated conversion of the triol into the trisphosphate which was oxidized with m-chloroperbenzoic acid to give, after column chromatography, 1-O-methyl- 6-0-(dimethyl-(1, 1,2-tri-methylpropyl) silyl) -α-D-manno¬ pyranoside 2,3,4-tris(di-benzylphosphate) . Example 3 l-O-Methyl-6-O- (dimethyl-(1, 1,2-trimethylpropyl) silyl) -α-D-mannopyranoside 2 ,3 ,4-tris(dibenzylphosphate) (500 mg) was dissolved in ethanol containing 4 equivalents of sodium acetate (10 ml) . Palladium on charcoal (Pd/C, 100 mg) was added and the mixture was hydrogenated with stirring. After 24 hours the solvent was removed to give the sodium salt of l-0-methyl 6-0-(dimethyl-(1, 1,2-trimethylpropyl) - silyl) -α-D-mannopyranoside-2, 3,4-trisphosphate. Example 4 The stability against phosphatase degradation was assayed by using alkaline phosphatase from bovine intestinal mucosa (Sigma) with a concentration of 1 Unit/ml in a 0,1M Tris HCl-buffer comprising 0.1 mM MgCl and 0.1 mM Zn Cl at pH 7.0. To 10 ml of the buffer was added 5 mg of 1.5 anhydro-D-arabinitol-2 , 3 ,4-trisphosphate (Cmpd 1) to a final concentration of 5 mmol phosporus/1. To another aliquot of 10 ml buffer was added equimolar concentration of l-O-metyl-6-O-butyl-α-D-mannopyranoside- 2, 3 ,4-trisphosphate (Cmpd 2 ) . The temperature was raised to 37°C and the stability of the compounds was followed by the determination of free phosphorus in the solutions. Samples were analyzed every hour for six hours and the following results were obtained. Compound 1 was outside while compound was 2 was inside the scope of the invention. Free phosphorus/total phosporus % These results show that the liberation of phosphorus from compound 2 (l-0-methyl-6-0-butyl-α-D-mannopyranoside-2 , 3 , 4- trisphosphate) is very slow. Thus the compound 2 is very stable against degradation. There is a rather quick libera¬ tion of phosphorus from compound 1, which means that it is not stable against degradation. Example 5 0.5 g of the sod τι salt of l-O-methyl-6-O-butyl-α-D- mannopyranoside-2 , 3 ,4-trisphosphate and 0.77 g sodium chloride were dissolved in 98.73 ml of water for injec¬ tion to form a solution suitable for injection into a person or an animal.

Claims: CLAIMS A compound of formula (I) CR 61 R 62 R 63 where three of R 11 /R 12 , 21 / R 22 , R 31 / R 32 , R 4 1 R 42 and O II Y - P - OR. OR„ where Y is (1) oxygen (2) (-CH 2 -) n , where n is 1-4 (3) (-CH 2-) n0, where n is 1-4 and where R and R fi independently are (1) hydrogen (2) a cation such as sodium, potassium and calcium (3) a lower alkyl such as methyl, ethyl, propyl, butyl, pentyl and where four of R ι;L /R 12 . R 2 ι/ R 22 ' R 3 τ7 R 2 and R 41 /R 42 are hydrogen and where the remaining or R,,, R, ->, R6 c 2 and R6__3 are (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 atom of oxygen, nitrogen or sulfur (k) a glycosyl residue (1) 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, silyl¬ thio, nitro or azido O II (3) - OC R where R 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 atom of oxygen, nitrogen or sulfur (k) carboxy or esterified carboxy (1) 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, phospinyl, phosphonyl, p?.-capto, alkylthio, arylthio, silyl, silyloxy, silylthio, nitro or azido or (4) -NR R_ where R and R independently are (1) hydrogen (2) hydroxyl (3) lower acyl such as forr l, acetyl, propionyl, butyryl, valeryl, pivaloyl or ;4) lower alkyl such as methyl, ethyl, propyl, butyl, pentyl or hexyl 2. A compound according to claim 1 where Y is oxygen and R and R_ independently are hydrogen or a cation. 3. A compound according to claim 2 where R 21 . R 1 and R 42 are O 'I - O - P - OR., I 7 0R 8 where R and R are (1) hydrogen (2) a cation such as sodium, potassium or calcium where R , R 32 _ R 41 . R 61 . R 62 are hydrogen; where R and R „ are different and are ( 1) hydrogen (2) _ °R q where R is as defined above and where R ^ _ is (1) -OR Q or where R g and R are as defined above. A compound according to claim 3 wherein Ry Q is (1) alkyl or substituted alkyl such as methyl, ethyl, propyl, butyl, isobutyl, pentyl or hexyl (2) aryl or substituted aryl such as phenyl or bi¬ phenyl or (3) silyl or substituted silyl. A compound according to claim 2 where R-,-,, R-,, and R 42 arβ 0 ii O - P - OR. OR, where R_ / and Ro_ are ( 1 ) hydrogen (2) a cation such as sodium, possium or calcium where R,*- R 32 ' R 4 ι' R 6 l ' R 62 are h Y άro< 3 en > where R and R. _ are different and are (1) hydrogen (2) -OR Q y where Ry_ is as defined above and where is (1) -OR g o II (2) -OC R 1Q where Ry and Rlu are as defined above, 6. A compound according to claim 5 where R n y and R.lu independently are (1) alkyl or substituted alkyl such as methyl, ethyl, propyl, butyl, isobutyl, pentyl or hexyl (2) aryl or substituted aryl such as phenyl or bi¬ phenyl or (3) silyl or substituted silyl. 7. A compound according to claim 2 where R ?2 , R.,, and R 41 arβ o II - O - P - OR. 0 R. where R_ and R are / O (1) hydrogen (2) a cation such as sodium, possium or calcium where R 21 . R 2 ' R 2 ' R 61' R 62 are n dro 9 en and where R and R are different and are (1) hydrogen (2) -OR,-, where R Q is as defined above y y and where R ^ _ is bJ (1) -0R g o where R q and R. n are as defined above. 8. A compound according to claim 7 where R n and R_ _. y lo independently are (1) alkyl or substituted alkyl such as methyl, ethyl, propyl, butyl, isobutyl, pentyl or hexyl (2) aryl or substituted aryl such as phenyl or bi¬ phenyl or (3) silyl or substituted silyl. A compound accor'I ^ ng to claim 2 where R__ , R and o II - O - P - OR I OR, where R„ and Ro 0 are (1) hydrogen (2) a cation such as sodium, potassium or calcium where R 22 . R ι' R ι' R βi and R f i are h y dr °g en ; where R . and R are different and are (1) hydrogen (2) -°R 9 where R g is as defined above and where R ^ _ is (1) -OR g where R -. and R1.U_ are as defined above. 10. A compound according to claim 9 where R_ and R_ independently are (1) alkyl or substituted alkyl such as methyl, ethyl, propyl, butyl, isobutyl, pentyl or hexyl (2) aryl or substituted aryl such as phenyl or bi¬ phenyl or (3) silyl or substituted silyl. 11. A compound according to claim 2 where R-,-,, R_, 2 and 0 II -O - P - OR_ OI where R 7 and R are (1) hydrogen (2) a cation such as sodium, potassium or calcium where R 22 , R 1 - R 4 - ' R 6i and R β2 are hydrogen; where R. and R are different and are (1) hydrogen (2) -OR,y., where R_y is as defined above and where Rb___J is (l) -OR g o (2) -OC R 10 where R n y and Rlu are as defined above. 12. A compound according to claim 11 where Ry_ and RI_U in- dependently are (1) alkyl or substituted alkyl such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl (2) aryl or substituted aryl such as phem 1 or bi¬ phenyl or (3) silyl or substituted silyl. 13. A compound according to claim 2 where R , R and where R_ and R R are (1) hydrogen (2) a cation such as sodium, potassium or calcium where R 22 ; R 3 - R 42 ' R 61 and R 62 are n y dro 9 en > where R and R _ are different and are (1) hydrogen (2) -OR n y where Ry is as defined above and where R._ is (1) -OR, where R Q y and Rlu are as defined above. 14. A compound according to claim 13 where R D y and Rl, .) in- dependently are (1) alkyl or substituted alkyl such as methyl, ethyl, propyl, butyl, isobutyl, pentyl or hexyl (2) aryl or substituted aryl such as phenyl or bi¬ phenyl or (3) silyl or substituted silyl 15. A compound according to claim 1 in substantially pure form. 16. A pharmaceutical composition containing a compound according to claim 1.

Inventors: PERSSON LARS, REHNBERG NICOLA, PERSSON, LARS, REHNBERG, NICOLA
Applicants: PERSSON LARS, PERSTORP AB, REHNBERG NICOLA, PERSSON, LARS, REHNBERG, NICOLA
Application year: 1995
Main classification: C07H11
IPC codes: A61K31, A61P29, A61P43, C07D309, C07H11, C07H15, C07H23