JPH06503813A - Monosaccharides with antiproliferative and anti-inflammatory activity, compositions and uses thereof - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Has anti-proliferative and anti-inflammatory activity Monosaccharides, compositions and uses thereof This application was filed on September 12, 1990. This is a continuation-in-part of U.S. Patent Application No. 071,581,542, filed under Continuation-in-part of U.S. Patent Application No. 07/294.838 filed January 9, 1989 It is.

Technical field The compounds of the invention are single monosaccharide inducers that exhibit anti-proliferative and anti-inflammatory activity. conductor and useful in treating mammals with inflammatory and/or autoimmune diseases. It is for use. The present invention provides pharmaceutical compositions containing these compounds and treatments for inflammation and/or Certain monosaccharides and their derivatives also encompass treatment methods for autoimmune diseases Bamboo is known to have therapeutic value in treating inflammatory and autoimmune diseases. A specific person The droxyl group forms derivatives such as the formation of monosaccharide derivatives. each Species blocking groups and methods are described, for example, in U.S. Pat. No. 2,715,121 and No. 4.056,322.

Various derivatives and methods of synthesis of 5 and 6 carbon monosaccharides are e.g. U.S. Patent Nos. Re, 30,354, Re, 30,379, Re, 32.2 No. 68, No. 4,056,322, No. 4,735,934, No. 4,738.9 No. 53, No. 4.996,195 and No. 5,010,054. It will be done. The therapeutic activities of various substituted monosaccharides are also disclosed in the above documents.

Known derivatives of α-D-glucose with advantageous therapeutic properties are amiprilose, 1. 2-0-isopyrrolidene 3-0-3-- (N,N--dimethylamino-n-propylene ropyru)-α-D-glucofuranose and its hydrochloride, amiprilose HCl (THERAFECTIN (trademark)). These two compounds are anti-inflammatory Known to have activity and demonstrated usefulness in treating signs and symptoms of osteoarthritis did.

More generally, these compounds have immunomodulatory activity and are therefore effective in treating psoriasis, eczema, or It has a therapeutic effect on low O autoimmune diseases such as systemic erythematous lupus.

Unfortunately, some monosaccharide derivatives showed beneficial therapeutic activity. These derivatives, such as THERAFECT [N(TM)] are often effective high doses were required to achieve good results. Treatment for inflammatory or autoimmune diseases Since therapy is often medium- to long-term, it can be administered orally, thereby promoting patient acceptance. There is a need to develop progressively more effective non-toxic compounds. The present invention is effective Described are additional monosaccharide derivatives with high .

It is therefore desirable to provide novel compounds and compositions that exhibit anti-proliferative and anti-inflammatory activity. This is the object of the invention.

Compounds useful in the treatment of mammals with inflammatory and/or autoimmune diseases and It is also an object of the invention to provide a composition.

commercially available drugs such as THERAFECT IN™ to facilitate oral administration. It is hoped that further efforts will be made to provide new compounds that exhibit significantly higher efficacy than the compounds that It is a purpose.

Disclosure of invention In order to achieve the above objects and in accordance with the objects of the invention as specifically and broadly described. Therefore, a monosaccharide having the following formula is provided. Compound of general structure 1 (wherein A is hydrogen, methyl or ethyl, R1 and R2 are H, methyl, C6-C1゜alkenyl, or together forming an isopropylidene ring, R3 is H1C6-C1G alkyl, C5-C1゜alkenyl, C5-C1゜alkyni benzyl, or 05-C1G ester, and R4 is H, C, -C 1゜alkyl, C6-C3゜alkenyl, C6-C1゜alkynyl, benzyl, or C6-C1G ester), Compound of formula 2 [In the formula, Xl is 0, and R5 is CI2-C2° alkyl or C,,R 2, Y (where n is l, 2.3 or 4, Y is cyano, pyrrolyl, pyrrolyl lolidinyl, methylpyrrolidinyl, bibecolinyl, imidazolyl, pyrazolyl, Pyrazolinyl, pyrazolidinyl, oxacylyl, oxazolidinyl, isoxa Silyl, imidazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, Monophorinyl, 0 (CH2) 3N (CH, > 2, (C, ~ C3 ° alco Kishi), CH2CH (CHa　)CH2N　(CH2)2, CHz　CH2N　(Cs- selected from C1°alkyl)2, or (03-C7 alkenyl), or Xl or NH, and R5 or C2-CIO alkyl, or C, H2 aY (where n is 1. 2. 3i or 4, Y is hydroxy, cyano, pyrrolyl, pyrrolidinyl, methylpyrrolidinyl, bipecolinyl, imidazolyl, Pyrazolyl, pyrazolinyl, pyrazolidinyl, oxab-1-nor, oxazolidi Nyl, isoxazolyl, isoozazolidinyl, imidazolinonyl, piperidinyl , piperazinyl, morpholinyl, O(CH2)s N(CH3)2, (C s-C1°alkoxy), or phenylated), and R6 and R7 is H or together form an isopropylidene ring], Compound of formula 3 or C1H2,, Y (wherein n is l, 2.3 or 4, Y is phenyl, Cyahachipyrrolyl, pyrrolidinyl, methylpyrrolidinyl, pipecolinyl, imidazo Lyle, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxacylyl, oxazoli Dinyl, isoxasilyl, isoozazolidinyl, imidazolidinyl, piperidinyl Nyl, piperazinyl, morpholinyl, O(CH2) s N (CHs) 2 or (selected from C, ~C3°alkoxy) or phenyl), and is where X2 is S, R8 or C6-C10 alkyl, or C,, R2, Y (formula In the middle, rl is l, 2°3 or 4, and Y is OH, phenyl, cyano, pyrrolyl. , pyrrolidinyl, methylpyrrolidinyl, pipecolinyl, imidazolyl, pyrazoli pyrazolinyl, pyrazolidinyl, oxacylyl, oxazolidinyl, isoo xacylyl, imidazolidinyl, imidazolidinyl, piperidinyl, piperazinyl ru, molporinyl, 0 (CH2) 3 N (CH3) 2 or (C, ~C3 ゜alkoxy), and R9 and R'' are H or isoproxy. ], and (3S)1.2-0-isopropylidene-α -D-ribohekissu 3-urosu 1.4:3.6-difuranose, and Methyl 3-0-1-(N-,N'-dimethylamino-n-propyl)-6-zo A compound selected from oxy-D-glucopyranosides.

Other embodiments according to the invention include pharmaceutical compositions containing an effective amount of one or more of the above compounds. and inflammatory diseases and/or autoimmunity, comprising administering an effective amount of the above compound. It is a method of treating diseases.

BEST MODE FOR CARRYING OUT THE INVENTION Does monosaccharide exist in equilibrium with the hemiacetal ring structure and the amount of open chain sugars? known. Preferred cyclic structures are furanose (5-membered ring structure) and pyranose (6-membered ring structure). member ring structure). Other ring structures can be formed or are less thermodynamically stable. , commonly rearrange to form pyranose or furanose structures. cyclic hemiacetate When tal reacts with alcohol, it forms acetal.

Glycosides are molecules with two ether (0-R group) substituents on the acetal carbon of the sugar. It can be defined as a cyclized derivative of nosaccharide. One of these ether substituents It is a calhocycle ring. The second ether substituent can be formed and called aglycones. Due to the second ether substituent, the forming glycoside is It is stable and has no equilibrium with its open chain structure. Glycosides with five-membered rings are Ranosides having a 6-membered ring are known as pyranosides.

The ILQ-like of the present invention is a derivative of the single monosaccharide fructose, especially fructose. Concerning furanosides. Fructofuranosides must be in α-D or β-D configuration I can do it. The fructofuranosides of the invention shown in formula 1 encompass both α or β configurations. substituted with one or more free hydroxyl groups, preferably at least one It has 3 free radicals. As discussed above, techniques for forming these derivatives of the present invention The technique is generally known in carbohydrate chemistry.

The flag 1 hefuranoside of the present invention has the formula l: (wherein the aglycone is methyl or is ethyl, preferably methyl, R1 and R2 are H, methyl, ethyl, C 6 to CIQ alkenyl or mutually forming an isopropylidene ring, R3 is H, C s~CIO argyl, C6~C1o alkenyl, C5~CIO alkynyl, 2- is octyne, benzyl, or C6-CIO ester, and R4 is HSC s~C1゜alkyl, C5~C5゜alkenyl, C6~C+o alkynyl, 2- octyne, benzyl, or 05-C1° ester).

Preferred fructofuranosides of formula 1 where A is methyl are shown in Table 1.

history' foot l dan I R1 (Ia) R' and RI = Isopropylidene I C+HII (Ib) C+ B+ C+ B+ HC+ Hu(Ic) R' and R1-isopropylide C+HII H(Id) R’ and Rz=impropylidene 2-octene Nyl 2-octenyl CIe) B+ and RI = imp a pylidene trans -2-octenyl trans-2tcutinyl (lf) R' and R1 = imp Lopylidene 2-octenyl cis-2-octenyl (1g) 2-octenyl -Octene HH female-2-octenyl The compounds contained in Table 1 are as follows Methyl 1.3-0-isopropylidene-6-0-hebutyl-α-D-fructof Ranoside (Ia), Methyl Otori 3-G〇-ethyl-6-0-hebutyl-α-D -Fructofuranoside (1b), Methyl I, 3-0-isopropylidene-4-0 -hebutyl-α-D-fructofuranoside (lc), methyl I, 3-Q~isoprop Lopylidene-4,6-di〇-(2-octenyl)-α-D-fructofuranosyl Do (1d), Methyl l, 3-Q-isopropylidene-4,6-di-0-(trans, 2-oc tenyl)-α-D-fructofuranoside (le), Methyl l, 3-0-impropylidene-4,6-di-0-(cis, 2-octenylidene) )-α-D-fructofuranoside (1f), Methyl 1,6-di0-(cis,2-octenyl)-α-D-fructofuranosyl (Ig), methyl I, 3-Q-isopropylidene-4-0-octanoyl α -D-fructofuranoside (lh), methyl 1.3-Q-isopropylidene-6 -0-octanoyl α-D-fructofuranoside (Ii), and Methyl I, 3-Q-isopropylidene-4,6-di-0-octanoyl-α-D -Fructofuranoside (1j).

The present invention relates to fructofuranose. If these compounds are A or hydrogen, the formula The same substituents as defined in 1 are present. Particularly preferred compounds are: 2.3-Q- Isopropylidene-4-Q-hebutyl-β-D-fructofuranose (1k) be.

The following sections 1-4 describe methods for preparing representative compounds of formula 1 of the present invention. these compounds The activity of is illustrated in Example 5.

Methyl 1.3-Q-isopropylidene-6-0-n-heptyl-α-D-frac Production process of tofuranoside (la) 1. Production of methyl α-D-fructofuranoside A silica gel column was used for the compound, and chloroform-methanol (9.1-8 :2) Corter-Garcia, R,, L, H and A.C.Richardson (Journal of t he Chemical 5ociety, Perkin 1, 3176-3 181, 1981), methyl α-D-fructof Ranoside 23.8%, [α)o”+81.6° (C1,02 ethanol) was obtained. tao (COrteZ-GarCia, 22.596, Ca〕o　”+　90° (C2, water)] Methyl β-D-fructofuranoside 28296, [α), "-47,8° (C1,23, methanol). (Cortez-Garcia , 3596, (α)D25-49° (C2, methanol)].

-Production of fructofuranoside Method I The reaction method was the same as Cort except that a longer reaction time (3 days) was used. According to the method described by Ez-Garcia. The best yield was 5096. [ α) D"+40.1' (C1,79, chloroform). (Cortez-Ga rcia 3306, [α) o” + 42. 5° (methanol)]. Compound The product had physical properties consistent with literature values.

Method 2: Methyl α-D-fructofuranoside (0.8 g, 4.1 mmol), dimethyl Toxypropane (5g, 49mmol, 6mt') and p-toluenesulfonic acid (0.1 g, 0.5 mmol) in 20 ml DMF was stirred at 25 °C for 24 h. Stirred. The solvent was filtered and the filtrate was evaporated to dryness. Column chromatography [petroleum ether-ethyl acetate (8:2-7:3), then chloroform-methanol Methyl 1,3-0-isopropylidene-α-D ~ frac Tofuranoside (0.38g, 39-pivaloyl-α-D-fructofuranoside) Production Methyl l, 3-0-isopropylidene-α-D-fructofuranoside (1, 3g, 5.55mmol) of methylene chloride (10TrLl) and pyridine ( 7 ml). Add pivaloyl chloride (0.68 g 15°68 mmol, 0.7 ml> was added at 0°C. The solution was stirred and the temperature rose to 25°C. Ta. After 18 hours, another 0. Add pivaloyl chloride (0.8 mmol) of I- , stirring was continued for 24 hours. The mixture was added to water and the solvent was evaporated. Clean the residue. Extracted with loloform, washed with water, brine, dried over sodium sulfate and concentrated. Shrunk. Column chromatography [petroleum ether-ethyl acetate (9:1 to 7:3) )) gives methyl 1.3-0-isopropylidene-6-0-pivaloyl-α-D -Fructofuranoside (1.3 g, 8396) was obtained. [α)D”+30.9° (C2,34, methylene chloride). 'H-N.

m, r, (CDCl2): δ4. 4-3. 9 (m, 8H), 3. 3 (s, 3H, 0CHz),! ,,45. 1゜9H, Co (CH2)3) ppm.

Step 4. Methyl 1.3-0-isopropylidene-4-0-benzyl-6-0-pi Production of baloyl-α-D-fructofuranoside Methyl 1.3-0-isopropylidene-6-〇-pivaloyl α-D-fructo Furanoside (1.3 g, 4.08 mmol) was dissolved in DrvfF (15 yd). ,5. Add 2rILl of benzyl bromide (7.4g, 43.7mmol) Ta. A total of 5.2 g of silver oxide (1) (22.4 mmol) was stirred into this solution. The mixture was added three times over an hour. Stirring was continued for 2 days at 25°C. Silver salt is filtered Filtered, washed with DMF and methylene chloride, and the solvent was removed under reduced pressure. The residue is Extracted with ethylene chloride, the extract was washed with water, brine, dried, and concentrated. . Measuring by column chromatography [petroleum ether-ethyl acetate (50:1)] Chil 1.3-0-isopropylidene-4-〇-benzyl-6-0-pivaloyl- α-D-fructofuranoside [α) o”+50.7° (C1,35, Loloform) was obtained. 'H-N, m, r, (CDC1z): δ3, 3 ( s, 3H, QCdana),! , 4 1. 3 (2s.

Step 5. Methyl 1.3-0-isopropylidene-6-〇-t-butyldimethylsilyl Production of lilu α-D-fructofuranoside Methyl 1.3-0-isopropylidene-α-D-fructofuranoside (0,25 g, 1.07 mmol) in DMF (50 rnl) was added imidazole (0.16 g, 2.3 mmol) and t-butyldimethylsilyl chloride (0.2 g, 1.3 mmol). 32 mmol) was added. The mixture was stirred at 25°C for 48 hours. add water, The solvent was evaporated under reduced pressure. Column chromatography [Petroleum ether-ethyl acetate (9 1-8: 2)) by methyl l, 3-0-isopropylidene-6-0-t -Butyldimethylsilyl-α-D-fructofuranoside (0.26g, 97%) and then the starting material methyl using chloroform-methanol (100:1) 1.3-0-isopropylidene-α-D-fructofuranoside (70■) was obtained . Methyl 1.3-0-isopropylidene-6-0-t-butyldimethylsilyl- α-D-Fructofuranoside: 'H-N.

m, r, (CDC13): 64. 1-3. 7 (m, 7H), 3.3 (s , 3H,0CHa), 2.6 (d, IH, OH), ], 45-1.3 5 (2s, 3H each; C(CH3)2), 0.9 (s, 9H, tBu), 0 °1 (s, 6H, Si (CH3)2) ppm.

-benzyl-6-0-t-butylmethylsilyl-α-D-fragtofuranoside manufacturing Methyl 1.3-0-isopropylidene-6-0-t-butyltmethylsilyl- α-D-fructofuranoside (0.26 g, 0.75 mmol) and benzylp Lomid (0.15 g, 0.9 mmol, 0.1 mN) in DMF (2 ml) solution, Thorium (25 μm, 0.83 mmol) was slowly added to 80% hydrogenation. mixture The mixture was stirred at 25°C for 40 minutes under nitrogen. Excess hydrogenated sodium is removed by adding methanol. The thorium was destroyed and the solvent was removed under reduced pressure at 25°C. Remove the residue with chloroform. Extracted with water, washed with brine, dried and concentrated. Column chromatography [ Petroleum ether-ethyl acetate (20:I~8:2): Methyl 1.3- 0-isopropylidene-4-0-benzyl-6-0-t-butyldimethylsilyl -α-D-fructofuranoside (0.28g, 85.6%) and methyl l,3 -0-isopropylidene-4-〇-benzyl-α-D-fructofuranoside (1 0■, 4%) was obtained. Methyl l, 3-0-isopropylidene-4-0-benzyl -6-0-t-butyldimethylsilyl-α-D-fructofuranoside: [α) D”+48.7° (CI.

58, Chloroform), 'H-N, m, r.

6 (s, 2H, 0CHz Pb), 4. 1-3. 7 (m.

7H), 3. 3 (s, 3H, 0CHz), 1. 4 1゜-benzyl-α -D-Fructofuranoside production method l Methyl 1.3-0-isopropylidene -4-〇-benzyl-6-〇-pivaloyl-α-D-fructofuranoside Dissolved in alcohol (20 ml) and added sodium methyl 1-(0.2 g), Stirred at 25°C for 20 hours. The reaction solution was Amberly 1-IR-120 (H゛ ) Neutralized with ion exchange resin, filtered and concentrated. Column chromatography [ Methyl 1.3-0 with petroleum ether-ethyl acetate (9:1-8:2) -isopropylidene-4-0-benzyl-α-D-fructofuranoside (1,1 5 g, 86.8% yield).

Method 2: Methyl 1.3-0-isopropylidene-4-pencyl-6-0-t-butyl Tyldimethylsilyl-α-D-fructofuranoside (0.2 g, 0.45 mmol ) and IMt Bu4NF THF (0.5 mj, 0.5 mmol) in THF (5mj') The solution was stirred at 25°C for 18 hours. Remove the solvent and chlorinate the residue. Methyl by matography [petroleum ether-ethyl acetate (8:2)]! ,3 -O-isopropylidene-4-0-benzyl-α-D-fructofuranoside (0 , 14g, 95%) was obtained.

Method 3: Methyl 1.3-0-isopropylidene-6-0-1-pivaloyl-α- D-fructofuranoside (0°2 g, 0.63 mmol) and benzyl bromide (0°14g, 0.81mmol, 0.1ml) in DMF (7') solution at 80% of sodium hydride (27 μm, 0.9 mmol) was added slowly. The mixture is 2 Stir at 5°C for 15 minutes under nitrogen. Excess sodium hydride by adding methanol The solvent was evaporated under reduced pressure at 25°C. The residue is methanol (5 ml) and sodium methylate (0.1 g) was added. Mixture at 25°C Stir for 10 hours, neutralize with Amberlite J"R-120 (H"") resin, Filter and concentrate. Column chromatography [Petroleum ether-ethyl acetate (9: l~8: 2) Njiru-α-D-fructofuranoside (0.13 g, 64%) was obtained. [α) o”+83.7° (C0,98, methylene chloride).’H-N, m, r, (CDCI=)8 (m, 4H), 3.6 (dd, IH), 3.3 ( s.

3H, 0CHz), 2.1 (s, IH, OH), 1. ．． 4-Benzyru 6- Production of 0-n-hebutyl-α-D-flagtofuranoside Methyl l, 3-0-isopropylidene-4-〇-benzyl-α-D-fructof Ranoside (1,63 g, 5.03 mmol) and bromoheptane (4.1 g, 2 3 mmol, 3. 6mN) 8096 sodium hydride in DMF (35mt’) solution Lium (0.6 g, 20 mmol) was added slowly. The mixture was heated to 1. Stirred for 5 hours. Destroy the excess sodium hydride by adding methanol and remove the solvent. was evaporated. The residue was extracted with chloroform, washed with water, brine, and dried. Dry over sodium sulfate and concentrate. Column chromatography (petroleum ether) - methyl 1.3-0-isopropylidene-4 by ethyl acetate (9:1) -0-benzyl-6-0-n-hebutyl-α-D-fructofuranoside (2 g, 94%).

[α) o”+51.9° (C1,29, methylene chloride).’HN , m, r, (CDCis): δ7.3H), 3.8 (d, IH), 3.6 -3.4 (m, 4H), 3.3 (s, 3H, 0CH3), 1.6 (9m.

0.9 (t, 3H, CH2) ppm.

Step 9. Methyl l, 3-0-isopropylidene-6-〇-n-hebutyl-α-D -Production method of fructofuranoside 1. methyl], 3-0-isopropylidene-4 -〇-benzyru-6-0-n-hebutyl-α-D-fructofuranoside (0,1 3 g, 0.3 mmol) in methanol of 1096 palladium (26 ■) on activated carbon The mixture in the bottle (5-) was shaken under hydrogen (25 lb/l sq. in.) for 8 hours. . The catalyst was filtered and the solvent removed. Column chromatography [petroleum ether-vinegar [1,3-0-isopropylidene-60-n-h] by ethyl acid (9:I)] Butyl-α-D-fructofuranoside (Ia) (70μ, 70%) was obtained.

Method 2: Methyl 1.3-0-isopropylidene-4-〇-benzyl-6-0-n -hebutyl-α-D-fructofuranoside (0.22 g, 0.52 mmol), active 1096 palladium on carbon (0.2 g, 400 mg/mmol/Bn) and ammonium fumarate (0,3 g) in methanol (IO mN) was refluxed for 2 hours. Add another 0.25 g of ammonium fumarate and reflux for 3 hours. It flowed. Add a final portion of 0.2 g ammonium fumarate and reflux separately. It lasted for 5 hours. After cooling, the catalyst was filtered and washed with methanol, and the filtrate was evaporated to dryness. Ta. By column chromatography [petroleum ether-ethyl acetate (9:1)] methyl 1.3-0-isopropylidene-6-0-n-hebutyl-α-D-fura Cutofuranoside (Ia) co, 14 g, 8196) was obtained. ((2) o”+ 27.4 (C1,01, methylene chloride). 'H-N.

m, r, , (CDCIs): δ4. 2-3. 9 (m, 5H), 3. 4-3.7 (m, 4H), 3.3 (s, 3H.

0CHa), 2.7 (d, LH), 1.6 (m, 2H).

■, 5-1.4 (2s, each 3H, C (CH2) 2), 1゜3 (br s , 8H), 0.9 (t, 3H, CHs) ppm, "C-NMR (CDC1m ):6 102.0 (C-2), 98.6 (C(CH,)2), 85.9° 5.29. 1,27.6. 25. 9. 22.6. 19°7, 14 ．． lppm, m, s,: m/z333 (M+H), 301 (M1H-CH 30-), 260 (M-CH2QC(CH3)2.

Example 2 Methyl 1,3-0-isopropylidene-4,6-di0-(2-octenyl)- Production of α-D-fructofuranoside (ld) Methyl l, 3-0-isopropylidene-α-D-fructofuranoside as described in Example 1 It was produced by the method of Cortez-Garcia et al. Methyl 1.3- 0-isopropylidene-α-D-fructofuranoside (0.3 g, 1.28 mmol ) and 1-bromo,2-octyne (0.73 g, 3.85 mmol) in DMF (4r/Ll) 8o% NaH (0.12g, 4.0mmol) was slowly added to the solution. and the mixture was stirred at 25° for 40 minutes under nitrogen. Add methanol to remove excess The sodium hydride was destroyed and the solvent was removed. The residue is treated with methylene chloride. Extracted and the solution was washed with water, brine and sodium bicarbonate. next The solution was dried over anhydrous sodium sulfate, filtered and evaporated to a residue. this The residue was dissolved in eluent and silicaed using petroleum ether-acetone (24:1). Chromatography on Kagel column and methyl 1,3-〇-isopropylidene- 4.6-di-0-(2-octenyl)-α-D-fructofuranoside (ld) ( 0.41 g, 71%) was obtained as a colorless oil. The compound is treated with sodium bicarbonate. processed and stored in the refrigerator. Compound: Its specific rotation, NMR and mass spec Confirmed by Torr analysis.

Methyl 1.3-0-isopropylidene-4,6-di〇-(trans, 2-oc Production of α-D-fructofuranoside (le) ■-Bromo-1-lan-su-2-octene was replaced with 1-bromo-2-octyne The method of Example 2 was followed with the following exceptions. Methyl! , 3-0-isopropylidene-4, 6-di-0-(1-lance,2-octenyl)-α-D-fructofuranoside Obtained in 70.096 yield as a colorless oil, its specific rotation, NMR and mass spectra This was confirmed by double analysis.

Example 4 2.3-0-isopropylidene-4-0-hebutyl-β, D-fructofurano Production process 1 of 1k: Production of 1,6-di-0-trityl-D-fructose D-fructose (10 g, 55.5 mmol) in pyridine (40 mJ) and Trityl chloride (35 g, 126.3 mmol) in loloform (25 ml) solution. was added, the mixture was stirred at 25° for 2 days, and another 5 g of trityl chloride was added. , stirring continued for 2 days. The solvent was removed under reduced pressure and the residue was extracted with chloroform. , saturated aqueous copper sulfate solution, washed with brine, dried over anhydrous sodium sulfate, and concentrated. Ta. Column chromatography [chloroform-methanol (100・[)]] [11 g, 30%] of 1.6-di-0-trityl-D-fructose was obtained.

This compound was confirmed by its specific rotation and NMR and mass spectrometry. did.

Step 2: 1,6-di-0-trityl-2,3-0-isopropylidene-β-D- Production of flag 1-sufuranose 1.6-di-0-trityl-D-fructose ( 2 g, 3 mmol), dimethoxypropane (5 ml) and p-1-luenesulfonate. A mixture of phosphoric acid (0.1 g) in DMF (20 TLl) was stirred at 25° for 3 h. . Sodium bicarbonate was added to neutralize the solution. After removal of salts and solvents, the residue was extracted with chloroform, washed with water and brine, dried and concentrated. mosquito 1,6-C0- by ram chromatography [petroleum ether-ethyl acetate] 1. Cutyl-2. 3-0-isopropylidene-β-D-fructosfuranose ( 0.9g (142%) was obtained. This compound is characterized by its specific rotation, NMR and mass spectrum. Confirmed by chromometry.

Step 3: 2.3-0-isopropylidene-4-0-hebutyl-1,6-di-o- Production of trityl-β-D-fructofuranose 1.6-Di〇-trityl-2,3-0-isopropylidene-β-D-fructo Sufuranose (0.5 g, 0.71 mmol) was dissolved in DMF (10 d) and hydrogen Thorium (6096.0.12g) was added. Mixture at 25°C for 20 minutes Stir, then add 1-bromoheptane (0.62 g, 3.5 mmol) and add 1. Stir for hours. Add methanol to destroy excess sodium hydride and remove solvent. Evaporated. The residue was extracted with chloroform, washed with water, brine, and anhydrous sulfuric acid. Dry over sodium and concentrate. Column chromatography [petroleum ether-vinegar 2.3-0-isopropylidene-4-0- by ethyl acid (too:l)) Hebutyl-1,6-di-0-trityl-β-D-fructosfuranose (0,4 7g, 82°596) was obtained. This compound is characterized by its specific rotation, NMR and mass spectrometry. Confirmed by pectrometry.

Production of Chi-β-D-fructofuranose Ammonia (approximately 100 mt') is mixed with hydroxyl It is passed through a potassium chloride tower, cooled to liquid with dry ice, and then cooled with dry ice. 2,3-0-isopropylidene-4-0-hebutyl-1,6-di-to Lythyl-β-D-fructofuranose (1.35 g, 1.68 mmol) in dry T Added to HF (30ml) solution. The solution is stirred and the lithium pieces remain blue. Added up to. The solution was stirred until the reaction was complete (checked by TLC). Eta The reaction was terminated by adding ethanol and the ammonia was allowed to evaporate overnight. Chloro in the residue Form was added and salts were removed. Column chromatography [petroleum ether-acetate] (8:2)) gives 2.3-0-isopropylidene-4-〇-hebutyl -β-D-fructofuranose (lk) (0.45 g.

84.196) was obtained. This compound has specific rotation, NMR and mass spectrometry. Confirmed by bird.

Example 5 Pharmacological activity of compounds of formula l Pharmacological efficacy tests performed to determine the immunomodulatory effects of test compounds in vitro. The assays are mixed lymphocyte reaction (MLR) and ConA blastogenesis assay. child These assays measure the inhibitory effects of the invented compounds on T lymphocyte activity and proliferation. It was used to determine the Inflammation at the cellular level is associated with recruitment, activation and proliferation of T lymphocytes. These assays have therapeutic potential in treating diseases involving inflammatory mechanisms. It is suitable for use as a sieve for novel compounds having .

MLR is the expansion of activated T cells in vitro by developmentally distinct stimulator cells. Classical assays used to measure T cell function by studying responses Yes. This was done by co-culturing tile cells from two different strains of mice. achieved. T cell proliferation is a cell activation cycle that occurs due to ongoing cell interactions. It occurs as a result of Gunar.

Identification method/MLR assay The Ba1b/c trout was euthanized by cervical dislocation, and its tiles were removed. tile single Cell suspension was prepared using a Teflon pestle using medium (1096 calf fat serum, 2 mM glutamine, 500 units penicillin/streptomycin, and 4 Hepes-buffered PRMI-16 supplemented with X10-'M2-mercaptoethanol 40). Cells were centrifuged at 1500 r’pm and Berrett removed red blood cells. For separation ACT (0.15M+-lith, 0.14M ammonium chloride, p H7,2). After 5 min incubation in a 37°C water bath, the cells Resuspend in medium and count. used as stimulator cells. C57B1/ Six tile cells were also prepared by this method.

Stimulator cells were incubated with 100 μg/mt' mitomycin C for 1 hour at 37°C. (in order to suppress the proliferation of stimulator cells) and then in the culture medium for 5 min. Washed twice.

Proliferative responses were determined in the presence of various doses of test compound or vehicle (DMSo); Mitigate 2.5X106 responsive cells and 5XIO' stimulator cells without allowing The cells were cultured in 96 wells of a black titer plate and measured.

, using Ba1b/c tile cells treated with mitomycin C as stimulator cells. Isogenic control cultures were also performed using the same method. The final culture was performed in triplicate. Ta.

DMSO solutions of compounds of the invention were prepared at a stock concentration of 120 mM. Next concentration in medium Diluted: 3.1O130, 100 and 300 μM in vehicle (DMSO) ) was used as a negative control.

After 5 days of incubation at 37°C with 596 CO□, the amount of cell proliferation was 20μ m(7)MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 di phenyl-tetrazolium bromide) (lO/rn in phosphate buffered saline) 1) was added to each cup and measured. Plates were incubated for 4 hours at 37°C. and then 180 μm of 10% sodium dodecyl sulfate in phosphate buffered saline. um was added. - After night incubation, the optical density (OD) of each well was set to 5 70-650nm Molecular Devices Microplate Reader I read it at The results are the average value of the allogeneic culture and the isogeneic culture for each test product concentration. This was determined by calculating the difference between the mean values of the gene cultures. The difference between the test product group is that of the control group. % change from control was determined. Test products found to inhibit proliferation is greater than -2096 inhibition of the control considered to be active (two of the controls are - () Expressed as %.

Mouse tile cell ConA blast cell development assay When culturing lymphocytes in vitro It is well known that several plant lectins stimulate cellular activity and proliferation.

Concanabolin, (ConA) selectively stimulates T lymphocyte renal cell responses . Therefore, the ConA blastogenesis assay demonstrates the immunomodulatory and antiproliferative activity of test compounds. Useful for screening sex.

Identification method: ConA assay 6-8 week old male C57BL/6 mice were transferred to Harlan Sprague Dawle. y (Indianapolis, IN).

The tiles were removed and homogenized to obtain a single cell suspension. Red blood cells are in hypotonic shock Separated by When measuring the viability and concentration of linocytic cells, 1096 fetal bovine serum, 100 u g/ml streptomycin, 100 U/ipenine Gin, 0.2M Hepes Noku Sofa, 5XIO-sM 2-mercaptoethano 4X16 in medium (RPMI-1640) supplemented with alcohol and 2mM glutamine. Adjusted to @cell/i. The tile cells are 2 x 10' cells 70.050 m1/< The seeds were sown in the black titer play 1. These cultures were treated with various doses of Add test compound and ConA at a final concentration of 4 or 1 Hg/ml.

Control cultures were media containing only cells, ConA and vehicle DMSO. It consisted of Some assays use positive control cyclosporine A (C3P) or and AZT were also tested. Methyl 1.3-0-isopropylidene-6-0-n-he Indomethacin and NDG for Butyl α-D-fructofuranoside test A was used as a control. All cultures were performed in triplicate.

A DMSO solution of the compound of the present invention was prepared and diluted with the medium. The assay concentration is The difference was: 1, 2.5, 10125.100.300 and 750μg /m1 or 0.001.0.01.0.1.1.2.5.1O125 and 1 00 u g/d.

Culture was incubated for 3 days at 37°C in a humid atmosphere containing 5% CO2 in the air. I did it. During the last 18 hours of incubation, 1 uCi of 3H-thymidine was also inked in each well. It was incubated. Cells were pelleted using a multi-channel harvester. as a measure of cell proliferation The amount of 2H-thymidine taken up by the culture is measured using a liquid scintillation counter. Measured with a meter.

The amount of radioactivity taken up is proportional to the amount of cell proliferation in each cell.

Student's T test is used to determine the significance of the difference between test and control values. Ta.

IL-1 attachment Interleukin-1 (IL-1) is a potent immune system with a wide range of pro-inflammatory activities. It is a regulatory cytokine. IL-1 is activated by activated cells such as macrophages. It is known that it is produced by IL-1 production in accessory cells is T and B lymphocytes activity and proliferation. Therefore, macrophage activation and IL-1 Activation and proliferation of cellular effectors of inflammation are modulated by inhibiting their production. can. Compounds of the present invention were screened for inhibitory activity in a classical IL-1 assay. Ta.

Identification method: IL-1 assay Harlan Sprague Dawle 6-8 week old male C57B1/6v mice Purchased from y. Peritoneal macrophages received 0.2 ml of complete Freund's supplement. Mice were induced by a single intraperitoneal injection. 48 hours later, induction Macrophages are removed from mice by washing using Hang's balanced salt solution. I took it out.

Macrophages were washed and placed in a microtiter at a density of 2X105 cells/Kuhomi medium. (C.

nA blastogenesis assay). Various uses for macrophage culture amount of the compound of the present invention and lOug/ml of macrophagia activator, lipopolysate. Lysaccharide was added (to stimulate IL-1 production).

Control cultures were macrophages, lipopolysaccharide and various doses of DM. It consisted of a medium containing only SO. Culture at 37°C for 24 hours in 5% air. It was incubated in a humidified atmosphere containing CO2. The compounds of the present invention are prepared in DMSO. and culture medium at the following concentrations: 0.001.001.1.25.10.25 and 10 Diluted to 0 μg/mj.

The amount of IL-1 produced in each individual tumor was measured using a bioassay for IL-1. Ta. This involved removal of the thymus from mice less than 8 weeks old. Thymocytes are located in each thymus was isolated through a stainless steel mesh sieve. Thymocytes were treated with 5% tallow serum and 1.5XlO' cells/in RPMl-1640 medium containing 1μg/yJPHA After a while, I put it in a microtiter well and cultured it. Triplicate replicate culture in air 596 Incubate the macrophage supernatant in the same medium at 37°C in a humidified atmosphere containing CO□. It was diluted and cultured.

After 48 hours, Kuhomi was pulsed with 0.5 uCi of 3H-thymidine. 18 hours later Harvest cells and measure radioactivity uptake (as a measure of cell proliferation) by liquid scintillation. quantified using a counter. between test and control values using Student's T test The significance of the differences was determined.

Effects of (Ib) to (I j) A summary of the inhibitory effects of the compounds is shown in Table 2. As demonstrated by these data, It was found to be a weak inhibitor of mitogens that induced T lymphocyte proliferation responses. (Ii), the potent inhibition of these compounds of the invention at 100 μg/i -5096 in the control) for ConA-stimulated T lymphocyte proliferation. Fructofuranoside inhibits dose-dependent inhibition.

Tables 3 and 4 show specific examples of the inhibitory effects of the compounds of the present invention on T lymphocyte proliferation activity. It is. As can be seen from Table 3, compound (Ik) was 1 u g/m1-100 For the significant inhibition of T lymphocyte proliferation observed at concentrations in the range of u g/ml inhibits in a dose-dependent manner. Table 4 shows compound (Ii) or lμg/mJ of ConA Significant inhibition observed at all doses for culture of T IJ lymphocytes. We demonstrate that cell proliferation exhibits significant, dose-independent regulation. The results shown in Table 5 are Chil I, 3-0-isopropylidene-6-〇-n-hebutyl-α-D-fructo Mouse cells derived from normal lungs that proliferate in response to furanoside or mitogen stimulation. - shows that a significant dose-dependent inhibitory effect on cell performance was obtained. untreated There were fewer T-cells in treated cultures at the end of the assay compared to control cultures. Ta.

'S:　/:　:l-:2 = Nimago =; 2: The compound of formula 1 is a mixed lymph Inhibitory to T lymphocyte activity and proliferation when assessing activity in cellular responses I also found out that there is. As can be seen from Table 6, when compared with the control, the formula l Lactofuranoside is a potent compound defined as greater than -5096 of the control culture. occurred in the MLR with moderate inhibition and moderate inhibition defined as 20% of the control. showed no dose-dependent decrease in proliferation.

Furthermore, the immunomodulatory effects of compounds (Ia), (Id) and (Ie) were Studies have demonstrated the inhibitory effects of these compounds on di-IL-1 production. Ta.

The results shown in Table 7 show that the compounds were present in the concentration range of 2.5 to 100 μg/ml. Significant inventive effects observed for all compounds inhibit macrophages in a dose-dependent manner. It was observed that IL-1 production was inhibited.

In summary, compounds of formula I have been shown to have immunomodulatory and antiproliferative effects. Therefore, these compounds of the present invention are effective against various inflammations and/or can be predicted to be useful in the treatment of autoimmune diseases.

A second aspect of the invention is glucose and allose derivatives. glucose and Allose and allose are six carbon monosaccharides, and due to the 3-carbon configuration of the sugar, mutually different. In particular, these compounds contain α-D or β-D glucofuranose and and monosubstituted ether derivatives of α-D or β-D allofuranoses and their congeners. Including the body.

General formulas 2 and 3 below include both α or β configurations. The compound is monosacca Substitution at the 3- or 6-position of the ride. Homologues of these compounds are 3- or Oxygen at the 6-position is substituted with an amino group or sulfur.

As will be clear from the following discussion, compounds of this embodiment are thick (can be classified into two groups). . Fully blocked mono-substituted compounds, i.e. two isopropylidene reserves. those with protective groups, and partially blocked mono-substituted compounds, i.e. only One with one isopropylidene protecting group. The applicant is GlucoFrance and Fully blocked and partially blocked derivatives of lofuranose can be used to treat autoimmune and/or was found to be effective in treating inflammatory diseases.

The 3-substituted derivatives of glucofuranose and allofuranose have the following general formula [In the formula, Xl is 0, R' let CIx ~ C207) L' kill, or C, R2, Y (where n is 1.2.3 or 4, Y is cyano, pyro Zolyl, pyrrolidinyl, methylpyrrolidinyl, bibecolinyl, imidazolyl, pyrrolidinyl lazolyl, pyrazolinyl, pyrazolidinyl, oxacylyl, oxazolidinyl, isoxasilyl, isoxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, molporinyl, O(CH2), N (CH,)2, (C, ~C1 0 alkoxy), CH2CH (CH2) CH2N (CH3)! , CH2CH2N (Ci ~ C +ofurkyl)2, or (C, ~C7 alkenyl)), or or XI or NH, and R5 is 02~c1° alkyl, or C7H2,Y (formula Medium, n is l, 2. 3 or 4, and Y is hydroxy, cyano, pyrrolyl, pyrrolyl lolidinyl, methylpyrrolidinyl, piperazinyl, imidazolyl, pyrazolyl, Pyrazolinyl, pyrazolidinyl, oxacylyl, oxazolidinyl, isoxazo Lyle, imidazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, mono Luforinyl, O(CH2)3 N (CH3)2, (C, ~CI.Alkoxy ), and phenyl), and Ra and R7 are hydrogen or form an isopropylidene ring].

R6 and R7 can be isolated by selective removal of the protecting groups at the 5,6 positions by the following general method. A partially blocked compound of formula (1), which is hydrogen, is obtained. Preferred compounds of formula ■ are: It is・ 1.2-0-isopropylidene-3-0-n-dodecyl-α-D-glucofurano (IIa), 1.2-0-isopropylidene-3-0-n-pentadecyl -α-D-glucofuranose (nb), 1.2-0-isopropylidene-3- 0-n-old cudodecyl-α-D-glucofuranose (IIc), 1.2-0-i Sopropylidene-3-0-3-(phenylpropyl)-α-D-glucofurano -s(I[d), 1,2.5,6-di-0-isopropylidene-3-0-3-- (morpholinylpropyl)-α-D-glucofuranose (IIe), 1.2:5.6-No〇-isopropylidene-3-〇-3--n-propoxy n-hebutyl-α-D-glucofuranose (IIf), 1.2-0-isopropylidene-3-〇-3--n-propoxy n-hebutyl -α-D-glucofuranose (IIg), 1.2:5,6-diO-isopropylidene-3-〇-2”-(ethylpyrrolidine )-α-D-glucofurano1,2-0-isopropylidene-3-0-2”-( ethylpyrrolidyl)-α-D-glucofuranose (I[i), 1,2-0-iso Propylidene-3-0-3--(propan-1'-ol)-α-D-glucof Lanose (If j), 1.2:5,6-di-0-isopropylidene-3-deoxy-3-amino-1= -(3″-hydroxy-n-propyl)-α-D-glucofuranose (nk), 1.2-0-isopropylidene-3-0-3-(N-,N'-dimethylamine -n-propyl)-α-D-allofuranose (■1), 1.2:5,6-di-0-isopropylidene-3-0-3-(phenylpropylidene) )-α-D-allofuranose (IIm), 1.2-0-isopropylidene-3-deoxy-3-N-1 (N", N"-dimethyl Thylamino-n-propyl-α-D-allofuranose (IIn), 1.2-0- Isopropylidene-3-deoxy-3=amino-3-n-hebutyl-α-D-a lofuranose (II o), 1.2-0-isopropylidene-3-deoxy-3-amino-3'-(propane) -1-ol)-α-D-glucofuranose (IIp), 1.2-0-isopropylidene-3-deoxy-3-N-3'-(phenylpropylidene) pill)-α-D-allofuranose (IIq), 1.2-0-isopropylidene-3-deoxy-3-amino-n-hebutyl-α -D-glucofuranose (■r), and 1.270-isopropylidene-3-deoxy-3-amino-n-3”-(phene Nylpropyl)-α-D-glucofuranose (IIs).

Representative examples of the above compounds having formula (1) are prepared by one of the following methods in Examples 6-11. Ta. The pharmacological activity of the compound of formula 2 is shown in Example 12.

Example 6 5. General method for selective hydrolysis of the 6-position Calide (1.0 g) was dissolved in tetrahydrofuran (1 ml), and 0 to 5 While stirring at °C, perchloric acid solution (3096, 1 rnl) was added dropwise. The reaction is T Monitored by LC and GC. Typical reaction times vary from 20 minutes to 1 hour. Ru. After completion of the reaction, neutralize to a pH of 9.0 with a saturated solution of potassium carbonate. formation hard The body salts are filtered through Celite and divided into several portions and added with tetrahydrofuran (50 m/). I washed it well. The combined filtrates were subjected to a rotary evaporator and the resulting residue was mixed with silica gel and Purify by flash chromatography using appropriate solvents. final product The yield ranges from 75 to 98%.

Kui Yu 1.2:5,6-di-0-isopropylidene-3-0-n-dodecyl-α-D- glucofuranose and l.

2-0-isopropylidene-3-0-n-dodecyl-α-D-glucofuranose Production process of (IIa) 1:1,2:5,6-di-0-isopropylidene-a-D -Glucofura/'7 (R' = CI2825)1.2・5,6-G-O-i Sopropylidene-α-ri-glucofuranose (5.2 g, 0.02 mol) and A mixture of dry powdered sodium hydroxide (3 equivalents) is heated in an oil bath at 120-130° did. This reaction was carried out under reduced pressure to remove water formed during the reaction. This reaction is Divide into approximately 30-45 portions depending on the batch size. Next, disconnect the vacuum line and Lomododecane (1,2 eq.) was added in one portion. The reaction mixture was kept for 30 minutes to 2 hours. The mixture was stirred at the same temperature. The reaction flask was then cooled and dichloromethane (100 ml) was added and the mixture was filtered through Celite and washed with a 100- or higher solvent. Ta. The solvent was removed using a rotary evaporator and the residue was dissolved in ether:hexane (10: Purified by flash chromatography using 90).

Partial block compound 1.1-0 is obtained by hydrolysis according to the general method described in Step 2 and Example 6. -isopropylidene-3-0-n-dodecyl-α-D-glucofuranose (If A) was obtained.

1.2:5.6-di-0-isopropylidene-3-〇-3-(n-propoxy) butyl)-α-D-glucofuranose (]If) and 1,2-0-isopropyl Lyden-3-0-3-(n-propoxy-heptyl)-α-D-glucofurano -Production process of (IIg) 1:1.2:5,6-di-0-isopropylidene-3 -0-1(n-propoxyheptyl)-α-D-glucofuranose (R5=-( CH2)30C7H,.

)Manufacturing of 1.2:5,6-di-0-isopropylidene-3-〇-3'-propanol α -D-glucofuranose is l.

25.6-di-0-isopropylidene-α-D-glucofuranose and trihydroxide (equivalent) under vacuum at 120-130°C. 30 minutes later , the vacuum line was removed and 1-bromopropanol (3 equivalents) was added. reaction mixture The mixture was heated at the same temperature for 45 minutes. Then the flask was cooled and ether was added. (100ml).

The solution was filtered through celite and washed with ether greater than I00mj' to remove the solvent. I left. The residue was flash chromatographed using 1006 ether in hexane. Purification by graphics afforded the title compound in yield 8406.

1.2:5.6-C0-isopropylidene-3-〇-3-propanol-α- D-glucofuranose (0°02 mol) and dry powder sulfur and lithium hydroxide (3 (equivalent) mixture was heated at 120-130"C under vacuum. After water evolution, Remove the vacuum line, add heptyl bromide (1,2 eq.) in one portion, and stir the mixture. was heated at the same temperature for 1 hour. Cool the reaction flask and add ether (100ml) was added. The solution was filtered through Celite and washed with 100 d of ether. If The dissolved solvent was rotary evaporated to remove ether and then 5% ether in hexane was added. Purified by flash chromatography using .

1.2:5,6-di-O-isopropylidene-3-〇-3--(n-propoxy Heptyl)-α-D-glucofuranose was obtained and analyzed by NMR and mass spectrometry. It was characterized by

Step 2: Hydrolyzed by the general method described in Example 6 to obtain partially blocked compound 1.2-0- Isopropylidene-3-0-3-(n-propoxyheptyl)-α-D-glue 2-0-isopropylidene-3-deoxo-3-amino or substituted amino -Production of α-D-glucofuranose Step 1: 1,2・5,6-di-0-isopropylidene-3-deoxy-3-azi Production of α-D-glucofuranose 1.2-5.6-diO-isopropylidene-3-tosyl a-D-allofurano (Methods 1nCarlohydrate Chemistry, ) (20 g) and anhydrous DMF (10 A mixture of sodium azide (2,5 eq.) in 0rdD was heated at 80 °C for 3 h. did. The progress of the reaction was monitored by TLC and GC. Once the reaction is complete, DMF was removed under reduced pressure and the residue was extracted with ether (157) and water (2 x 25). , saturated sodium bicarbonate solution (2X20d) then prine (lX25ml' ). The organic layer was dried over MgSOA, filtered, and the solvent was rotary evaporated. It was removed using a machine. This compound (95% yield) was sufficiently pure by TLC. Therefore, it was used in the next step.

Step 2: l, 2,5,6-di-0-isopropylidene-3-deoxy-3-ami Production of no-α-D-glucofuranose The azide compound (5 g) obtained in step 1 was mixed with H2, palladium-charcoal (1096,50 ■) and methanol (100-) for 6 hours at a pressure of 35 psi. Catalytic reduction was carried out using an element adder. The reaction mixture was then filtered using Celite and the methane The solvent was removed using a rotary evaporator. residual obtained One homogeneous spot was observed on TLC and the complete azide group peak was detected by IR. It showed a significant disappearance. The yield of pure compound was 9596.

Step 3: Hydrolysis according to the general method described in Example 6 to obtain partially blocked compound 1.2-G. 0-isopropylidene-3-deoxy-3-amino-α-D-glucofuranose I got it.

Step 4: l, 2: 5.6-di-0-isopropylidene-3-deoxy-3-ami Production of non-n-hebutyl-α-D-glucofuranose The 3-deoxy-3-amino compound obtained in step 3 was heated at 70 to 80°C for 3 to 4 hours. Heat with 1-bromoheptane in a ratio of 2.2. Progress of the reaction was monitored by TLC and GC. I tracked it down. After completion of the reaction, the product was extracted with ethyl acetate and saturated with sodium bicarbonate. The solution was washed with brine and then the organic layer was dried over anhydrous MgSOA.

The crude compound was obtained by removing the solvent and purified by flash chromatography. other The amino substituent of can be synthesized by the same procedure using the appropriate alkyl halide compound. can. Alkyl halides themselves can be further functionalized.

Step 5: Hydrolysis according to the general method described in Example 6 to obtain partially blocked compound 1,2-di 0-isopropylidene-3-deoxy-3-amino-n-hebutyl-α-D-g Rucofructose (IIr) was obtained.

Example 10 1.2:5,6-diO-isopropylidene-3-0-substituted α-D-allofurano - and 1,2-0-isopropylidene-3-0-substituted α-D-allofurano manufacturing Step 1: l,2,5,6-di-O-isopropylidene-α-D-allofuranose was dried using the same method and ratios described for the glucofuranose derivative in Example 7, Step 1. Dry powdered sodium hydroxide and a suitable alkylhydride or substituted alkylhydride. Treated by ride.

Hydrolysis was carried out by the general method described in Step 21 Example 6 to obtain a partially blocked compound.

Example 11 1.2:5.67 di-0-isopropylidene-3-deoxy-3-amino-n- Hebutyl-α-D-allofuranose and 1. ．． 2-0-isopropylidene-3 -Production of -deoxy-3-amino-n-hebutyl-α-D-allofuranose (■0) Construction Step 1: 1,2.5,6-di-O-isopropylidene-3-deoxy-3-ami Production of non-n-hebutyl-α-D-allofuranose 1.2:5,6-di-0-isopropylidene-α-D-liforohexofuranose -3-Urose (rMethodsin Carlohydrate Chem istry J, vol. 6, p. 125) and hep. Mix thylamine in a ratio of 1=2 and heat to 50-80°C under reduced pressure for 30 minutes to 2 hours. did. Once the water evolution had finished (reaction progress was monitored by TLC and GC), the true The empty line was removed. The product was dissolved in anhydrous THF and dissolved in anhydrous THF. Add dropwise to a stirred caspension of aluminum halide (LAH, 2 eq.). reaction The reaction was carried out at 5-10° C. with vigorous stirring and was completed in 2-3 hours. then excessive LAH was prepared in water and 1 ei of 15% sodium hydroxide solution (1 ei each for 1 g of LAH used). m1) was carefully added and decomposed. The reaction mixture was then filtered through Cely 1- The solution was washed with THF and the solvent was removed. The residue was dissolved in ethyl acetate and washed with water. , dried and then the solvent was removed. Flash chromatography using appropriate solvents Purified by graphics. This method converts other amino-substituted compounds into hebutylamine. However, it can be produced by substituting other suitable amine compounds.

Step 2: Hydrolyzed by the general method described in Example 6 to obtain partially blocked compound 1.2-0- Isopropylidene-3-deoxy-3-amino-n-hebutyl-α-D-alof Lanose (I[g) was obtained.

Example 12 Pharmacological activity of compounds of formula 2 The compounds inhibit T cell proliferation, activation and macrophage IL-1 production as described in Example 5. Screening assays to measure immunomodulatory, anti-proliferative and anti-inflammatory activities. I tested it. The compounds of the present invention affect fibroblast proliferation and the production of pro-inflammatory mediators. The lotus effect was also tested.

Since the early 1970s, important mediators of the inflammatory process have been leukotrienes and It is known that it is a prostaglandin. These are tissue cells and inflammatory sites (Flower et al., rAnalgesics -anti pyretics and anti-inflammmatovy Agents; Drugs Emphoyed in the Treat ment of GoutJ, The Pharmacological B a5 is of Therapensics.

New York, 1985). In inflammatory diseases, damage to mammalian cells is Occurs due to physical trauma or a combination of antigens and antibodies, which are mediators of inflammation thought to be responsible for the physiological and visible signs of inflammation in turn. It will be done. This is due to the recruitment, activation and proliferation of T lymphocytes in localized areas of inflammation. Correlates with In psoriasis, a modest increase in the production of prostaglandins and leukotri arachidonic acid formation in psoriatic skin, mainly resulting in a several-fold increase in LTBda degrees. Is there an increase? LTB is a major factor responsible for promoting the inflammatory process that worsens the disease. It is a biological mediator (Anderson, T. F., New Rea sonsfor Using Time-Honored Empiric T therapyJ.

Con5ultant, I 985), in autoimmune diseases caused by arthritic components. , synovial fibroblast proliferation is responsible for the production of inflammatory mediators. The following data is from the book The invented compounds exhibit pharmacological activity in reducing fibroblast production of LTB and PGE. Demonstrate that the These have effects on regulating the activity of infiltrating T-lymphocytes. , is an antiproliferative agent in skin fibroblast culture. Furthermore, this activity Physiologically tolerable doses of the conjugate were administered to T-cell and human fibroblast proliferation. indicates that it can be used locally or systemically to inhibit

The assay modulates BUD-8 human dermal fibroblast proliferation, PGE, and L This was done to demonstrate the ability of the compounds of the invention to modulate TB production.

Identification method/Fibroblast assay Human skin cell fibroblast cell line, BUD-8 is American Type C obtained from the ulture collection before each assay. This is 56 o It is a uniform lineage of fibroblasts derived from the normal skin of Caucasian women.

BUD-8 cell culture was carried out in 25af flasks at 37°C under 5% CO2 atmosphere in air. The amount was increased compared to the previous use. Approximately 4-5 times, at 5-day intervals, or in clusters, The cells were transferred. This separates the cells with a Teflon scraper, washes them, and then This was achieved by reseeding cells at a lower density into fresh tissue culture flasks.

The effect of the compound of the present invention on the proliferation ability of human BUD-8 skin fibroblasts is as described above. Using the same culture conditions used for the Con-A blastogenesis assay, - Measured using a thymidine uptake assay. Cultured skin cells are Teflon It was mechanically separated from the surface of the tissue culture flask using a lever. Cells are washed and The cells were resuspended in incubation medium and viability was determined. These cells then multiply 2XIO' cells for proliferation assay 10. ITnl/Denseness of microchitter depressions For quantitative assays of PGE2 and LTB, lx10' cells were tested at 10. Plating was done in triplicate at a density of 1 m//microtiter depressions. these Indomethacin, or Leukotrie, which inhibits prostaglandin production in cells Ink containing nordihydroguaiaretic acid (NDGA), which inhibits the production of (positive control).

After 18 hours of incubation, the BUD-8 skin cell supernatant sample was transferred to one set of microtiters. PGE2 or LT Frozen until assayed for B4 content.

After 3 days of culture, add 1 μCi"H-thymidine to each culture well of the microchitter plate. It was added in a volume of 50 μm.

After 18 hours, each culture of BUD-8 has undergone compounding such as rounding or granulation of the cells. Tested morphologically for evidence of substance-induced toxicity. Thymidine-pulsed cells are then precipitated. The amount of 3H-thymidine incorporated was counted using a liquid scintillation counter. .

The concentrations of the invention compounds used in these assays were: 1 Oug/ml Group 5 : 1100u/m/Group 2: lug/ml Group 6: 300ug/rn Group 13: l Oug/mN 7th group near 00ug/m14 group 25ug/m1 The incubation medium used for culturing BUD-8 cells was 1096 tallow serum. , 1100u/rnl streptomycin, 1100u/ml penicillin, 0. 2M Hebes buffer solution, 5X10-'M 2-mercap-1-ethanol and It was RPMI-1640 containing 2mM glutamine.

Radioimmunoassay (New England Nuclear) is BUD-8 It was used to quantify the amount of PGE in skin cell culture supernatant. That is, each polypropylene 0.1-strain-PGE2.0.1rnl12J-PGE2 and 0.1-strain-PGE2.　 1 ml PGE2 standard or PGE2 containing sample was mixed. BUD-8 skin culture The Yer supernatant was diluted 1=2 before addition to the radioimmunoassay. Refrigerate the tube overnight Ta. Next, polyethylene glycol solution (16%, 6,000 m).

W,) to precipitate the immune complex, and measure the radioactivity of the precipitate using a gamma counter. I counted.

The LTB and amount of BUD-8 skin cell culture supernatant samples were determined by radioimmunoassay (New It was quantified by Nuclear (England). In other words, each polypropylene 0.1 ml anti-LTB4.0.11d3H-LTB4 and 0.1 ml anti-LTB4.　1mj LTB, standard or LTB4 containing samples were mixed.

BUD-8 skin cell culture supernatant was used for direct radioimmunoassay. The tube is overnight Refrigerated. Charcoal solution (0.596 charcoal at 0.5 mN) Norit A) was added and the tube was centrifuged. The radioactivity of the supernatant liquid is determined by liquid scintillation. counted with a ration counter.

Students test T-lymphocytes or test compound versus medium only control. was used to demonstrate the significance of the difference in value for skin cells cultured in the presence of .

Compound (IIa), which affects the T lymphoblastogenic response to ConA ( The inhibitory effects of IIg) and (IIk) are listed in Table 8. These compounds are T It was found to exhibit dose-independent inhibition of lymphocyte proliferation. All test compounds is strongly inhibitory at a concentration of 1100 u/- of the compound (more than 50% of the control response). Kii). Compounds of the invention that mediate the regulation of the proliferative response of T lymphocytes to ConA Specific examples of the products are shown in Table 9. Statistically significant inhibition of T cell proliferation between 100 and 750 It is represented by compound (I[g) at a concentration in the range of u g/ml.

Further immunomodulatory effects of these compounds were demonstrated in MLR assays (Table 1 0). A strong dose-independent inhibition (greater than control −5096) was observed with compound (II g) and (IIa) were observed at some concentrations. Is this a compound or activated It has been shown to inhibit T lymphocyte function when cultured.

Peritoneal macrophage IL-1 production in mice was determined using a compound of the invention as described in Example 11. It was also found that it was inhibited by Compound (I [g) is 1O125 and 100μ The significant decrease in IL-1 activity observed in macrophage IL- showed a dose-dependent inhibition of 1 production. IL-1 is active in inflammation and autoimmune diseases These data are potent stimulators of certain B and T lymphocytes. shows the broad immunomodulatory effects of the compounds of the present invention. Unregulated fibroblast proliferation and and biosynthetic activity underpin inflammatory diseases in which joint damage (such as osteoarthritis) is observed. The activity of the compounds of the present invention was tested on fibroblast cell cultures. . Studies were conducted to determine the antiproliferative effects of compounds, and these effects were associated with fibroblasts. Pro-inflammatory mediators PGE2 and LTB were correlated with abundance in cell cultures.

The compounds of the present invention have a potential effect on fibroblast proliferation and biosynthetic activity. I also tested it. Compound (■g) showed significant anti-inflammatory activity at 100.25 and IOug/ml. It showed a dose-independent anti-inflammatory effect on BUd-8 skin cell fibroblasts because it showed proliferative activity. Table 12) indicates that it exhibits a proliferation effect. Evidence of cytotoxicity of the test compound observed at the highest concentrations.

This anti-proliferative effect has a significant dose-independent inhibition on fibroblast production of pro-inflammatory mediators. Correlated with the harmful effect (LTB, the amount is l=l　OOu-g/ml of compound (I[ The concentration of g) was significantly decreased in BUd-8 skin cell cultures (Table 13).

Cytotoxicity was again observed in cultures containing 300 and 750 ug/ml of compound.

Table 14 shows the dose-independent inhibitory effect on fibroblast PGE* production. From this table, compound concentrations of 1.10 and 25 ug/d are found in the BUd-8 skin cell line. It can be seen that this is correlated with a significant decrease in the amount of PGE1 in the fibroblast culture. Compound Induced cytotoxicity was observed only at the highest tested dose.

Unregulated fibroblast proliferation and activation contributes to inflammatory diseases such as osteoarthritis and psoriasis. These data suggest that it could be used as a therapeutic agent for the treatment of these diseases. This strongly suggests the possibility of using the invented compound.

Completely blocked 6-substituted derivatives of glycofuranose and allofuranose are The following general formula 3 [wherein, X2 is 0, R' is C- to C20 alkyl, or CnH2aY (where n is l, 2. 3 or 4, Y is phenyl, cyano, pyrrolyl, methylpyrrolidinyl, Piperazinyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, xasilyl, oxazolidinyl, isoxasilyl, imidazolidinyl, imida Zolidinyl, piperidinyl, piperazinyl, morpholinyl, 0 (CR2) 3 N (CHs) 2, (05-C1o alkoxy), NH or N (CH 3) Select from 2), or X2 is S, R8 is 05-C1o alkyl, or Cn H2,, Y (wherein, n is 1, 2, . 3 or 4, and Y is OH, phenyl, cyano, pyrrolyl, pyrrolidinyl, Tylpyrrolidinyl, piperazinyl, imidazolyl, pyrazolyl, pyrazolinyl, Pyrazolidinyl, oxacylyl, oxazolidinyl, isoxasilyl, isoo xazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl 0 (CH2) 3N (CHa)2 or (C6~C+o alkoxy) ), and and R9 and R'' are hydrogen or form an isopropylidene group] More shown.

Selective removal of the protecting group at the 3.5-position was achieved by the general method described in Example 6, and R9 and a partially blocked compound of formula (2) in which R10 is hydrogen is obtained. Preferred formulation of formula 3 The compound is: 1.2-0-isopropylidene-6-〇-hebutyl-α-D-glucofurano (]IIId, 1,2-0-isopropylidene-6-0-nonyl-α-D-g Lucofuranose (IIIb), 1,2-〇-isopropylidene-6-〇-dodecy Le-α-D-glucofuranose (I[c), 1.2-0-isopropylidene-6 -〇-pentadecyl-α~D-glucofuranose (IIId), 1.2-0-i Sopropylidene-6-0-3-(phenylpropyl)-α-D-glucofurano (I[Ie), 1.2:3,5-di-0-isopropylidene-6-〇-meth xyoctyl-α-D-glucofuranose (■g), 1.2-0-isopropylidene-6-〇-propionitrile-α-D-glucof Lanose (I[h), 1.2:3,5-di○-isopropylidene-6-deoxy C-6-amino-[2'-aminoethyl-2"-(N--methylpyrrolidyl)- α-D-glucofuranose (I[i), 1.2:3,5-diO-isopropylidene-6-deoxy-6-amino-3' -(phenylpropyl)-α-D-glucofuranose (II[j), 1.2:3 ,5-diO-isopropylidene-6-deoxo-6-N-(N--propylbylidene becorinyl)-α-D-glucofuranose (I[k), 1.2:3,5-di-0-isopropylidene-6-deoxy-6-aminoeth Xoethanol-α-D-glucofuranose (■1), 1.2-0-isopropylidene-6-deoxy-6-amino-3'-(propane -1'-ol)-α-ri-glucofuranose (IIIm), 1.2: to 3,5-di-0-isopropylidene-6-deoxy-6-thio-n- Butyl-α-D-glucofuranose (I[In), 1.2-0-isopropylidene-6-deoxy-6-thousand-n-hebutyl-α- D-glucofuranose (■0), 1.2:3,5-di-0-isopropylidene-6-deoxy-6-thio-2'- (ethyl-N#-pyrrolidyl)-α-D-glucofuranose (I[p), 1.2 -0-isopropylidene-6-deoxy-6-thio-2'-(ethylpyrrolidyl )-α-D-glucofuranose (I[q), 1.2+3.5-di0-isopropylidene-6-deoxy-6-thousandoh3”- (N=, N--dimethyl-amino-isobutyl)-α-D-glucofuranose ( ■r), 1.2:3,5-di0-isopropylidene-6-deoxy-6-thousandoh3'- (propan-1'-ol)-α-D-glucofuranose (IIIs), and 1.2-0-isopropylidene-6-deoxy-6-thousand-3'-(phenylpropylidene) lopil)-α-D-glucofuranose (I[It).

Methods for synthesizing representative compounds according to this embodiment are shown in the examples below. The activity of the selected compound is This is shown in Example 17.

Example 13 1.2:3,5-zyl-0-isobropylidene-6-deoxy-6 to 1,000 ohn- Butyl-α-D-glucofuranose and I,2-0-isopropylidene-6- Deoxy-6-thio-n-hebutyl-α-D-glucofuranose (IIIo) manufacturing The production of 6-dioxy-6-thio α-D-glucofuranose is described in U.S. Pat. No. 96,195.

Step 2: I, 2: 3.5-diO-isopropylidene-6-deoxy-6-thio -Production of n-hebutyl-α-D-glucofuranose: 1.2:3,5-di-0-isopropylidene-6-deoxy-6-thio α-D - Glucofuranose (2,76 g, 0.01 mol) and dry, powdered sodium hydroxide (1,20 g) in an oil bath under reduced pressure (0,1 mmHg). Heated to 90-95°C. Once bubbles have formed in the flask (40 minutes), remove the vacuum tube. After removing the ink, ■-bromoheptane (2.15 g, 0.012 mol) was added. . The mixture was heated to the same temperature for 45 min (the progress of the reaction was followed by TLC), then The flask was then cooled to ambient temperature. Add dichloromethane (75 ml) and Stir for minutes. The formed mixture is filtered and the residue is dissolved in dichloromethane over 75 yJ. Divide into smaller amounts and wash. The solvent was removed and the residue was ether:hexane=30 Purified by flash chromatography using Nia0. number of pure compounds The weight was 3.33g (89.2%).

NMR (CDCIn) 66.01 (d, IH, Hl).

4.59 (d, IH, H2), 1.34 (m, 12H).

0.89 (t, 3H, CH2CH3). CIMS: 375 (M+1).

Step 3: 1g (7)l, 2: 3,5-di0-i/propylidene-6-deoxy -6-thio-n-hebutyl-α-D-glucofuranose in tetrahydrofuran ( lyd) and add hydrochloric acid (3M, 1ml) dropwise over 10 minutes at o~10''C. added. The reaction mixture was stirred at the same temperature for 1.5 hours and then added with saturated potassium carbonate solution. The solution was neutralized to I)H=9°0. The mixture was extracted with ethyl acetate (100 mυ) and dissolved. The medium was removed using a rotary evaporator. The crude product was obtained by evaporation of the solvent, Et 20: By flash chromatography using hexane = 60, :40 Purified. The yield of pure compound was 0.77 g (86.2%). NMR ( CDC13): δ5.96 (d, IH, Hl), 4.45 (d, IH, H2 ).

0.87 (t, 3H, CH2CH,), CIMS: 335 (M+1), 2 77 (MC, H,).

Example 14 1.2:3.5-C0-isopropylidene-6-0-n-nonyl-α-D-g lucofuranose and l.

2-0-isopropylidene-6-0-n-nonyl-α-D-glucofuranose ( Production process of II[b) 1:1,2:3,5-di-0-isopropylidene-6-0 -n-nonyl-α-D-glucofuranose (Rs = C + sH1a).

1.2: Synthesis of 3.5-di-0-isopropylidene-a-D-glucofuranose (as described in U.S. Pat. No. 4,996.195) with pivaloyl chloride and 1 ．． React with 2-〇-isopropylidene-α-D-glucofuranose at the 6-position followed by cyclization at the 3 and 5 positions with dimethoxypropane and finally the 6-pi This was achieved by hydrolyzing baloyl ester. This compound is similar to that described in Example 7, Step 1. with dry powdered sodium hydroxide and nonyl bromide by exactly the same procedure as Processed.

Step 2: Hydrolyzed by the general method described in Example 6 to obtain partially blocked compound 1.2-0- Isopropylidene-6-0-n-nonyl-α-D-glucofuranose (I[b) I got it.

Example I5 1.2:3.5-C-O-isopropylidene-6-deoxy-6-amino-α- D-glucofuranose and 1,2-0-isopropylidene-6-deoxy-6 -Production process of amino-α-D-glucofuranose 1: I, 2: 3,5-di0- Production of isopropylidene-6-deoxy-6-amino-α-D-glucofuranose Construction 1.2:3,5-di-O-isopropylidene-6-tosyl-α-D-glucofura North (manufactured as described in U.S. Pat. No. 4,996.195) (10 g) and sodium azoate (2,5 eq.) in dry dimethylformamide (100 m The mixture in j) was heated at 80-90°C for 2 hours. Progress of the reaction was monitored by TLC and Monitored by GC. After completion of the reaction, DMF was removed under reduced pressure.

The residue was dissolved in ether (150 mj), water (IX 50 ml), sodium bicarbonate. The organic layer was dried and the solvent was removed. This way The product 1,2:3,5-di-O-isopropylidene-6-deoxy -6-azido-α-D-glucofuranose was determined by GC, TLC and NMR. It was found to be 98% pure. Then 1.2:3.5-di〇-isopropyl Den-6-deoxy-6-azido-α-D-glucofuranose was prepared in Example 9, Step 2. Catalytic reduction with hydrogen using P’d/C was performed using the same procedure as described above. . Pure product, 1,2:3,5-di-0-isopropylidene-6-deoxy-6 The yield of -amino-α-D-glucofuranose was 96%.

Step 2: Hydrolyzed by the general method described in Example 6 to obtain partially blocked compound 1.2-0- Isopropylidene-6-deoxy-6-amino-α-D-glucofuranose was obtained. Ta.

Example 16 A process for producing rhodeoxy-6-amino or 6-amino substituted glucofuranose The general method is 1,2:3,5-di-0-isopropylidene-6-tosyl-α-D-glue. Cofuranose and appropriately substituted amines (2,2 equivalents), e.g. 3-phenyl-1 -Propylamine (I[D) by reacting with 80-90°C for 2-3 hours. It was. The progress of the reaction was followed by TLC and GC. After the completion of the reaction, the product is Dissolved in ethyl acetate (100mN) and saturated sodium bicarbonate solution (2X20mN ), washed with prine (1X20me), dried Mg5O+), and removed the solvent. I left.

Then 1,2:3,5-diO-isopropylidene-6-deoxy-6-amino- 3'=(phenylpropyl)-α-D-glucofuranose is a suitable solvent system. Purified by flash chromatography using .

Step 21 Hydrolyze according to the general method described in Example 6 to obtain partially blocked compound 1.2-0- Isopropylidene-6-deoxy-6-amino-3'-(phenylpropyl)- α-D-glucofuranose was obtained.

Example 17 Pharmacological activity of compounds of formula 3 Compounds of formula 3 were tested for immunomodulatory and antiproliferative effects. Results of these studies are listed in the table data below.

Compounds (IIIe), (I[i), (II[n) and (I[p)] are tested It shows a strong anti-proliferative effect (greater than 50% of the control) together with the compound at dose It was found to inhibit the mouse tile cell blastogenesis response in a dependent manner (Table 15).

A specific example of an inhibitory effect on the ConA-mediated blastogenic response of mouse hypolymphocytes is It is shown in Table 16. Compound (■p) was added to the plate at a concentration ranging from 10 to 750 ug/rnl. The proliferative response of lymphocytes was significantly reduced. The additional immunomodulatory effects of the compounds of the present invention are observed in MLR cultures (Table 17), in which compounds (I’d), (Ill e) and (■i) produce a potent dose-independent inhibition of T lymphocyte proliferation. This was demonstrated. Compound (1[d) showed an effect on the MLR at concentrations ranging from lO to 300 μM. The -potency ratio compounds (IIIe) and (Id) showed a strong inhibitory effect on It was found that it is active only in

Test results on the regulatory effect of the compound of the present invention on mouse peritoneal macrophage production The results are shown in Table 18. Compounds with IL-1 activity of 2.5.10 and 1100 u/- A significant decrease was demonstrated in the medium containing (■i).

Compound (IIIe) was IL-1 at 2.5, 10125 and 1100u/ml. activity was significantly inhibited. Both compounds inhibited IL-1 activity in a dose-independent manner I found out that it was effective.

The compounds of the present invention also include the following monosaccharide = (3S)1.2-0-isopropyl Lyden-α-D-ribohexosu-3-ulose-1,4:3,6-difurano vinegar Methyl 3-0-3-- (N-, N--dimethylamino-n-propyl)-6- Zooxy-D-glucopyranoside 1.2-0-isopropylidene-α-D-ribohexosu-3-urose 1, 4: Production of 3,6-difuranose (IV) 2g of 1.2:5,6-diO-isopropylidene-α-D-liphohexofura Dissolve nor-3-ulose in tetrahydrofuran (2 ml) and heat at 0-5°C. It was cooled to

Aqueous perchloric acid (2 mI!, 30%) was added dropwise over 10 minutes with stirring.

The progress of the reaction was monitored by TLC. Once the hydrolysis is complete (40 minutes), the solution The liquid was neutralized with saturated potassium carbonate solution and extracted with ethyl acetate.

The solvent was removed to obtain a crude product, and Nori Riki Gel rG' (10-40μ) was used. By medium pressure ram chromatography eluting with ether:hexane = 50.5°. and purified. Yield of white crystalline material: 1.48 g (87.6%), m, p, 81~ It was 82°C. IR (KBr): 3390cm-' (broad OH), N o>C=O (stretching), 'H-NMR (CDCa) δ5,97N (d, IH), 4.51-4.41 (m, 4H), 4゜26 (m, IH) , 3.78 (m, IH), 3.07 (d, IH), 1.58 (d, 3H), 1.40 (s.

3H), 13CNMR (CDC12, APT) 2 δ 113.99,110 ．． 93 (C-3 and C-9), 106.98, 84.04, 82.78, 7 1.07 (C-1, C-2, C-4, C-5), 73.56 (C6).

27.22, 27.18 (C-8, C-9). CIMSl, 2-○-isopro Pyridene-α-D-ribohegysos-3-ulose 1.4:3.6-difurano Pharmacological activity of Compound ■ was tested in the BUD-8 skin cell fibroblast assay as described in Example 12. Ta. As can be seen from Tables 19.20 and 21 below, the compounds of the present invention are l, l0125, and l0125, respectively, when compared to control cultures containing no Bud-8 skin cell fibroblast proliferation in cultures containing A significant dose-independent decrease occurred. Cytotoxicity was observed at these concentrations of test compound I couldn't. Cytotoxic effects were observed at the highest tested concentrations (300 ug/in and 750 ug/in b) was approved.

These anti-proliferative effects of PGE2 and LTB4 on Bud-8 skin cell fibroblasts. In this case both pro-inflammatory mediators correlated with a decrease in cyst production (Tables 20 and 21). A significant decrease in quality and quantity is seen at some non-toxic doses of compound II.

Example 20 Methyl 3-0-3”-(If, N”-dimethylamino-n-propyl)-6-zo Production of oxy-D-glucopyranoside (V) -(N'', N--dimethylaminopropyl)-6-0-p-1-luenesulfony Production of Ru α-D-glucofuranose (1) 10 g of 1,2-0-isopropylidene-3-〇-3゛-(dimethylaminopropylidene) Dissolve the α-D-glucofuranose in 30 ml of anhydrous pyridine and place in an ice water bath. The mixture was cooled to 5°C. p-Toluenesulfonylchloride dissolved in 20ml pyridine (6.25 g, 1 eq.) was added to the stirred solution over 30 minutes. Then the reactant was allowed to reach ambient temperature in 1 hour. After a total reaction time of 3 hours, the solvent was removed in vacuo and The residue was dissolved in dichloromethane (200rnl) and the organic phase was dissolved in 25m7 of saturated Washed with sodium carbonate solution. The combined organic phases were washed with water and brine, and Dry over magnesium aqueous sulfate and evaporate to yield 14.3 g (95%) of tosylate. , obtained as a solidified glassy substance by trituration with ether. CIMs: 460 ( M+1).

Step 2: l, 2-0-isopropylidene-6-deoxy-3-0-3--(N- , N=-dimethylaminopropyl)-α-D-glucofuranose (II) 10 g of 1,2-0-isopropylidene-3-0-3-(N-,N'~dimethylidene) ruaminopropyl)-6-〇　-p　-1-luenesulfonyl-α-D-gluco Dissolve furanose (I) in 60 ml of freshly distilled tetrahydrofuran and mix. The mixture was gradually added to 50 ml of 1.7 g (2 equivalents) of lithium aluminum halide. The mixture was added to a THF stirred suspension. After the addition was complete, the mixture was refluxed for 2 hours.

Then cool in a water bath and remove excess lithium aluminum halide with 2 ml of water, then Quenched with 5rnl of 15% sodium hydroxide solution. The mixture is celite The filtrate was evaporated to 5.91 g (94%) of 1. 2-〇-isoprop Ropylidene-6-deoxy-3-0-:3”-(N-,N-dimethylaminoproxypropylene) ropyru)-α-D-glucofuranose (n) product was obtained. This product must be purified. It was used in the next step without removing it. CIMS: 290 (M+1) NMR (CDCL): δ5.92 (d, IH.

H,), 4.55 (d, tH,) (2), 3.95 (m.

2H, H, and H4), 3, 83 (m, IH.

Production of dimethylaminopropyl)-D-glucobylanose (Ill) 3gc7) 1.2-0-isopropylidene-3-0-3-xyα-D-gluco Furanose (2) was dissolved in IO-tetrahydrofuran, and 5-3N hydrochloric acid was added. added.

The mixture was stirred at 50°C for 2 hours, cooled and diluted with 20% sodium hydroxide solution. It was peaceful. The solvent was removed in vacuo and the residue was extracted with hot ethyl acetate. The remaining organic phase is sulfuric acid. Drying over magnesium and evaporation yielded 2.2 g (85.4%) of free sugar. 6 -dioxy-3-0-3--(N-.

N'-dimethylaminopropyl)-D-glucobylanose (3) is directly passed to the next step. used for.

Step 4: Methyl 3-O-1-(N-, N=-dimethylaminopropyl)-6-zo Production of oxy-D-glucopyranoside (V) 6-dioxy-3-0-1-(N'', N-dimethylaminopropylene-D~g Lucobilanose (I[) (1°8g) containing about 5% by weight of anhydrous hydrogen chloride LOm(!) was dissolved in anhydrous methanol. After 2.5 h at ambient temperature, methanol was evaporated and the residue was neutralized with saturated potassium carbonate and extracted several times with dichloromethane. . The combined extracts were dried over magnesium sulfate and evaporated to obtain the crude product, which was flashed. Soy chromatography (100% ethyl acetate, then 20% methane in ethyl acetate) 1.64 g (86.5%) of methyl 3-0-3'-(N =.

N'-dimethylamino-n-propyl)-6-zooxy-D-glucopyranoside The compound was obtained. 'HNMR indicates the presence of a mixture of α- and β-isomers in a 6:4 ratio showed that.

Methyl-3-0-3-1(N-,N″-dimethylamino-n-propyl)-6- Pharmacological activity of zooxy-D-glucopyranoside (V) Methyl 3-0-3-- (N-,N--dimethylamino-n-propyl) of the present invention )-6-zooxy-D-glucopyranoside is G5-109-V-20 human skin demonstrated an inhibitory effect on cell fibroblasts.

Compounds that inhibit fibroblast proliferation have been shown to be effective in chronic skin diseases such as psoriasis and osteoarthritis. It is used as a skin disease drug for TF3 treatment of autoimmune diseases that cause joint inflammation. Possibility of use. Antiproliferative activity may be associated with other tissues such as the lining of blood vessels, or Nodules can be observed whose uncontrolled proliferation produces disease and thereby prevents latent disease. Expanding the scope of application to the proliferation ability of human GS-109-V-20 skin fibroblasts Methyl-3-0-3--(N-,N''-dimethylamino-n-propyl)-6- The effect of zooxy-D-glucopyranoside was determined using 3H-thymidine incorporation assay. It was measured using Cultured skin cells were removed from the surface of the tissue culture flask using Teflon clay. Separation was performed mechanically using a vacuum cleaner.

Cells were washed, resuspended in incubation medium, and viability determined. Next this IXIO3 cell density 10.1ml/microtiter in triplicate Re-test and plate. Methyl 3-O-3--(N-,N--di Methylamino-n-propyl)-6-deogycy D-glucopyranoside compound 0.1 ml of incubation medium was added.

After 3 days of culture, I#uCi 3H-thymidine was added to each culture in the microtiter plate. It was added to Kuhomi in a volume of 50 μl. After 18 hours, each GS-109-V-20 cal Char is examined morphologically for evidence of drug-induced toxicity such as cell rounding or granulation. I tried it. Next, 3H-thymidine-pulsed cells are precipitated, and the amount of 3H-thymidine uptake is were counted using a liquid scintillation counter.

Methyl: 3-0-1-(N", N--dimethylamino-n-propyl)-6- Zooxy-D-glucopyranocytes are not sterilized by filtration and are strongly sonicated. More directly suspended in the medium. The dose range for this compound is G5-109-V-20 This compound was used to determine the effect of this compound on cell proliferation. The following doses were used: ・R) I: Ou glml Group 7: lOug/mj' Group 2: 0.00 tug/rd group 8: 25 ug/m1R3: 0.01 u glml Group 9: 100Hg/m1gLi: 0.　I　　glml　Control group・ Group 5: l u glml Control: 2 x 10-’M indomethanone J! $6: 2. 5 u glml Control: 2 Xl0-’MDGA concrete Method/Incubation medium The incubation medium used for culturing GS-109-V-20 cells was 10% Tallow baby serum, 100 u g/ml streptomycin, 100 U/ml penicillium Phosphorus, 0.2M Hepes buffer solution, 5×I O-’M 2-mercaptoe RPMI-1640 medium containing tanol and 2mM glutamine.

Specific method: human skin cells Skin cell fibroblast cell line to human 1, G5-109-V-20 is American Obtained from Type Culture Collection. this is gardner syndrome, an autosomal dominant condition that predisposes to cancer and multiple polyps of the colon. A fibroblast-like cell line originally derived from the skin of an 18-year-old Caucasian man. There is (American Type Culture Co11ection.

Catalog of All Lines and Hybridoma s, 6th edition, 150.1988). These cells can be normal or transformed. In contrast, fibroblasts are considered to be in an initiated state and are normal. are selected for use because they have a wider population doubling time and survival period than cells. Ta.

In this respect, they are more widespread than normal fibroblasts, but are immortalized transformed tumor cells. The biological characteristics of psoriatic or rheumatoid synovial fluid fibroblasts, which do not proliferate as extensively as the Reflect closely.

G5-109-V-20 cell numbers were measured at 37°C in an atmosphere containing 5% CO□ in the air. , grown in 25 cm2 flasks for use in the described assays. Approximately 4 Cells were transferred at ˜5 day intervals or when confluent. This is a tribulation Detach the cells by washing, wash, and place the cells at a lower density in a new tissue culture flask. This was achieved by reseeding.

Statistical analysis of data The Studen I-Test compares to values for skin cells cultured in the presence of the test compound. It was used to measure the significance of the difference in value difference in the irradiation medium alone.

Methyl 3-0-3-- (N-,N--dimethylamino-n-propyl) of the present invention )-Proliferative ability of skin cells cultured in the presence of 6-zooxy-D-glucobyranosodide The difference between that observed in the and control cultures can be seen in the data shown in Table 22. Wear.

A significant inhibitory effect was caused by methyl 3-0-3--(N-,N--dimethylamino-n- non-dose-dependent effects on cultures supplemented with (propyl)-6-zooxy-D-glucopyranoside. It was observed using a chronological method. Inhibition was similar despite the concentration used without evidence of cytotoxicity. It is important to note that this compound may have these effects through a novel mechanism. It can be suggested that the

The compounds of the present invention represented by formulas I, ■, ■, ■ and ■ are suitable for dry and atopic skin. Inflammations such as arthritis, osteoarthritis, osteoarthritis, dermatosis, and systemic It is used in the treatment of mammals suffering from cancer and/or autoimmune diseases. these compounds The proliferative activity of has led to its application as a therapeutic agent for the treatment of unregulated proliferation of specific cell types. Expand your potential range. These valuable pharmacological properties make the compounds of the present invention Its physiologically acceptable salts may be used, for example, in the treatment of chronic inflammatory rheumatic diseases. Particularly suitable for use as active compound in pharmaceutical compositions.

The compounds may be present alone as microcapsules, in admixture with each other, or in an acceptable pharmaceutical composition. It can be administered in combination with a drug carrier. Thus, the present invention provides at least one embodiment of the present invention. A pharmaceutical composition comprising an effective amount of the compound, with or without a pharmaceutically acceptable carrier. It also relates to things. Where appropriate, compounds containing amino functionality may be acid addition salts.

A preferred acid addition salt is the hydrochloride.

The present invention also encompasses methods of treating animals or humans suffering from inflammatory and/or autoimmune diseases. Contains. This method is effective in preparing at least one compound of the invention or an acid addition salt thereof. administering the amount to an animal or human with or without a pharmaceutically acceptable carrier. Including. The compositions of the invention may be administered orally, topically, enterally, internally, or as desired. If necessary, it can be administered parenterally. Oral administration is preferred.

Suitable solid or liquid formulations include granules, powders, coated tablets, etc. agents, microcapsules, herbal medicines, tablets, elixirs, suspensions, emuls John, drops or injection solutions. Sustained-release formulations of the active compound can also be used. . These formulations contain excipients, disintegrants, binders, coatings, leavening agents, lubricants, or lubricants. It may also contain additives such as agents, flavors, sweeteners or solubilizers. Shiba The additives used are, for example, magnesium carbonate, titanium dioxide, lactose, and manganese. Nitol and other sugars, talc, lactalbumin, gelatin, starch, cellulose base and its derivatives, animal and vegetable oils, polyethylene glycols, polysols bases, and solvents such as sterile water, and monohydric and polyhydric alcohols, i.e. It's glycerol.

Preferably, the pharmaceutical composition is manufactured and administered in dosage units. Each unit is according to the invention and/or at least one physiologically acceptable compound of It contains a dose of its acid addition salt as the active ingredient. The dose is about 1-100μ, preferably Preferably, the amount may be in the range of 10 to 200 g/kg body weight/day. in vitro test In experiments, the effective amount to achieve 50% inhibition of cultured cells is approximately 1-200 ug/200 ug of culture medium. ml, preferably in the range of 10 to 100 ug'/mj'.

international search report international search report Continuation of front page (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IT, LU, NL, SE), AU, CA, HU, JP, KR, No. 5O (72) Inventors Wistler, Roy, E. Le.

West, Indiana, United States 47906 Lahuietz, Laura le drive 320 (72) Inventor: Thomas, Albert, Bui.

Evergreen Hills, Vernon Hills, Illinois 60061, United States venue

Claims (1)

[Claims] 1. Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, A is H, methyl or ethyl, and R1 and R2 are H, methyl, ethyl, C5-C10 alkenyl or together Forms an isopropylidene ring, R3 is H, C5-C10 alkyl, C5-C10 alkenyl, C5-C10 alkynyl, 2-octyne, benzyl, or or C5-C10 ester, and R4 is H, C5-C10 alkyl, C5-C10 alkenyl, C5-C10 alkyl. quinyl, 2-octyne, benzyl, or C5-C10 ester) fructofuranose compound. 2. A is methyl, R1 and R2 are each ethyl, cis-2-octane, or together iso Forms a propylidene ring, R3 is H, C7H15, cis-2-octene, tran cis-2-octene, 2-octyne, or octanoyl, and R4 is H, C7H15, cis-2-octene, trans-2-octene, 2-octene, 2. The compound according to claim 1, which is cutin or octanoyl. 3. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 4. A method of treating an animal or human suffering from an inflammatory and/or autoimmune disease, comprising administering an effective amount of a compound according to claim 1. 5. Methyl 1,3-O-isobropylidene-6-O-hebutyl-α-D-frac Tofuranoside, methyl 1,3-di-O-ethyl-6-O-hebutyl-α-D-ph Lactofuranoside, methyl 1,3-O-isopropylidene-4-O-heptyl-α-D-fructof Ranoside, methyl 1,3-O-isopropylidene-4,6-di-O-(2-octenyl)-α-D-fructofuranoside, methyl 1,3-O-isopropylidene-4,6-di- O-(trans-2-octenyl)-α-D-fructofuranoside, Methyl 1,3-O-isopropylidene-4,6-di-O-(cis,2-octenyl) )-α-D-fructofuranoside, Methyl 1,6-di-O-(cis,2-octenyl)-α-D-fructofuranoside Methyl 1,3-O-isopropylidene-4-O-octanoyl-α-D-frac Tofuranoside, methyl 1,3-O-isopropylidene-6-O-octanoyl-α-D-fructofuranoside, methyl 1,3-O-isopropylidene-4,6-di-O-octanoyl-α-D- fructofuranoside, and 2,3-O-isobropylidene-4-O-hebutyl-β,D-fructofurano 2. A compound according to claim 1, selected from: 6. 6. A pharmaceutical composition comprising a compound according to claim 5 and a pharmaceutically acceptable carrier. 7. A method of treating an animal or human suffering from an inflammatory and/or autoimmune disease, comprising administering an effective amount of a compound according to claim 5. 8. Formula 2 ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, or 4, and Y is cyano, pyrrolyl, pyrrolidinyl, methylpyrrolidinyl, pyrrolidinyl, Pecorinyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxy Sazolyl, oxazolidinyl, isoxazolyl, isoozazolidinyl, imida Zolidinyl, piperidinyl, piperazinyl, morpholinyl, O(CH2)3N(CH3)2, (C5-C10 alkoxy), CH2CH(CH2)CH2N(CH3)2, CH2CH2N(C5-C10 alkoxy) or (C3-C7 alkenyl)), or X1 is NH and R5 is C2-C10 alkyl, or CnH2nY (wherein n=1, 2, 3 or is 4, and Y is hydroxy, cyano, pyrrolyl, pyrrolidinyl, methylpyrrolidinyl, pipecolinyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl. R6 and R7 is hydrogen or forms an isopropylidene ring. 9. 9. A compound according to claim 8, wherein R6 and R7 together form an isopropylidene ring. 10. 10. A compound according to claim 9, wherein the compound is a glycofuranose. 11. 10. A compound according to claim 9, wherein the compound is an allofuranose. 12. 9. A compound according to claim 8, wherein R6 and R7 are each hydrogen. 13. 13. A compound according to claim 12, wherein the compound is glucofuranose. 14. 13. A compound according to claim 12, wherein the compound is an allofuranose. 15.1,2-O-isopropylidene-3-O-n-dodecyl-α-D-glucofuranose, 1,2-O-isopropylidene-3-O-n-pentadecyl-α-D-glucofuranose, 1,2-O-isopropylidene-3-O-n-otakudecyl-α-D-glucof Lanose, 1,2-O-isopropylidene-3-O-3'-(phenylpropyl)-α-D-glucofuranose, 1,2:5,6-di-O-isopropylidene-3-O-3 '-(morpholinylpropyl)-α-D-glucofuranose, 1,2:5,6-di-O-isopropylidene-3-O-3'-n-propoxy-n-hebutyl-α-D- Glucofuranose, 1,2-O-isopropylidene-3-O-3'-n-propoxy-n-hebutyl-α-D-glucofuranose, 1,2:5,6-di-O-isopropylidene-3 -O-2'-(ethylpyrrolidyl)-α-D-glucofuranose, 1,2-O-isopropylidene-3-O-2'-(ethylpyrrolidyl)-α-D-glucofuranose, 1, 2-O-isopropylidene-3-O-3'-(propylidene) (1'-ol)-α-D-glucofuranose, 1,2:5,6-di-O-y Sopropylidene-3-deoxy-3-amino-(3'-hydroxy-n-propylidene) )-α-D-glucofuranose, 1,2-O-isopropylidene-3-O-3′-(N′,N′-dimethylamine-n-propyl)-α-D-allofuranose, 1, 2;5,6-di-O-isopropylidene-3-O-3'-(phenylpropyl)-α-D-allofuranose, 1,2-O-isopropylidene-3-deoxy-3-N-3 ′(N′, N′-di methylamino-n-propyl)-α-D-allofuranose, 1,2-O-isopropylidene-3-deoxy-3-N-3'-(phenylpropylidene) pyru)-α-D-allofuranose, 1,2-O-isopropylidene-3-deoxy-3-amino-hebutyl-α-D-allofuranose, 1,2-O-isopropylidene-3-deoxy-3 -amino-2'-(propan-1-ol)-α-D-glucofuranose, 1,2-O-isopropylidene-3-deoxy-3-amino-n-hebutyl-α-D-glucofuranose, and 1,2-O-isopropylidene-3-deoxy-3-amino-3'-(phenyl 10. A compound according to claim 9 selected from: (propyl)-α-D-glucofuranose. 16. 10. A pharmaceutical composition comprising a compound according to claim 9 and a pharmaceutically acceptable carrier. 17. inflammation and/or is a method of treating animals or humans suffering from autoimmune diseases. 18. 16. A pharmaceutical composition comprising a compound according to claim 15 and a pharmaceutically acceptable carrier. 19. 16. Inflammation and/or or methods of treating animals or humans suffering from autoimmune diseases. 20. Formula III ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) [In the formula, is 4, and Y is phenyl, cyano, pyrrolyl, methylpyrrolidinyl, pipecoli Nyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl , oxazolidinyl, isoxazolyl, isoxazolidinyl, imidazoli or X2 is NH; R8 is H; or CnH2nY (wherein n is 1, 2, 3 or 4 and Y is OH, cyano, pyrrolyl, pyrrolidinyl, methylpyrrolidinyl, pipecolinyl, midazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, oxazolyl sazolidinyl, isoxazolyl, isoxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, O(CH2)3N(CH2)2 or (C5-C10 alkoxy) or phenyl or X2 is S and R8 is C5-C10 alkyl, or CnH2Y, where n is 1, 2, 3 or is 4, and Y is OH, phenyl, cyano, pyrrolyl, pyrrolidinyl, methylpyrrolyl. loridinyl, pipecolinyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazo Lysinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazo and R9 and R10 are hydrogen or form an isopropylidene group. A compound that has the following properties: 21. 21. A compound according to claim 20, wherein the compound is glucofuranose. 22. 21. A compound according to claim 20, wherein the compound is an allofuranose. 23.1,2-O-isopropylidene-6-O-hebutyl-α-D-glucofura North, 1,2-O-isopropylidene-6-O-nonyl-α-D-glucofuranose, 1,2-O-isopropylidene-6-O-dodecyl-α-D-glucofuranose, 1,2- O-isopropylidene-6-O-pentadecyl-α-D-glucofurano 1,2-O-isopropylidene-6-O-3'-(phenylpropyl)-α-D-glucofuranose, 1,2-O-isopropylidene-6-O-3'-(N' , N'-dimethylamino-n-propyl)-α-D-glucofuranose, 1,2:3,5-di-O-isopropylidene-6-O-methoxyoctyl-α-D-glucofuranose, 1, 2-O-isopropylidene-6-O-propionite Lyle-α-D-glucofuranose, 1,2:3,5-di-O-isopropylidene-6-deoxy-6-amino-[2′-aminoethyl-2′′-(N′-methylpyrrolidyl )-α-D-glucofura North, 1,2:3,5-di-O-isopropylidene-6-deoxy-6-amino-3'-(phenylpropyl)-α-D-glucofructose, 1,2:3,5-di- O-isopropylidene-6-deoxy-6-N-(N'-propylpipecolinyl)-α-D-glucofuranose, 1,2:3.5-di-O-isopropylidene-6-deoxy-6 -amino-eth xyethanol-α-D-glucofuranose, 1,2-O-isopropylidene-6-deoxy-6-amino-3'-(propan-1'-ol)-α-D-glucofuranose, 1,2: 3,5-di-O-isopropylidene-6-deoxy-6-thio-n-he Butyl-α-D-glucofuranose, 1,2-O-isopropylidene-6-deoxy-6-thio-n-hebutyl-α-D-glucofuranose, 1,2:3,5-di-O-isopropylene Liden-6-deo xy-6-thio-2'-(ethylpyrrolidyl)-α-D-glucofuranose, 1,2-O-isopropylidene-6-deoxy-6-thio-2'-(ethylpyrrolidyl) lysyl)-α-D-glucofuranose, 1,2:3,5-di-O-isopropylidene-6-deoxy-6-thio-3'- (N',N'-dimethyl-aminoisobutyl)- α-D-glucofuranose, 1,2:3,5-di-O-isopropylidene-6-deoxy-6-thio-3′-(propan-1′-ol)-α-D-glucofuranose, and 1,2-O-isopropylidene-6-deoxy-6-thio-3'-(phenylpropylidene) 14. The compound according to claim 13, selected from: 24. 21. A pharmaceutical composition comprising a compound according to claim 20 and a pharmaceutically acceptable carrier. 25. 20. Inflammation and/or or methods of treating animals or humans suffering from autoimmune diseases. 26. 24. A pharmaceutical composition comprising a compound according to claim 23 and a pharmaceutically acceptable carrier. 27. 24. Inflammation and/or or methods of treating animals or humans suffering from autoimmune diseases. 28. (3S) 1,2-O-isopropylidene-α-D-ribohexos-3-ulose-1,4:3,6-difuranose, and methyl 3-O-3'-(N',N'-dimethylamino -n-propyl)-6-de A compound selected from oxy-D-glucopyranoside. 29. 29. A pharmaceutical composition comprising a compound according to claim 28 and a pharmaceutically acceptable carrier. 30. 29. Inflammation and/or or methods of treating animals or humans suffering from autoimmune diseases.