GB2133399A - alpha alpha -Trehalose-6,6'-middle chained aliphatic acid diester and a pharmaceutical agent containing the same - Google Patents
alpha alpha -Trehalose-6,6'-middle chained aliphatic acid diester and a pharmaceutical agent containing the same Download PDFInfo
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- GB2133399A GB2133399A GB08228817A GB8228817A GB2133399A GB 2133399 A GB2133399 A GB 2133399A GB 08228817 A GB08228817 A GB 08228817A GB 8228817 A GB8228817 A GB 8228817A GB 2133399 A GB2133399 A GB 2133399A
- Authority
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- United Kingdom
- Prior art keywords
- alpha
- trehalose
- aliphatic acid
- acid diester
- chained aliphatic
- Prior art date
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- 239000002253 acid Substances 0.000 title claims abstract description 35
- 125000001931 aliphatic group Chemical group 0.000 title claims abstract description 32
- 150000005690 diesters Chemical class 0.000 title claims abstract description 29
- 239000008177 pharmaceutical agent Substances 0.000 title claims abstract description 6
- 239000004615 ingredient Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 abstract description 42
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 abstract description 17
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 abstract description 16
- 239000003054 catalyst Substances 0.000 abstract description 8
- 230000003115 biocidal effect Effects 0.000 abstract description 4
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 abstract description 3
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 230000005951 type IV hypersensitivity Effects 0.000 abstract description 3
- 208000027930 type IV hypersensitivity disease Diseases 0.000 abstract description 3
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
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- 238000006243 chemical reaction Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
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- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
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- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 244000299461 Theobroma cacao Species 0.000 description 2
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 2
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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- 235000001046 cacaotero Nutrition 0.000 description 2
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- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 230000022534 cell killing Effects 0.000 description 2
- -1 chloro- Chemical class 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
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- 239000007788 liquid Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000191938 Micrococcus luteus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- IPIVAXLHTVNRBS-UHFFFAOYSA-N decanoyl chloride Chemical compound CCCCCCCCCC(Cl)=O IPIVAXLHTVNRBS-UHFFFAOYSA-N 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 235000014593 oils and fats Nutrition 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
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- 102220079670 rs759826252 Human genes 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
- C07H13/06—Fatty acids
Abstract
Disclosed herein is a novel alpha , alpha -trehalose-6,6'-middle chained aliphatic acid diester represented by the following formula (I): <IMAGE> in which n represents an integer from 6 to 10. This compound is produced, for instance, by converting alpha , alpha -trehalose into 2,3,2',3'-tetra-o-benzyl- alpha , alpha -trehalose then reacting it with a middle chained aliphatic acid or its active derivative into a novel intermediate 2,3,2',3'-tetra-o- benzyl- alpha , alpha -trehalose-6,6'-middle chained aliphatic acid diester and further reducing de-benzylating it using a reduction catalyst. The compound according to the invention has an excellent antitumor activity, antibiotic activity and action for delayed-type hypersensitivity, and is useful for pharmaceuticals. Pharmaceutical agents containing an alpha , alpha -trehalose-6,6'-middle chained aliphatic acid diester of the formula (I) as an effective ingredient are also disclosed.
Description
SPECIFICATION α,α-terhalose-6,6'-middle chained aliphatic acid diester and a pharmaceutical agent containing the same (i) Field of the Invention:
This invention relates to a novel a,a-trehalose-6,6'-middle chained aliphatic acid diester and a pharmaceutical agent containing the same as an effective ingredient.
(ii) Description of the Prior Art: α,α-terhalose is a compound belonging to a so-called disacharide composed on two glucose molecules and it is broadly distributed in nature. Various derivatives of this compound have been synthesized and pharmacological activities thereof have been examined. For instance, it has been reported that a mixture of various diesters in which the aliphatic acids are bonded at different positions shows an antitumor activity.
SUMMARY OF THE INVENTION
In the course of synthesizing various 6,6'-aliphatic acid diesters of a,aArehalose and studying their pharmacological effects, the present inventors have found that an α,α-terhalose-6,6'-middle chained aliphatic acid diester represented by the following formula (I):
in which n represents an integer from 6 to 10 has an excellent antitumor activity, antibiotic activity and action for delayed-type hypersensitivity, and is useful for pharmaceuticals, and thus accomplished the present invention.
Accordingly, it is an object of this invention to provide a novel ci',a-trehalose-6,6'-middle chained aliphatic acid diester represented by the above formula (I).
Another object of this invention is to provide a pharmaceutical agent containing as an effective ingredient an a,o-trehalose-,6'-middle chained aliphatic acid diester represented by the above formula (1).
DETAILED DESCRIPTION OF THE INVENTION
AND PREFERRED EMBODIMENTS
The α,α-terhalose-6,6'- middle chained aliphatic acid diester (I) (hereinafter simply referred to as a trehalose middle chained aliphatic acid diester) according to this invention can be produced, for instance, in accordance with the following reaction scheme, by converting sx,-trehaiose (II) into 2,3,2',3'-tetra-o-benzyl-α,α-terhalose (III) then reacting it with a middle chained aliphatic acid (IV) or its active derivative into a novel intermediate 2,3,2',3'-tetra-o-benzyl-α,α-terhalose-6,6'-middle chained aliphatic acid diester (V) and further reducing de-benzylating it using a reduction catalyst::
ca3 ( CE 2 ) ncr30 Os reduction catalyst EloXL OOC (Ce2) CH3 reduction catalyst HO OH OH OH in which Bn represents a benzyl group and n has the same meaning as stated above.
In the above process, the 2,3,2',3'-tetra-o-benzyl-α,α-terhalose represented by the formula (III) is prepared by reacting the trehalose represented by the formula (II) with benzaldehyde in a conventional manner to form 4,6,4',6'-di-o-benzylidene-α,α-terhalose and then reacting it with benzylchloride into a 2,3,2',3'-tetra-o-benzyl derivative and further reacting the same with an acid.
The reaction between the compound (III) and the middle chained aliphatic acid (IV) or its active derivatives is carried out under the usual condition of esterifying reaction by reacting the middle chained aliphatic acid (IV) or its active derivative in a molar ratio, preferably of, 1.8-2.4 mole per one mole of the compound (III) under the pressure of an acid remover such as pyridine and triethylamine.
The reaction is preferably conducted under the presence or absence of a solvent between 0 C under ice cooled to 300C for 1-24 hours.
The solvent used herein includes, for example, methylene chloride, chloroform, benzene, toluene, ether, tetrahydrofuran and dioxane.
The reducing de-benzylating reaction for the thus obtained compound (V) is carried out through catalyst, preferably, in 0.5-10 mol per one mol of the compound (V) in a suitable solvent.
The reduction catalyst includes, for example, palladium black, palladium-carbon and Raney nickel.
The solvent used herein includes, for example, alcohols such as methanol, ethanol and isopropanol;
halogenated compounds such as chloroform and methylene chloride, as well as a mixture of these
solvents.
Pharmacological activities of the trehalose middle chained aliphatic acid diester (I) according to this invention are shown below.
(1) Cell-killing activity of trehalose middle chained aliphatic acid diester:
(a) Cells of Leukemia L-51 78Y were used and conditioned to be 105 cells/ml in RPMI 1640
medium container 10% ox fetal serum, and specimens were applied into the medium to a
predetermined concentration. After 48 hours' culture in an incubator at 370C under 5% CO2, the
number of living cells were counted under microscope and compared with a control group to determine
the multiplication factors. They were plotted on a logarithmic probability paper and values for IC50 were
determined based on the curve thus obtained. The concentration for each specimen was 25, 50, 100, 200 and 400 1ig/ml respectively.
The results are shown in Table 1.
TABLE 1
Test compound (indicated by the number of Cso n in formula (I) ) (lig/ml) Compounds of 6 350 the Invention 8 255 10 93 Comparative 14 400 Compounds 20 A00 (b) Cell-killing activities of the trehalose middle chained aliphatic acid diester against the cells of
Leukemia L-1 210 were examined in the same manner as in (a). The results are as shown in Table 2.
TABLE 2
Test compound (indicated by the number of 1050 n in formula (I)) (,ug/ml) Compounds of 6 350 the Invention 8 150 10 210 Comparative 14 > 1000 Compounds 20 > 1000 (2) Anticancer activities of trehalose middle chained aliphatic acid diester:
Std-ddy male mice of 5-week age were used as six mice per group and cancer cells of sarcoma 1 80 were transplanted by 5 x 106 cells into the peritoneal cavity of each mouse.From after 24 hours, a test compound suspended in 30% propylene glycol was intraperitoneally administered in an amount of 1 50 mg/kg once per day continuously for 5 days. 7 days after the transplantation of the cancer cells, abdominal ascites were sampled to determine the amount of abdominal ascites and the cell ratio. The tumor growth ratio (T/C (%)) was determined by using TPCV (total pack cell volume) which is the product of the amount of abdominal ascites and the cell ratio from the formula specified below, and the anitcancer activity of the test compound was judged. The results are shown in Table 3.
TPCV for treated group T/C(%) = x 100
TPCV for control group TABLE 3
Test compound (indicated by Tumor growth the number of ratio n in formula (I)) T/C (%) Compounds of 6 9.1 the Invention 8 1.9 10 6.2 Comparative 14 37,7 Compounds 20 55.8 Control group 100 As described above, the trehalose middle chained aliphatic acid diester has the anticancer activity, which is remarkably stronger than that of the corresponding compounds having 1 6-22 carbon atoms.
(3) Antimicrobial Activity
The minimal inhibitory concentrations (MIC) of the compounds of the invention were examined against various bacteria. The results are shown in Table 4. The tests were conducted according to the
MIC measurement method authorized by Japan Society of Chemotherapy and, for the culture medium the Mueller-Hinton medium (Difco Laboratories, U.S.A.) was employed. The test compounds were dissolved in 25% DMSO to have the concentration of 1 mg/ml, thereafter dilluted to the predesignated concentration with sterile distilled water.
Results:
TABLE 4
MIC value (tg/ml) Test Compound; present comparative indicated by the number of invention product L ninformula(l) wormula (I) Bacterialit7ains s s 14 20 Bacillus subtilis ATCC 6633 50 12.5 > 100 > 100 Staphylococcus aureus ATCC 50 12.5 owl00 > 100 6538P Staphylococcus epidermides 100 00 > 100 > 100 ATCC 12228 Streptococcus faecalis var. 50 > 100 6100 > 100 gimogenes IFO 3939 Sarcina lutea ATCC 9341 1 100 I > 100 > 100 > 100 (4) Action on Delayed-type Hypersensitivity:
Several groups of ICR 5 weeks old female mice, each group consisting of 10 mice, were provided and subcutaneously injected with sheep red blood cells (SRBC) of 3 x 109 cells/ml by 0.05 ml/mouse at the footpads of right hind paw, after which, test compounds were immediately injected intraperitoneally* (0 day). Four days thereafter, the same amount of SRBC (0.05 ml/mouse) was subcutaneously injected to each mouse at the footpad of the left hind paw and, after further 24 hours, the thickness of the left footpad was measured with slide calipers.
Other groups which were administered with physiological saline solution in place of test
compounds were used as controls and, further other groups which were subjected to the 2nd injection
alone were used as bases.
The swelling ratio of footpad, was obtained from the following equation: T-B Swelling ration (%) = x 100 C-B in which T, C and B represent the thickness of the footpad of the left hind paw of the test groups, control
groups, and the base groups respectively.
The results are shown in Table 5.
Results:
TABLE 5
Test Compound; indicated by the number Thickness of footpad Swelling ratio of n in formula (I) (mm) (%) 6 3.71 126 Compounds of the invention 8 3.75 133 10 3.82 138 Comparative 14 3.61 109 Compounds 20 3.55 98 Control 3.56 100 *Dose: 100 mg/kg, Vehicle: normal saline - 1 drop of Tween 80.
The trehalose middle chained aliphatic acid diester according to this invention is an almost nontoxic and thus safe compound as apparent from the facts, for example, that sucrose aliphatic acid esters similar to the present compound are allowed as food additives and broadly used as non-deleterious surfactants in the field of foods, medicines, cosmetics or the likes.
Further, the compound of this invention can be formed into various types of preparations depending on the manner of application such as oral or non-oral adminstration, for example, oral preparations such as tablets, capsules, powder, granules and liquids, as well as non-oral formulations such as injection solution for subcutaneous, intramuscular or intravenous injection, transfusion and suppository and the like.
The above-mentioned preparations can be made according to any methods known per se. That is, the trehalose middle chained aliphatic acid diester can be formed into tablets, capsules, powder or granules by formulating the compound optionally in combination with excipients such as starch, lactose and mannitol; binders such as sodium carboxymethyl cellulose and hydroxypropyl cellulose; disintegrators such as crystalline cellulose and calcium carboxymethyl cellulose; lubricants such as talc and magnesium stearate; fluidity improvers such as light anhydrous silicic acid and the like. Further, liquids and injections can be prepared by dissolving the trehalose middie chained aliphatic acid diester into vegetable oils or the likes to form an oil-soluble injection solution, or by dissolving or suspending the compound by a conventional manner into water or the like to form a syrup.Furthermore, suppositories can be prepared by dispersing the compound in ordinarily employed substrates, for example, cacao butter, synthetic oils and fats or the like and then solidifying them.
Although the amount for the application of the trehalose middle chained aliphatic acid diester according to this invention varies depending on the degree of the disease, it is preferably administered for adult in a dosage of 0.1-2000 mg/kg for oral administration and 0.05-1000 mg/kg for non-oral administration, all at one or portionwise for several times per one day.
This invention is to be described by way of the following examples.
EXAMPLE 1
To 2.11 g of 2,3,2',3'-tetra-o-benzyl-a,-trehalose were added pyridine 20 ml and dichioromethane 20 ml and dissolved, to which 1.26 g of decanoyl chloride were added dropwise under stirring while ice cooled at OOC. After 30 minus stirring, the temperature was raised to room temperature and stirring was continued for further one hour. The reaction mixture thus obtained was charged into ice-water and extracted with chloroform, which was then distilled off under reduced pressure. The residue was purified by way of silica gel column chromatography to obtain 2.79 g of 2,3,2',3'-tetra-o benzyl-6,6'-di-o-decanoyl-a',ct'-trehalose as a colorless oily product (yield: 92%).
EXAMPLE 2
2.67 g of 2,3,2',3'-tetra-o-benzyl -6,6'-di-o-decanoyl-a-trehalose obtained in Example 1 was dissolved in 40 ml of chlorofor?in and the solution was subjected to catalytic reduction for one hour by adding 1.00 g of palladium black as a catalyst and introducing hydrogen gas into the solution.
The reaction solution thus obtained was filtered to eliminate the catalyst and the filtrates were concentrated and dried to solid under reduced pressure. The residue was crystallized from isopropanol to obtain 1.06g of 6,6'-di-o-decanoyl-a,aArehalose as colorless needle crystals (yield: 62%).
EXAMPLE 3
The compounds shown in Table 6 below were obtained in the same manner as in Example 1. The
Table 6 also contains the compound obtained in Example 1.
TABLE 6
Bn: Benzyl
c=1.0 [α]D25 IRmaxKBrcm-1 chloro-) R mp ( C) form NMR(60MHz, CDCl3) #ppm CH3(CH2)6 Oily + 82.3 1735 0.86t(6H), 1.26m(20H), 2.26t Compound (4H, J=7Hz), 3.2-4.5m(12H), 5.15d (2H, J=3.5Hz), 4.65s(4H), 4.86d CH3(CH2)8 Oily + 65.8 1740 0.88t (6H), 1.25m(28H), 2.30t Compound (4H, J=7Hz), 3.2-4.5m(12H), 5.20d (2H, J=3.5Hz), 4.71s(4H), 4.92d (4H, 7.1-7.6m(20H) CH3(CH2)10 Oily + 66.5 1740 0.88t (6H), 1.21m(36H), 2.23t Compound (4H, J=7Hz), 3.2-4.4m(12H), 5.11d (2H, J=3.5Hz), 4.62s(4H), 4.81d (4H), 6.9-7.3m(20H) EXAMPLE 4
The compounds shown in Table 7 were obtained in the same manner as in Example 2. The Table 7 also contains the compounds Qbtained in Example 2. TABLE 7
c=1.0 [α;]D20= IR#maxKBrcm-1 (chloro-) R mp ( C) form NMR(60MHz, CDCl3) #ppm CH3(CH2)6 170-171 + 116.6 1735 0.90t (6H), 1.12m(20H), 2.28t (4H, J=7Hz), 3.8-5.1m(12H) 5.72d(2H, J=3.5Hz), 6.12s(6H) CH3(CH2)8 157-163 + 108.8 1740 0.88t (6H), 1.18m(28H), 2.32t (4H, J=7Hz), 3.8-5.2m(12H), 5.78d (2H, J=3.5Hz), 6.08s(6H) CH3(CH2)10 161-164 + 88.4 1730 0.88t (6H), 1.22m(36H), 2.30t (4H, J=7Hz), 3.8-5.1m(12H), 5.70d (2H, J=3.5Hz), 5.96s(6H) EXAMPLE 5: Tablet
One tablet having the following ingredients each in the indicated amount was prepared in a conventional manner.
Trehalose middle chained aliphatic 100 mg
acid diester (decanoate)
D-mannitol 150 mg
Crystalline cellulose 50 mg
Starch 28 mg
Calcium carboxymethyl cellulose 16 mg
Talc 4 mg
Magnesium stearate 2 mg
Total amount 350 mg
EXAMPLE 6: Capsule
Granules having the following ingredients each in the indicated amount were prepared in a conventional manner and they were fiiled in a number 3 capsule.
Trehalose middle chained aliphatic 25 mg
acid diester (caprylate)
Crystalline cellulose 17 mg
Light anhydrous silicic acid 7 mg
Magnesium stearate 1 mg
EXAMPLE 7: Injection solution
One pack of an injection solution was prepared from the following ingredients each in the indicated amount in a conventional manner.
Trehalose middle chained aliphatic 25 mg
acid diester (decanoate)
To make with olive oil into 1 ml
EXAMPLE 8: Suppository
The following ingredients each in the indicated amount were melted and stirred and the molded to solidify into one piece of suppository in a conventional manner.
Trehalose middle chained aliphatic 100 mg
acid diester (laurate)
Cacao butter 1100 mg
Total amount 1200 mg
Claims (2)
1. An a,a-trehalose-6,6'-middle chained aliphatic acid diester represented by the following formula (I):
in which n represents an integer from 6 to 1 0.
2. A pharmaceutical agent containing as an effective ingredient an α,α-trehalose-6,6'-middle chained aliphatic acid diester represented by the following formula (I);
in which n represents an integer from 6 to 10.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08228817A GB2133399B (en) | 1982-10-08 | 1982-10-08 | A,a-trehalose-6,6'-middle chained aliphatic acid diester and a pharmaceutical agent containing the same |
| IT49382/82A IT1157236B (en) | 1982-10-08 | 1982-10-28 | ALFA, ALFA-TREALOSIO-6,6'-DIESTER OF ALIPHATIC ACID WITH MEDIUM CHAIN AND A PHARMACEUTICAL AGENT THAT CONTAINS IT |
| DE19823241199 DE3241199A1 (en) | 1982-10-08 | 1982-11-08 | (ALPHA), (ALPHA) -TREHALOSE-6,6'-DIESTER MEDIUM CHAIN ALIPHATIC ACID, AND PHARMACEUTICAL AGENTS WITH A CONTENT THEREOF |
| FR828219241A FR2534259B1 (en) | 1982-10-08 | 1982-11-17 | MEDIUM CHAIN ALIPHATIC ACID DIESTER IN POSITIONS 6, 6 'OF A, A-TREHALOSE AND ITS APPLICATION IN THERAPEUTICS |
| CH7049/82A CH650264A5 (en) | 1982-10-08 | 1982-12-03 | 6,6'-DIESTER FROM ALPHA, ALPHA-TREHALOSE WITH A MEDIUM-CHAIN ALIPHATIC ACID, AND PHARMACEUTICAL AGENT CONTAINING THEM. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08228817A GB2133399B (en) | 1982-10-08 | 1982-10-08 | A,a-trehalose-6,6'-middle chained aliphatic acid diester and a pharmaceutical agent containing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2133399A true GB2133399A (en) | 1984-07-25 |
| GB2133399B GB2133399B (en) | 1985-08-07 |
Family
ID=10533476
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08228817A Expired GB2133399B (en) | 1982-10-08 | 1982-10-08 | A,a-trehalose-6,6'-middle chained aliphatic acid diester and a pharmaceutical agent containing the same |
Country Status (5)
| Country | Link |
|---|---|
| CH (1) | CH650264A5 (en) |
| DE (1) | DE3241199A1 (en) |
| FR (1) | FR2534259B1 (en) |
| GB (1) | GB2133399B (en) |
| IT (1) | IT1157236B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5049664A (en) * | 1988-08-26 | 1991-09-17 | Sawai Pharmaceutical Co., Ltd. | Trehalose derivatives |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT388166B (en) * | 1986-06-03 | 1989-05-10 | Oesterr Zuckerfab Evidenz | Process for the preparation of novel water-soluble carbohydrate derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2319373A1 (en) * | 1975-07-29 | 1977-02-25 | Anvar | (2,2)-Diesterified diholosides prodn. - from cpd. with all other hydroxy gps. silylated, and a fatty acid or its reactive deriv. |
-
1982
- 1982-10-08 GB GB08228817A patent/GB2133399B/en not_active Expired
- 1982-10-28 IT IT49382/82A patent/IT1157236B/en active
- 1982-11-08 DE DE19823241199 patent/DE3241199A1/en active Granted
- 1982-11-17 FR FR828219241A patent/FR2534259B1/en not_active Expired - Lifetime
- 1982-12-03 CH CH7049/82A patent/CH650264A5/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5049664A (en) * | 1988-08-26 | 1991-09-17 | Sawai Pharmaceutical Co., Ltd. | Trehalose derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2133399B (en) | 1985-08-07 |
| FR2534259A1 (en) | 1984-04-13 |
| DE3241199A1 (en) | 1984-04-12 |
| FR2534259B1 (en) | 1990-03-02 |
| CH650264A5 (en) | 1985-07-15 |
| IT8249382A0 (en) | 1982-10-28 |
| IT1157236B (en) | 1987-02-11 |
| DE3241199C2 (en) | 1987-08-06 |
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| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |