Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-10-11
2002-05-28
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S054000, C536S118000, C536S124000
Reexamination Certificate
active
06395886
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to an anticancer drug, and in particular to an anticancer drug comprising, as an effective ingredient, a certain sulfoquinovosylacylglycerol derivative and/or a salt thereof.
Among the sulfoquinovosylacylglycerol derivatives that are the effective ingredients of the anticancer drug of the present invention, the &bgr;-anomers of sulfoquinovosylacylglycerol derivatives are novel compounds. Thus, the present invention also relates to these novel &bgr;-anomers of sulfoquinovosylacylglycerol derivatives.
Further, the present invention relates to a novel pyranoside that is useful as an intermediate for producing sulfopyranosylacylglycerol derivatives including the sulfoquinovosylacylglycerol derivatives of the present invention, and a process for producing the same.
Sulfoquinovosylacylglycerol derivatives have, as a basic skeleton, 6-deoxy-6-sulfo-D-glycopyranosylglycerol wherein the hydroxyl group bonded to carbon at the 6-position of D-glucose (carbon at the n-position of a sugar is sometimes referred to as “C-n” hereinafter) is substituted by a sulfo group and glycerol is introduced to the hydroxyl group bonded to the C-1. Either one or both of two hydroxyl groups in the glycerol moiety form ester bonds with a fatty acid or acids. As the sulfoquinovosylacylglycerol derivatives, there are various derivatives in accordance with sorts of the fatty acid ester-bonded to the glycerol. Among these sulfoquinovosylacylglycerol derivatives, some derivatives are known to exhibit physiological activity which may be applied to medicinal drugs.
For example, in Chemical & Pharmaceutical Bulletin, 46(4), (1998), Ohta et al. report that a certain sulfoquinovosylacylglycerol derivative obtained from marine red alga,
Gigartina tenella
exhibits inhibitory activity against eukaryotic DNA polymerases &agr; and &bgr;, and inhibitory activity against HIV-reverse transcriptase.
In Biochemical Pharmacology, 55, 537-541 (1998), Mizushina et al. describe that a certain sulfoquinovosylacylglycerol derivative obtained from a pteridophyte exhibits inhibitory activity against calf DNA polymerase &agr; and rat DNA polymerase &bgr;, but does not have any influence on the inhibitory activity against HIV-reverse transcriptase.
On the other hand, in British Journal of Cancer, 75 (3), 324-332 (1997), Sahara et al. state that a sulfoquinovosylacylglycerol fraction contained in a solvent extract of sea urchin intestines exhibits an anticancer effect in vivo and in vitro. However, the sulfoquinovosylacylglycerol fraction whose anticancer effect was found by Sahara et al. is in a from of mixture which mainly contains monoacylglycerol wherein its fatty acid acyl moiety is an acyl moiety of a C
16
saturated fatty acid, but also contains monoacylglycerol wherein its acyl moiety is an acyl moiety of other fatty acid as well as monoacylglycerol wherein its acyl moiety is an acyl moiety of an unsaturated fatty acid. Thus, an independent effect of each of the derivatives is not made clear. Addition-ally, Sahara et al. state in the same literature that a fraction containing a mixture of sulfoquinovosyldiacylglycerol derivatives contained in the solvent extract of sea urchin intestines did not exhibit any anticancer effect.
Usually, sulfoquinovosylacylglycerol derivatives are extracted from natural products such as algae and higher plants. In many cases, however, the sulfoquinovosyl-acylglycerol derivatives extracted from natural products are mixtures of acylglycerols wherein acyl moieties of fatty acids constituting glyceride moieties are different. Therefore, in order to obtain a single sulfoquinovosyl-acylglycerol derivative, a further purification is required. Moreover, according to such an extraction method from a natural product, it is difficult to obtain natural raw materials quantitatively and qualitatively stably.
Jpn. Pat. Appln. KOKAI Publication No. 7-149786 discloses a glyceroglycolipid as a carcinogenesis promoter inhibiting agent, and a process for synthesizing the same. However, the glyceroglycolipid disclosed in this publication is a compound wherein all the hydroxyl groups of galactose constituting the sugar moiety of the glyceroglycolipid are either protected by protecting groups such as benzyl groups, or non-substituted. In other words, the glyceroglycolipid disclosed in this publication is not any sulfopyranoside having a sulfo group at the C-6. According to the synthesizing process disclosed in this publication, basically glycerol is directly bonded to galactose. In this synthesizing process, many steps are necessary for protection or de-protection of not only the hydroxyl groups of the galactose, but also of the hydroxyl groups of the glycerol. For example, two hydroxyl groups of the glycerol are protected before they are bonded to the C-1 of the galactose, and after the bonding, the hydroxyl groups are de-protected. Then, they are again protected for reaction for the galactose. After the reaction, they are de-protected and then fatty acids are introduced thereto..
Furthermore, Dona M, Gordon and Samuel J, Danishefsky have reported a process for producing sulfoquinovosylacylglyceride by reacting glucal with isopropylideneglycerol (J. Am. Chem. Soc., 1992, 114, 659-663). However, glucal, which is used as the starting material in this synthesizing process, is very expensive.
BRIEF SUMMARY OF THE INVENTION
Accordingly, an object of the present invention is to provide a novel anticancer drug comprising, as an effective ingredient, a certain sulfoquinovosylacylglyceride.
Another object of the present invention is to provide a compound which can be used as an intermediate useful for industrially synthesizing sulfopyranosylacylglycerol derivatives such as sulfoquinovosylacylglycerol derivatives, in large quantities and high yields at low costs by fewer steps, as well as a process for producing the same.
The present inventors have now found that a compound represented by the following Formula (1):
where R
101
represents an acyl moiety of a saturated higher fatty acid, and R
102
represents a hydrogen atom or an acyl moiety of a saturated higher fatty acid, or a pharmaceutically acceptable salt thereof exhibits an anticancer effect, even in a single form.
Furthermore, the present inventors have found that sulfoquinovosylacylglycerol derivatives can be effectively produced in fewer steps than steps for protecting/de-protecting many hydroxyl groups in the glycerol moiety, as are needed in the process of synthesizing glyceroglycolipid disclosed in Jpn. Pat. Appln. KOKAI Publication No. 7-149786, by using, as an intermediate, a pyranose derivative having 2-propenyloxyl group substituted at the C-1 and having an alkyl- or arylsulfonyloxy group, or a substituted carbonylthio group substituted at C-6.
Thus, the present invention provides an anticancer drug comprising, as an active ingredient, at least one compound selected from the group consisting of the compounds represented by the above-mentioned Formula (1) and the pharmaceutically acceptable salts thereof.
Among the compounds represented by Formula (1), compounds wherein the bond between the C-1 of the glucose and the glycerol is a &bgr;-bond are new compounds. These new &bgr;-anomers of the sulfoquinovosylacylglycerol derivatives (which may be referred to as “&bgr;-derivatives” hereinafter) are represented by the following Formula (2):
where R
101
and R
102
are as defined in Formula (1).
The present invention also provides, as an intermediate useful for production of sulfopyranosylacylglycerol derivatives such as sulfoquinovosylacylglycerol derivatives, a 1-O-(2-propenyl)-6-O-sulfonylpyranoside represented by the following Formula (A):
where R
1
, R
2
and R
3
each independently represents an alkyl or substituted silyl group, and R
4
represents an alkylsulfonyl or arylsulfonyl group, as well as a 1-O-(2-propenyl)-6-deoxy-6-carbonylthiopyranoside represented by the following Formula (B):
wherein R
1
, R
2
and R
3
each independently represents an alkyl or substituted silyl group, and R
5
represen
Masaki Kazuyoshi
Nakayama Kotaro
Ohta Keisuke
Sakaguchi Kengo
Sugawara Fumio
Crane L. E.
Frishauf, Holtz Goodman, Langer & Chick, P.C.
Toyo Suisan Kaisha Ltd.
Wilson James O.
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