Glycoside indoles

Details Glycoside indoles Glycoside indoles

1998-02-25

2001-10-02

Prats, Francisco (Department: 1651)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S001110, C536S004100, C536S017300, C536S017500, C536S128000, C424S062000, C424S063000, C424S725000, C424S070100, C514S025000, C514S415000, C514S469000, C514S443000, C548S469000, C549S049000, C549S456000

Reexamination Certificate

active

06297363

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to a class of novel glycoside indoles. More specifically, the present invention relates to a class of glycoside indoles which are isolated from Calanthe discolor Lindl. and derivatives thereof.
BACKGROUND OF THE INVENTION
The alcohol extract from Calanthe discolor Lindl. is known to be useful for promotion of hair growth and restoration. (JP. A 5-294813) However, the components of this extract have not been identified.
Therefore, there is a need to isolate and identify the active components of the alcohol extract of Calanthe discolor Lindl. There also is a need for compounds that are derivatives of these active components which may be more active and possess other physiological activities.
SUMMARY OF THE INVENTION
The present invention provides a compound of the formula:
where:
X is O, S, or NR
3
;
R
1
and R
2
are independently H, OR
4
, SR
5
, NR
6
R
7
, C
1
-C
4
alkyl, or halogen;
Z
1
and Z
2
are H, OR
8
, SR
9
or NR
10
R
11
;
R
3
, R
4
, R
5
, R
6
and R
7
are independently H or C
1
-C
4
alkyl; and
R
8
, R
9
, R
10
and R
11
are independently H, or a saccharide moiety;
and wherein the compound comprises at least two saccharide moieties.
One embodiment of the invention provides a compound 3-O-&bgr;-D-glucopyranosyl(1-6)-&bgr;-D-glucopyranosylindole.
Yet another embodiment of the invention provides a compound 2-S-&bgr;-D-glucopyranosyl-3-O-&bgr;-D-glucopyranosyl-2-mercaptoindole.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a class of novel glycoside indoles. These compounds have a variety of applications, which include increasing skin blood flow, promoting hair growth and whitening the skin.
More specifically, the present invention comprises a class of chemical compounds described as disaccharide indoles. The compounds of the present invention can be described by general formula I:
wherein the compound has at least two saccharide moieties.
The two or more saccharide moieties can be linked together to form a disaccharide or a polysaccharide chain or they can be attached to different positions of the ring moiety. As used in this invention, a “saccharide” moiety refers to a moiety having one or more carbohydrate moieties. Exemplary carbohydrate includes, glucose, mannose, talose, galactose, allose, altrose, talose, fructose, sorbose, and arabinose. The carbohydrate moiety can be a monosaccharide, disaccharide or a trisaccharide moiety. Exemplary disaccharides include lactose, maltose, cellobiose, and sucrose. The carbohydrate moiety can be in a straight chain form, a furanose form or a pyranose form. In addition, the carbohydrate moiety can be modified such that one or more of the hydroxy groups in the carbohydrate is replaced with hydrogen, halogen, amino, C
1
-C
4
alkoxy or C
1
-C
4
alkyl group. Exemplary modified carbohydrate moieties include, 5-deoxyglucose, glucosamine, 2,3-dideoxyglucose, 2-fluoroglucose, 5-fluoroglucose, 3-methyl-3-deoxyglucose, 2-methoxy glucose, 2,3-O-isopropylidene glucose, 2-acetylglucose, 2,3-diacetylglucose, and 2,3-difluoroglucose.
Substituents R
1
and R
2
can independently be substituted at the six-membered or the five-membered ring moiety. Preferably, R
1
and R
2
are substituted at the six-membered ring moiety. Preferably, R
1
and R
2
are independently H, OR
4
, SR
5
, NR
6
R
7
, C
1
-C
4
alkyl, or halogen. Alkyl groups according to the invention are aliphatic hydrocarbons which can be straight or branched chain groups. Alkyl groups optionally can be substituted with one or more substituents, such as halogen, aryl, hydroxy, alkoxy, carboxy, oxo and cycloalkyl. There may be optionally inserted along the alkyl group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms. Exemplary alkyl groups include methyl, ethyl, i-propyl, n-butyl, t-butyl, fluoromethyl, trifluoromethyl, chloromethyl, trichloromethyl, and pentafluoroethyl. More preferably, at least one of R
1
and R
2
is H, and most preferably R
1
and R
2
are H.
X is O, S, or NR
3
. Preferably, X is NR
3
. Z
1
and Z
2
are H, OR
8
, SR
9
or NR
10
R
11
. Preferably Z
1
is OR
8
. Preferably Z
2
is H or SR
9
.
R
3
, R
4
, R
5
, R
6
and R
7
are independently H or C
1
-C
4
alkyl. Preferably R
3
is H.
R
8
, R
9
, R
10
and R
11
are independently H, or a saccharide moiety. Preferably R
8
is a monosaccharide or a disaccharide moiety, more preferably R
8
is &bgr;-D-glucopyranosyl or &bgr;-D-glucopyranosyl (1-6) -&bgr;-D-glucopyranosyl moiety. Preferably R
9
is a monosaccharide moiety, more preferably &bgr;-D-glucopyranosyl.
Particularly preferred compounds of the present inventions include 3-O-&bgr;-D-glucopyranosyl(1-6)-&bgr;-D-glucopyranosylindole and 2-S-&bgr;-D-glucopyranosyl-3-O-&bgr;-D-glucopyranosyl-2-mercaptoindole.
The compounds of the present invention can be isolated from Calanthe discolor Lindl. For example, a method for preparing an extract from Calanthe discolor Lindl. and uses hereof as a hair growth promoter are disclosed in U.S. patent application Ser. Nos. 08/661,970 and 08/167,828. Alternatively, the compounds of the present invention can be synthesized from readily available starting materials.
Various substituents on the compounds of the present invention can be present in the starting compounds, added to any one of the intermediates or added after formation of the final products by known methods of substitution or conversion reactions. If the substituents themselves are reactive, then the substituents can themselves be protected according to the techniques known in the art. A variety of protecting groups are known in the art, and can be employed. Examples of many of the possible groups can be found in “Protective Groups in Organic Synthesis” by T. W. Green, John Wiley and Sons, 1981. For example, nitro groups can be added by nitration and the nitro group can be converted to other groups, such as amino by reduction, and halogen by diazotization of the amino group and replacement of the diazo group with halogen. Acyl groups can be added by Friedel-Crafts acylation. The acyl groups can then be transformed to the corresponding alkyl groups by various methods, including the Wolff-Kishner reduction and Clemmenson reduction. Amino groups can be alkylated to form mono- and di-alkylamino groups; and mercapto and hydroxy groups can be alkylated to form corresponding ethers. Primary alcohols can be oxidized by oxidizing agents known in the art to form carboxylic acids or aldehydes, and secondary alcohols can be oxidized to form ketones. Thus, substitution or alteration reactions can be employed to provide a variety of substituents throughout the molecule of the starting material, intermediates, or the final product, including isolated products.
The compounds of the present invention have a variety of physiological properties including increasing blood flow, promoting hair growth and whitening of skin. These physiological properties can be elicited by administering the compound topically, orally, or parenterally. The compound can be administered directly or it can be admixed with a suitable pharmaceutical carrier (i.e., vehicle). A pharmaceutically acceptable vehicle, is usually nontoxic and nontherapeutic. Examples of such vehicles are water, saline, Ringer's solution, dextrose solution, and Hank's solution. Nonaqueous vehicles, such as fixed oils, sesame oil, ethyl oleate, or triglycerides may also be used. Vehicles can also include viscosity enhancing agents, such as sodium carboxymethylcellulose, sorbitol, or dextran. The vehicle will also usually contain minor amounts of additives, such as substances that enhance isotonicity and chemical stability.
Examples of buffers include phosphate buffer, bicarbonate buffer and Tris buffer, while examples of preservatives include thimerosal, m- or o-cresol, formalin and benzyl alcohol. Standard formulations will either be liquid, gel or solids depending on the mode of administration. Thus, in a non-liquid formulation, the vehicle may comprise dextrose, human serum albumin, preservatives, etc., to which

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