CA1336096C - Isolation of castanospermine and its use as an antidiabetic agent - Google Patents
Isolation of castanospermine and its use as an antidiabetic agentInfo
- Publication number
- CA1336096C CA1336096C CA000616801A CA616801A CA1336096C CA 1336096 C CA1336096 C CA 1336096C CA 000616801 A CA000616801 A CA 000616801A CA 616801 A CA616801 A CA 616801A CA 1336096 C CA1336096 C CA 1336096C
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- CA
- Canada
- Prior art keywords
- castanospermine
- seeds
- dowex
- aqueous
- ion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
A novel process for the isolation of castanospermine from the seeds of Castanospermum australe by extracting the ground seeds with aqueous 2-propanol, subjecting the aque-ous extract to chromatographic treatment and isolating the castanospermine from the aqueous eluate. Castanospermine is useful for inhibiting the formation of glucose and can thus be used as an antidiabetic agent.
Description
ISOLATION OF CASTANOSPERMINE
AND ITS USE AS AN ANTIDIABETIC AGENT
BACRGROUND OF THE INVENTION
Castanospermine is an alkaloid having the following formula:
HO
~0..",~
HO OH
Systematically, this compound is named ~lS,6S,7R,8R,8aR)-1,6,7,8-tetrahydroxyindolizidine.
The isolation of of this compound from castanosPermum australe has been described by L.D. Hohenshutz, et al., PhytochemistrY, ~Q, 811 (1981). The procedure involves a tedious extraction and a subsequent washing with pyridine and only small quantities of the desired product are ob-tained. R.C. Bernotas, et al., Tetrahedron Letters, 25, 165 (1984) obtained castanospermine by total synthesis and thereby established the absolute configuration of the com-pound.
Several publications have appeared which describe cas-tanospermine as an inhibitor of a number of plant enzymes.
See Y.T. Pan, et al., BiochemistrY, 22, 3975 ~1983);
R. Saul, et al., Archives of BiochemistrY and BioPhysics~
221, 593 (1983); R. Saul, et al., Archives of BiochemistrY
and BioPhvsics, 230, 668 ~1984~. More recently, Saul et al., Proc. Nat'l. Acad. Sci. USA, 82, 93 (198S) have indi-cated that castanospermine inhibits intestinal glycosidases (i.e., maltase and sucrase) in rats when administered by injection and that diarrhea and high levels of intestinal bacterial flora were observed when high doses were admini-stered. However, they gave no indication that castano-spermine would be useful for any purposes as a result ofthese facts.
DESCRIPTION OF THE I~V~ 10N
It has now been found that castanospermine possesses digestive enzyme inhibitory properties and thus can be used as an antidiabetic agent and as an inhibitor of increased lipid biosynthesis. Thus, when carbohydrate is ingested either as glucose or in a form such as maltose, sucrose or starch in food or drink, the blood glucose level rises to elevated concentrations. In healthy subjects, this hyper-glycemic state quickly returns to normal, the glucose inthe blood being rapidly metabolized and stored and/or utilized by the organism. In diabetes mellitus, however, the glucose tolerance of the patient is lowered and the abnormally high blood sugar levels which develop remain elevated for prolonged periods of time. A similar response to that seen in man can also be observed in other animals, including livestock, poultry, pet animals and laboratory animals. Such a condition can be described as postprandial hyperglycemia. One method for treating such a condition would be by administration of some substance which would prevent the conversion of complex sugars to glucose and S thus prevent the development of the excessive glucose levels. In the present invention, it has been found that, where the high levels of glucoæe are a result of the hydro-lysis of complex sugars, administration of castanospermine inhibits the initial formation of glucose in the blood and thus makes it possible to avoid the problems which would be associated with prolonged high levels of blood sugar.
Equivalent to castanospermine for the purposeæ of this invention are the salts of castanospermine with pharmaceu-tically acceptable acids and, particularly, with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; and with organic acids such as acetic acid, propionic acid, methanesulfonic acid and ~-toluenesulfonic acid.
The mechanism whereby the above result is achieved is the following although the utility described above should not be limited by the precise details of this mechanism.
Enzymes which catalyze the hydrolysis of complex carbohy-drates convert non-absorbable carbohydrate into absorbable sugars. The rapid action of these enzymes leads to acute and undesirable elevations in blood glucose in diabetes.
The compounds of the present invention are potent inhi-bitors of these enzymes and, when co-administered with a carbohydrate meal, they prevent harmful hyperglycemic ex-cursions of this type.
30This inhibition of the formation of glucose can be useful in other ways too. Thus, the carbohydrates ingested C-33161 ~3~
by an organism appear in the form of glucose and are meta-bolized into lipids such as triglycerides, cholesterol, phospholipids and the like. Too large a carbohydrate intake results in increased biosynthesis of lipids, causing hyperlipemia and excessive accumulation of lipids, both in adipose tissue and in other systems in the organism which can lead to obesity, atherosclerosis, myocardial infarction and other kinds of heart diseases. The inhibition of the formation of glucose accomplished by castanospermine would thus be useful in the control of these other conditions.
In addition, the present invention is directed to a new process for the isolation of castanospermine from castanosPermum australe by a procedure that avoidæ the tedious extraction procedure and the use of the obnoxious solvent pyridine as described in the published procedure mentioned earlier while providing the desired product in greatly improved overall yields. Details of this procedure are set forth in the example.
The following test procedures can be used to demon-strate the activity of castanospermine.
Inhibitory Action Aqainst Increase of Blood Glucose inSucrose-Administered Mice Male ICR-swiss mice with body weight of 25-35 g were fasted overnight. Sucrose was administered orally by gavage at a do8e of 2 g/kg 15 minutes after the similar administration of castanospermine at doses of 0.125 to 60 mg/kg. Animals were sacrificed at 30 minutes after sucrose administration and blood glucose levels were measured by a method using glucose dehydrogenase. The results are shown in Table 1 below. The increase in glucose in the blood could be significantly inhibited by administering castano-spermine at a dose of 0.125 mg/kg or higher.
C-33161 ~4~
~- 1 336096 Blood Glueose Dose of Number of Coneentration (mg%) CastanosPermine Miee Tested at 30 Min. After Suerose 0 mg/kg 8 205 0.125 4 159 0.25 4 167 0.5 4 153 1.0 4 146 2.0 4 116 Blank 4 107 ~Blank: 0.5~ methoeel alone was administered.) InhibitorY Action Aqainst Increase of Blood Glueose in Starch-Administrated Miee Male ICR-Swiss miee with body weight of 25-35 g were fasted overnight. Stareh was administered orally by gavage at a dose of 1 g~kg 15 minutes after the similar adminis-tration of eastanospermine at doses of 1.9 to 60 mg/kg.
Animals were sacrifieed at 45 minutes after stareh adminis-tration and blood glucose levels were measured by a method using glueose dehydrogenase. The results are shown in Table 2 below. The inerease in glueose in the blood eould be signifieantly inhibited by administering castanospermine at a dose of 3.8 mg/kg or higher.
Dose of the Blood Glucose Compound of Number ofConcentration (mg%) at Thi8 InventionMice Tested45 min. After Starch 0 mg/kg 8 126 1.9 3 139 3.8 4 83 7.5 4 85 Blank 4 72 (Blank: 0.5% methocel alone was administered.) C-33161 -5~
In practicing the method of this invention, an amount of castanospermine effective to inhibit postprandial hyper-glycemia is admini~tered to a mammal in need thereof by a suitable route. For the purposes of this invention, oral administration is preferred.
The effective amount of the compound, that is, the amount sufficient to inhibit postprandial hyperglycemia, depends on various factors such as the size, type and age of the animal to be treated, the particular compound or pharmaceutically acceptable salt employed, the frequency of administration, the severity of the condition and the time of administration. Generally speaking, the compounds would be administered orally at a dose of 10 mg to 500 mg at mealtime, with a dose of 40 mg to 200 mg being preferred.
More specifically, the present compounds would be adminiæ-tered to humans in single unit doses ~individual capsules) containing 50 mg of active ingredient with the material being administered three times a day at mealtime.
In practicing the method of this invention, the active ingredient can be incorporated in a composition comprising a pharmaceutical carrier and from about S to about 90 per-cent by weight of castanospermine or a pharmaceutically-acceptable salt thereof. The term ~pharmaceutical carrier~
refers to known pharmaceutical excipients useful in formulating pharmaceutically active compounds for internal admini tration to animals, and which are substantially non-toxic and non-sensitizing under conditions of use. The compositions can be prepared by known techniques for the preparation of tablets, capsules, elixirs, syrups, emul-sions, dispersions and wettable and effervescent powders,and can contain suitable excipients known to be useful in the preparation of the particular type of composition 1 33~6 desired. Suitable pharmaceutical carriers and formulation technigues are found in standard texts, such as Reminqton's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
The following example is presented to illustrate the present invention. Rowever, it should not be construed as limiting it in any way.
Commercially available mature seeds of CastanosPermum australe (300 g, wet weight) were ground and continuously extracted for 24 hours in a Soxhlet apparatus with 1.0 1 of a 3:7 (v/v) mixture of water and 2-propanol. The extract was concentrated in vacuo to a final volume of 250 ml and was filtered. After extraction with petroleum ether ~10 x 100 ml), the aqueous extract was subjected to column chro-matoqraphy with Dowex 50W-X4 (H+) ion-exchange resin (2.5 cm x 32 cm). The column was washed with distilled water (200 ml) and the desired alkaloid was eluted with 400 ml of 2 N aqueous ammonium hydroxide. The basic eluate was con-2C centrated in vacuo to 125 ml and applied to another column containing Dowex l-X4(OH ) ion-exchange resin (2.5 cm x 20 cm). The column was eluted with 125 ml of water and the eluate was concentrated to a final volume of 30 ml.
Trituration of the concentrate with 300 ml of acetone yielded 3.5 g of castanospermine as colorless crystals (1.2%, calculation on the basis of the weight of fresh seeds). The isolated crystals had the following physical properties:
mp: 212-225C
Elemental analysis:
Found: C, 50.53%; H, 8.04%; N, 7.26%.
Calc for C8H15NO4: C, 50.79%; H, 7.94%; N, 7.41~.
optical rotation = ~25 + 75.5o (c 1.72, H2O) Mass Spectral Data: 190 (MH+), 172 (M~+-H2O).
~ Trade-mark
AND ITS USE AS AN ANTIDIABETIC AGENT
BACRGROUND OF THE INVENTION
Castanospermine is an alkaloid having the following formula:
HO
~0..",~
HO OH
Systematically, this compound is named ~lS,6S,7R,8R,8aR)-1,6,7,8-tetrahydroxyindolizidine.
The isolation of of this compound from castanosPermum australe has been described by L.D. Hohenshutz, et al., PhytochemistrY, ~Q, 811 (1981). The procedure involves a tedious extraction and a subsequent washing with pyridine and only small quantities of the desired product are ob-tained. R.C. Bernotas, et al., Tetrahedron Letters, 25, 165 (1984) obtained castanospermine by total synthesis and thereby established the absolute configuration of the com-pound.
Several publications have appeared which describe cas-tanospermine as an inhibitor of a number of plant enzymes.
See Y.T. Pan, et al., BiochemistrY, 22, 3975 ~1983);
R. Saul, et al., Archives of BiochemistrY and BioPhysics~
221, 593 (1983); R. Saul, et al., Archives of BiochemistrY
and BioPhvsics, 230, 668 ~1984~. More recently, Saul et al., Proc. Nat'l. Acad. Sci. USA, 82, 93 (198S) have indi-cated that castanospermine inhibits intestinal glycosidases (i.e., maltase and sucrase) in rats when administered by injection and that diarrhea and high levels of intestinal bacterial flora were observed when high doses were admini-stered. However, they gave no indication that castano-spermine would be useful for any purposes as a result ofthese facts.
DESCRIPTION OF THE I~V~ 10N
It has now been found that castanospermine possesses digestive enzyme inhibitory properties and thus can be used as an antidiabetic agent and as an inhibitor of increased lipid biosynthesis. Thus, when carbohydrate is ingested either as glucose or in a form such as maltose, sucrose or starch in food or drink, the blood glucose level rises to elevated concentrations. In healthy subjects, this hyper-glycemic state quickly returns to normal, the glucose inthe blood being rapidly metabolized and stored and/or utilized by the organism. In diabetes mellitus, however, the glucose tolerance of the patient is lowered and the abnormally high blood sugar levels which develop remain elevated for prolonged periods of time. A similar response to that seen in man can also be observed in other animals, including livestock, poultry, pet animals and laboratory animals. Such a condition can be described as postprandial hyperglycemia. One method for treating such a condition would be by administration of some substance which would prevent the conversion of complex sugars to glucose and S thus prevent the development of the excessive glucose levels. In the present invention, it has been found that, where the high levels of glucoæe are a result of the hydro-lysis of complex sugars, administration of castanospermine inhibits the initial formation of glucose in the blood and thus makes it possible to avoid the problems which would be associated with prolonged high levels of blood sugar.
Equivalent to castanospermine for the purposeæ of this invention are the salts of castanospermine with pharmaceu-tically acceptable acids and, particularly, with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; and with organic acids such as acetic acid, propionic acid, methanesulfonic acid and ~-toluenesulfonic acid.
The mechanism whereby the above result is achieved is the following although the utility described above should not be limited by the precise details of this mechanism.
Enzymes which catalyze the hydrolysis of complex carbohy-drates convert non-absorbable carbohydrate into absorbable sugars. The rapid action of these enzymes leads to acute and undesirable elevations in blood glucose in diabetes.
The compounds of the present invention are potent inhi-bitors of these enzymes and, when co-administered with a carbohydrate meal, they prevent harmful hyperglycemic ex-cursions of this type.
30This inhibition of the formation of glucose can be useful in other ways too. Thus, the carbohydrates ingested C-33161 ~3~
by an organism appear in the form of glucose and are meta-bolized into lipids such as triglycerides, cholesterol, phospholipids and the like. Too large a carbohydrate intake results in increased biosynthesis of lipids, causing hyperlipemia and excessive accumulation of lipids, both in adipose tissue and in other systems in the organism which can lead to obesity, atherosclerosis, myocardial infarction and other kinds of heart diseases. The inhibition of the formation of glucose accomplished by castanospermine would thus be useful in the control of these other conditions.
In addition, the present invention is directed to a new process for the isolation of castanospermine from castanosPermum australe by a procedure that avoidæ the tedious extraction procedure and the use of the obnoxious solvent pyridine as described in the published procedure mentioned earlier while providing the desired product in greatly improved overall yields. Details of this procedure are set forth in the example.
The following test procedures can be used to demon-strate the activity of castanospermine.
Inhibitory Action Aqainst Increase of Blood Glucose inSucrose-Administered Mice Male ICR-swiss mice with body weight of 25-35 g were fasted overnight. Sucrose was administered orally by gavage at a do8e of 2 g/kg 15 minutes after the similar administration of castanospermine at doses of 0.125 to 60 mg/kg. Animals were sacrificed at 30 minutes after sucrose administration and blood glucose levels were measured by a method using glucose dehydrogenase. The results are shown in Table 1 below. The increase in glucose in the blood could be significantly inhibited by administering castano-spermine at a dose of 0.125 mg/kg or higher.
C-33161 ~4~
~- 1 336096 Blood Glueose Dose of Number of Coneentration (mg%) CastanosPermine Miee Tested at 30 Min. After Suerose 0 mg/kg 8 205 0.125 4 159 0.25 4 167 0.5 4 153 1.0 4 146 2.0 4 116 Blank 4 107 ~Blank: 0.5~ methoeel alone was administered.) InhibitorY Action Aqainst Increase of Blood Glueose in Starch-Administrated Miee Male ICR-Swiss miee with body weight of 25-35 g were fasted overnight. Stareh was administered orally by gavage at a dose of 1 g~kg 15 minutes after the similar adminis-tration of eastanospermine at doses of 1.9 to 60 mg/kg.
Animals were sacrifieed at 45 minutes after stareh adminis-tration and blood glucose levels were measured by a method using glueose dehydrogenase. The results are shown in Table 2 below. The inerease in glueose in the blood eould be signifieantly inhibited by administering castanospermine at a dose of 3.8 mg/kg or higher.
Dose of the Blood Glucose Compound of Number ofConcentration (mg%) at Thi8 InventionMice Tested45 min. After Starch 0 mg/kg 8 126 1.9 3 139 3.8 4 83 7.5 4 85 Blank 4 72 (Blank: 0.5% methocel alone was administered.) C-33161 -5~
In practicing the method of this invention, an amount of castanospermine effective to inhibit postprandial hyper-glycemia is admini~tered to a mammal in need thereof by a suitable route. For the purposes of this invention, oral administration is preferred.
The effective amount of the compound, that is, the amount sufficient to inhibit postprandial hyperglycemia, depends on various factors such as the size, type and age of the animal to be treated, the particular compound or pharmaceutically acceptable salt employed, the frequency of administration, the severity of the condition and the time of administration. Generally speaking, the compounds would be administered orally at a dose of 10 mg to 500 mg at mealtime, with a dose of 40 mg to 200 mg being preferred.
More specifically, the present compounds would be adminiæ-tered to humans in single unit doses ~individual capsules) containing 50 mg of active ingredient with the material being administered three times a day at mealtime.
In practicing the method of this invention, the active ingredient can be incorporated in a composition comprising a pharmaceutical carrier and from about S to about 90 per-cent by weight of castanospermine or a pharmaceutically-acceptable salt thereof. The term ~pharmaceutical carrier~
refers to known pharmaceutical excipients useful in formulating pharmaceutically active compounds for internal admini tration to animals, and which are substantially non-toxic and non-sensitizing under conditions of use. The compositions can be prepared by known techniques for the preparation of tablets, capsules, elixirs, syrups, emul-sions, dispersions and wettable and effervescent powders,and can contain suitable excipients known to be useful in the preparation of the particular type of composition 1 33~6 desired. Suitable pharmaceutical carriers and formulation technigues are found in standard texts, such as Reminqton's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
The following example is presented to illustrate the present invention. Rowever, it should not be construed as limiting it in any way.
Commercially available mature seeds of CastanosPermum australe (300 g, wet weight) were ground and continuously extracted for 24 hours in a Soxhlet apparatus with 1.0 1 of a 3:7 (v/v) mixture of water and 2-propanol. The extract was concentrated in vacuo to a final volume of 250 ml and was filtered. After extraction with petroleum ether ~10 x 100 ml), the aqueous extract was subjected to column chro-matoqraphy with Dowex 50W-X4 (H+) ion-exchange resin (2.5 cm x 32 cm). The column was washed with distilled water (200 ml) and the desired alkaloid was eluted with 400 ml of 2 N aqueous ammonium hydroxide. The basic eluate was con-2C centrated in vacuo to 125 ml and applied to another column containing Dowex l-X4(OH ) ion-exchange resin (2.5 cm x 20 cm). The column was eluted with 125 ml of water and the eluate was concentrated to a final volume of 30 ml.
Trituration of the concentrate with 300 ml of acetone yielded 3.5 g of castanospermine as colorless crystals (1.2%, calculation on the basis of the weight of fresh seeds). The isolated crystals had the following physical properties:
mp: 212-225C
Elemental analysis:
Found: C, 50.53%; H, 8.04%; N, 7.26%.
Calc for C8H15NO4: C, 50.79%; H, 7.94%; N, 7.41~.
optical rotation = ~25 + 75.5o (c 1.72, H2O) Mass Spectral Data: 190 (MH+), 172 (M~+-H2O).
~ Trade-mark
Claims (4)
1. A novel process for obtaining castanospermine from the seeds of Castanospermum australe which comprises:
a) extracting the ground seeds with a mixture of water and 2-propanol;
b) washing the aqueous extract with petroleum ether;
c) chromatographing the aqueous extract on an acid resin and eluting with ammonium hydroxide;
d) rechromatographing the eluate on a basic resin and eluting with water; and e) concentrating the aqueous eluate followed by triturating the acetone to give castanospermine.
a) extracting the ground seeds with a mixture of water and 2-propanol;
b) washing the aqueous extract with petroleum ether;
c) chromatographing the aqueous extract on an acid resin and eluting with ammonium hydroxide;
d) rechromatographing the eluate on a basic resin and eluting with water; and e) concentrating the aqueous eluate followed by triturating the acetone to give castanospermine.
2. The process of claim 1 wherein the acid resin is Dowex 50W-X4 (H+) ion-exchange resin.
3. The process of claim 1 or 2 wherein the basic resin is Dowex 1-X4 (OH-) ion-exchange resin.
4. A process for obtaining castanospermine from the seeds of Castanospermum australe which comprises:
a) extracting the ground seeds with a mixture of water and 2-propanol;
b) washing the aqueous extract with petroleum ether;
c) chromatographing the aqueous extract on Dowex 50W-X4 (H+) ion-exchange resin and eluting with ammonium hydroxide;
d) rechromatographing the eluate on Dowex 1-X4 (OH-) ion-exchange resin and eluting with water; and e) concentrating the aqueous eluate followed by tri-turating with acetone to give castanospermine.
a) extracting the ground seeds with a mixture of water and 2-propanol;
b) washing the aqueous extract with petroleum ether;
c) chromatographing the aqueous extract on Dowex 50W-X4 (H+) ion-exchange resin and eluting with ammonium hydroxide;
d) rechromatographing the eluate on Dowex 1-X4 (OH-) ion-exchange resin and eluting with water; and e) concentrating the aqueous eluate followed by tri-turating with acetone to give castanospermine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000616801A CA1336096C (en) | 1985-05-24 | 1994-01-20 | Isolation of castanospermine and its use as an antidiabetic agent |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US73812785A | 1985-05-24 | 1985-05-24 | |
| US738,127 | 1985-05-24 | ||
| CA000509494A CA1327970C (en) | 1985-05-24 | 1986-05-20 | Isolation of castanospermine and its use as an antidiabetic agent |
| CA000616801A CA1336096C (en) | 1985-05-24 | 1994-01-20 | Isolation of castanospermine and its use as an antidiabetic agent |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000509494A Division CA1327970C (en) | 1985-05-24 | 1986-05-20 | Isolation of castanospermine and its use as an antidiabetic agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1336096C true CA1336096C (en) | 1995-06-27 |
Family
ID=25671002
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000616801A Expired - Fee Related CA1336096C (en) | 1985-05-24 | 1994-01-20 | Isolation of castanospermine and its use as an antidiabetic agent |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1336096C (en) |
-
1994
- 1994-01-20 CA CA000616801A patent/CA1336096C/en not_active Expired - Fee Related
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed | ||
| MKLA | Lapsed |
Effective date: 20010627 |