Title:
BICYCLO (3.3.1) NONENES USEFUL FOR THE TREATMENT OF DIABETES AND HYPERTRIGLYCERIDEMIA
Document Type and Number:
WIPO Patent Application WO/2000/054760
Kind Code:
A2
Abstract:
Bicyclo[3.3.1]nonenes, pharmaceutical compositions containing the nonenes and methods of using the compounds and compositions as hypoglycemic or hypotriglyceridemic agents are described. The bicyclo[3.3.1]nonenes and corresponding compositions are useful for lowering blood glucose levels, treating hyperglycemia and treating diabetes. The nonenes and corresponding compositions are also useful for lowering serum triglyceride levels and treating hypertriglyceridemia.
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Inventors:
FORT DIANA M
Application Number:
PCT/US2000/006624
Publication Date:
September 21, 2000
Filing Date:
March 14, 2000
Export Citation:
Assignee:
SHAMAN PHARMACEUTICALS INC (US)
International Classes:
A61K31/122; A61K31/155; A61K31/425; A61K31/445; A61K31/64; A61K31/70; A61K36/38; A61K38/28; A61K45/06; (IPC1-7): A61K31/00
Domestic Patent References:
| WO2000002455A1 | 2000-01-20 | |||
| WO1997013489A2 | 1997-04-17 |
Foreign References:
| DE19700788A1 | 1998-07-16 | |||
| EP0599307A1 | 1994-06-01 | |||
| US5972357A | 1999-10-26 |
Other References:
DATABASE WPI Section Ch, Week 199750 Derwent Publications Ltd., London, GB; Class B04, AN 1997-539685 XP002152173 & JP 09 227398 A (ZERIA SHINYAKU KOGYO KK) , 2 September 1997 (1997-09-02)
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; FUKUYAMA, YOSHIYASU: "Tricyclic phloroglucin derivatives of Garcinia subelliptica activating the enzyme activity of acetylcholine synthase" retrieved from STN Database accession no. 127:195469 XP002152172 & JP 09 227545 A (MITSUBISHI CHEMICAL INDUSTRIES LTD., JAPAN) 2 September 1997 (1997-09-02)
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; FUKUYAMA, YOSHIYASU: "Tricyclic phloroglucin derivatives of Garcinia subelliptica activating the enzyme activity of acetylcholine synthase" retrieved from STN Database accession no. 127:195469 XP002152172 & JP 09 227545 A (MITSUBISHI CHEMICAL INDUSTRIES LTD., JAPAN) 2 September 1997 (1997-09-02)
Attorney, Agent or Firm:
Mckinney, Jeffrey A. (CA, US)
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Claims:
What is claimed is:
| 1. | A method for lowering blood glucose levels comprising administering to a mammal a therapeutically effective amount of an isolated or a purified compound of the formula (II) a: or a pharmaceutically acceptable salt thereof, wherein R, is selected from the group consisting of hydroxy and oxygen; R, is selected from the group consisting of hydroxy, oxygen and benzoyl; wherein both R, and R, are not simultaneously oxygen R3 is selected from the group consisting of hydrogen, methyl, methylhalide, 3methyl2butenyl; and (CH2) XCOOR4 ; wherein X is 0 to 2; wherein R2 and R3 can form a ring, said ring selected from the group consisting of a furan ring and a pyran ring; wherein R4 is selected from the group consisting of hydrogen and C, C3 alkyl; RS is selected from the group consisting of hydrogen and C,C6 alkyl; R6 is selected from the group consisting of 3methyl2butenyl, isobutyryl, 2methylbutyryl, and benzoyl; R, is 3methyl2butenyl; and R8 is selected from the group consisting of hydrogen, methyl, methylhalide, 4methyl3pentenyl, and(CH2) xCOOR4. |
| 2. | The according to claim 1 wherein the compound is selected from the group consisting of 4hydroxy1isobutyryl8methyl3,5,7tris (3methyl2butenyl)8 (4 methyl3pentenyl)exobicyclo [3.3.1] nonene2,9dione; 4hydroxv1 1)8exomethyl3.5,7tris (3methyl2<BR> <BR> <BR> <BR> butenyl)8e. [. |
| 3. | l] non3ene2,9dione; 3benzovl4hydroxy8.8dimethyl1,5,7tris (3methyl2butenyl)exo bicyclo [. |
| 4. | 1] non3ene2. 9dione; 5benzoyl4hydroxy8,8dimethyl1,3,7tris (3methyl2butenyl)exo bicyclo [. |
| 5. | 1] non3ene2.9dione; 4hydroxy5(3'hydroxybenzoyl)8,8dimethyl1,3,7tris(3methyl2 butenyl)erobicyclo [. |
| 6. | 1] non3ene2,9dione; 4hydroxv8exomethyl5,7exobis(3methyl2butenyl)1(2methyl 1oxopropyl)8endo (4methyl3pentenyl) bicyclo [3.3.1] non3ene2,9dione; and 4hydroxy8exomethyl5,7exobis (3methyl2butenyl)1(2methyl 1oxobutyl)8endo (4methyl3pentenyl) bicyclo [3.3.1] non3ene2,9dione. |
| 7. | 3 The method according to claim 1 wherein the compound is a oxidation derivative selected from the group consisting of 1 (2methyl1oxopropyl)2, 12dioxo3,10ßbis(3methyl2butenyl) 6D(1methyl1hydroxyethyl)11 ßmethyl11 a(1methyl1hydroxyethyl)11 ßmethyl11 a (4methyl3pentenyl)5oxatricyclo and 1(2methyl1oxopropyl)2,12dioxo3,10ßbis(3methyl2butenyl) 6hydroxyl l ßmethyl11 a4 (methyl3pentenyl)5oxatricyclo[6.3.1.04, 1]3 dodecene. |
| 8. | The method according to claim 1 wherein the mammal is hyperglycemic. |
| 9. | The method according to claim 1 wherein the mammal is suffering from NIDDM. |
| 10. | The method according to claim 1, wherein the compound is administered at a dose of about 0.5 to about 1000 mg per kg per day. |
| 11. | The method according to claim 1. wherein the compound is a pharmaceutically acceptable salt of sodium, potassium, lithium, calcium, magnesium, zinc or iron. |
| 12. | The method according to claim 1, wherein the compoundis administered in conjunction with another antihyperglycemic agent selected from the group consisting of a sulfonylurea, a nonsulfonylurea insulin secretagogue, a biguanide, a thiazolidinedione. aadrenoceptor agonist, an aglycosidase inhibitor and insulin. |
| 13. | The method according to claim 8, wherein the sulfonylurea is selected from the group consisting of acetohexamide, chlorpropamide, tolazamide, tolbutamide, glyburide, glypizide and glycazide. |
| 14. | The method according to claim 8 wherein the biguanide is metfbrmin or buformin. |
| 15. | The method according to claim 8, wherein the aglucosidase inhibitor is acarbose or miglatol. |
| 16. | The method according to claim 8, wherein the thiazolidinedione is selected from the group consisting of troglitazone, pioglitazone, rosiglitozone and ciglitazone. |
| 17. | A method for lowering blood glucose comprising administering to a mammal a therapeutically effective amount of a composition comprising an isolated or a purified compound of the formula (III) a: Formula (III) a or a pharmaceutically acceptable salt thereof, wherein R', is selected from the group consisting of O and OH; R', is selected from the group consisting of O and OH, wherein R'. and R'2 are not simultaneously O; and R'3 is H or CH3. |
| 18. | The method according to claim 13, wherein the compound is selected from the group consisting of : 4hydroxy1isobutyryl8methyl3,5,7tris (3methyl2butenyl)8 (4 methyl3pentenyl)exobicyclo [3.3.1] nonene2,9dione; and 4hydroxy1 (2methylbutyryl)8exomethyl 3,5,7tris (3methyl2 butenyl)8exobicyclo [3.3.1] non3ene2,9dione. |
| 19. | The method according to claim 13, wherein the composition consists essentially of the compound of formula (III) a. |
| 20. | The method according to claim 13, wherein the compound is administered at a dose of about 0.5 to about 1000 mg per kg per day. |
| 21. | The method according to claim 13, wherein the compound is a pharmaceutically acceptable salt of sodium, potassium, lithium, calcium, magnesium, zinc or iron. |
| 22. | The method according to claim 13, wherein the compound is administered in conjunction with another antihyperglycemic agent selected from the group consisting of a sulfonylurea, a nonsulfonylurea insulin secretagogue, a biguanide, a thiazolidinedione, aadrenoceptor agonist, an aglycosidase inhibitor and insulin. |
| 23. | The method according to claim 18, wherein the sulfonylurea is selected from the group consisting of acetohexamide, chlorpropamide, tolazamide, tolbutamide, glyburide, glypizide and glycazide. |
| 24. | The method according to claim 18, wherein the biguanide is selected from the group consisting of metformin and buformin. |
| 25. | The method according to claim 18, wherein the aglucosidase inhibitor is selected from the group consisting of acarbose and miglatol. |
| 26. | The method according to claim 18, wherein the thiazolidinedione is selected from the group consisting of troglitazone, pioglitazone, rosiglitozone and ciglitazone. |
| 27. | A method for lowering serum triglyceride levels comprising administering to a mammal a therapeutically effective amount of an isolated or a purified compound of the formula (II) b: or a pharmaceutically acceptable salt thereof, wherein R" ; is selected from the group consisting of hvdroxy, oxygen and C,C6 alkoxy; R", is selected from the group consisting of hydroxy, oxygen, benzoyl and C,C6 alkoxy ; wherein both R", and Rare not simultaneously oxygen; R"3 is selected from the group consisting of hydrogen, methyl, methylhalide. 3methyl2butenyl; and (CH,) xCOOR" ; wherein X is 0 to 2; wherein R", and R"3 can form a ring, said ring selected from the group consisting of a furan ring and a pyran ring ; wherein R", is selected from the group consisting of hydrogen and C,C, alkyl; R"5 is selected from the group consisting of hydrogen and ClC6 alkyl; R"6 is selected from the group consisting of 3methyl2butenyl, isobutyryl, 2methylbutyryl, and benzoyl; R". is 3methyl2butenyl; and R"8 is selected from the group consisting of hydrogen, methyl, methylhalide, 4methyl3pentenyl, and(CH2) XCOOR''4. |
| 28. | The method according to claim 23 wherein the compound is selected from the group consisting of 4hydroxy1isobutyryl8methyl3,5,7tris (3methyl2butenyl)8 (4 methyl3pentenyl)exobicyclo [3.3.1] nonene2,9dione; 4hydroxy1(2methylbutyryl)8exomethyl3,(2methylbutyryl)8exomethyl3, 5,7tris (3methyl2 butenyl)8exobicyclo [3.3.1] non3ene2,9dione; 7tris (3methyl2butenyl)exo bicyclo [3.3.1] non3ene2,9dione; 7tris (3methyl2butenyl)exo bicyclo [3.3.1] non3ene2,9dione; 4hydroxy5 (3'hydroxybenzoyl)8, 8dimethyl1,3,7tris (3methyl2 butenyl)exobicyclo [3.3.1] non3ene2,9dione; 4hydroxy8exomethyl5,7exobis (3methyl2butenyl)1(2methyl 1oxopropyl)8endo (4methyl3pentenyl) bicyclo [3.3.1] non3ene2,9dione ; and 4hydroxy8exomethyl5,7exobis (3methylbut2enyl)1(2methyl 12 oxobutyl)8endo (4methylpent3enyl) bicyclo [3.3.1] non3ene2,9dione. |
| 29. | The method according to claim 23 wherein the compound is an oxidation derivative selected from the group consisting of 1 (2methvlloxopropyl)2.12dioxo3,10bis (3methyl2butenyl) <BR> <BR> <BR> <BR> 6D(Imethyl1hydroxvethyl)11methyll l o (4methyl3pentenyl)5oxatricyclo and 1(9methvlIoxopropyl)2* 12dioxo3, 10ßbis (3methyl2butenyl) 6hydroxy13methyl11 a4 (methyl3pentenyl)5oxatricyclo [6.3.1.04, 1]3 dodecene. |
| 30. | The method according to claim 23, wherein the compound is administered at a dose of about 0.5 to about 1000 mg per kg per day. |
| 31. | The method according to claim 23, wherein the compound is a pharmaceutically acceptable salt of sodium, potassium, lithium, calcium, magnesium, zinc or iron. |
| 32. | The method according to claim 23, wherein the compound is administered in conjunction with another antihyperlipidemic agent. |
| 33. | A method for lowering serum triglyceride levels comprising administering to a mammal a therapeutically effective amount of a composition comprising an isolated or a purified compound of the formula (III) b: Formula (III) b or a pharmaceutically acceptable salt thereof, wherein R', is selected from the group consisting of O and OH; R', is selected from the group consisting of O and OH, wherein R', and R', are not simultaneously O; and R'3 is H or CH3. |
| 34. | The method according to claim 29, wherein the compound is selected from the group consisting of : 4hydroxy1isobutyryl8methyl3,5,7tris (3rriethyl2butenyl)8 (4 methyl3pentenyl)exobicyclo nonne2,9dione; and 4hydroxy1(2methylbutyryl)8exomethyl(2methylbutyryl)8exomethyl 3,5,7tris (3methyl2 butenyl)8exobicyclo [3.3.1] non3ene2,9dione. |
| 35. | The method according to claim 29, wherein the composition consists essentially of the compound of formula (III) b. |
| 36. | The method according to claim 29, wherein the compound is administered at a dose of about 0.5 to about 1000 mg per day. |
| 37. | The method according to claim 29, wherein the compound is a pharmaceutically acceptable salt of sodium, potassium, lithium, calcium, magnesium, zinc or iron. |
| 38. | The method according to claim 29, wherein the compound is administered in conjunction with another antihyperlipidemic agent. |
| 39. | A method for lowering blood glucose levels comprising administering to a mammal a therapeutically effective amount of a Hypericum spp. extract enriched in bicyclo [3.3.1] nonenes of formula (II) a: or a pharmaceutically acceptable salt thereof, wherein R, is selected from the group consisting of hydroxy and oxygen ; R is selected from the group consisting of hydroxy, oxygen and benzovl; wherein both R, and R are not simultaneously oxygen R, is selected from the group consisting of hydrogen, methyl, methylhalide, 3methyl2butenyl; and (CH2) XCOOR4 ; wherein X is 0 to 2; wherein R, and R, can form a ring, said ring selected from the group consisting of a furan ring and a pyran ring; wherein R4 is selected from the group consisting of hydrogen and C, C3 alkyl; R, is selected from the group consisting of hydrogen and C,C6 alkyl; R6 is selected from the group consisting of 3methyl2butenyl, isobutyryl, 2methylbutyryl, and benzoyl; R, is 3methyl2butenyl; and R8 is selected from the group consisting of hydrogen, methyl, methylhalide, 4methyl3pentenyl, and(CH2) XCOOR4. |
| 40. | A method according to claim 35, wherein the bicyclo [3.3.1] nonenes have a degree of purity at least about 2.5% by weight. |
| 41. | A method according to claim 35, wherein the bicyclo [3.3.1] nonenes have a degree of purity greater than about 5% by weight. |
| 42. | A method for lowering blood glucose levels comprising administering to a mammal a therapeutically effective amount of a Hypericum spp. extract enriched in bicyclo [3.3.1] nonenes offormula (III) b: Formula (III) b or a pharmaceutically acceptable salt thereof, wherein R', is selected from the group consisting of O and OH; R'2 is selected from the group consisting of O and OH, wherein R', and R'2 are not simultaneously O; and R'3 is H or CH3. |
| 43. | A method according to claim 38, wherein the bicyclo [3.3.1] nonenes have a degree of purity at least about 2.5% by weight. |
| 44. | A method according to claim 38, wherein the bicyclo [3.3.1] nonenes have a degree of purity greater than about 5% by weight. |
Description:
INTERNATIONALSEARCHREPORT'"*"°"'"App"'°" PCT/US00/06624 C.(Continuation)DOCUMENTSCONSIDEREDTOBERELEVANT Category* cotationofdocument,withindication, where appropriate,oftherelevant passages RelevanttodaimNo. XDATABASEWPI13-15, SectionCh,Week19975035,38 DerwentPublicationsLtd.,London,GB; ClassB04,AN1997-539685 XP002152173 &JP09227398A(ZERIASHINYAKUKOGYOKK) ,2 September1997(1997-09-02) abstract AEP0599307A(SCHWABEWILLMARGMBH&CO)13-22, 1June1994(1994-06-01)35-40 thewholedocument AWO9713489A(GRETHLEINECKHART;SCHWABE13-22, WILLMARGMBH&CO(DE);LANGFRIEDRICH)35-40 17April1997(1997-04-17) thewholedocument P,AUS5972357A(ISHIKAWAHIROHARUETAL)1-40 26October1999(1999-10-26) page2,line46-line52 column3,line10-line24 column15,line23-line27 A&CHEMICALABSTRACTS,vol.128,no.14,1-40 6April1998(1998-04-06) Columbus,Ohio,US; abstractno.172103, YAMAGUCHI,NORIOETAL.:"Maillard reactioninhibitorsforcosmeticsor pharmaceuticals" abstract A& JP10036257A(KIKKOMANCORP.)1-40 10February1998(1998-02-10) ADATABASECHEMABS'Online!1-40 CHEMICALABSTRACTSSERVICE,COLUMBUS, OHIO,US; FUKUYAMA,YOSHIYASU:"Tricyclic phloroglucinderivativesofGarcinia subellipticaactivatingtheenzyme activityofacetylcholinesynthase" retrievedfromSTN Databaseaccessionno.127:195469 XP002152172 abstract &JP09227545A(MITSUBISHICHEMICAL INDUSTRIESLTD.,JAPAN) 2September1997(1997-09-02) 1 INTERNATIONALSEARCHREPORT t,,. <-------j IrrtHonaldpplicationNo ritormatton on patent tamiy membea PCT/US 00/06624 PatentdocumentPublication Patent family Publication citedinsearchreportdate member (s) date WO0002455A20-01-2000AU 4958199A01-02-2000 DE19700788A16-07-1998NONE JP9227398A02-09-1997NONE EP0599307A01-06-1994DE 4239959A01-06-1994 AT 170080T15-09-1998 DE 59308924D01-10-1998 ES 2121918T16-12-1998 WO9713489A17-04-1997DE 19619512C31-07-1997 AT 174511T15-01-1999 AU 709877B09-09-1999 AU 1589197A30-04-1997 BR 9611096A05-10-1999 CA 2233277A17-04-1997 CN 1198097A04-11-1998 DE 19646977A15-01-1998 DE 59601019D28-01-1999 EP 0854726A29-07-1998 ES 2118686T01-10-1998 GR 3029412T28-05-1999 HU 9900657A28-09-1999 JP 11500743T19-01-1999 NO 981352A25-03-1998 PL 328136 A 18-01-1999PL 328136 A 18-01-1999 US5972357A26-10-1999JP 10036257A10-02-1998 JP 10121044A12-05-1998 JP 11029465A02-02-1999 JP9227545A02-09-1997NONE