WO1996040161A1 - Ether derivatives of pseudopterosin - Google Patents
Ether derivatives of pseudopterosin Download PDFInfo
- Publication number
- WO1996040161A1 WO1996040161A1 PCT/US1996/009177 US9609177W WO9640161A1 WO 1996040161 A1 WO1996040161 A1 WO 1996040161A1 US 9609177 W US9609177 W US 9609177W WO 9640161 A1 WO9640161 A1 WO 9640161A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition according
- hydrogen
- pseudopterosin
- carbon atoms
- propene
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/256—Polyterpene radicals
Definitions
- the present invention relates generally to synthetic derivatives of pseudop- terosin and their use in the treatment of inflammation and pain. More particularly, the present invention involves the discovery that certain specific ether derivatives of pseudopterosin are useful pharmaceutical agents which are especially effective in reducing inflammation and pain.
- Caribbean gorgonians (O. Gorgonacea, Ph. Cnidaria) are a diverse group of marine animals which are commonly known as sea whips and sea fans. A wide variety of Caribbean gorgonians are found in abundance in the shallow-water reefs of the West Indian region. A few of the Caribbean gorgonians have been analyzed for their chemical content and found to be a source of many diverse organic substances such as steroids, prostaglandins, lactones, sesquiterpenoid derivatives and diterpenoid metabolites. Some of these substances have been found to be biologically active.
- Pseudop- terogorgia is one type of gorgonian that has been studied extensively in an effort to isolate and identify potentially useful pharmacologically active compounds.
- a group of naturally occurring diterpenoid glycosides have been isolated and identified. This isolated group of diterpenoid glycosides are commonly referred to as pseudopterosins.
- pseudopterosins Over ten different pseudopterosins have been isolated from Pse ⁇ dopterogorgia . Only a few of these naturally occurring pseudopterosins have been shown to have pharmaceutical activity. These active pseudopterosins have been used exclusively as anti-inflammatory and/or analgesic agents.
- ether derivatives of pseudopterosin are effective anti-inflammatory and analgesic agents.
- the ether derivatives have the formula:
- A is an alkyl, aryl or amide group having from 2 to 20 carbon atoms
- R l f R 2 and R 3 are hydrogen or an acyl residue having from 1 to 6 carbon atoms
- R 4 is a hydrogen or CH 2 OH
- R 5 is an organo group having from 1 to 10 carbon atoms.
- the ether derivatives in accordance with the present invention are effective in treating both inflammation and pain.
- the ether derivatives are also stable. As a result, they are resistant to in vivo metabolization and consequently remain active during treatment involving in vivo administration.
- the stability of the ether derivatives also provides the added benefit of increasing the shelf life of the pharmaceutical preparations in which they are incorporated.
- the ether derivatives are useful in treating the same types of inflammatory disorders which have been treated using other pseudopterosins.
- the ether derivatives are useful in treating inflammatory diseases of the lungs including emphysema and chronic inflammation due to smoking.
- the ether derivatives are also useful in treating degenerative diseases associated with radiation exposure.
- the ether derivatives have also been found to be effective in treating cartilage and other connective tissue which has been degraded by arthritis or other degenerative disease.
- the present invention includes methods for treating mammals to reduce inflammation and/or pain wherein an ether derivative of pseudopterosin having the formula set forth above is administered to mammals.
- the ether derivatives are administered in the same manner as other known anti-inflammation and analgesic agents.
- the present invention also includes compositions for use as anti- inflammatory agents and analgesic agents which comprise an effective amount of one or more of the above-identified ether derivatives of pseudopterosin and a pharmaceutically acceptable carrier.
- A is an alkyl, aryl or amide group having from 2 to 20 carbon atoms
- R,, R 2 and R 3 are hydrogen or an acyl residue (-C(O)R) having from 1 to 6 carbon atoms
- R 4 is a hydrogen or CH 2 OH
- R 5 is an organo group having from 1 to 10 carbon atoms.
- Specific exemplary ethers are those where:
- ethers include those where A is cycloalkyl, cycloalkenyl, -
- the R,, R 2 and R 3 groups are preferably hydrogen or acetate. In preferred compounds, all three positions are hydrogen.
- Other exemplary groups which may be attached at the R 1 r R 2 and R 3 positions are acyl groups having from 1 to 6 carbon atoms.
- Groups which may be attached at R 4 are hydrogen (when a pentose sugar moiety is desired) or CH 3 or CH 2 0H (when a hexose sugar is desired).
- R 5 is alkanes, alkenes or alkynes having from 1 to 10 carbon atoms.
- Other exemplary groups are alcohols, aldehydes, epoxides, ketones, acids or other solubility modifying groups as part of an alkyl residue of from 4 to 10 carbon units.
- R 5 is a propene derivative.
- R 3 is preferably a propane derivative.
- R 6 is 2-methyl-1 -propene.
- pseudopterosin ether derivatives in accordance with the present invention may be synthesized by derivatizing the various different naturally occurring pseudopterosin compounds which are isolated from sea whips according to known procedures.
- the following references set forth the procedures which may be used to isolate naturally occurring pseudopterosin: Look et al., Proc. Natl.
- Pseudopterosin A (1 50 mg in 50 ml acetone) was placed in a 100 ml flask.
- K 2 C0 3 (1 50 mg)
- sodium iodide 500 mg
- the solution was stirred and refluxed for 5 hours.
- 0.5 ml benzylchloride was added and the solution was refluxed for another 6 hours.
- the yellow solution was concentrated by rotary evaporation. Water (50 ml) and CH 2 CI 2 (30 ml) were added to the concentrate and the solution was transferred to a separatory funnel and extracted 3 times with CH 2 CI 2 (3 x 50 ml).
- Pseudopterosin A (1 50 mg in 70 ml acetone) was placed in a 100 ml flask.
- K 2 C0 3 1 1 50 mg
- sodium iodide (580 mg)
- 1 -bromooctadecane (2300 mg) were added.
- the solution was stirred and refluxed overnight.
- 25 ml toluene the solution was again placed in a 100 ml flask.
- K 2 C0 3 (1 1 50 mg), sodium iodide (580 mg) and 1 -bromooctadecane (2300 mg) were added.
- the solution was stirred and refluxed overnight.
- 25 ml toluene the solution was again stirred and refluxed overnight.
- Pseudopterosin A (1 50 mg in 50 ml acetone) was placed in a 100 ml flask.
- Pseudopterosin A 1 50 mg in 50 ml acetone was placed in a 100 ml flask.
- the ether derivatives in accordance with the present invention are useful for treating inflammation and pain.
- the ether derivatives may be used in the same manner as pseudopterosin A and other related anti-inflammatory and analgesic agents.
- the ether derivatives are effective for both topical application and in vivo use.
- compositions which contain ether derivatives of pseu ⁇ dopterosins in accordance with the present invention are useful in the treatment of rheumatoid arthritis, osteoarthritis, rheumatic carditis, collagen and/or auto ⁇ immune diseases such as myasthenia gravis, allergic diseases, bronchial asthma and ocular and skin inflammatory diseases such as poison ivy.
- the compositions are also useful in treating proliferative diseases such as psoriasis.
- compositions are also useful as adjuvant therapy associated with organ and tissue transplants and any neurological disease involving metabolism of nervous tissue phospholipid such as multiple sclerosis. Because of their selective antagonism of chemical irritation (i.e., PMA inflammation) the compositions can be useful in the treatment of insect bites, bee or wasp stings or any venom in which a major constituent is the enzyme phospholipase A 2 .
- the compositions are potent non-narcotic analgesics and may be used to alleviate pain resulting from traumatic injury or acute progressive disease, such as post operative pain, burns, or other conditions involving a coincident inflammation.
- the ether derivatives of pseudopterosin in accordance with the present invention are administered to mammals including humans in an effective amount on the order of 10 to 50 mg per day per kilogram of body weight.
- the drug may be administered orally, parenterally, topically or by other standard administration routes.
- any of the well-known lotions or other solutions typically used as a carrier for anti-inflammatory and analgesic agent may be used.
- the dosage form may be by tablet containing normal acceptable additives, excipients, etc.
- the parenteral form contains typical aqueous intravenous solution ingredients such as propylene glycol, dextrose and physiological saline or other suitable lipid solubilizing carrier.
- pseudopterosin A-methyl ether The analgesic and anti-inflammatory properties of pseudopterosin A-methyl ether are demonstrated in the following well known pharmacological efficacy studies:
- the pseudopterosin ethers were topically applied in acetone to the inside pinnae of the ears of mice in a solution containing the edema-causing irritant, phorbol 1 2-myristate 13-acetate (PMA).
- PMA phorbol 1 2-myristate 13-acetate
- PMA alone (2 ⁇ g/ear) or in combination with 50 yg/ear of test compound was applied to the left ears (5 mice per treat- ment group) and acetone is applied to all right ears.
- the mice were sacrificed, the ears removed, and bores taken and weighed. Edema was measured by subtracting the weight of the right ear (ace ⁇ tone control) from the weight of the left ear (treated). Results were recorded as percent decrease (inhibition) or percent increase (potentiation) in edema relative to the PMA control group edema.
- the ether derivatives were also tested to determine their usefulness in inhibiting degradation of cartilage. Bovine articular cartilage explants labeled with 35 Sulfate were used to monitor chondrocyte-mediated cartilage degradation in the presence of plasminogen, at concentrations similar to that measured in synovial fluid (0.4 ⁇ M), cartilage is extremely sensitive to the effects of IL-1 -stimulated degradation.
- Stimulated chondrocytes produce and activate plasminogen activator (uPA), causing conversion of plasminogen to plasmin.
- Plasmin is not only an effective activator of the MMP's, but also an effective proteoglycanase.
- Inhibitors were added to the assay concomitant with the cytokine IL-1 , and their effect was monitored by measuring differences in 35 S glycosaminoglycan release, as compared to appropriate controls.
- Plasminogen (from human plasma) was obtained from Athens Research and Technology, Athens, Georgia. Recombinant Human lnterleukin-1 - ⁇ was obtained from R&D Systems, Minneapolis, Minnesota. DMEM was obtained from Gibco, Grand Island, New York. 35 S-Sodium Sulfate was obtained from Amersham, Arlington Heights, Illinois. Preparation of Explants
- Bovine (calf) radiocarpal joints were acquired from a local abbatoir immediately after sacrifice and transported on ice. The joints were then washed thoroughly and placed in ice containing approximately 25% Povidine (10% Povidone-lodine topical solution). The joints were then dissected in a sterile hood using good sterile technique. Media (DMEM containing 4.5 g/L D-Glucose and L- Glutamine, without sodium pyruvate) was supplemented with HEPES buffer and sodium bicarbonate, and the pH adjusted to 7.4.
- DMEM containing 4.5 g/L D-Glucose and L- Glutamine, without sodium pyruvate
- the media was further supple- mented with penicillin and streptomycin (100 units/mL and 100 ⁇ g/ml, respec ⁇ tively) and 50 yg/mL L-ascorbic acid.
- penicillin and streptomycin 100 units/mL and 100 ⁇ g/ml, respec ⁇ tively
- 50 yg/mL L-ascorbic acid 50 yg/mL L-ascorbic acid.
- the cartilage surfaces were exposed, and the synovial fluid was wiped away with sterile gauze.
- a sterile cork-borer with a diameter of 3.5 millimeters was used to remove uniform plugs of cartilage. Proper orientation was maintained by distinguishing the underlying bony layer in the plugs (only the articulating surface of the cartilage plugs were used in the experiments).
- the plugs were placed in a sterile flask, washed four times with 50 mL of fresh media, and then placed in an incubator (37 degrees centigrade, with 5% C0 2 /95 % air, with adequate humidity) and allowed to equilibrate for 1 hour.
- a 1 mm thick slice of the articulating surface was sliced off of each individual cartilage plug, using a specially designed template to obtain uniform thickness.
- the cartilage disks were then labeled en mass with 35 Sulf ate at a concentration of approximately 10 ⁇ Ci/mL for approximately 72-96 hours, with hand-stirring every few hours. Subsequent to labeling, explants were equilibrated with fresh media each 48 hours.
- ether derivatives For testing of ether derivatives, individual explants were transferred to 96- well plates containing 250 /JL of media with or without Plasminogen plus IL-1 , and with or without ether derivative.
- a negative control consists of media alone, while the two positive controls are IL-1 alone, and Plasminogen plus IL-1 (a plasminogen control was not considered necessary, since it gave the same results as media alone). All other groups in any assay would contain ether derivative along with concomitant plasminogen plus IL-1 .
- Five samples were routinely used, with concentrations of plasminogen plus IL-1 of 0.4 ⁇ M and 0.5 ng/mL, respectively.
- the assay is allowed to incubate for 96 hours, prior to counting a 50 ⁇ sample of supernatant from each well. A 50 ⁇ L sample of a papain digest of each explant is also counted for each respective well. From the counts released into the supernatant over four days, and the total counts present, the data can be expressed as % glycosaminoglycan (GAG) over the four days). The media alone % GAG release values are subtracted from all other values where plasminogen plus IL-1 were present (media alone represents the background for the system). All groups with inhibitor present are then compared to the values for the plasminogen plus IL-1 without inhibitor, and a % inhibition is calculated. Results lnterleukin- 1 mediated cartilage degradation.
- Human recombinant Inter- leukin-1 - ⁇ induces degradation in bovine articular cartilage explants in a dose- dependent manner.
- Control explants, without IL-1 - ⁇ always displays a basal release less than or equal to 10% of the total glycosaminoglycan (GAG) pool labeled with 35 Sulfate.
- GAG glycosaminoglycan
- IL-1 - ⁇ at a concentration of 2.5 ng/mL initiates a two-fold increase in degradation over control. At 10 ng/mL there is approximately a 35% release of 35 S-labeled GAG.
- lnterleukin- 1 mediated cartilage degradation in the presence of 0.4 ⁇ M plasminogen.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96918214A EP0835117B1 (en) | 1995-06-07 | 1996-06-04 | Ether derivatives of pseudopterosin |
AU60923/96A AU6092396A (en) | 1995-06-07 | 1996-06-04 | Ether derivatives of pseudopterosin |
DE69633281T DE69633281T2 (en) | 1995-06-07 | 1996-06-04 | ETHER DERIVATIVES OF PSEUDOPTEROSINE |
DK96918214T DK0835117T3 (en) | 1995-06-07 | 1996-06-04 | Ether derivatives of pseudopterosin |
AT96918214T ATE274912T1 (en) | 1995-06-07 | 1996-06-04 | ETHER DERIVATIVES OF PSEUDOPTEROSIN |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/487,859 US5624911A (en) | 1995-06-07 | 1995-06-07 | Ether derivatives of pseudopterosin |
US08/487,859 | 1995-06-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996040161A1 true WO1996040161A1 (en) | 1996-12-19 |
Family
ID=23937406
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/009177 WO1996040161A1 (en) | 1995-06-07 | 1996-06-04 | Ether derivatives of pseudopterosin |
Country Status (9)
Country | Link |
---|---|
US (1) | US5624911A (en) |
EP (1) | EP0835117B1 (en) |
AT (1) | ATE274912T1 (en) |
AU (1) | AU6092396A (en) |
DE (1) | DE69633281T2 (en) |
DK (1) | DK0835117T3 (en) |
ES (1) | ES2227591T3 (en) |
PT (1) | PT835117E (en) |
WO (1) | WO1996040161A1 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002044191A2 (en) * | 2000-11-28 | 2002-06-06 | The Regents Of The University California | Anti-inflammatory compounds derived from pseudopterogorgia elisabethae |
US6680062B2 (en) | 2001-10-05 | 2004-01-20 | Color Access, Inc. | Anti-irritating rosacea treatment |
CA2686125A1 (en) * | 2007-04-30 | 2008-11-06 | University Of Prince Edward Island | Pseudopterosin-producing bacteria and methods of use |
US9180112B2 (en) * | 2010-03-23 | 2015-11-10 | Ermis Labs, LLC | Dermal compositions containing gorgonian extract |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4745104A (en) * | 1985-04-15 | 1988-05-17 | The Regents Of The University Of California | Pseudopterosin and synthetic derivatives thereof |
US4849410A (en) * | 1985-04-15 | 1989-07-18 | The Regents Of The University Of California | Pseudopterosin and synthetic derivatives thereof |
US5597808A (en) * | 1995-06-07 | 1997-01-28 | Osteoarthritis Sciences, Incorporated | Use of pseudopterosins for promoting wound healing |
-
1995
- 1995-06-07 US US08/487,859 patent/US5624911A/en not_active Expired - Lifetime
-
1996
- 1996-06-04 EP EP96918214A patent/EP0835117B1/en not_active Expired - Lifetime
- 1996-06-04 WO PCT/US1996/009177 patent/WO1996040161A1/en active IP Right Grant
- 1996-06-04 AT AT96918214T patent/ATE274912T1/en not_active IP Right Cessation
- 1996-06-04 AU AU60923/96A patent/AU6092396A/en not_active Abandoned
- 1996-06-04 DK DK96918214T patent/DK0835117T3/en active
- 1996-06-04 PT PT96918214T patent/PT835117E/en unknown
- 1996-06-04 ES ES96918214T patent/ES2227591T3/en not_active Expired - Lifetime
- 1996-06-04 DE DE69633281T patent/DE69633281T2/en not_active Expired - Fee Related
Non-Patent Citations (1)
Title |
---|
THE JOURNAL OF ORGANIC CHEMISTRY, Volume 55, issued 1990, ROUSSIS et al., "New Antiinflammatory Pseudopterosins from the Marine Octocoral Pseudopterogorgia Elisabethae", pages 4916-4922. * |
Also Published As
Publication number | Publication date |
---|---|
EP0835117B1 (en) | 2004-09-01 |
DK0835117T3 (en) | 2005-01-10 |
ES2227591T3 (en) | 2005-04-01 |
ATE274912T1 (en) | 2004-09-15 |
DE69633281T2 (en) | 2005-09-15 |
AU6092396A (en) | 1996-12-30 |
EP0835117A4 (en) | 1999-07-21 |
EP0835117A1 (en) | 1998-04-15 |
US5624911A (en) | 1997-04-29 |
PT835117E (en) | 2005-01-31 |
DE69633281D1 (en) | 2004-10-07 |
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