CA1288771C - Pseudopterosin and synthetic derivatives thereof - Google Patents

Abstract

PSEUDOPTEROSIN AND SYNTHETIC DERIVATIVES THEREOF

Abstract of the Disclosure Methods for treating mammals to reduce pain, reduce cell proliferation and/or reduce inflammation are described based on administering to the mammals compounds having the formula

Description

~2~387~

PSEUDOPTEROSIN AND SYNTHETIC DERIVATIVES THEREOF

Backgro nd_of the Invention The present invention relates generally to compounds having anti-inflanunatory, anti-proliferative and analgesic activity and methods for using these compounds to reduce inflammation, cell proliferation and pain in mammals. More specifically, the present invention relates to natural and synthetic tricarbocyclic diterpene glycosides and their seco analogs which have been found to have anti-inflammatory, anti-proliferative and analgesic activity when administered to mammals.
This invention was made with Government support under Grant No: 80-AA-D-00120 with the National Oceanic &
Atmospheric Administration to the University of California. The Government has certain rights in this invention.
Caribbean gorgonians (O. Gorgonacea, Ph. Cnidaria) ~ are a diverse group of marine animals ~hich are commonly -~ 20 known as sea feathers, 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, prostaglan~ins, lactones, sesquiterpenoid derivatives and diterpenoid metabolites. Some of these substances have been found to be biologically active.
Since only a small percentage of the total number of Caribbean gorgonian species have been examined for natural chemical products, there has been a continuing effort by a number of researchers to examine additional gorgonian species in order to isolate possible novel natural chemical compounds.
Recently, a number of selected Caribbean gorgonians were studied in depth to isolate and identify natural 387~
62196~473 chemical products (Look, S.~., Studies of the Natura]. Products Chemistry of Selected Caribbean Gorgonians, Ph.D. ~issertation, University of California, 1983). Numerous novel chemicals wexe isolated and identified during this study. One of the novel natural chemical compounds isola-ted during the study was pseudop-terosin. Pseudopterosin is a tricarbocyclic diterpene glycoside having the chemical structure ~ ~ OH

_ummary of the Invention The present invention i5 based on the discovery that pseudopterosin and certain natural and synthetic derivatives of pseudopterosin, along with their seco- analogs, are effective as:
anti-inflammatory agents; anti-proliferative agents; and analgesic agents.
One feature of the present invention involves a method for treating mammals suffering from pain to reduce pain which comprises administering to the mammal a pain reducing effective amount of a composition consisting ~28~37~

essentially of a compound having the generalized structure ~ ~O~OR.

Rl, wherein Rl, R2, R3 and R4 are hydrogen or an acyl function (-COR) having from 1 to 6 carbon atoms, R5 is hydrogen or CH2OH, and R6 is a hydrocarbon having from 1 to 10 carbon atoms; and a pharmaceutically acceptable carrier compound therefor.
Another feature of the present invention involves a method for treating mammals to reduce inflammation com-prising the step of administering a compound as set forth in the preceding paragraph to the mammal in an in1am-mation reducing effective amount. A further feature involves the use of the compounds defined in the pre-ceding paragraph in a method for treating mammals toreduce the proliferation of proliferating cells.
The present invention also includes a new group of synthetic compounds which are useful in the above methods and which are synthetic derivatives of pseudopterosin.

:: , . :
" .:

.: :

~/
~ ~ iZ~377~L

62196-~73 These synthetic compounds have the generali~ed structure ~OR, Rs, wherein Rl, R2, R3 and R4 are hydrogen or an acyl residue (-COR) having from 1 to 6 carbon atoms;
R5 is hydrogen or CH2OH;
R6 is a hy~rocarbon having from 1 to 10 carbon atoms; or an alkyl residue having from 4 to 10 carbon atoms; and wherein if R6 is 2-methyl-1-propene, then R5 is CH2OH or if R6 is 2-methyl-1-propene and R5 is hydrogen, then no more than three of said Rl, R2,R or R4 are hydrogen and if one of Rl, R2, R3 or R4 is acetate, then no more than two of said Rl, R2, R3 or R4 are hydrogen and wherein Rl, R2, R3 and R4 are not all acetate.
The present invention also includes pharmaceutical compo-sitions for use as an anti-in1ammatory agents, anti-proliferative agents and/or analgesic agents which consist essentially of an effective amount of one or more of the above defined synthetic com-pounds and a pharmaceutically acceptable carrier.
The above discussed and many other features and attendant advantages of the present invention will become apparent as the ~ 4 -~ ~;

~2~387~

- 4a - 62196-473 invention becomes better understood by reference to the following detailed description.
Detailed Descri~tion of the Invention The compounds of the present invention fall into three basic groups:
(l) naturally occurring pseudopterosin and the naturally occurring derivatives of pseudopterosin which have been isolated from Caribbean gorgonians of the genus Pseudoptero~orgla;
~ 2) synthetic derivatives of pseudopterosin; and ~3) the bicyclic - 4a -~, . ~, . . .

~ 2~

derivatives or seco-analogs of the natural and synthetic pseudopterosin compounds of groups (1) and (2).
The generalized structure for pseudopterosin compounds belonging to groups (1) and (2) above is ~O~OR, R~, wherein Rl, R2, R3 and R4 are hydrogen or an acyl residue (-COR) having from 1 to 6 carbon atoms, R5 is hydrogen or ~5 CH2OH and R6 is a hydrocarbon having from 1 to 10 carbon atoms.
Naturally occurring pseudopterosin compounds which have been isolated from Caribbean gorgonia are those where:
Compound I - Rl~ R2, R3 and R4 = H; R5 = H; and R6 = 2-methyl-1-propene-(pseudopterosin A) Compound II - R1, R2, R4 = H; R3 = Acetate; R5 =
H; and R6 = 2-methyl-1-propene Compound III - Rl, R3~ R4 = H; R2 = Acetate; R5 =
H; and R~ ~- 2-methyl-1-propene All of the above described pseudopterosin natural products can be isolated and purified by the same chemical methods. Freshly collected Pseudoptero~orgia species are stripped of lateral branchlets and the combined branchlets are stored frozen. The defrosted animals are ground in warm 10~ methanol in chloroform and the insoluble tissues are filtered. The filter cake is re-extracted twice with the same solvent. The extracts are combined and the solvents are removed by evaporation at reduced pressure and at a temperature under 40C. The 621g6-473 residual tar is dissolved in chloroform, dried by the addition of liberal quantities of anhydrous magnesium sulfate, the magnesium sulfate is filtered, and the solvent is once again removed at reduced pressure. The yield of residual "crude extract" is generally between 6 and 9% of the dry weight o-f the animal tissue.
The various naturally occurring pseudopterosin compounds are isolated from the "crude extract" by a series of sequential silica gel chromatographic techniques. ~ppro~imately 30 grams of extract is dissolved in isooctane and applied to a column (10 x 6 cm) of TLC-grade silica gel made in a sintered-glass vacuum funnel. The chromatography is conducted with solvent mixtures beginning with 100~ isooctane and ending with lOOg ethyl acetate.
The process creates 12-15 "fractions" which contain various percentages of pseudopterosin derivatives. The final purification of the natural products is accomplished by high-performance liquid chroma-tography on 1.3 x 50 cm silica gel columns with appropriate isooctane-ethyl acetate mixtures.
In most cases pseudopterosins are isolated as viscous oils or amorphous solids, but in one case (Compound II), the derivative was crystalline. Additional details of isolation and purification of pseudop-terosin and its naturally occurring derivatives are set forth in the published dissertation of S.A.
~ook.
The known naturally occurring pseudopterosin compounds are limited to those in which R6 is 2-methyl-1-propene, Rs is hydrogen and at least 3 of Rl, R2, R3 and R4 are hydrogen and no more than one of Rl, R2, R3 or R4 is acetate.
Synthetic derivatives of the naturally occurring pseudopterosin compounds include compounds according to the above general structure in which i R6 is 2-methyl-1-propene, then Rs i9 CH2O~I, or if R6 is 2-methyl-1-"' ~''", 7~

propene and R5 is hydrogen, then three or less of said Rl, R2, R3 or R4 are hydrogen, and if one of Rl, R2, R3 or R4 is acetate, then two or less of said Rl, R2, R3 or R4 are hydrogen.
Exemplary groups which may be attached at the Rl, R2, R3 or R4 position in addition to acetate are simple acyl derivatives having from 1 to 6 carbon atoms.
Exemplary groups which may be attached at the R6 position are alcohols, aldehydes, epoxides, ketones, acids, or other solubility-modifying groups as part of an alkyl residue from 4 to 10 carbon atoms.
Hydrogen is substituted at position R5 when a pen-tose sugar moiety is desired with R5 being CH20H when a hexose moiety is desired.
Specific exemplary synthetic pseudopterosin compounds include:
Compound IV - Rl, R2, R3, R4 = Acetate; R5 = H;
and R6 = 2-methyl-1-propene.
Compound V _ Rl, R2, R3, R~ = hydrogen; R5 = H;
and R6 = isobutyl oxide.
- Compound VI - Rl, R2, R3, R4 = hydrogen; R5 = H;
and R6 = 1-keto-2~methylpropane.
Compound VII - Rl, R2, R3, R4 = H; R5 = El; and R6 =

2-methylpropane.
The procedures for substituting the wide variety of R groups into the pseudopterosin compound are conven-tional in nature and involve substitution of the Rl-R4 group either on a ribose (R5 = hydrogen) or hexose (R5 =
CH20H) ring structure or the R6 group on the tricarbo-cyclic diterpene structure.
Exemplary synthesis of the selected synthetic de-rivatives is as follows:
Compound IV - Pseudopterosin (29 mg, 0.067 mM) was dissolved in 2 ml dry pyridine and excess acetic anhydride (ca. 1 ml) was added with stirring at room temperature. After 24 hours, 10 ml dichlormethane was ~Z8~7~

added and the organic phase was subsequently washed with 1 N hydrochloric acid, 5% sodium bicarbonate and saturated brin~ solutions. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to yield the tetra-acetate ; derivative IV (32 mg, 79%) as a mobile oil. Successful acetylation and the full assignment of this derivative was accomplished by combined spectral techniques.
Compound V - Pseudopterosin (97 mg, 0.22 mm) was dissolved in 5 ml methylene chloride at room temperature.
Metachloroperbenzoic acid (MCPBA) (49.2 mg, 0.26 mM), buffered with sodium biphosphate, was dissolved all at once, the solution was stirred for 22 hours, and next excess aq. sodium bisulfite was added. The organic phase was extracted first with saturated sodium bicarbonate solution, then with brine and finally dried over anhydrous magnesium sulfate. Removal of solvent after filtering left 97.2 mg (97%) of a viscous oil i.dentified ; as the corresponding epoxide on the basis of complete structural analysis involving spectral methods.
Compound VI - Compound V (21.3 mg, 0.0~8 mM) in 3 ml anhydrous diethyl ether was treated with 0.2 ml boron trifluoride etherate (Aldrich Chem. Co.) at 0. The solution was stirred for 20 min, 5 ml distilled water was added, and the organic phase was increased by the addi-tion of an additional 5 ml ether. The ether layer was washed with 5~ sodium bicarbonate, dried over anhydrous magnesium sulfate and reduced in vacuo. The crude product was purified by silica gel HPLC to yield the ketone derivative ( 13 mg, 61%) as a colorless viscous oil.
Compound VII - Pseudopterosin (58 mg, 0.13 mM) was combined with 5 ml ethyl acetate and a catalytic amount (ca. 20 mg) of 10% Palladium on carbon and the sealed flask was purged with hydrogen. The reaction was allowed to proceed for 72 hours and the catalyst was filtered.

': , ' ' :

~2~38~

59~206F

Removal of solvent at reduced pressure gave the dihydro product (32.7 mg, 56~) as a viscous oil which was sufficiently pure for further investigation on the basis of NMR analysis.
`` 5 The bicyclic derivatives or seco analogs of the previously defined pseudopterosin compounds have the generalized structure:

`~O~OR.
o~a, R2 R~j These derivatives or analogs are the same as the previous compounds except that they are the 1,12-seco analogs of the corresponding pseudopterosin compounds and they encompass alpha linked sugars. The various R groups listed in the formula have the same definition as the R
groups for the pseudopterosin compound as previously discussed.
Exemplary natural seco analogs of pseudopterosin are:
Compound VIII - Rl, R2, R3 = H; R4 = Acetate; R5 =
H; and R6 = 2-methyl-1-propene.
Compound IX ~ 1' R2~ R3, R4 = H; R5 = H; and R6 3~ = 2-methyl-1-propene.
Compound X ~ 1' 2' R4 H; R3 = Acetate; R5 =
H; and R6 = 2-methyl-1-propene.
The above naturally occurring seco analogs of pseudopterosin are isolated from Caribbean gorgonians in the same manner as pseudopterosin. Detaîls of an exemplary procedure are set forth in the dissertation of 7~

5g-206F

S.A. Look which has been previously referenced.
Preparation of 1,12-seco analog derivatives corre-sponding to the synthetic derivatives o pseudopterosin may be carried out by the same methods defined in detail for pseudopterosin.
The compounds of the present invention have been found to be effective anti-inflammatory agent , anti-proliferative agents and analgesic agents for use in treating mammals. Examples demonstrating the effec-tiveness of selected representative exemplary compounds are set forth below.
-Exemplary compounds I - X were tested according to the following well known pharmacological methods:
a. Mouse Ear Anti-Inflammatory Assay Test compound and phorbol m~ristate acetate (PMA) are topically applied simultaneously to the pinnae of the ears of mice. Three hours twenty minutes after appli-~` cation, mice are sacrificed, ears removed and standard sized bores taken. Edema (inflammation) is measured as the difference in weight between control and treated ears.
b. Sperm Motility Assay Male sea urchins are induced to spawn by injectionof 0.5M KCl into the coelomic cavity. Sperm is collected via a pasteur pipette and stored in a test tube on ice.
One drop of undiluted sperm is added to 25 ml of filtered fresh seawater, then 1.0 ml volumes of this solution are immediately added to test tubes containing 10 microlîter test solution. Aliquots of sperm from each tube are observed microscopically for motility at a time two minutes after addition of sperm to test solution.
c. Fertilized Sea Urchin E~_Inhibition of ~` Cleavage Assay for Anti-proliferation Sea urchins are induced to spawn by injection of 0.5M KCl into the coelomic cavity. Test compound is added to a 1% slurry of eggs within 5 minutes following - ,, ; ~ .
; . : ' ~Z8~7~7~

fertilization and incubated until the completion of the division in control slurry, 90-120 minutes. Inhibition is measured as the percent of undivided cells in the slurry at the end of this incubation.
d. Phenylquinone Assay for A alge ia Test compound is injected subcutaneously into mice.
After 30 minutes, phenylquinone is injected intra-peritoneally to cause pain as indicated by writhing.
Absence of or a statistically significant decrease in writhing is considered evidence of analgesia [Hendershot, L.C. and G. Forsaith, Pharmacol. Exp. Ther. 125, 237 (1959)-The results of the pharmacological testing are set forth in the following Tables I - VI.

7~

a~
e ~1 ~ * ~ ~ JJ
J n~ V1 D~ U7 U~
~ ~ ~ E t;~ o ~ .
JJ
. t` ~ ~O I
~: ~; ~1 . . . . . .
ol . o oo o o o . U~ +1 ~ I +1 +~ +~ ~1 0 u~
a 3 ~1 ~ ~
a~5~ o c t::
u~~ ~ ~
'~ 10 ~ u~1~ ~a o~ 'Z ~ O
~ ~ ~ ~ , O Q~ ,~ ~
oo ~ ~ . .
o V V
Q.
` P~ o H ¦ c c z ¦ ~ ~ ~P ~ ~ ~D u ~ 'O ~
~ ~ ,. -o~ ~ ~a ~ C ~ ~ u~ N u~ o o o J~ ~
c~ ~u~ o . , . . . . ~ ~
_ ~ O ~ _~ VD N Ul O O ~ U
~ ~J r~ U) O .,~
C--~ :~ r~l ,~ 3 o EO~
.
u~ a~
~ ~ .~ , 2 5 a) H 0 U V
tn a~ .,, .,., _~ _ JJ ~ JJ
~ cr ~ u~ ~n Wo~ a) ~ ~ o .~.
U Ei ~ _ q n ~ ~ ~: ~ ~ ~
J V ~ h ~E: ~ #
.~ ~1E~

.:

.

7~

:~ 5 _ o~
.' ~ S ~ ~ O J~
3 c 1` ,~ c O W ~ ~ ~ ~ ::5 ~: ~ ~
o U~
~ 3 In ~ o ~ ~ o lS ,~, ~, v 3 al h . o ~
u c ~1~ o e ~ ~ ~ C~J ~

~ Z C
o ~ U~
~o ~. ~

H ~U O O ~) ~0 J~J 1~ .~
~, E ~ -- ~
~+ ~
*

-` --13--~2~

, ~ C

~:Y ~ ~ ~
~ ~ ~ ~ * # ~ , o 0 ~r r~ ~ _ C ~ O V

~: O a~ Q V
O O 'I ~

o 0 Z ~ ,~
a ~ u~

o o ~d ~d _~ C e 1 ~ D

U C O O O O O~3 ~

c ~1 ," .. , ~, ... v ~ o ~ ~ u ~ c '' .
. -7~

U~ ~ ~ ~ * ~ s ~ ~
U~ ~ ~ O ~ ~0 ~P O 1`~ 0 O ~1~ 0 0 d O O In~15a~ ~ ¢1 o o ~~ CP oc~, ~ ~ ~ r~
Q ~: ~ ~ ~ _~ I~ ~ ~ co r~ ~ ~ ~ ~ o ct ~ a~ 'P
,. 0 . . - .. .. - - - - ..

:~
,cO ~
O ~ C

c) O
~ ~ e~ o o o "~ o ~ u~ o ~ u~ o u~ C~
o ,~ o ~ I _J ~ ~ U~ ~ ~ U~ ~ ~ Ul~ ~o ~ ~ ~ U~

._~
~
~ ~:

u ¢ o c ~ o o o o o o ~,., E ~ E E~ E E~ E~

~281~7~

~1 15 a~ ~
. .
~

V U~ ~ O O
e o lU L~ C ~ ~ J~
oq .. .. O u~ u~
a) ~ ~ a~ 0 0 ~ U .
_~ ~ 3 o~ +1 ~1 ~1 +1 ~1 o o ~2 ~ ~ ~ ~ ~ u~
O ~ 0 0 0 ~O U~
C) a) ~ ~ . . O . _ P O ~ J-I ~ t ~n o o o s ~ ~ ~
-c :: o tn ~ ~. ~
> O . ~ o ~
~ ~ .~ oo ~ O--I Z ~ D ~ V V
~ :~ C . ,~ C~ ~
~4 C~
U~ 1 ~ oo oo o ~ ~
o 00~ a~ u~o u~ o o ~ u ~ ~ o ~ u~ c e O ~ 7 ~ ~ A

O C,~ ~J U ,~

. , :.

~2~ 7~

5 o a) _, O ~a)o ~ i ~
. I I I i ~ I +

.
. . ~ ~ eiW ~ ~ ~ OD ~ In .~ ~ o i ~ t~ r ~i ~

,~, ~ o o ~ ~ o U~ .r ~ .r ~io ~ ~ C~ ~ ~ ~D
Z- c~ O ~ ~ ~ f~ ~;r r~

25c ~, U~ In ~ U~ U~
0~ I ~ ~ ~ I ~ I ~ ~ I r~

H :~ H H ~'' HX ~e aJ C ~ ~ '1:~ ra ~ ~ ~ ~ i ~ ~ ~ q~ c ~ ~~, ~ ~ ~
3 0 ~ E O O O O e.) 3 ~ o 3 ~, o 30 c i . Q, ~ C~ C E . Q. ~ . c~ ~

h a) O O O a~ O~1) O O O O O
E~ ~ ~ O

... . .. .

77~L

ul # ~ ~

~ ~a ~ ~o N ~o i` ~
,~ 3 o o O , ;~
a~ . . +, ~ ~ +
O a~ ~ o u~
~ . x U') ~- ~ o a~ u~
o t~s ~ v t~C Zl ~ ~ ~ ~ ~ ~ ".

: 20 E~ C~.
E ~1 ~ In o o O cr a ~1 .~, C . .
'' .C .,~
.:~ p, O :~
J-l H H 1--1 H ~1 O H H ~ ~ CJ
U

el ~ C~ O O O O
~ s e E e E~

The vehicle or carrier for the compounds the assays was as follows: For the mouse ear inflammatory assay, the vehicle was acetone. Controls received 25 micro-liters of acetone. Test compounds were applied to the experimental animals in 25 microliter volumes. ~or the sperm motility and fertilized sea urchin egg assays, the compounds were dissolved in lO microliters undenatured ethanol.
For the- phenylquinone writhing assays, phenyl-quinone was administered at 2 mg per kg intraperitoneally in 5% ethanol-95% physiological saline. Test compound was administered subcutaneously in sesame oil at con-centrations up to 5 mg per ml depending on the test compound dosage protocol. The highest dose was 50 mg per Kg. Control groups received sesame oil subcutaneously.
A summary of the results of the test~ng for anti-inflammatory and analgesic activity is set forth in Table VII.
' .~

.

,. --19--- ~L28~7~L

TABLE VI I

.V,. ~ ~ ~

u~ 5 o ~ O v ~ o 1( 3 ~ z ~ c ~ ~ z :~ o U~

~ .....
e a ~ ¢ ~ 2 ~ o~

..
E
U~ ~C
o -Q- O I~ ~ H ~ ~--J X X
E z H H H ~ H 1--~

, ~. ' ~28~37~

Application of 50 microgram pseudopterosin A (Com-pound I) results in a 69% decrease in edema. The standard anti-inflammatory agent indomethacin, by comparison, produces only a 50% decrease in edema at the same dose. Pseudopterosin also totally inhibits cell division at doses as low as 7 x lO 6M, and sperm motility at the standard test dose of 16 microgram/ml (lO 5m).
Pseudopterosin also provides analgesia against chemically induced pain. The other exemplary synthetic and natural derivatives of pseudopterosin which were tested provided similar results.
Pseudopterosin compounds in accordance with the present invention are a combination of a ribose, arabinose or hexose sugar moiety and a diterpene moiety.
Exemplary diterpene or aglycone moieties were tested for analgesic and anti-inflammatory activity in the same manner as compounds I-X. The aglycones which were tested were:

~ ~

~ COMPOUND XI
.~

59~206F

~
~Me COMPOUND XI I

~OAc(H) ~O~(Ac) COMPOUND XIII

`

,, 7~

None of the three aglycones (XI-XIII) were found to have anti-inflammatory or analgesic activity. It is believed that the unique combination of the diterpene moiety and the sugar moiety in pseudopterosin and pseudopterosin derivative compounds is responsible for the biological activity of the compounds. The particular group (Rl -R6) does not appear to be critical so long as the R groups are within those classes of hydrocarbon groups set forth in this specification. R groups having greater number of carbon atoms are preferred in many cases since they produce a compound having higher lipophilicity which provides improved membrane transport characteristics which are useful when the compounds are applied topically.
The following side effect of pseudopterosin A (Com-pound I) was observed. Doses of 12.5 mg/kg to 50 mg/kg, administered subcutaneously to mice (dissolved in sesame oil, 0~1 cc volume/lO gm body weight) produce central nervous system excitation, brief involuntary muscle contraction of the hind limbs resulting in lateral jumping movements, excessive preening of wound sites, and flushing of the tail and ears. These e~fects begin within a few minutes of administration and last up to one hour. Doses as low as 3 mg/kg pro~uce slight to moderate central nervous system excitation.
Doses up to 50 mg/kg administered intraperltoneally to mice have no effect. At lO0 mg/kg and above, pseudo-pterosin produces mild excitation and writing in some animals, with return to normal activity within 30 3~ minutes. Mortality at lO0 mg/kg = 2.10 on day after administration, at 200 mg/kg = 2/4 also on day after administration.
The novel pseudopterosin compounds in accordance with the present invention are useful in the treatment of rheumatoid arthritis, osteoarthritis, rheumatic carditis, collagen and/or auto-immune dis~ases such as myasthenia .. ...

~ ~ .

~2~17~

:.
gravis, allergic diseases, bronchial asthma and ocular and skin inflammatory diseases such as poison ivy. The compounds are also useful in treating proliferative diseases such a psoriasis.
The compounds 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) pseudopterosin compounds 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 A2. The compounds are patent 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 pseudopterosin compounds 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. The dosage form may be by table~ containing normal acceptable additives, excipients, etc. The parenteral form contains typical aqueous intravenous solution ingredients such as propylene glycol and physiological saline or other suitable lipid solubilizing carrier.
Having thus described exemplary embodiments of the present invention, it should be noted by those skilled in the art that the within disclosures are exemplary only and that various other alternatives, adaptations and modifications may be made within the scope of the present invention. Accordingly, the present invention is not limited to the specific embodiments as illustrated herein, but is only limited by the following claims.

:'

Claims (22)

1. A derivative of pseudopterosin having the structure:

wherein R1, R2, R3 and R4 are hydrogen or an acyl residue having from 1 to 6 carbon atoms, R5 is hydrogen or CH2OH;
R6 is a hydrocarbon having from 1 to 10 carbon atoms; or an alkyl residue having from 4 to 10 carbon atoms; and wherein if R6 is a 2-methyl-1-propene, then R5 is CH2OH or if R6 is a 2-methyl-1-propene and R5 is hydrogen, then no more than three of said R1, R2, R3, R4 are hydrogen and if one of R1, R2, R3, R4 is acetate, then no more than two of said R1, R2, R3, R4 are hydrogen and where-in R1, R2, R3 and R4 are not all acetate.

2. A derivative of pseudopterosin according to claim 1 wherein R5 is hydrogen.

3. A derivative of pseudopterosin according to claim 1 wherein R6 is 2-methyl-1-propene oxide.

4. A derivative of pseudopterosin according to claim 3 where-in R6 is 2-methyl-1-propene oxide and R1, R2, R3 and R4 are hydrogen

5. A derivative of pseudopterosin having the structure:

wherein R1, R2, R3 and R4 are hydrogen or an acyl residue having from 1 to 6 carbon atoms, R5 is hydrogen or CH2OH; and R6 is 1-keto-2-methylpropane.

6. A derivative of pseudopterosin according to claim 5 where-in R1, R2, R3 and R4 are hydrogen.

7. A derivative of pseudopterosin having the structure:

wherein R1, R2, R3 and R4 are hydrogen or an acyl residue having from 1 to 6 carbon atoms, R5 is hydrogen or CH2OH; and wherein R6 is an alkyl group possessing between 4 and 10 carbon atoms.

8. A derivative of pseudopterosin according to claim 7 where-in R6 is 2-methyl-propane and R1, R2, R3 and R4 are hydrogen.

9. A derivative of pseudopterosin according to claim 4 where-in R5 is hydrogen.

10. A derivative of pseudopterosin according to claim 6 where-in R5 is hydrogen.

11. A derivative of pseudopterosin according to claim 8 where-in R5 is hydrogen.

12. A derivative of pseudopterosin comprising the 1,12-seco analogs of compounds having the formula set forth in claim 1.

13. A composition for use as an analgesic agent or an anti-inflammatory agent in treating mammals, said composition consisting essentially of an effective amount of a pseudopterosin derivative according to claim 1 and a pharmaceutically acceptable carrier for said pseudopterosin derivative.

14. A composition according to claim 13 wherein said deriva-tive is a compound according to claim 2 or 3.

15. A composition according to claim 13 wherein said deriva-tive is a compound according to claim 4 or 5.

16. A composition according to claim 13 wherein said deriva-tive is a compound according to claim 6 or 7.

17. A composition according to claim 13 wherein said deriva-tive is a compound according to claim 8 or 9.

18. A composition according to claim 13 wherein said deriva-tive is a compound according to claim 10 or 11.

19. A composition according to claim 13 wherein said deriva-tive is a compound according to claim 12.

20. A composition for use as an analgesic agent or an anti-inflammatory agent in treating mammals, said composition consisting essentially of an effective amount of an active ingredient in admix-ture with a pharmaceutically acceptable diluent or carrier, wherein the active ingredient is a compound of formula wherein R1, R2, R3 and R4 are hydrogen or an acyl residue (-COR) having from 1 to 6 carbon atoms, R5 is hydrogen or CH2OH, and R6 is a hydrocarbon having from 1 to 10 carbon atoms.

21. A composition according to claim 20 in tablet form.

22. A composition according to claim 20 wherein the diluent or carrier is an aqueous intravenous solution suitable for paren-teral administration.